Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 201
Healthy volunteers: yes

Brief summary:
The purpose of this study is to assess the safety/tolerability of the 2 different vaccine regimens of priming with trivalent Ad26.Mos.HIV and boosting with trivalent Ad26.Mos.HIV and Clade C gp140 plus adjuvant or priming with tetravalent Ad26.Mos4.HIV and boosting with Ad26.Mos4.HIV and Clade C glycoprotein (gp)140 plus adjuvant. Immune responses of the different vaccine schedules will be assessed.

Detailed description:

Arms:
arm 1: Participants will receive Ad26.Mos.HIV vaccine at Week 0 and 12, followed by Ad26.Mos.HIV vaccine + Clade C glycoprotein 140 vaccine containing 250 micrograms (mcg) of total protein mixed with adjuvant (aluminum phosphate) at Week 24 and 48. arm 2: Participants will receive placebo at Weeks 0, 12, 24 and 48. arm 3: Participants will receive Ad26.Mos4.HIV vaccine at Week 0 and 12; followed by Ad26.Mos4.HIV vaccine + Clade C glycoprotein 140 vaccine containing 250 micrograms (mcg) of total protein mixed with adjuvant (aluminum phosphate) at Week 24 and 48. Participants will be included in an optional Long-term Extension (LTE) phase (3 years or 4 years Follow-up after Week 72, every 6 months visit) to assess immunogenicity and safety (serious adverse events \[SAEs\]). arm 4: Participants will receive placebo at Weeks 0, 12, 24 and 48.

Interventions: intervention 1: Ad26.Mos.HIV intervention 2: Ad26.Mos4.HIV intervention 3: Clade C gp140 intervention 4: Placebo
Intervention descriptions: intervention 1: Recombinant replication-deficient Ad26 vectored vaccine and consists of 3 Ad26 vectors, one containing a mosaic insert of envelope (Env) sequence, and 2 vectors containing mosaic inserts of Gag and Pol sequences (Ad26.Mos.1.Env + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol). Total dose is 5\*10\^10 viral particle per 0.5 milliliter (mL) injection administered intramuscularly. intervention 2: Recombinant replication-deficient Ad26 vectored vaccine and consists of 4 Ad26 vectors, 2 containing a mosaic insert of envelope (Env) sequence, and 2 vectors containing mosaic inserts of Gag and Pol sequences (Ad26.Mos.1.Env + Ad26.Mos.2S.Env + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol). Total dose is 5\*10\^10 viral particle per 0.5mL injection administered intramuscularly. intervention 3: Clade C gp140 vaccine containing 250 mcg of total protein, mixed with aluminum phosphate adjuvant, per 0.5 mL injection administered intramuscularly. intervention 4: Normal saline 0.9 percent (%), 0.5 mL injection administered intramuscularly.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 28 October 2021
Janssen Vaccines & Prevention B.V.*
Clinical Protocol
A randomized, parallel-group, placebo-controlled, double-blind Phase 1/2a study in
healthy HIV uninfected adults to assess the safety/tolerability and immunogenicity of
2 different prime/boost regimens; priming with trivalent Ad26.Mos.HIV and boosting with
trivalent Ad26.Mos.HIV and Clade C gp140 plus adjuvant OR priming with tetravalent
Ad26.Mos4.HIV and boosting with tetravalent Ad26.Mos4.HIV and Clade C gp140 plus
adjuvant
VAC89220HPX2004
IPCAVD-011
Protocol VAC89220HPX2004 Amendment 5; Phase 1/2a
JNJ-55471468, JNJ-55471494, JNJ-55471520, JNJ-55471585, JNJ-64219324
These compounds are being investigated in Phase 1/2a clinical studies.
*Janssen Vaccines & Prevention B.V. (formerly known as Crucell Holland B.V.) is a Janssen
pharmaceutical company of Johnson & Johnson and is hereafter referred to as the sponsor of the
study. The sponsor is identified on the Contact Information page that accompanies the protocol.
Status: 
Approved
Date: 
28 October 2021
EDMS number: 
EDMS-ERI-109992464, 12.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient will
maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise.
NCT02788045


JNJ-55471468, JNJ-55471494, JNJ-55471520, JNJ-55471585, JNJ-64219324
Clinical Protocol VAC89220HPX2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Approved, Date: 28 October 2021
TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 4
PROTOCOL AMENDMENTS....................................................................................................................... 5
SYNOPSIS.................................................................................................................................................. 11
TIME AND EVENTS SCHEDULE .............................................................................................................. 17
ABBREVIATIONS...................................................................................................................................... 22
1. 
INTRODUCTION................................................................................................................................ 23
1.1. 
Background.................................................................................................................................... 23
1.1.1. 
Nonclinical Studies..................................................................................................................... 23
1.1.1.1. 
Repetitive gp120/gp140 Vaccinations..................................................................................... 23
1.1.1.2. 
Ad26/gp140 and Ad26/Ad35 Vaccinations.............................................................................. 24
1.1.1.3. 
Ad26/Ad5 and Repetitive gp140 Vaccinations........................................................................ 24
1.1.1.4. 
Tetravalent Ad26 Vaccinations................................................................................................ 24
1.1.2. 
Clinical Studies........................................................................................................................... 24
1.1.2.1. 
Prototypes and Similar Vaccines............................................................................................. 24
1.1.2.1.1. 
Ad5 and Ad26 Vaccines....................................................................................................... 25
1.1.2.1.2. 
gp120 Vaccines.................................................................................................................... 26
1.1.2.2. 
Current Studies........................................................................................................................ 26
1.2. 
Overall Rationale for the Study...................................................................................................... 28
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 28
2.1. 
Objectives and Endpoints.............................................................................................................. 28
2.1.1. 
Objectives................................................................................................................................... 28
2.1.2. 
Endpoints.................................................................................................................................... 29
2.2. 
Hypothesis..................................................................................................................................... 30
3. 
STUDY DESIGN AND RATIONALE................................................................................................. 30
3.1. 
Overview of Study Design.............................................................................................................. 30
3.2. 
Study Design Rationale.................................................................................................................. 31
4. 
SUBJECT POPULATION.................................................................................................................. 32
4.1. 
Inclusion Criteria for the Main Study.............................................................................................. 32
4.2. 
Exclusion Criteria for the Main Study............................................................................................. 34
4.3. 
Prohibitions and Restrictions......................................................................................................... 36
4.4. 
Inclusion and Exclusion Criteria for the Optional Long-term Extension Phase ............................. 37
5. 
TREATMENT ALLOCATION AND BLINDING................................................................................. 38
6. 
DOSAGE AND ADMINISTRATION .................................................................................................. 39
7. 
TREATMENT COMPLIANCE............................................................................................................ 40
8. 
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 40
9. 
STUDY EVALUATIONS.................................................................................................................... 41
9.1. 
Study Procedures........................................................................................................................... 41
9.1.1. 
Overview..................................................................................................................................... 41
9.1.2. 
Visit Windows............................................................................................................................. 42
9.1.3. 
Screening Phase (Weeks -4 to 0)............................................................................................... 44


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Clinical Protocol VAC89220HPX2004 Amendment 5
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Approved, Date: 28 October 2021
9.1.4. 
Vaccination ................................................................................................................................. 45
9.1.5. 
Post-vaccination Follow-Up Phase............................................................................................. 47
9.1.6. 
Follow-Up Phase ........................................................................................................................ 48
9.1.7. 
Early Withdrawal/Exit Visit.......................................................................................................... 48
9.1.8. 
Optional Long-term Extension Phase......................................................................................... 48
9.2. 
Immunogenicity Evaluations.......................................................................................................... 49
9.3. 
Safety Evaluations......................................................................................................................... 50
9.4. 
Human Immunodeficiency Virus Testing and Vaccine Induced Seropositivity.............................. 54
9.4.1. 
Human Immunodeficiency Testing ............................................................................................. 54
9.4.2. 
Management of Subjects who Become HIV-infected During the Study..................................... 54
9.4.3. 
VISP............................................................................................................................................ 54
9.4.4. 
Social Impact .............................................................................................................................. 55
9.5. 
Sample Collection and Handling.................................................................................................... 55
10. SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/WITHDRAWAL
FROM THE STUDY........................................................................................................................... 56
10.1. 
Completion ..................................................................................................................................... 56
10.2. 
Discontinuation of Study Treatment............................................................................................... 56
10.3. 
Contraindications to Vaccination.................................................................................................... 56
10.4. 
Withdrawal From the Study............................................................................................................ 57
10.5. 
Withdrawal From the Use of Samples in Future Research............................................................ 57
11. STATISTICAL METHODS................................................................................................................. 58
11.1. 
Subject Information ........................................................................................................................ 58
11.2. 
Analysis Populations...................................................................................................................... 58
11.3. 
Sample Size Determination ........................................................................................................... 58
11.4. 
Immunogenicity Analyses.............................................................................................................. 59
11.5. 
Safety Analyses............................................................................................................................. 59
11.6. 
Analysis Time Points...................................................................................................................... 60
11.7. 
PSRT.............................................................................................................................................. 61
11.8. 
DRC................................................................................................................................................ 61
11.9. 
Study Holding Rules....................................................................................................................... 62
12. AE REPORTING................................................................................................................................ 63
12.1. 
Definitions...................................................................................................................................... 64
12.1.1. 
AE Definitions and Classifications.............................................................................................. 64
12.1.2. 
Attribution Definitions.................................................................................................................. 65
12.1.3. 
Severity Criteria .......................................................................................................................... 65
12.2. 
Situations Requiring Special Notification ....................................................................................... 66
12.2.1. 
AESI............................................................................................................................................ 66
12.3. 
Procedures..................................................................................................................................... 67
12.3.1. 
All AEs........................................................................................................................................ 67
12.3.2. 
SAEs........................................................................................................................................... 68
12.3.3. 
HIV Infection ............................................................................................................................... 69
12.3.4. 
Pregnancy................................................................................................................................... 69
12.4. 
Contacting Sponsor Regarding Safety........................................................................................... 70
13. PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 70
13.1. 
Procedures..................................................................................................................................... 70
13.2. 
Contacting Sponsor Regarding Product Quality............................................................................ 70
14. VACCINE INFORMATION ................................................................................................................ 71
14.1. 
Physical Description of Study Vaccines......................................................................................... 71
14.2. 
Packaging and Labeling................................................................................................................. 72
14.3. 
Preparation, Handling, and Storage............................................................................................... 72
14.4. 
Vaccine Accountability................................................................................................................... 73
15. STUDY-SPECIFIC MATERIALS....................................................................................................... 73


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16. ETHICAL ASPECTS......................................................................................................................... 74
16.1. 
Study-specific Design Considerations........................................................................................... 74
16.2. 
Regulatory Ethics Compliance....................................................................................................... 76
16.2.1. 
Investigator Responsibilities....................................................................................................... 76
16.2.2. 
Independent Ethics Committee or Institutional Review Board................................................... 76
16.2.3. 
Informed Consent ....................................................................................................................... 78
16.2.4. 
Privacy of Personal Data ............................................................................................................ 79
16.2.5. 
Long-term Retention of Samples for Additional Future Research.............................................. 79
17. ADMINISTRATIVE REQUIREMENTS.............................................................................................. 80
17.1. 
Protocol Amendments.................................................................................................................... 80
17.2. 
Regulatory Documentation ............................................................................................................ 80
17.2.1. 
Regulatory Approval/Notification ................................................................................................ 80
17.2.2. 
Required Prestudy Documentation............................................................................................. 81
17.3. 
Subject Identification, Enrollment, and Screening Logs................................................................ 81
17.4. 
Source Documentation................................................................................................................... 82
17.5. 
Case Report Form Completion ...................................................................................................... 82
17.6. 
Data Quality Assurance/Quality Control ........................................................................................ 83
17.7. 
Record Retention ........................................................................................................................... 83
17.8. 
Monitoring ...................................................................................................................................... 84
17.9. 
Study Completion/Termination....................................................................................................... 84
17.9.1. 
Study Completion/End of Study.................................................................................................. 84
17.9.2. 
Study Termination....................................................................................................................... 84
17.10. On-Site Audits................................................................................................................................ 85
17.11. Use of Information and Publication ................................................................................................ 85
18. COVID-19 APPENDIX: GUIDANCE ON STUDY CONDUCT DURING THE COVID-19
PANDEMIC........................................................................................................................................ 87
REFERENCES............................................................................................................................................ 89
INVESTIGATOR AGREEMENT............................................................................................................... 117
LAST PAGE.............................................................................................................................................. 117
LIST OF ATTACHMENTS
Attachment 1: 
Division of Aids Table for Grading the Severity of Adult and Pediatric AEs –
Including Modifications.............................................................................................................. 91
Attachment 2: 
HIV-risk Assessment.................................................................................................... 113
Attachment 3: 
Test of Understanding.................................................................................................. 115
Attachment 4: 
Social Impact Questionnaire........................................................................................ 116
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Study Design VAC89220HPX2004........................................................................................... 31
Table 2: 
AE Notification and Safety Pause/AE Review Rules1 .............................................................. 62


JNJ-55471468, JNJ-55471494, JNJ-55471520, JNJ-55471585, JNJ-64219324
Clinical Protocol VAC89220HPX2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Approved, Date: 28 October 2021
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol 
21 Jan 2016
Amendment 1 
16 Sep 2016
Amendment 2 
Amendment 3 
20 September 2017
27 March 2020
Amendment 4 
28 July 2020
Amendment 5 
This document
Amendments below are listed beginning with the most recent amendment.
Amendment 5 (This document)
The overall reason for the amendment: In this amendment, the LTE phase is being shortened by one year, since
this vaccine regimen did not provide statistically significant protection against HIV infection  in study
HPX2008/HVTN 705.
Rationale: The LTE phase is being shortened by one year. Visit 26 and Visit 27 will be removed and Visit 25
will become the last visit in the study. Participants who already had their Visit 25 or Visit 26 will be contacted to
perform an extra unscheduled exit visit, to be performed within 6 weeks after local approval of protocol
amendment 5.
SYNOPSIS
Time and Events Schedule
1.2 Overall Rationale for the Study
3.1 Overview of Study Design
9.1.1 Overview
9.1.2 Visit Windows
9.1.8 Optional Long-term Extension Phase
10.1 Completion
11.6 Analysis Time Points
16.1 Study-specific Design Considerations
16.2.3 Informed Consent
Rationale:The background section of the protocol has been updated with a summary of the HPX2008/HVTN 705
results.
1.1.2.2 Current Studies
REFERENCES
Amendment 4 (28 July 2020)
The overall reason for the amendment: In this amendment, it is clarified that if a visit of the LTE phase can’t be
scheduled within the allowed window, it will be assessed on a case-by-case basis whether this visit can still be
performed. In addition, an appendix has been included to outline temporary measures while access to the sites is
restricted during public health crises such as e.g., COVID-19 outbreak and to provide investigators with flexibility
to conduct study assessments while ensuring the safety and well-being of the subjects and site staff during the
pandemic. These measures will not be described in the body of the protocol but rather outlined in an Appendix
(Section 18).


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Clinical Protocol VAC89220HPX2004 Amendment 5
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Approved, Date: 28 October 2021
Rationale: It is clarified that if a visit of the LTE phase can’t be scheduled within the allowed window, it will be
assessed on a case-by-case basis upon discussion between investigator and sponsor whether this visit can still be
performed. In addition, a clarification has been added to interpret 1 month as 30 days, and 1 week as 7 days;
hence, the visit window for visit 23 ought to be interpreted as -28 days/+60 days.
Time and Events Schedule
9.1.2 Visit Windows
Rationale: A COVID-19 Appendix has been added to provide guidance to investigators for managing study-related
procedures during the COVID-19 pandemic. For health and safety reasons, subjects may not be able to come to the
study site for scheduled procedures.
SYNOPSIS
Time and Events Schedule
3.1 Overview of Study Design
9.1.2 Visit Windows
18 COVID-19 APPENDIX: GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
Amendment 3 (27 March 2020)
The overall reason for the amendment: In this amendment, Janssen is offering an additional optional 2-year
extension to those participants who have completed the current optional 3-year LTE phase. This will allow a total
LTE phase of 5 years after the end of the main study to assess durability of immunologic responses.
Rationale: Based on the currently available durability data of immune responses22,23, the sponsor aims to evaluate
the persistence of these responses over 5.5 years after the last (4th) vaccination. Therefore, an optional 2-year
extension of the 3-year LTE phase was introduced.
SYNOPSIS
Time and Events Schedule
1.2 Overall Rationale for the Study
3.1 Overview of Study Design
4.4 Inclusion and Exclusion Criteria for the Optional Long-term Extension Phase
9.1.1 Overview
9.1.2 Visit Windows
9.1.8 Optional Long-term Extension Phase
10.1 Completion
11.6 Analysis Time Points
16.1 Study-specific Design Considerations
16.2.3 Informed Consent
REFERENCES
Rationale: It is clarified that subjects may be excluded from donating blood following vaccination in the study due
to vaccine induced seropositivity (VISP) for as long as VISP persists, as the screening HIV tests most often used
on donated blood (ELISA) will often be positive.
4.3 Prohibitions and Restrictions
Rationale: Text has been added to allow modifications in study visits and assessments in the event of emergencies
(possibly affecting a site, a region, a country or world-wide).
Time and Events Schedule
9.1.1 Overview
9.1.2 Visit Windows
Rationale: The Confidentiality Statement was revised and the statement ‘CONFIDENTIAL –FOIA Exemptions
Apply in U.S.’ was added to the running footer, to comply with an update from Janssen’s Legal department.


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Approved, Date: 28 October 2021
Title page
Amendment 2 (20 September 2017)
The overall reason for the amendment: In this amendment, an optional Long-term Extension (LTE) phase was
introduced to assess the durability of immunologic responses up to approximately 3 years after the end of the
main study. In addition, clarifications and adjustments were added with regards to the Week 16 interim
immunogenicity analysis, the eligibility criteria of the main study, the need for microscopic reflex testing, the
definition of the per protocol immunogenicity population, the possibility to perform guest visits, and the follow-
up procedures of the main study.
Rationale: To assess the durability of the immune responses, an optional LTE phase of approximately 3 years
was introduced for subjects randomized to Group 2A, who have received all 4 vaccinations and are negative for
HIV infection at the end of the main study. The vaccination regimen of Group 2A (including Ad26.Mos4.HIV
and Clade C gp140) forms the basis for the regimens that will likely be evaluated in future studies.
SYNOPSIS
Time and Events Schedule
1.2 Overall Rationale for the Study
2.1.1 Objectives
2.1.2 Endpoints
3.1 Overview of Study Design
4.1 Inclusion Criteria for the Main Study
4.2 Exclusion Criteria for the Main Study
4.3 Prohibitions and Restrictions
4.4 Inclusion and Exclusion Criteria for the Optional Long-term Extension Phase
5 TREATMENT ALLOCATION AND BLINDING
8 PRESTUDY AND CONCOMITANT THERAPY
9.1.1 Overview
9.1.2 Visit Windows
9.1.6 Follow-Up Phase
9.1.7 Early Withdrawal/Exit Visit
9.1.8 Optional Long-term Extension Phase
9.3 Safety Evaluations
9.4.1 Human Immunodeficiency Testing
9.4.2 Management of Subjects who Become HIV-infected During the Study
10.1 Completion
10.2 Discontinuation of Study Treatment
10.4 Withdrawal From the Study
11.3 Sample Size Determination
11.6 Analysis Time Points
12.3.1 All AEs
12.3.2 SAEs
12.3.3 HIV Infection
16.1 Study-specific Design Considerations
16.2.3 Informed Consent
Rationale: In order to accelerate the availability of preliminary immunogenicity data, an interim immunogenicity
analysis will be performed once approximately 60 subjects have completed the Week 16 visit.
5 TREATMENT ALLOCATION AND BLINDING
11.6 Analysis Time Points


JNJ-55471468, JNJ-55471494, JNJ-55471520, JNJ-55471585, JNJ-64219324
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Approved, Date: 28 October 2021
Rationale: It was clarified that subjects are not eligible for participation to the study if they received an
experimental vaccine (other than a prophylactic or therapeutic HIV vaccine candidate) within the last 12 months
prior to the Day 1 visit (Vaccination 1).
4.2 Exclusion Criteria for the Main Study
8 PRESTUDY AND CONCOMITANT THERAPY
Rationale: It was indicated that microscopic reflex testing will not be carried out in the event of abnormal
urinalysis tests that are considered by the investigator to have a menstrual origin.
9.3 Safety Evaluations
Rationale: A definition of the per protocol immunogenicity population was added to exclude subjects with major
protocol deviations from the immunogenicity population.
11.2 Analysis Populations
11.4 Immunogenicity Analyses
Rationale: It was indicated that subjects who are temporarily not able to attend the per protocol visits at their
clinical site due to travel (eg, vacation, business travel) may visit any other clinical site participating in this
clinical study for non-vaccination visits.
9.1.1 Overview
Rationale: It was clarified that a (remote) safety follow-up communication 24-72 hours post vaccination is not
required if the vaccination was missed.
Time and Events Schedule
9.1.5 Post-vaccination Follow-Up Phase
Rationale: It was clarified that subjects who prematurely discontinue study treatment will be encouraged to
complete the post-vaccination follow-up visits of the last vaccination received and a 12 and 24 weeks follow-up
visit after the last vaccination received.
Time and Events Schedule
10.2 Discontinuation of Study Treatment
Rationale: Minor clarifications and corrections.
SYNOPSIS  
An error in the abbreviation of Protocol Safety Review
Team (PSRT) was corrected
9.3 Safety Evaluations 
Added language that laboratory test ranges will be
applied according to subject’s sex at birth.
9.4.3 VISP  
It was indicated that the central lab will carry out a
follow-up testing algorithm in response to a positive
result in an HIV-Ab test.
9.4.4 Social Impact 
It was indicated that more details regarding completion
of the social impact questionnaire can be found in the
Study Procedures Manual.
10.4 Withdrawal From the Study  
It was clarified that subjects who are vaccinated and
who withdraw will not be replaced.
12.3.2 SAEs 
Administrative change
Attachment 4 
It was clarified that adaptations to the social impact
questionnaire are allowed for local purposes, after IRB
and sponsor approval.


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Clinical Protocol VAC89220HPX2004 Amendment 5
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Approved, Date: 28 October 2021
Amendment 1 (16 Sep 2016)
The overall reason for the amendment: The contraceptive requirements have been adapted, to align with recent
changes in company policy to become aligned with the general standards for contraceptive use in vaccine trials..
Rationale: Changes in the contraceptive requirement in the inclusion criteria to align with updated company
policies regarding standard contraceptive use in vaccine studies.
4.1. Inclusion Criteria
4.3. Prohibitions and Restrictions
Rationale: Omission of stratification by region in original protocol rectified.
SYNOPSIS
3.1. Overview of Study Design
5. TREATMENT ALLOCATION AND BLINDING
Rationale: The HIV RNA test at screening and baseline has been deleted, since evaluation of VISP is not
relevant at these timepoints.
TIME AND EVENTS SCHEDULE
9.4.1. Human Immunodeficiency Testing
12.3.3.HIV Infection
Rationale: Specifications added for the screening window: Eligible subjects who are late for the baseline visit
should have screening tests repeated.
9.1.3 Screening Phase (Weeks -4 to 0)
Rationale: From 1 Jun 2016 onwards, the name of Crucell Holland B.V. has been changed to Janssen Vaccines
& Prevention B.V.
Title page
Rationale: It is clarified that the extra 2 weeks of screening to allow for start of hormonal contraception are
applicable for female subjects and for female partners of male subjects.
SYNOPSIS
TIME AND EVENTS SCHEDULE
3.1 Overview of Study Design
4. SUBJECT POPULATION
9.1.2 Visit Windows
9.1.3 Screening Phase (Weeks -4 to 0)
Rationale: Minor clarifications
TIME AND EVENTS SCHEDULE 
9.3. Safety Evaluations
Changed wordings from ‘positive’ to ‘abnormal’ urinalysis.
SYNOPSIS  
TIME AND EVENTS SCHEDULE
9.1.5. Post-vaccination Follow-Up Phase
11.7. PSRT
Time indication of 72 hours simplified to 3 days.
5. TREATMENT ALLOCATION AND  
BLINDING  
Specified that blind should not be broken before eDC (electronic
data capture) database is closed.
Rationale: Minor corrections
9.3. Safety Evaluations 
Removed redundant reference to Section 12.1.1.
1.1.2.2. Current Studies 
Typographical error corrected


JNJ-55471468, JNJ-55471494, JNJ-55471520, JNJ-55471585, JNJ-64219324
Clinical Protocol VAC89220HPX2004 Amendment 5
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Approved, Date: 28 October 2021
12.3.2. SAEs 
Updated methods of reporting SAE to include email
12.1.2. Attribution Definitions 
Definition of ‘related AE’ has been altered to align with definition
in more recent study protocols
17.5. Case Report Form Completion 
Removed statement that all data should be recorded in CRF
10.5. Withdrawal From the Use of Samples 
in Future Research  
16.2.3. Informed Consent
Removed wordings in reference to optional research samples as
this is not applicable for this study.
16.2.5. Long-term Retention of Samples 
for Additional Future Research
Corrected the cross-reference to Section 10.5


JNJ-55471468, JNJ-55471494, JNJ-55471520, JNJ-55471585, JNJ-64219324
Clinical Protocol VAC89220HPX2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Approved, Date: 28 October 2021
SYNOPSIS
A randomized, parallel-group, placebo-controlled, double-blind Phase 1/2a study in healthy HIV uninfected
adults to assess the safety/tolerability and immunogenicity of 2 different prime/boost regimens; priming
with trivalent Ad26.Mos.HIV and boosting with trivalent Ad26.Mos.HIV and Clade C gp140 plus adjuvant
OR priming with tetravalent Ad26.Mos4.HIV and boosting with tetravalent Ad26.Mos4.HIV and Clade C
gp140 plus adjuvant
The proposed clinical study will be a first-in-human  evaluation (for Ad26.Mos4.HIV) to evaluate the
safety/tolerability and immunogenicity of a regimen  including trivalent Ad26.Mos.HIV and a regimen
including tetravalent Ad26.Mos4.HIV.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Primary Objectives
 
To assess safety/tolerability of the 2 different vaccine regimens.
 
To assess Envelope (Env)-binding antibody (Ab) responses of the 2 different vaccine regimens.
Secondary Objectives
 
To assess neutralizing Ab (nAb) responses, Ab functionality (as assessed by phagocytosis), and Ab
isotyping.
 
To assess T-cell responses.
Exploratory Objectives
 
To explore Ab functionality (other than phagocytosis).
 
To explore Ab Fc characterization.
 
To explore T-cell and Ab epitope mapping.
 
To explore gene expression of peripheral blood mononuclear cells (PBMCs).
 
To explore B-cell responses.
 
To explore immune responses against the viral vector.
 
To assess the social impact of participation in a human immunodeficiency virus (HIV)-vaccine study
for subjects via a social impact questionnaire.
 
To explore durability of the immune responses to the vaccine regimen in the group selected for the
optional Long-term Extension (LTE) phase.
Endpoints
Primary Endpoints
 
AEs throughout the study
 
Local and systemic solicited adverse events (AEs) for 7 days post-vaccination.
 
AEs for 28 days after each vaccination.
 
Discontinuations from vaccination/from study due to AEs.


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Serious AEs (SAEs) and AEs of special interest (AESIs) during the course of the study, including
the optional LTE phase.
 
Env-specific binding Abs (titers and breadth).
Secondary Endpoints
 
Env-specific nAbs (titers and breadth) (for Tier 1 and Tier 2 viruses; note: Tier 2 will be assessed only
if Tier 1 shows positive results).
 
Env-specific functional Abs (phagocytosis score and breadth).
 
Env-specific binding Ab isotypes (IgA, IgG1-4) (titers and breadth).
 
Interferon (IFN)γ PBMC responders to mosaic peptide pools of Env/group-specific antigen
(Gag)/polymerase (Pol) and potential T-cell epitopes (PTE).
 
Cluster of differentiation (CD)4+ and CD8+ T-cell functionality (% cells producing ia, IFNγ, IL-2, IL-
4, TNFα).
 
T-cell development with emphasis on follicular helper T-cells and memory differentiation.
 
Available samples from time points after last vaccination until the final main study visit at Week 72
will be used for determination of durability of the immune responses.
Exploratory Endpoints
 
Ab functionality evaluation (by other than phagocytosis).
 
Ab Fc (sub)typing.
 
Epitope mapping of Ab to Env and T-cell responses to Gag/Pol/Env and PTE.
 
Regulation of genes (clusters) that predict specific immune responses and human leukocyte antigen
typing.
 
Ab-producing B-cells and characterization of B-cell memory development.
 
Adenovirus serotype 26 (Ad26) nAbs (titer).
 
Available samples from time points during the optional LTE phase will be used for determination of
long-term durability of the immune responses.
Hypothesis
No formal statistical hypothesis will be tested. This study will evaluate whether 2 vaccine regimens, priming
with Ad26.Mos.HIV or Ad26.Mos4.HIV and boosting with Clade C gp140 together with Ad26.Mos.HIV
or Ad26.Mos4.HIV, are safe, well-tolerated, and immunogenic, providing broad, functional, and durable
humoral and cellular responses.
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, parallel, interventional, Phase 1/2a study in healthy
HIV-uninfected adult men and women aged 18 through 50 years. A target of 198 subjects will participate
in this study, randomized into one of 4 subgroups: 55 subjects will receive vaccination with Ad26.Mos.HIV
and Clade C gp140 in Subgroup 1A, 11 subjects will receive placebo in Subgroup 1B, 110 subjects will
receive vaccination with Ad26.Mos4.HIV and Clade C gp140 in subgroup 2A and 22 subjects will receive
placebo in Subgroup 2B. Randomization will be stratified by region. Subjects will be enrolled regardless
of their baseline Ad26 seropositivity.


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The main study will be conducted in 3 phases: a 4-week screening period (with 2 extra weeks to allow for
start of hormonal contraception  for female subjects or female partners of male subjects); a 48-week
vaccination period during which subjects will be vaccinated at baseline (Week 0) and Weeks 12, 24, and
48; and a follow-up period to the final main study visit at Week 72. An optional LTE phase (approximately
3 or 4 years after Week 72, depending on the length of follow-up which subjects consent to) will be
performed for subjects randomized to Group 2A, who have received all 4 vaccinations and are negative for
HIV infection at Week 72. The vaccination regimen of Group 2A (including Ad26.Mos4.HIV and Clade C
gp140) forms the basis for the regimens that will likely be evaluated in future studies. The duration of the
subject's participation will be approximately 76 weeks for subjects not participating in the optional LTE
phase and approximately 220 or 268 weeks for subjects participating in  the optional LTE phase
(approximately 3 or 4 years after the end of the main study, respectively).
After vaccination, subjects will remain under observation at the study site for at least 30 minutes for
presence of any acute reactions and solicited events. In addition, subjects will record solicited local (at
injection site) and systemic events in a diary for 7 days post-vaccination. Further safety evaluations will
include monitoring of AEs, physical examinations, vital sign measurements, clinical laboratory tests, and
pregnancy testing until Week 72. Blood samples will be taken at specific clinic visits to assess immune
responses. Subjects will complete a social impact questionnaire at specific clinic visits. A Protocol Safety
Review Team (PSRT) and Data Review Committee (DRC) will be commissioned for this study.
A COVID-19 Appendix provides guidance to investigators for managing study-related procedures during
the COVID-19 pandemic.
Study Design VAC89220HPX2004
Group 
Subgroup 
N 
Week 0 
Week 12 
Week 24 
Week 48
Group 1 
A 
55 
Ad26.Mos.HIV  
Ad26.Mos.HIV
Ad26.Mos.HIV  
+ 
Clade C gp140 
(250 mcg + adjuvant)a 
Ad26.Mos.HIV
+
Clade C gp140
(250 mcg + adjuvant)a
B 
11 
Placebo 
Placebo 
Placebo 
+ 
Placebo 
Placebo
+
Placebo
Group 2 
Ab 
110 
Ad26.Mos4.HIV  
Ad26.Mos4.HIV
Ad26.Mos4.HIV  
+ 
Clade C gp140 
(250 mcg + adjuvant)a 
Ad26.Mos4.HIV
+
Clade C gp140 (250
mcg + adjuvant)a
B 
22 
Placebo 
Placebo 
Placebo 
+ 
Placebo 
Placebo
+
Placebo
a250 mcg refers to total protein content; sterile aluminum phosphate suspension will be used as adjuvant. Aluminum content
will be 0.425 mg/0.5 mL dose.
bAn optional LTE phase (approximately 3 or 4 years after Week 72 depending on the length of follow up which subjects
consent to) will be performed for subjects randomized to Group 2A, who have received all 4 vaccinations and are negative for
HIV infection at Week 72.
PSRT
The PSRT will review blinded safety data reports on a regular basis (at least 2 times per month) starting
from one week after first vaccination until the last subject has completed the Week 52 visit, and thereafter
as needed.


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After a sentinel group of 10 subjects received the first injection, further vaccinations will be paused until a
3-day safety evaluation is performed. This evaluation will be performed by the PSRT and the PI(s) of the
subjects involved and will be based on the information received from the investigator(s) by email/telephone.
If an administration of vaccine is considered, by PSRT review, to raise significant safety concerns, all
enrollment and vaccinations will be suspended until recommendations are issued. In specific cases a Data
Review Committee (DRC) meeting will be triggered.
The PSRT will include, but will not be limited to medical and safety representatives from the sponsor, sites,
Division of Acquired Immune Deficiency Syndrome (DAIDS), Beth Israel Deaconess Medical Center
(BIDMC), HIV Vaccine Trials Network (HVTN), International AIDS Vaccine Initiative (IAVI), and
Military HIV Research Program (MHRP). The PSRT responsibilities, authorities, and procedures will be
documented in its charter.
DRC
A DRC will be established for this study, which will monitor data to ensure the safety and well-being of
the subjects enrolled. The DRC will review data as indicated below. The conclusions of the DRC will be
communicated to the investigators, the Institutional Review Board/Independent Ethics Committee, and the
national regulatory authorities, as appropriate.
The DRC will specifically review safety data (solicited and unsolicited AEs, SAEs, and available laboratory
assessments) at 3 time points:
 
Review blinded safety data (4 weeks of follow-up) after 15% of subjects have received their first
injection. The DRC will review these interim safety results and will allow administration of the first
dose of Ad26.Mos4.HIV/placebo (first injection) in the VAC89220HPX2003 study only if no
significant safety concerns are identified.
 
Review blinded safety data (4 weeks of follow-up) after 30% of subjects have received their first
injection.
 
Review blinded safety data (4 weeks of follow-up) after 30% of subjects have received their third
injection.
In addition, ad hoc review may be performed further to the occurrence of any AE/SAE leading to a study
holding situation or at request of the PSRT.
The DRC will include medical experts in vaccines and the HIV therapeutic area and at least one statistician.
The DRC may include members from both inside and outside Janssen, but will not include any study team
personnel or people otherwise directly involved in the study conduct, data management, or statistical
analysis for the study. The DRC responsibilities, authorities, and procedures will be documented in its
charter.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 4 weeks (with 2 extra weeks to allow for start of
hormonal contraception  for female subjects or female partners of male subjects) before the first
administration of study vaccine/placebo at Week 0.
Study subjects must be healthy (on the basis of physical examination, medical history, laboratory
assessments, and vital signs measurement), HIV-uninfected adult men and women, aged ≥18 to ≤50 years,
and assessed by the clinic staff as being at low risk for HIV infection.
For entering the optional LTE phase, subjects must have been randomized to Group 2A during the main
study, have received all 4 vaccinations and be negative for HIV infection at the end of the main study.


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DOSAGE AND ADMINISTRATION
Each subject will receive study vaccine/placebo at 4 time points (see Table Study Design) according to
randomization, on Day 1 and Weeks 12, 24, and 48, administered by intramuscularinjection into the deltoid.
For visits with only one injection (ie, at Weeks 0 and 12), preferably the deltoid of the non-dominant upper
arm is used. When 2 injections are to be given at one visit (ie, at Weeks 24 and 48), it is required to use a
different deltoid for each injection. Exceptions on injection site are allowed only if medically indicated.
 
Ad26.Mos4.HIV:
 
Total dose is 5x1010 virus particles (vp) per 0.5 mL injection
 
Ad26.Mos.HIV:
 
Total dose is 5x1010 vp per 0.5 mL injection
Ad26.Mos4.HIV and Ad26.Mos.HIV are classified as genetically modified organisms (GMOs). Based on
nonclinical biodistribution and shedding data with related vectors, the investigational vaccine is not
expected to pose any risk to the environment. Any local requirements related to GMOs must be fulfilled by
the investigator.
 
Clade C gp140:
 
Clade C gp140 with 250 mcg total protein, mixed with aluminum phosphate adjuvant (0.425 mg
aluminum) at the pharmacy, per 0.5 mL injection
 
Placebo:
 
0.9% saline, 0.5 mL injection
IMMUNOGENICITY EVALUATIONS
Humoral immune response assays will include, but are not limited to Env-Ab-binding assays, virus
neutralization assay, and assays for Ab functionality.
Cellular immune response assays will include, but are not limited to interferon gamma enzyme-linked
immunospot assay, intracellular cytokine staining, and multiparameter flow cytometry.
SAFETY EVALUATIONS
All AEs and situations requiring special notification will be reported from the time a signed and dated
informed consent form (ICF) is obtained until 28 days after first dose of study vaccine, and thereafter,
pre-dose and for 28 days after each subsequent dose of study vaccine/placebo. All SAEs and AEs leading
to discontinuation from the study vaccination (regardless of the causal relationship) and AESIs (ie,
confirmed HIV infection) are to be reported for the duration of the main study. During the optional LTE
phase, only SAEs and AESIs are to be reported. Other AEs are not collected during the optional LTE phase
as the optional LTE phase begins 6 months after the last vaccination and it is very unlikely that an AE
related to the study vaccine would only present that long after the last vaccination.
After each vaccination, subjects will remain under observation at the study site for at least 30 minutes for
presence of any acute reactions and solicited events.
In addition, symptoms of the following solicited AEs will be collected via a diary  for 7 days
post-vaccination (day of vaccination and the subsequent 7 days). The diary will be used as a source
document.


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 
Solicited local AEs: pain/tenderness, erythema, and swelling/induration (measured using the ruler
supplied).
 
Solicited systemic AEs: fever (temperature measurement), fatigue, headache, nausea, myalgia, and
chills.
 
Temperature should be measured at approximately the same time each day using the thermometer
supplied.
STATISTICAL METHODS
Anticipating a dropout rate of approximately 10%, the sample sizes will allow detection of approximately
1.5-fold differences in Env-binding Ab titers between the groups with Ad26.Mos4.HIV (approximately
100 evaluable subjects) and their corresponding group with Ad26.Mos.HIV only (approximately
50 evaluable subjects); with 80% probability, assuming a 1-sided 5% Type I error and a standard deviation
of 0.4 on the log10 scale.
While mild to moderate vaccine reactions (local site and systemic responses) are expected, AEs that
preclude further vaccine administration or more serious ones that would limit product development are not
anticipated. With 110 individuals in the tetravalent Ad26.Mos4.HIV vaccine regimen, the observation of 0
such reactions would be associated with a 95% confidence that the true rate is <2.7%. For the combined
active groups (n=165), there would be 95% confidence that the true rate is <1.8% when 0 events are
observed.
Immunogenicity Analyses
No formal hypothesis on immunogenicity will be tested. Descriptive statistics (actual values and changes
from reference with 95% confidence interval) will be calculated for continuous parameters. Frequency
tabulations will be calculated for discrete parameters. Graphical representations of changes in immunologic
parameters will be made as applicable.
Safety Analyses
No formal statistical testing of safety data is planned. Safety data will be analyzed descriptively.






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remaining eligibility criteria for the optional LTE phase will be verified. Subjects who attend their Week 72 visit prior to the sponsor's unblinding at the Week 28
analysis, will be enrolled in the optional LTE phase ifthey consent and sign the ICF appendix for the optional LTE phase and meet the eligibility criteria for the
optional LTE phase. When the Week 28 sponsor unblinding subsequently occurs, subjects that started the optional LTE phase but turn out not to be in Group 2A of
the main study will be withdrawn from the optional LTE phase. If signing the ICF appendix is not possible at Week 72, signing should be performed at an extra visit
(Visit 17bis) as soon as possible after Week 72 and at the latest before any assessment is done on the first visit of the optional LTE phase. See Time and Events
Schedule for the Optional Long-term Extension Phase.
4For those subjects who are unable to continue participation in the study, an exit visit will be conducted as soon as possible.
5Within 24-72 hours post-vaccination a member of the site staff will have a (remote) safety follow-up communication with the subject (by e-mail, telephone, or visit;
according to the subject's preference). A (remote) safety follow-up communication 24-72 hours post-vaccination is not required if the vaccination was missed.
6Must be signed before first study-related activity.
7Complete physical exam will be performed at screening and final main study visits. At all other visits, an abbreviated, symptom-directed exam will be performed as
indicated by the investigator. Weight will be measured at every visit.
8Only at screening.
9Only pre-dose.
10Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Section 17.4. Check clinical status again before first dose
of study vaccine.
11Observation at the study site for at least 30 min for presence of any acute reactions and solicited events.
12Local and systemic solicited events will be recorded for 7 days post-vaccination; AEs will be recorded from signing of ICF onwards until 28 days after first
vaccination, and thereafter, pre-dose and for 28 days after each subsequent vaccination; SAEs, AEs leading to treatment discontinuation, and AESIs will be recorded
throughout the study.
13For the sentinel group of 10 subjects, this will need to be an actual visit at 3 days post vaccination.
14Microscopic reflex testing in the event of abnormal urinalysis.
15For female subjects only.
16For both male and female subjects.
17If medical status and physical examination on Day 1 suggests significant changes may have occurred since screening, the clinically relevant screening assessments
will be repeated and the Day 1 visit rescheduled. If the repeat screening assessment causes the subject to fall outside the screening window, all screening safety
procedures should be repeated so that they are not more than 28 days prior to the Day 1 visit. In case a Grade 3 or 4 laboratory abnormality, or any laboratory
abnormality accompanied by clinically relevant signs or symptoms occurs (from the baseline visit onwards), all attempts will be made to perform a confirmatory test
within 48 hours after the results have become available. After that, laboratory tests will be repeated weekly until values are resolved or stable.
18Urine or vaginal swab may be used.


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Time and Events Schedule for the Optional Long-term Extension Phase (From Week 72Onwards, Group 2AOnly)
Phase 
Long-term Extension 4 years3
Long-term Extension 3 years3
Visit #
17
bis1
181
19
20 
21 
22 
23/Final Visit4
24 
25/Final Visit4
Visit Week 
961
120 
144 
168 
192 
216
240 
264
Visit Day5
673
± 4 wks
841 
± 4 
wks 
1009 
± 4 
wks 
1177
± 4
wks
1345 
± 4 wks 
1513
- 4 wks/+ 2 months
1681 
± 4 wks 
1849
± 4 wks
Informed consent 
 
3
Review of inclusion/
exclusion criteria

HIV-risk assessment 
 
 
 
 
 
 
 

Counseling on HIV  
 
 
 
 
 
 
 

Concomitant meds2 
 
 
 
 
 
 
 

SAE and AESI recording 
 
 
 
 
 
 
 

Social impact questionnaire 
 
 
 
 
 
 
 

HIV EIA  
 
 
 
 
 
 
 

HIV RNA  
 
 
 
 
 
 
 

Humoral immuno. assays 
 
 
 
 
 
 
 

Cellular immuno. assays 
 
 
 
 
 
 
 

AESI = adverse event of special interest; EIA = enzyme immunoassay; HIV = human immunodeficiency virus; RNA = ribonucleic acid; SAE = serious
adverse event; wks = weeks.
The timing and events outlined here are subject to modification in the event of emergencies (possibly affecting a site, a region, a country or world-wide).
Instructions on specific modifications will depend on the particular situation and could vary by site. At a minimum, all efforts will be made to interact with
a participant via telemedicine at the time of a protocol-defined visit. Whereas the implementation of alternative processes should be consistent with the
protocol to the extent possible, it may, therefore, not be possible to conduct all assessments at the defined time (or within the designated window). The
health and safety of the participant and site staff will be the driving factor in such decision making along with government and/or institutional
guidances/mandates. Any such deviations and the reason for any contingency measures implemented, would clearly be described in the study report and
IRB/EC and HA notification would be made if required. The COVID 19 Appendix in Section 18 provides guidance to investigators for managing study related
procedures during the COVID 19 pandemic.
1This visit only needs to occur if the ICF appendix for the optional LTE phase is not signed at Week 72. Visit 17bis should occur as soon as possible
after the Week 72 visit. The ICF appendix for the optional LTE phase needs to be signed at the latest before any assessment is done on the first visit of
the optional LTE phase.
2Restricted to concomitant therapies given in conjunction with an SAE and any chronic or recurrent use of immunomodulators/suppressors and oral or
parenteral corticosteroids. Subjects will also be asked during all visits whether they are participating in another clinical study.


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3 An optional 2-year extension of this 3-year optional LTE is introduced in protocol amendment 3. Subjects will be informed of the option to participate
in this 2-year extension at the next possible visit after approval of this amendment. Subjects willing to participate will need to sign the ICF appendix for
the 2-year extension at Visit 23. As of protocol amendment 5, this optional extension is reduced from 2 years to 1 year.
4 Subjects not willing to participate in the 2-year extension will have their final study visit at Visit 23. For subjects willing to participate : As of protocol
amendment 5, the LTE will be shortened by one year, so Visit 26 and Visit 27 have been removed and Visit 25 will be the final visit. Participants who
already had their Visit 25 or Visit 26 will be contacted to perform an extra unscheduled exit visit, to be performed within 6 weeks after local approval of
protocol amendment 5. This can be either a telephone call or an actual site visit and will need to include the same assessments as in the current Visit 25,
except for the social impact questionnaire and blood sampling for HIV and immunogenicity testing. In case a safety issue (including a recent HIV
exposure) emerges during the call, the participant might be asked to come to the site for further evaluation.
5 If a visit can’t be scheduled within the allowed window, it will be assessed on a case-by-case basis upon discussion between the investigator and the
sponsor whether this visit can still be performed. Note that 1 month should be interpreted as 30 days and 1 week as 7 days; hence, the visit window for
visit 23 ought to be interpreted as -28 days/+60 days.


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ABBREVIATIONS
Ab 
antibody
Ad26 
adenovirus serotype 26
ADCP  
antibody-dependent cellular phagocytosis
AE 
adverse event
AESI 
adverse event of special interest
ALT  
alanine aminotransferase
AST  
aspartate aminotransferase
β-hCG  
β-human chorionic gonadotropin
BIDMC  
Beth Israel Deaconess Medical Center
CBC  
complete blood count
CD  
cluster of differentiation
CRF  
case report form
DAIDS  
Division of Acquired Immune Deficiency Syndrome
DMC  
Data Monitoring Committee
DRC  
Data Review Committee
eDC  
electronic Data Capturing
ELISA  
enzyme-linked immunosorbent assay
ELISPOT 
enzyme-linked immunospot assay
Env 
envelope
FDA  
Food and Drug Administration
FIH  
first-in-human
FSH  
follicle stimulating hormone
Gag 
group-specific antigen
GMO  
genetically modified organism
gp 
glycoprotein
HCV  
hepatitis C virus
HIV(-1) 
human immunodeficiency virus (type 1)
HLA  
human leukocyte antigen
HHS  
Health and Human Services
HVTN  
Human immunodeficiency virus Vaccine Trials Network
IAVI 
International Acquired Immune Deficiency Syndrome Vaccine Initiative
ICF  
informed consent form
ICS  
intracellular cytokine staining
IEC  
Independent Ethics Committee
IFN  
interferon
IM  
intramuscular
IRB  
Institutional Review Board
IWRS  
interactive web response system
LTE 
Long-term Extension
MHRP  
Military Human immunodeficiency virus Research Program
Mos 
mosaic
MVA  
Modified Vaccinia Ankara
nAb 
neutralizing antibody
OHRP  
Office for Human Research Protections
PBMC  
peripheral blood mononuclear cell
Pol 
polymerase
PSRT  
Protocol Safety Review Team
PTE 
potential T-cell epitope
RNA 
ribonucleic acid
SAE 
serious adverse event
SIV  
simian immunodeficiency virus
SHIV  
simian human immunodeficiency virus
TOU  
Test Of Understanding
ULN  
upper limit of normal
US  
United States
VISP  
Vaccine Induced Seropositivity
vp 
viral particle


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1. 
INTRODUCTION
A safe and effective human immunodeficiency virus (HIV) vaccine is the presently elusive
cornerstone of HIV prevention.21 Optimally, both a robust cluster of differentiation (CD) CD4+
and CD8+ T-cell responses and a potent humoral response with multiple effectors should be
induced by a vaccine. An objective of the HIV-vaccine development program being pursued by
the sponsor and its partners is to optimize a vaccine candidate for improved potency, where
potency is defined as the quantitative response, frequency, and amplitude of a variety of potent
antibody (Ab) and Ab-mediated cellular effector mechanisms, coupled with appropriate cellular
responses. A second objective is to increase the breadth of response, defined as immune
recognition of diverse strains/clades of HIV to include multiple clades.
A successful global prophylactic HIV vaccine will likely need to protect against the diverse strains
and clades of HIV that may be encountered. Improving the magnitude and breadth of epitope
coverage is thought to be key to development of a successful Ab and T-cell based preventive HIV
vaccine. Strategies to accomplish this include the use of vaccines containing immunogens from a
number of prevalent clades and/or using mosaic sequences, ie, proteins assembled from natural
sequences of the different clades by in silico recombination, optimized for potential T-cell
epitopes.5
Vaccines used in this study are Ad26.Mos4.HIV, Ad26.Mos.HIV, and Clade C gp140 (for details
see Section 14).
For the most comprehensive nonclinical and clinical information regarding Ad26.Mos4.HIV,
Ad26.Mos.HIV, and Clade C gp140, see the latest version of the Investigator's Brochures and
Addenda for Ad26.Mos4.HIV, Ad26.Mos.HIV, and Clade C gp140.12,13
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.
Other organizations are also involved in this study, referred to in this protocol as "partners". For
this protocol, the partners are the Division of Acquired Immune Deficiency Syndrome (DAIDS),
Beth Israel Deaconess Medical Center (BIDMC), HIV Vaccine Trials Network (HVTN),
International AIDS Vaccine Initiative (IAVI), and Military HIV Research Program (MHRP).
1.1. 
Background
1.1.1. 
Nonclinical Studies
1.1.1.1. 
Repetitive gp120/gp140 Vaccinations
In order to mimic the native trimeric structure of the HIV Env gp “spike” (glycoprotein 120
[gp120]/gp41) and induce native Envelope (Env)-reactive antibodies, trimeric gp140 proteins
based on human Clade A and Clade C sequences were developed and found to induce significantly
higher titers of potent neutralizing antibody (nAb) responses for a cross-clade set of tier 1 (Clades
A, B, and C) and tier 2 (Clade C) viruses than the corresponding gp120 monomers in guinea pigs.18
Although tier 1/2 pseudovirus neutralization is likely not predictive of neutralization capacity


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against circulating HIV-1 viruses, the results suggest a broader and more avid Ab recognition of
native HIV-1 Env.
1.1.1.2. 
Ad26/gp140 and Ad26/Ad35 Vaccinations
The protective efficacy  of boosting with gp140 protein following priming with adenovirus
serotype 26 (Ad26) vectors was evaluated in stringent simian immunodeficiency virus (SIV)- and
simian-human immunodeficiency (SHIV)-challenge models in non-human primates (Part 1).1
Boosting with adjuvanted SIVMAC32H gp140 protein afforded 50% protection against the complete
series of 6 heterologous, intrarectal challenges with SIVMAC251 in animals that were primed with
the Ad26 vector expressing SIVSME543 Env/group-specific antigen (Gag)/polymerase (Pol)
antigens, which was significantly higher than in animals that were similarly primed, but boosted
with the corresponding Ad35 vector expressing SIVSME543 Env/Gag/Pol antigens (17% protection).
Binding Ab titers and Ab-dependent cellular phagocytosis (ADCP) responses correlated with
protection against acquisition of infection. Cellular immune responses measured by interferon
(IFN)γ enzyme-linked immunospot assay (ELISPOT) assays in response to SIVMAC239 and
SIVSME543 Env/Gag/Pol peptide pools were also detected in all animals after vaccination. By
intracellular cytokine staining (ICS) assays, gp140 boosting primarily expanded Env-specific IFNγ
CD4+ T-lymphocyte responses in the Ad26/gp140 group.
1.1.1.3. 
Ad26/Ad5 and Repetitive gp140 Vaccinations
A similar level of protection (40%) was seen after a series of 6 heterologous, intrarectal challenges
with SHIV-SF162P3 in a first group of animals primed with Ad26 and Ad5HVR48 vectors
expressing mosaic, consensus, or natural Clade C HIV-1 Env/Gag/Pol antigens and boosted six
times 2 years later with HIV-1 Clade C Env gp140 trimer (Part 2).1 A second group of animals
received only the 6 gp140 immunizations. Although the gp140 vaccine afforded only minimal
protection, 40% of Ad/gp140-vaccinated animals were completely protected against this challenge
series. As for Section 1.1.1.2, binding Ab titers and ADCP responses correlated with protection
against acquisition of infection.
1.1.1.4. 
Tetravalent Ad26 Vaccinations
In ongoing clinical trials the trivalent Ad26.Mos.HIV viral vector is being used. But subsequent
non-clinical data in rabbits have shown that the addition of a vector, expressing Mos2S  Env
protein, to Ad26.Mos1.Env increases the magnitude of binding Ab titers and neutralizing capacity
for Tier 1A Clade C HIV virus in the absence of negative effects on Clade B neutralization
capacity. Thus, addition of Ad26.Mos2S.Env to Ad26.Mos.HIV has the potential to substantially
increase the breadth of humoral immune responses.
1.1.2. 
Clinical Studies
1.1.2.1. 
Prototypes and Similar Vaccines
There is considerable clinical experience with vaccines similar to Ad26.Mos.HIV and Clade C
gp140 that demonstrated their class safety and tolerability.


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1.1.2.1.1. 
Ad5 and Ad26 Vaccines
In 2 previous HIV-efficacy studies utilizing Ad5, a trend towards increased HIV-1 infection was
observed in vaccine recipients as compared with placebo recipients.3,7 The HVTN 502/Step
(Merck Ad5) study showed no efficacy and a trend towards increased HIV-1 infections in vaccine
recipients as compared with placebos. A significant but unexplained increase of HIV-1 infections
was seen in vaccine recipients as compared with placebos in the subgroup of men who were
baseline Ad5 seropositive and uncircumcised.3 The HVTN 503/Phambili (Merck Ad5, MRKAd5)
study was terminated and unblinded early, but follow-up of these individuals revealed increased
HIV-1 infections in vaccine recipients as compared with placebo, particularly in men, which
occurred after approximately 24 months of follow-up during the unblinded period.7 There was also
differential dropout of high-risk placebos during this time period. Additionally, a third study, the
HVTN 505 (NIH VRC deoxyribonucleic acid [DNA]/Ad5) study8, revealed no efficacy at the
interim analysis. More HIV-1 infections were observed in vaccine recipients as compared with
placebos in this study, including after the DNA prime and prior to the Ad5 boost, but these
differences were not statistically meaningful. To clearly understand whether vaccine-associated
increase of HIV-1 acquisition has occurred in one or more studies, a meta-analysis was recently
conducted using up-to-date participant-level data from the 3 efficacy trials and three Phase 1-2
studies.9 The meta-analysis provides evidence for increased risk associated with the MRKAd5
vaccine overall and in various subgroups except circumcised and Ad5-negative men. While the
meta-analysis does not provide a reliable basis for predicting whether rAd5-vectored vaccines for
other pathogens or other rAd-vectored vaccines for HIV-1 would increase susceptibility to
infection in HIV-1 at-risk populations, for large efficacy trials of such vaccines it provides a
rationale for adding monitoring plans enabling detection of such increased susceptibility.
The mechanism for this possible increase in HIV-1 acquisition risk remains unclear, but a leading
hypothesis involves activation of vector-specific CD4+ T-lymphocytes at mucosal surfaces
following Ad5 vaccination, potentially resulting in increased targets for HIV-1 infection.2,10 This
hypothesis has never been directly evaluated in humans with Ad5 vectors. Nevertheless, to assess
the extent of mucosal CD4+ T-cell activation with Ad26 vectors, a randomized, double-blinded,
placebo-controlled clinical study (IPCAVD-003) was performed to determine whether vaccination
of healthy human subjects with an Ad26 vector expressing HIV-1 Env would result in increased
numbers or activation status of total or vector-specific CD4+ T-lymphocytes in the colorectal
mucosa. The findings of this study are reassuring in that this vector did not detectably increase the
numbers or activation status of total or vector-specific CD4+ T-cells in colorectal mucosa in
humans.
The rationale to continue clinical development of Ad26 vector-based vaccines for HIV-1 is based
on data showing that: (1) Ad26 is biologically substantially different than Ad5; (2) Ad26-based
vaccines afford superior protective efficacy compared with Ad5-based vaccines against SIVMAC251
challenges in rhesus monkeys; and (3) Ad26 did not increase the number or activation status of
total or vector-specific CD4+ T-lymphocytes at mucosal surfaces in humans following vaccination
in a randomized, double-blind, placebo-controlled clinical study (IPCAVD-003).


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In 3 Phase 1 studies (IPCAVD-001, IPCAVD-003, and IPCAVD-004)12, Ad26.ENVA.01, at
intramuscular (IM) doses over the range 109 to 1011 virus particles (vp), was found to induce Env-
specific humoral and cell-mediated responses when given on up to 3 occasions to more than 200
healthy subjects. Ad26.ENVA.01 was generally well tolerated in these studies. An IM dose of
5x1010 vp was found to provide the optimal balance of immunogenicity and reactogenicity.
Therefore, this is the dose of Ad26.Mos.HIV chosen for further evaluation in this study.
In IPCAVD-003, 24 HIV-1 negative subjects were randomized 3:1 to receive a single vaccination
with Ad26.ENVA.01 or placebo. Eight of the subjects were Ad26 seropositive at screening. The
T-cell responses by IFNγ ELISPOT assays were slightly lower in the baseline Ad26-seropositive
subjects; ICS and enzyme-linked immunosorbent assay (ELISA) responses proved comparable
between subjects who were Ad26 seropositive and Ad26 seronegative at baseline, both in
peripheral blood and in colorectal mucosa. In addition, systemic and mucosal responses persisted
for at least 1 year in the majority of subjects after a single IM vaccine dose. These data suggest
that the impact of baseline Ad26 nAbs, at the titers observed in that study, on the immunogenicity
of this Ad26 vaccine is modest. Additionally, there were no consistent increases in Ad26-specific
CD4+ T-lymphocyte responses at mucosal surfaces following vaccination in either Ad26-
seronegative or Ad26-seropositive subjects.
1.1.2.1.2. 
gp120 Vaccines
A monovalent gp120 protein (AIDSVAX B) was tested in 671 healthy subjects at 3 doses,
100, 300, and 600 mcg.11 The 300-mcg dose was found to be the most effective, inducing a higher
Ab response without significant side effects. In the Thai trial RV14420, the only vaccine study to
date to demonstrate efficacy in prevention of acquisition of HIV, a bivalent gp120 protein
(AIDSVAX B/E; 300-mcg dose) was used as a booster following priming with a recombinant
canarypox vector (ALVAC-HIV) and afforded more than 30% protection from infection in the
absence of either CD8+ T-cells or nAb to primary HIV isolates. Therefore, a similar dose
(250 mcg) of Clade C gp140 was chosen for evaluation in this study.
1.1.2.2. 
Current Studies
Currently, 2 first-in-human (FIH) studies in healthy HIV-uninfected subjects are evaluating
safety/tolerability and immunogenicity of the following vaccines:
 
Clade C gp140 (HIV-V-A003).
 
Ad26.Mos.HIV, Modified Vaccinia Ankara (MVA)-Mosaic, and Clade C gp140
(HIV-V-A004; FIH for Ad26.Mos.HIV).
HIV-V-A003 is a single-center, randomized, placebo-controlled, double-blind, Phase 1 study to
evaluate safety/tolerability, and immunogenicity of 2 dose levels (50 and 250 mcg) of Clade C
gp140, with or without aluminum phosphate adjuvant, in healthy HIV-uninfected adult subjects.
The blinded evaluation that was performed by the Data Monitoring Committee (DMC) at Week 6
(2 weeks after all of the 50 enrolled subjects had received their second and last vaccination) showed
that Clade C gp140, administered as 50 or 250 mcg, with or without aluminum phosphate adjuvant,
was well tolerated and no safety concerns were identified. All reported adverse events (AEs) were


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of mild and moderate severity, there were no serious AEs (SAEs), withdrawals, or
discontinuations. The DMC concurred with proceeding with the clinical development as planned
and with administration of Clade C gp140 in HIV-V-A004.
HIV-V-A004 is a multi-center, randomized, parallel-group, placebo-controlled, double-blind
Phase 1/2a study to evaluate safety/tolerability, and immunogenicity of various prime/boost
regimens containing Ad26.Mos.HIV, MVA-Mosaic, and/or Clade C gp140 (with aluminum
phosphate adjuvant) components in approximately 400 healthy HIV-uninfected adult subjects. As
pre-specified in the protocol, enrollment was paused when approximately 10% of subjects had
received their first injection (Ad26.Mos.HIV) and the Protocol Safety Review Team (PSRT) has
reviewed blinded safety data of 2 weeks after this first injection of 39 subjects and on 18 June 2015
all members agreed that the study could resume enrollment. Most AEs were of mild and moderate
severity. Three Grade 3 AEs were reported that were considered related to vaccination: headache,
chills, and myalgia. There were no SAEs, withdrawals, or discontinuations. The independent Data
Monitoring Committee (DMC) also reviewed the 2 week safety data after 30% of subjects had
their first vaccination. They recommended continuing the study without modification. A 50 year-
old male subject reported a severe allergic reaction having started 12 hours after first vaccination
administration. Symptoms and signs mentioned by the subject included facial swelling, blurred
vision, difficulty swallowing, and generalized rash of the face, extremities, and chest tightness.
There was an emergency room (ER) visit (per ambulance) with administration of benadryl, but no
hospitalization. Clinical observations by ER physician noted an alert and oriented person, with
symptoms of, but with no clinical signs of allergic reaction (no rash, no
lip/tongue/oropharyngeal/uvular swelling, normal findings of cardiovascular and respiratory
system). Reaction was resolved within one day of onset. Concurrent diseases were drug abuse and
bipolar disorder (not disclosed by subject to the investigator), with hallucinatory decompensation
and chest pain one week after the severe allergic reaction. Following that, the subject was
withdrawn from study due to non-compliance (history of drug abuse and non-reported psychiatric
issues).
Study VAC89220HPX2008/HVTN 705 (hereafter abbreviated to HPX2008/HVTN 705) is an
ongoing, multicenter, randomized, parallel-group, placebo-controlled, double-blind Phase 2b
proof-of-concept efficacy study in approximately 2,600 HIV-uninfected sexually active women
aged 18 to 35 years. The study is being conducted in approximately 25 sites, with the majority of
these throughout South Africa. Study participants were selected from populations at high risk of
acquiring HIV infection in southern Africa settings with overall moderate to high HIV incidence.
The predominant circulating HIV-1 is a Clade C virus. The study is investigating the preventive
vaccine efficacy, safety, and tolerability of a heterologous regimen with 4 vaccinations consisting
of tetravalent Ad26.Mos4.HIV and aluminum phosphate-adjuvanted Clade C gp140, with
vaccinations at Months 0, 3, 6, and 12. The primary analysis recently demonstrated that the vaccine
regimen did not provide statistically significant protection against HIV infection. The vaccine
efficacy over Months 7 to 24 in the per-protocol cohort did not differ significantly from zero, with
a point estimate (95% confidence interval) of25% (-10% to 49%). The regimen did not cause harm
and was generally well-tolerated.15


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1.2. 
Overall Rationale for the Study
The proposed clinical study will be an  FIH evaluation (for Ad26.Mos4.HIV) in healthy
HIV-uninfected subjects to evaluate the safety/tolerability and immunogenicity of a regimen
including trivalent Ad26.Mos.HIV and a regimen including tetravalent Ad26.Mos4.HIV. Better
Clade C responses are to be expected with the tetravalent Ad26.Mos4.HIV compared to the
trivalent Ad26.Mos.HIV.
To assess the durability of the immune responses, an optional Long-term Extension (LTE) phase
of approximately3 years was introduced for subjects randomized to Group 2A, who have received
all 4 vaccinations and are negative for HIV infection at the end of the main study. The vaccination
regimen of Group 2A (including Ad26.Mos4.HIV and Clade C gp140) forms the basis for the
regimens that will likely be evaluated in future studies.
Based on the currently available durability data of immune responses22,23 the sponsor aims to
evaluate the persistence of these responses over 5.5 years after the last (4th) vaccination. Therefore,
an optional 2-year extension of the 3-year LTE phase was introduced with protocol amendment 3.
Recent results of study HPX2008/HVTN 705 demonstrated that the vaccine regimen used in
HPX2008 (which is the same regimen being used in HPX2004) did not provide statistically
significant protection against HIV infection  (see Section 1.1.2.2). Therefore, with protocol
amendment 5, the 2-year LTE extension was shortened to 1 year (corresponding to a follow-up of
approximately 4,5 years after the last [4th] vaccination).
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1. 
Objectives and Endpoints
2.1.1. 
Objectives
Primary Objectives
The primary objectives are to assess:
 
Safety/tolerability of the 2 different vaccine regimens of priming with trivalent
Ad26.Mos.HIV and boosting with trivalent Ad26.Mos.HIV and Clade C gp140 plus adjuvant
or priming with tetravalent Ad26.Mos4.HIV and boosting with Ad26.Mos4.HIV and Clade C
gp140 plus adjuvant.
 
Env-binding Ab responses of the 2 different vaccine regimens.
Secondary Objectives
The secondary objectives are to assess:
 
Neutralizing Ab responses, Ab functionality (as assessed by phagocytosis), and Ab isotyping.
 
T-cell responses.


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Exploratory Objectives
The exploratory objectives are:
 
Ab functionality (other than phagocytosis).
 
Ab Fc characterization.
 
T-cell and Ab epitope mapping.
 
Gene expression of peripheral blood mononuclear cells (PBMCs).
 
B-cell responses.
 
Immune responses against the viral vector.
 
The social impact of participation in an HIV-vaccine study for subjects via a social impact
questionnaire.
 
To explore durability ofthe immune responses to the vaccine regimen in the groups selected
for the optional LTE phase.
2.1.2. 
Endpoints
Primary Endpoints
 
AEs throughout the study
 
Local and systemic solicited AEs for 7 days post-vaccination.
 
AEs for 28 days after each vaccination.
 
Discontinuations from vaccination/from study due to AEs.
 
SAEs and AEs of special interest (AESIs) during the course of the study, including the
optional LTE phase.
 
Env-specific binding Abs (titers and breadth).
Secondary Endpoints
 
Env-specific nAbs (titers and breadth) (for Tier 1 and Tier 2 viruses; note: Tier 2 will be
assessed only if Tier 1 shows positive results).
 
Env-specific functional Abs (phagocytosis score and breadth).
 
Env-specific binding Ab isotypes (IgA, IgG1-4) (titers and breadth).
 
IFNγ PBMC responders to mosaic peptide pools of Env/Gag/Pol and PTE.
 
CD4+ and CD8+ T-cell functionality (% cells producing ia, IFNγ, IL-2, IL-4, TNFα).
 
T-cell development with emphasis on follicular helper T-cells and memory differentiation.
 
Available samples from time points after last vaccination until the final main study visit at
Week 72 will be used for determination of durability of the immune responses.
Exploratory Endpoints
 
Ab functionality evaluation (by other than phagocytosis).


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 
Ab Fc (sub)typing.
 
Epitope mapping of Ab to Env and T-cell responses to Gag/Pol/Env and PTE.
 
Regulation of genes (clusters) that predict specific immune responses and human leukocyte
antigen (HLA) typing.
 
Ab-producing B-cells and characterization of B-cell memory development.
 
Ad26 nAbs (titer).
 
Available samples from time points during the optional LTE phase will be used for
determination of long-term durability of the immune responses.
2.2. 
Hypothesis
No formal statistical hypothesis will be tested. This study will evaluate whether 2 vaccine
regimens, priming with Ad26.Mos.HIV or Ad26.Mos4.HIV and boosting with Clade C gp140
together with Ad26.Mos.HIV or Ad26.Mos4.HIV, are safe, well-tolerated, and immunogenic,
providing broad, functional, and durable humoral and cellular responses.
3. 
STUDY DESIGN AND RATIONALE
3.1. 
Overview of Study Design
This is a randomized, double-blind, placebo-controlled, parallel, interventional, Phase 1/2a study
in healthy HIV-uninfected adult men and women aged 18 through  50 years. A target of
198 subjects will participate in this study, randomized into one of 4 subgroups: 55 subjects will
receive vaccination with Ad26.Mos.HIV and Clade C gp140 in Subgroup 1A, 11 subjects will
receive placebo in Subgroup 1B, 110 subjects will receive vaccination with Ad26.Mos4.HIV and
Clade C gp140 in subgroup 2A and 22 subjects will receive placebo in Subgroup 2B.
Randomization will be stratified by region. Subjects will be enrolled regardless of their baseline
Ad26 seropositivity. Subjects will receive study vaccine or placebo according to the time points in
Table 1.
The main study will be conducted in 3 phases: a 4-week screening period (with 2 extra weeks to
allow for start of hormonal contraception for female subjects or female partners of male subjects);
a 48-week vaccination period during which subjects will be vaccinated at baseline (Week 0) and
Weeks 12, 24, and 48; and a follow-up period to the final main study visit at Week 72. An optional
LTE phase (approximately 3 or 4 years after Week 72 depending on the length of follow-up which
subjects consent to) will be performed for subjects randomized to Group 2A, who have received
all 4 vaccinations and are negative for HIV infection at Week 72. The vaccination regimen of
Group 2A (including Ad26.Mos4.HIV and Clade C gp140) forms the basis for the regimens that
will likely be evaluated in future studies. The duration of the subject's participation will be
approximately 76 weeks for subjects not participating in  the optional LTE phase and
approximately 220 or 268 weeks for subjects participating in  the optional LTE phase
(approximately 3 or 4 years after the end of the main study, respectively).
After vaccination, subjects will remain under observation at the study site for at least 30 minutes
for presence of any acute reactions and solicited events. In addition, subjects will record solicited


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local (at injection site) and systemic events as described in Section 9.1.1. See Section 12.1.3 for
grading of severity of solicited AEs. Further safety evaluations will include monitoring of AEs,
physical examinations, vital sign measurements, clinical laboratory tests, and pregnancy testing
until Week 72. Blood samples will be taken at specific clinic visits to assess immune responses.
Subjects will complete a social impact questionnaire at specific clinic visits. For details see
Attachment 4. A PSRT and Data Review Committee (DRC) will be commissioned for this study.
See Sections 11.7 and 11.8 for details.
For details on Analysis Time Points, see Section 11.6.
The COVID-19 Appendix in Section 18 provides guidance to investigators for managing study-
related procedures during the COVID-19 pandemic.
Table 1: 
Study Design VAC89220HPX2004
Group 
Subgroup 
N 
Week 0 
Week 12 
Week 24 
Week 48
Group 1 
A 
55 
Ad26.Mos.HIV  
Ad26.Mos.HIV
Ad26.Mos.HIV  
+ 
Clade C gp140 
(250 mcg + 
adjuvant)a 
Ad26.Mos.HIV
+
Clade C gp140
(250 mcg +
adjuvant)a
B 
11 
Placebo 
Placebo 
Placebo 
+ 
Placebo 
Placebo
+
Placebo
Group 2 
Ab 
110 
Ad26.Mos4.HIV  
Ad26.Mos4.HIV
Ad26.Mos4.HIV  
+ 
Clade C gp140 
(250 mcg + 
adjuvant)a 
Ad26.Mos4.HIV
+
Clade C gp140
(250 mcg +
adjuvant)a
B 
22 
Placebo 
Placebo 
Placebo 
+ 
Placebo 
Placebo
+
Placebo
a250 mcg refers to total protein content; sterile aluminum phosphate suspension will be used as adjuvant. Aluminum
content will be 0.425 mg/0.5 mL dose.
bAn optional LTE phase (approximately 3 or 4 years after Week 72 depending on the length of follow-up which
subjects consent to) will be performed for subjects randomized to Group 2A, who have received all 4 vaccinations
and are negative for HIV infection at Week 72.
3.2. 
Study Design Rationale
Vaccines and Dose Selection Rationale
The rationale behind selection of study vaccines and doses is described in Section 1.1.
Blinding, Control, Study Phase/Periods, Treatment Groups
A placebo control will be used to establish the frequency and magnitude of changes in clinical
endpoints that may occur in the absence of active treatment. Randomization will be used to


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minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that
known and unknown subject attributes (eg, demographic and baseline characteristics) are evenly
balanced across treatment groups, and to enhance the validity of statistical comparisons across
treatment groups. Blinded treatment will be used to reduce potential bias during data collection
and evaluation of clinical endpoints.
4. 
SUBJECT POPULATION
Screening for eligible subjects will be performed within 4 weeks (with 2 extra weeks to allow for
start of hormonal contraception for female subjects or female partners of male subjects) before the
first administration of study vaccine/placebo at Week 0.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the
following 2 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.
For a discussion of the statistical considerations of subject selection see Section 11.3.
4.1. 
Inclusion Criteria for the Main Study
Each potential subject must satisfy all of the following criteria to be enrolled in the study.
1. 
Each subject must sign an informed consent form (ICF) indicating that he or she
understands the purpose of and procedures required for the study and is voluntarily willing
to participate in the study.
2. 
Subjects are ≥18 to ≤50 years old on the day of signing the ICF.
3. 
Subject must be healthy on the basis of physical examination, medical history, and vital
signs measurement performed at screening.
4. 
Subjects must meet following laboratory criteria prior to randomization*:
a) Hemoglobin: Women ≥10.5 g/dL; Men ≥11.0 g/dL
b) White cell count: 2,500 to 11,000 cells/mm3, inclusive
c) Absolute neutrophil count: >1,000 cells/mm3
d) Platelets: 125,000 to 450,000 per mm3, inclusive
e) Urinalysis: protein <1+, blood <1+ (men) and <2+ (women), and glucose negative
f) Alanine aminotransferase/aspartate aminotransferase: <1.25x upper limit of normal
(ULN)
g) Creatinine: <1.1x ULN
*If laboratory screening tests are out of range, repeat of screening tests is permitted once.


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5. 
Subjects are negative for HIV infection at screeninga.
6. 
All female subjects of childbearing potential must have a negative serum (-human
chorionic gonadotropin [-hCG]) at the screening visit, and a negative urine pregnancy
test pre-dose on Day 1b.
7. Contraceptive requirements for heterosexually active female subjects (from 28 days prior
first vaccination up until 3 months after last vaccination)c:
a) If not of childbearing potential: postmenopausal (>45 years of age with amenorrhea
for at least 2 years, or any age with amenorrhea for at least 6 months and a serum
follicle stimulating hormone [FSH] level >40 IU/L) or surgically sterile: no
additional contraception required.
b) If of child-bearing potential, but has a vasectomized partner (after vasectomy: 
sperm count below the limit of detection if procedure occurred <1 year agod): no
additional contraception required.
c) If of child-bearing potential, but has a non-vasectomized partner, or partner had a
positive sperm count after a vasectomy procedure of <1 year agod, should be
practicing an acceptable effective method of contraception. Acceptable methods for
this study include:
 Hormonal contraception,
 Intrauterine device (IUD),
 Intrauterine hormone-releasing system (IUS),
 Male or female condom with or without spermicide,
 Cap, diaphragm or sponge with vaginal spermicide, or
 Sexual abstinence *
*Sexual abstinence is considered an effective method onlyif defined as refraining from heterosexual intercourse during the
entire period of risk associated with the 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.
Women who are not heterosexually active at screening, but become sexually active during
the study must agree to utilize an effective method of birth controlas mentioned above.
8. 
Contraceptive requirements for heterosexually active male subjects (from day of first
vaccination until 3 months after last vaccination):
a If possible, the site should select an assay that is US FDA-approved
b Note: negative urine pregnancy also required prior to the second, third, and fourth vaccinations
c Verbal assurance should be given that adequate birth control measures have been followed for 28 days prior to first
vaccination
d Based on verbal confirmation


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a) If male subject had a vasectomy (after vasectomy: sperm count below the limit of
detection if procedure occurred <1 year agod): no additional contraception required.
b) If male subject did not have a vasectomy or had a positive sperm count after a
vasectomy procedure of <1 year agod: contraceptive methods will depend on
child-bearing potential of female partner: same criteria to be followed as for female
subjects in inclusion criterion 7.
9. 
A woman must agree not to donate eggs (ova, oocytes) for the purpose of assisted
reproduction after the first dose until 3 months after receiving the last dose of study
vaccine/placebo. A man must agree not to donate sperm after the first dose until 3 months
after receiving the last dose of study vaccine/placebo.
10. Subjects are willing/able to adhere to the prohibitions and restrictions specified in the
protocol and study procedures.
11. Subjects are amenable to HIV-risk reduction counseling and committed to maintaining
behavior consistent with low risk of HIV exposure through the last required protocol clinic
visit.
12. Subjects are assessed by the clinic staff as being at low risk for HIV infection  (see
Attachment 2).
13. Passed the Test Of Understanding (TOU). The TOU must be completed by all subjects, as
the first assessment after signing of the ICF.
4.2. 
Exclusion Criteria for the Main Study
Any potential subject who meets any of the following criteria will be excluded from participating
in the study:
1. 
Subject has chronic hepatitis B (measured by hepatitis B surface antigen test) or active
hepatitis C (measured by hepatitis C virus [HCV] Ab test; if positive, HCV ribonucleic
acid [RNA] PCR test will be used to confirm active versus past HCV infection), active
syphilis infection, chlamydia, gonorrhea, or trichomonase. Active syphilis documented by
serology unless positive serology is due to past treated infection.
2. 
In the 12 months prior to randomization, subject has a history of newly acquired herpes
simplex virus type 2, syphilis, gonorrhea, non-gonococcal urethritis, chlamydia, pelvic
inflammatory disease, trichomonas, mucopurulent cervicitis, epididymitis, proctitis,
lymphogranulomavenereum, chancroid, or hepatitis B.
3. 
Subject has any condition, including any clinically significant acute or chronic medical
condition, 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
e Trichomonas testing will only be performed for female subjects


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confound the protocol-specified assessments. In case of questions, the investigator is
encouraged to contact the study responsible physician.
4. 
Subject has had major surgery (eg, requiring general anesthesia) within the 4 weeks before
screening, or will not have fully recovered from surgery, or has surgery planned through
the course of the study.
Note: Subjects with planned surgical procedures to be conducted under local anesthesia
may participate.
5. 
Subject has had a thyroidectomy or active thyroid disease requiring medication during the
last 12 months (not excluded: a stable thyroid supplementation).
6. 
Subject has had major psychiatric illness and/or substance abuse problems during the past
12 months (including hospitalization or periods of work disability) that in the opinion of
the investigator would preclude participation.
7. 
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 vaccine/placebo.
8. 
Subject is a man who plans to father a child while enrolled in this study, or within 3 months
after the last dose of vaccine/placebo.
9. 
Subject has been in receipt of any licensed vaccine within 14 days prior to the first dose of
study vaccine/placebo, plans to receive within 14 days after the first study vaccination, or
plans to receive within 14 days before or after the second, third or fourth vaccination.
10. Subject has used experimental therapeutic drugs within 30 days of randomization. For
experimental vaccines see exclusion criterion 11.
11. Subject is a recipient of a prophylactic or therapeutic HIV vaccine candidate at any time,
or a recipient of other experimental vaccine(s) within the last 12 months prior to the Day
1 visit (Vaccination 1). For subjects who received an experimental vaccine (except HIV
vaccine) more than 12 months prior to the Day 1 visit (Vaccination 1), documentation of
the identity of the experimental vaccine must be provided to the sponsor, who will
determine eligibility on a case-by-case basis.
Exceptions: Subjects can be included where the vaccine received was subsequently
licensed (see exclusion criterion 9). Subjects with proof of having received only a placebo
vaccine can also be included.
12. Subject is currently in, or plans participation in, another interventional study during the
study period. Participation in an observational study is allowed with prior approval of the
sponsor.
13. Subject has been in receipt of blood or immunoglobulin products in the past 3 months.
14. Subject has known allergies, hypersensitivity, or intolerance to vaccines or its
excipients12,13.


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15. Subject has a history of chronic urticaria (recurrent hives) or a history of chronic or
recurrent 
eczema 
and/or 
atopic 
dermatitis 
that 
requires 
oral/parenteral
immunomodulators/immunosuppressors.
16. Subject has chronic or recurrent use of immunomodulators/suppressors, eg, cancer
chemotherapeutic agents, and oral or parenteral corticosteroids. Inhaled, ocular, and
topical steroids are allowed.
17. Subject who cannot communicate reliably with the investigator.
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.
NOTE: Investigators should ensure that all study enrollment criteria have been met during the
screening period. 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 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. 
Agree to follow the contraceptive requirements as noted in Section 4.1 during the main
study.
2. 
Following vaccination  subjects may be excluded from donating blood products due to
induced vaccine seropositivity (see Section 9.4.3) for as long as VISP persists.
3. 
Male subjects must agree not to donate sperm from the first administration of study
vaccine/placebo until 3 months after the last dose of study vaccine/placebo.
4. 
Female subjects must agree not to donate eggs (ova, oocytes) for the purpose of assisted
reproduction until 3 months after the last dose of study vaccine/placebo.
5. 
Use of any experimental medication (including experimental vaccines other than the study
vaccine) during the main study is disallowed. Vaccination with any licensed vaccine within
14 days prior to or after any of the study vaccinations is disallowed. However, if a vaccine
is indicated in a post-exposure setting (eg, rabies or tetanus), it must take priority over the
study vaccine. Subjects who enter the optional LTE phase are allowed to use any
experimental medication  during the optional LTE phase, except for prophylactic or
therapeutic HIV vaccine candidates which are disallowed and experimental
immunomodulators/suppressors which need prior sponsor approval.
6. 
Chronic or recurrent use of immunomodulators/suppressors, eg, cancer chemotherapeutic
agents, and oral or parenteral corticosteroids is prohibited during the main study. During
the optional LTE phase, use of these medications is discouraged, except when required by


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the medical condition of the subject, and each use should be reported during clinical visits.
Inhaled, ocular, and topical steroids are allowed (see Section 8).
7. 
Concurrent participation in another clinical study without prior sponsor approval is
disallowed during the main study. Subjects who enter the optional LTE phase are allowed
to participate in another clinical study, except for studies with prophylactic or therapeutic
HIV vaccine candidates which are disallowed and studies with experimental
immunomodulators/suppressors which need prior sponsor approval.
4.4. 
Inclusion and Exclusion Criteria for the Optional Long-term Extension
Phase
Each potential subject must satisfy all of the following inclusion criteria to be enrolled in the
optional LTE phase of the study upon completion of the final main study visit at Week 72. For the
optional 2-year extension of the LTE phase, there are no inclusion criteria, except for the signing
of the ICF appendix in criterion 1.
1. 
Each subject must sign an ICF appendix for the optional 3-year LTE phase indicating that
he or she understands the purpose of and procedures required for the optional LTE phase
and is voluntarily willing to participate in the optional LTE phase of the study. Subjects
willing to participate in the optional 2-year extension of the LTE phase will need to sign
the ICF appendix for the 2-year extension at Visit 23.
2. 
Subject must be randomized to Group 2A of the main study.
Note: Upon sponsor unblinding at the Week 28 analysis, subjects randomized to Group 2A
who have received all 4 vaccinations, will be asked to participate in the optional LTE phase
and sign the ICF appendix for the optional LTE phase at Week 72. Subjects who attend
their Week 72 visit prior to the sponsor's unblinding at the Week 28 analysis, will be
enrolled in the optional LTE phase if they consent and sign the ICF appendix for the
optional LTE phase and meet the eligibility criteria for the optional LTE phase. When the
Week 28 sponsor unblinding subsequently occurs, subjects that started the optional LTE
phase but turn out not to be in Group 2A of the main study will be withdrawn from the
optional LTE phase.
3. 
Subject must have received all 4 vaccinations of the main study.
4. 
Subject must be negative for HIV infection at the final main study visit at Week 72.
5. 
Subject must be willing/able to adhere to the prohibitions and restrictions for the optional
LTE phase, as specified in the protocol and study procedures.
Any potential subject who meets any of the following exclusion criteria at the end of the main
study will be excluded from participating in the optional LTE phase of the study. For the optional
2-year extension of the LTE phase, there are no exclusion criteria.


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1. 
Subject has any condition 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.
2. 
Subject is planning to participate in an interventional study during the optional LTE phase,
concerning a prophylactic or therapeutic HIV vaccine candidate.
3. 
Subject is planning to participate in an interventional study during the optional LTE phase,
concerning an experimental immunomodulator/suppressor that is not allowed per the
sponsor. Documentation of the identity of the experimental immunomodulator/suppressor
must be provided to the sponsor, who will determine eligibility on a case-by-case basis.
5. 
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization
Central randomization will be implemented in this study. Subjects will be randomly assigned to
one of 2 treatment groups and to one of 2 subgroups within each group based on a computer-
generated randomization schedule prepared before the study by or under the supervision of the
sponsor. The randomization will be evaluated by using randomly permuted blocks and stratified
by region.
The interactive web response system (IWRS) will assign a unique treatment code, which will
dictate the treatment assignment and matching study vaccine 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.
Blinding
The subjects, study-site personnel (except for those with primary responsibility for study vaccine
preparation and dispensing), and investigator will be blinded to study vaccine allocation until
Week 72, with the exception of the partial unblinding for the start of the optional LTE phase (see
below). The sponsor will be blinded to study vaccine allocation until the Week 28 analysis (see
Section 11.6).
An interim immunogenicity analysis will be performed once approximately 60 subjects have
completed the Week 16 visit and will be unblinded at the group level, but not at the subject level.
Study-site personnel (except for those with primary responsibility for study vaccine preparation
and dispensing), the sponsor (except for programming, statistics, clinical, and clinical immunology
personnel involved in the analysis, and the sponsor committee involved in making future decisions
for the program) and subjects will remain blinded to study vaccine allocation.
The pharmacist with primary responsibility for vaccine preparation (see Section 14.3) will not be
blinded to the study vaccine. In order to preserve blinding, he/she will place an overlay on the
syringes.


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The investigator will not be provided with randomization codes. The codes will be maintained
within the IWRS, which has the functionality to allow the investigator to break the blind for an
individual subject.
Data that may potentially unblind the treatment assignment will be handled with special care to
ensure that the integrity of the blind is maintained and the potential for bias is minimized. This can
include making special provisions, such as segregating the data in question from view by the
investigators, clinical team, or others as appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken by the investigator until the Week 72
electronic Data Capture (eDC) database is locked for the subjects, study-site personnel (except for
those with primary responsibility for study vaccine preparation and dispensing), and investigator.
However, for the purpose of the optional LTE phase, the investigator, the study-site personnel, and
the subject will be informed if the subject qualifies for the optional LTE phase (ie, if the subject is
randomized to Group 2A) when the subject reaches the Week 72 visit, or as soon as possible
following Week 72 upon sponsor unblinding at the Week 28 analysis. This will result in the partial
unblinding of the investigator, the study-site personnel, and the subjects as only those subjects
randomized to Group 2A qualify for the optional LTE phase. Subjects randomized to Groups 1A,
1B and 2B will not be informed of their treatment assignment until after the Week 72 eDC database
lock.
Otherwise, the blind should be broken only if specific emergency treatment/course of action would
be dictated by knowing the treatment status of the subject. In such cases, the investigator may in
an emergency determine the identity of the treatment by contacting the IWRS. It is recommended
that the investigator contacts the sponsor or its designee if possible to discuss the particular
situation, before breaking the blind. Telephone contact with the sponsor or its designee will be
available 24 hours per day, 7 days per week. In the event the blind is broken, the sponsor must be
informed as soon as possible. The date and reason for the unblinding must be documented by the
IWRS, in the appropriate section of the Case Report Form (CRF), 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.
Subjects who have had their treatment assignment unblinded should continue to return for safety
and immunogenicity evaluations, but will be withdrawn from study vaccine administration (see
Section 10.2).
In general, randomization codes will be disclosed fully only if the study is completed and the
clinical eDC database is closed. However, if an interim analysis is specified, the randomization
codes and, if required, the translation of randomization codes into treatment and control groups
will be disclosed to those authorized and only for those subjects included in the interim analysis.
See Section 11.6.
6. 
DOSAGE AND ADMINISTRATION
Each subject will receive study vaccine/placebo at 4 time points according to randomization, on
Day 1 and Weeks 12, 24, and 48, administered by IM injection into the deltoid. For visits with


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only one injection (ie, at Weeks 0 and 12), preferably the deltoid of the non-dominant upper arm
is used. When 2 injections are to be given at one visit (ie, at Weeks 24 and 48), it is required to use
a different deltoid for each injection. Exceptions on injection site are allowed only if medically
indicated.
For information on vaccination windows, see Section 9.1.2. If a subject cannot be vaccinated
within the allowed window, then that vaccination should not be administered. However, if the
window is missed due to a study pause (see Section  11.9), vaccination will be assessed on a
case-by-case basis, upon discussion between sponsor and investigator. If a subject misses more
than one study vaccination, he/she will be withdrawn from further study vaccination (see
Section 10.4). Study vaccines are as follows:
 
Ad26.Mos4.HIV:
 
Total dose is 5x1010 vp per 0.5 mL injection
 
Ad26.Mos.HIV:
 
Total dose is 5x1010 vp per 0.5 mL injection
 
Clade C gp140:
 
Clade C gp140 with 250 mcg total protein, mixed with aluminum phosphate adjuvant
(0.425 mg aluminum) at the pharmacy, per 0.5 mL injection
 
Placebo:
 
0.9% saline, 0.5 mL injection
7. 
TREATMENT COMPLIANCE
Subjects will receive doses of study vaccine/placebo at 4 time points administered by IM injection
by qualified study-site personnel at the study sites.
The date and time of each study vaccine administration will be recorded in the CRF.
8. 
PRESTUDY AND CONCOMITANT THERAPY
Prestudy therapies administered up to 30 days before the screening visit will be recorded in the
CRF at screening. In case a subject received an experimental vaccine more than 12 months prior
to the Day 1 visit (Vaccination 1) and is determined to be eligible, administration of this
experimental vaccine will be recorded in the CRF.
Concomitant therapies must be recorded in the CRF throughout the study from the signing of the
ICF to the final main study visit at Week 72. Beyond Week 72 (during the optional LTE phase),
only concomitant therapies given in conjunction with an SAE will be collected, as well as any
chronic or recurrent use of immunomodulators/suppressors and oral or parenteral corticosteroids
(see below).
Use of any experimental medication (including experimental vaccines other than the study
vaccine) during the main study is disallowed. Vaccination with any licensed vaccine within the


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14 days prior to or after any dose of study vaccine/placebo is prohibited. However, if a vaccine is
indicated in a post-exposure setting (eg, rabies or tetanus), it must take priority over the study
vaccine. Subjects who enter the optional LTE phase are allowed to use any experimental
medication during the optional LTE phase, except for prophylactic or therapeutic HIV vaccine
candidates which are disallowed and experimental immunomodulators/suppressors which would
need prior sponsor approval.
Study subjects can receive medications, such as acetaminophen, non-steroidal anti-inflammatory
drugs, or antihistamines as needed, although their use must be documented and use of these
medications as routine prophylaxis prior to study vaccination is discouraged.
Chronic or recurrent use of:
 
Immunomodulators/suppressors, eg, cancer chemotherapeutic agents
 
Oral or parenteral corticosteroids, eg, glucocorticoids
is an exclusion criterion (Section 4.2), and these medications are prohibited during the main study.
During the optional LTE phase, use of these medications is discouraged, except when required by
the medical condition of the subject, and each use should be reported during clinical visits. Ocular
and topical steroids are allowed, as well as inhaled steroids for the treatment of pulmonary
conditions.
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
The Time and Events Schedule summarizes the frequency and timing of safety  and
immunogenicity measurements applicable to the main study and the optional LTE phase.f
Evaluation of the safety/tolerability and immunogenicity of the vaccine regimens will include
laboratory assessments, physical assessment by clinical staff, and subject reports on signs and
f The timing and events outlined in the Time and Events Schedule are subject to modification in the event of
emergencies (possibly affecting a site, a region, a country or world-wide). Instructions on specific modifications
will depend on the particular situation and could vary by site. At a minimum, all efforts will be made to interact
with a participant via telemedicine at the time of a protocol-defined visit. Whereas the implementation of
alternative processes should be consistent with the protocol to the extent possible, it may, therefore, not be possible
to conduct all assessments at the defined time (or within the designated window). The health and safety of the
participant and site staff will be the driving factor in such decision making along with government and/or
institutional guidances/mandates. Any such deviations and the reason for any contingency measures implemented,
would clearly be described in the study report and IRB/EC and HA notification would be made if required.


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symptoms following vaccinations. Additional study visits may be required if in the investigator’s
opinion, further clinical or laboratory evaluation is needed.
Subjects 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. The study staff is responsible for providing appropriate training to the subject to avoid
missing or incorrect data. The diary card will be reviewed by the study personnel at visits indicated
on the Time and Events Schedule.
From screening to the final main study visit at Week 72, the total blood volume to be collected
from each subject will be approximately 1,200 mL. The total blood volume to be collected during
the optional LTE phase (Group 2A only) will be approximately 470 mL over a 3-year period or
628 mL over a 4-year period for subjects who consent to the optional 1-year extension of the
optional LTE phase. The total blood volume to be collected is considered to be within the United
States (US) Department of Health and Human Services (HHS) Office for Human Research
Protections (OHRP), and US FDA guidelines of 550 mL in any 8-week period. Daily volumes for
humoral immunogenicity testing will be approximately 20 mL/visit and for cellular
immunogenicity testing approximately 50-102 mL/visit during the main study and 50 mL/visit
during the optional LTE phase.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
Subjects who are temporarily not able to attend the per protocol visits at their clinical site due to
travel (eg, vacation, business travel) may visit any other clinical site participating in this clinical
study for non-vaccination visits. Please refer to the Study Procedures Manual for the guest visit
procedure details.
9.1.2. 
Visit Windows
The maximum screening period is 4 weeks, with the exception of female subjects or female
partners of male subjects starting hormonal contraception. In this case, the maximum screening
period is 6 weeks.
For the study visits, following windows will be allowed as indicated:
 Visit 3: Day 8 ± 1 day
 Visit 4: Day 15 ± 5 days
 Visit 5: Day 29 ± 5 days
 Visit 6: Day 85 -1 week, +3 weeks (second vaccination)
 Visit 7*: Visit 6 + 14 days (Day 99) ± 5 days


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 Visit 8*: Visit 6 + 28 days (Day 113) ± 5 days
 Visit 9: Day 169 -1 week, +3 weeks (third vaccination)
 Visit 10*: Visit 9 + 14 days (Day 183) ± 5 days
 Visit 11*: Visit 9 + 28 days (Day 197) ± 5 days
 Visit 12: Day 253 ± 5 days
 Visit 13: Day 337 -1 week, +3 weeks (fourth vaccination)
 Visit 14*: Visit 13 + 14 days (Day 351) ± 5 days
 Visit 15*: Visit 13 + 28 days (Day 365) ± 5 days
 Visit 16: Day 421 ± 3 weeks
 Visit 17: Day 505 ± 3 weeks
 Visit 18 to 22 inclusive and Visit 24-25 inclusive: Days 673, 841, 1009, 1177, 1345, 1681,
1849, ± 4 weeks
 Visit 23: 1513 -4 weeks/+2 months
*If a subject is not vaccinated on the given day of vaccination, the timings of the visits
2 and 4 weeks post-vaccination (see Time and Events Schedule) will be determined relative to the
actual day of vaccination.
If a subject cannot be vaccinated within the allowed window, then that vaccination should not be
administered. However, if the window is missed due to a study pause (see Section  11.9),
vaccination will be assessed on a case-by-case basis upon discussion between investigator and
sponsor. If a subject misses more than 1 study vaccination, he/she will be withdrawn from further
study vaccination.
For the LTE phase (from Week 72 onwards): If a visit can't be scheduled within the allowed
window, it will be assessed on a case-by-case basis upon discussion between investigator and
sponsor whether this visit can still be performed.
In the event of emergencies (possibly affecting a site, a region, a country or world-wide), it may
not be possible to conduct all assessments at the defined time (or within the designated window).
See Section 9.1.1 and Appendix 18, COVID-19 APPENDIX: GUIDANCE ON STUDY
CONDUCT DURING THE COVID-19 PANDEMIC for details.


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9.1.3. 
Screening Phase (Weeks -4 to 0)
Only healthy subjects negative for HIV infection (if possible, the site should select an assay that
is FDA-approved) and complying with the inclusion and exclusion criteria specified in Section 4
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.
Screening may be conducted in part after a sponsor- and Independent Ethics Committee
(IEC)/Institutional Review Board (IRB)-pre-approved non-study specific screening consent
process, but only if the relevant pre-screening tests are identical to the per protocol screening tests
and are within 4 weeks (with 2 extra weeks to allow for start of hormonal contraception for female
subjects and female partners of male subjects) prior to first vaccination. However, no study specific
procedures, other than screening assessments, will be performed until the subject has signed the
study-specific ICF. The non-study specific ICF will be considered source data.
During screening, subjects must pass the TOU, a questionnaire provided to the subject to document
his/her understanding of the study (see Section 16.1 and Attachment 3). The TOU must be
completed by all subjects, as the first assessment after signing of the ICF.
The following evaluations will be performed to determine eligibility requirements as specified in
the inclusion and exclusion criteria:
 
Medical history
 
Physical examination, including weight and height
 
Vital signs measurement
 
Review of pre-study medications
 
HIV-risk assessment (see Attachment 2) and counseling on avoidance of HIV infection
 
Review of inclusion/exclusion criteria
 
Blood sampling for complete blood count (CBC) with differential and platelets, blood
chemistry, hepatitis B/C serology, and HIV testing (including pre- and post-HIV-test
counseling)
 
Sexually-transmitted infection  testing (syphilis, chlamydia, gonorrhea, trichomonas [for
female subjects; urine or vaginal swab may be used])
 
Pregnancy counseling for both male and female subjects
 
Female subjects of childbearing potential: serum -hCG pregnancy testing
 
Urinalysis
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 vaccination (Visit


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2) within 28 days from signing ICF (with 2 extra weeks to allow for start of hormonal contraception
for female subjects or female partners of male subjects).
Subjects with laboratory values or vital signs (eg, elevated blood pressure) not meeting eligibility
criteria on the screening visit may have one repeat testing if the abnormality is not clinically
significant and may be a testing aberrancy. The screening visit may be split into multiple
days/visits. If the repeat screening assessment causes the subject to fall outside the screening
window, all screening safety procedures should be repeated so that they are not more than 28 days
prior to the Day 1 visit. These subjects will not be considered screen failures, if their repeat labs
meet the inclusion criteria.
After medical history, physical examination, and laboratory data have been reviewed for
completeness and adherence to inclusion/exclusion criteria, the subject can be deemed to be
eligible for the study.
All pre-dose AEs will be recorded on the CRF, together with information about any concomitant
medications.
In case a subject meets all eligibility criteria but is unable to adhere to the allowed screening period,
all screening procedures (except ICF and TOU) should be repeated so that they fall within the
allowed screening period.
If a subject is a screen failure but at some point in the future is expected to meet the subject
eligibility criteria, the subject may be rescreened on one occasion only. Subjects who are
rescreened will be assigned a new subject number, undergo the informed consent process, and then
restart a new screening phase.
9.1.4. 
Vaccination
Visit 2/Randomization/Vaccination 1
After re-check of inclusion/exclusion criteria (including concomitant medication), abbreviated
physical examination (including weight measurement), measurement of vital signs, and a urine
pregnancy test (for women of childbearing potential), eligible subjects will be randomized as
described in Section 5.
If medical status and/or physical examination suggest(s) significant changes have occurred since
screening, the clinically relevant screening assessments will be repeated and the Day 1 visit
rescheduled. If the repeat screening assessment causes the subject to fall outside the screening
window, all screening safety procedures should be repeated so that they are not more than 28 days
prior to the Day 1 visit. These subjects will not be considered screen failures, if their repeat labs
meet the inclusion criteria.
Pre-dose samples for hematology, biochemistry, HIV testing, urinalysis, and immunogenicity will
be collected. Human leukocyte antigen will also be tested using the baseline blood sample. Pre-
dose AEs will also be collected, together with information about any concomitant medications.


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Study vaccine will be prepared by the site pharmacist, who will place an overlay on the syringes
(to preserve blinding) and will send it to the clinic. After each vaccination, subjects will remain
under observation at the study site for at least 30 minutes for presence of any acute reactions and
solicited local (at injection site) and systemic events (see Section 9.3), and vital signs measurement
will be repeated.
Subjects 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 for 7 days post-vaccination
(day of vaccination and the subsequent 7 days).
In addition to an HIV-risk assessment, counseling related to avoidance of HIV infection, pre- and
post-HIV-test counseling, and pregnancy counseling will be provided to all subjects (men and
women).
Visit 6/Vaccination 2
An abbreviated physical examination (including weight measurement) and measurement of vital
signs, will be performed for all subjects pre-vaccination. A urine pregnancy test must be performed
before vaccination for women of childbearing potential, and results must be available and negative
prior to vaccination. Pre-dose samples for hematology, biochemistry, HIV testing, and urinalysis
will be collected. A pre-dose blood sample for the immunogenicity assays will be drawn. Pre-dose
AEs will also be collected, together with information about any concomitant medications. After
each vaccination, subjects will remain under observation at the study site for at least 30 minutes
for presence of any acute reactions and solicited local (at injection site) and systemic events (see
Section 9.3), and vital signs measurement will be repeated.
Subjects 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 for 7 days post-vaccination
(day of vaccination and the subsequent 7 days).
In addition to an HIV-risk assessment, counseling related to avoidance of HIV infection, pre- and
post-HIV-test counseling, and pregnancy counseling will be provided to all subjects (men and
women).
Subjects will complete a social impact questionnaire (Attachment 4).
Visit 9/Vaccination 3
The procedures for Visit 9 will be the same as at Visit 6 as detailed above, with the exception of
the social impact questionnaire which will not be completed.
Visit 13/Vaccination 4
The procedures for Visit 13 will be the same as at Visit 6 as detailed above.


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9.1.5. 
Post-vaccination Follow-Up Phase
Visits 2a, 3, 4, and 5
At Visit 2a (24-72 hours post-vaccination), a member of the site staff will have a (remote) safety
follow-up communication with the subject (by e-mail, telephone, or visit, according to the
subject’s preference). The subject will be brought in for a clinic visit based on this assessment, if
deemed necessary by the investigator/sub-investigator or upon request of the subject. Exception:
for the sentinel group of 10 subjects, this will need to be an actual visit at 3 days post first
vaccination. A (remote) safety follow-up communication 24-72 hours post-vaccination is not
required if the vaccination was missed.
Visit 3 is a clinic visit for safety follow-up only, and will include an abbreviated physical
examination  (including weight measurement), vital signs measurement, and recording of
concomitant medications and any AEs. In addition to an HIV-risk assessment, counseling related
to avoidance of HIV infection will be provided to all subjects.
Visit 4 is a clinic visit that will include an abbreviated physical examination (including weight
measurement), vital signs measurement, recording of concomitant medications and any AEs, and
review of the diary for 7 days post-vaccination (day of vaccination and the subsequent 7 days).
Samples will be collected for safety laboratory testing (CBC and serum chemistry) and humoral
immunogenicity assays. In addition to an HIV-risk assessment, counseling related to avoidance of
HIV infection will be provided to all subjects.
Visit 5 is a clinic visit that will include an abbreviated physical examination (including weight
measurement), vital signs measurement, recording of concomitant medications and any AEs, and
collection of samples for humoral and cellular immunogenicity assays. In addition to an HIV-risk
assessment, counseling related to avoidance of HIV infection will be provided to all subjects.
Visits 6a, 7, and 8
The procedures for Visits 6a, 7, and 8 will be the same as for Visits 2a, 4, and 5, respectively.
Exception: no special requirements for the sentinel group for Visit 6a. At visits 7 and 8, both
humoral and cellular immunogenicity samples will be collected.
Visits 9a, 10, and 11
The procedures for Visits 9a, 10, and 11 will be the same as for Visits 2a, 4, and 5, respectively.
Exception: no special requirements for the sentinel group for Visit 9a. At Visits 10 and 11, both
humoral and cellular immunogenicity samples will be collected.
Visit 12
Visit 12 is a clinic visit for safety follow-up only, and will include an abbreviated physical
examination (including weight measurement), vital signs measurement, recording of concomitant
medication, recording of SAEs, AEs leading to treatment discontinuation, and AESIs, and
collection of samples for safety laboratory testing (CBC and serum chemistry). In addition to an


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HIV-risk assessment, counseling related to avoidance of HIV infection will be provided to all
subjects.
Visits 13a, 14, and 15
The procedures for Visits 13a, 14, and 15 will be the same as at Visits 2a, 4, and 5, respectively.
Exception: no special requirements for the sentinel group for Visit 13a. At Visits 14 and 15, both
humoral and cellular immunogenicity samples will be collected.
9.1.6. 
Follow-Up Phase
Follow-up visits will be performed at the clinic at Week 60 and 72. Each visit includes a vital signs
measurement, recording of concomitant medications, recording of SAEs, AEs leading to treatment
discontinuation, and AESIs, and collection of samples for immunogenicity and safety laboratory
testing (CBC and serum chemistry). In addition to an HIV-risk assessment, counseling related to
avoidance of HIV infection will be provided to all subjects.
A complete physical exam will be performed at the final main study visit (Week 72). At Week 60,
an abbreviated, symptom-directed exam will be performed as indicated by the investigator. Weight
will be measured at both visits.
At the final main study visit (Week 72), samples for HIV testing and urinalysis will be collected.
Pre- and post-HIV-test counseling will be provided to all subjects. Subjects will also complete a
social impact questionnaire (Attachment 4).
9.1.7. 
Early Withdrawal/Exit Visit
In the event of early withdrawal from the main study (ie, before Week 72), the following
procedures will be performed: an abbreviated physical examination  (including weight
measurement), vital signs measurement, recording of concomitant medications and any AEs, and
collection of samples for safety laboratory testing (CBC and serum chemistry), the
immunogenicity assays, urinalysis, and HIV testing. In addition to an HIV-risk assessment,
counseling related to avoidance of HIV infection, pre- and post-HIV-test counseling, and
pregnancy counseling will be provided to all subjects (men and women). A urine pregnancy test
will be carried out for women of childbearing potential. Additionally, subjects will complete a
social impact questionnaire (Attachment 4).
9.1.8. 
Optional Long-term Extension Phase
An optional LTE phase (approximately 3 years after Week 72) will be performed for subjects
randomized to Group 2A, who have received all 4 vaccinations and are negative for HIV infection
at Week 72.
The sponsor will be unblinded to study treatment at the Week 28 analysis and will notify the
investigator and study-site personnel of subjects randomized to Group 2A. At Week 72, subjects
randomized to Group 2A who have received all 4 vaccinations, will be asked to participate in the
optional LTE phase and sign the ICF appendix for the optional LTE phase. During the first visit
of the optional LTE phase, the remaining eligibility criteria for the optional LTE phase will be


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verified. Subjects who attend their Week 72 visit prior to the sponsor's unblinding at the Week 28
analysis, will be enrolled in the optional LTE phase if they consent and sign the ICF appendix for
the optional LTE phase and meet the eligibility criteria for the optional LTE phase. When the
Week 28 sponsor unblinding subsequently occurs, subjects that started the optional LTE phase but
turn out not to be in Group 2A of the main study will be withdrawn from the optional LTE phase.
If signing the ICF appendix is not possible at Week 72, signing should be performed at an extra
visit (Visit 17bis) as soon as possible after Week 72 and at the latest before any assessment is done
on the first visit of the optional LTE phase.
An optional 2-year extension of this 3-year optional LTE is introduced in protocol amendment 3.
Subjects will be informed of the option to participate in this 2-year extension at the next possible
visit after approval of this amendment. Subjects willing to participate will need to sign the ICF
appendix for the 2-year extension at Visit 23. Subjects not willing to participate in the 2-year
extension will have their final study visit at Visit 23. For subjects willing to participate : As of
protocol amendment 5, the LTE will be shortened by one year, so Visit 26 and Visit 27 have been
removed and Visit 25 will be the final visit. Participants who already had their Visit 25 or Visit 26
will be contacted to perform an extra unscheduled exit visit, to be performed within 6 weeks after
local approval of protocol amendment 5. This can be either a telephone call or an actual site visit
and will need to include the same assessments as in the current Visit 25, except for the social
impact questionnaire and blood sampling for HIV and immunogenicity testing. In case a safety
issue (including a recent HIV exposure) emerges during the call, the participant might be asked to
come to the site for further evaluation.
Subjects will attend follow-up visits at the clinic from Week 96 until the final visit at Week 216
(for subjects who consent to be followed-up for approximately 3 years after week 72) or Week 264
(for subjects who consent to be followed-up for approximately 4 years after week 72). Each visit
includes recording of any SAEs, AESIs, and concomitant medications (any medication given in
conjunction 
with 
an 
SAE, 
as well 
as 
any 
recurrent 
or 
chronic 
use 
of
immunomodulators/suppressors and corticosteroids), and collection of samples for cellular and
humoral immunogenicity assays.
Samples for HIV testing will be collected. In addition to an HIV-risk assessment, counseling
related to avoidance of HIV infection, pre- and post-HIV test counseling will be provided to all
subjects.
Also, at each visit, subjects will complete a social impact questionnaire (Attachment 4).
9.2. 
Immunogenicity Evaluations
Humoral immune response assays will include, but are not limited to Env-Ab-binding assays, virus
neutralization assay, and assays for Ab functionality.
Cellular immune response assays will include, but are not limited to IFNγ ELISPOT assay, ICS,
and multiparameter flow cytometry.


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9.3. 
Safety Evaluations
Details regarding the PSRT and DRC are provided in Section 11.7 and 11.8, respectively.
Any clinically relevant changes occurring during the study must be recorded on the AE section of
the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be
followed by the investigator until resolution or until a clinically stable endpoint is reached.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the Time and Events Schedule:
AEs
All AEs will be reported from the time a signed and dated ICF is obtained until 28 days after first
dose of study vaccine, and thereafter, pre-dose and for 28 days after each subsequent dose of study
vaccine/placebo. Unsolicited AEs with the onset date outside the timeframe defined above
(>28 days after previous study vaccination), which are ongoing on the day of the subsequent
vaccination, should be recorded on the CRF AE page. All SAEs and AEs leading to discontinuation
from the study vaccination and AESIs (ie, confirmed HIV infection) are to be reported for the
duration of the main study (see Section 12.3.1 for details). During the optional LTE phase, only
SAEs and AESIs are to be reported. Other AEs are not collected during the optional LTE phase as
the optional LTE phase begins 6 months after the last vaccination and it is very unlikely that an
AE related to the study vaccine would only present that long after the last vaccination.
Adverse events will be followed by the investigator as specified in Section 12.
For solicited AEs, the following applies.
Solicited AEs
After vaccination, subjects will remain under observation at the study site for at least 30 minutes
for presence of any acute reactions and solicited events. In addition, subjects will record solicited
events in a diary for 7 days post-vaccination. All subjects will be provided with a diary and
instructions on how to complete the diary (Section 9.1.1). Diary information will be transcribed
by the study personnel in the appropriate CRF pages.
Injection Site (Local) AEs
Subjects will be asked to note in the diary occurrences of pain/tenderness, erythema and
induration/swelling at the study vaccine injection site daily for 7 days post-vaccination (day of
vaccination and the subsequent 7 days). The extent (largest diameter) of any erythema, and
induration/swelling should be measured (using the ruler supplied) and recorded daily.
 
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


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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).6
 
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.
 
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.16,17
Note: any other injection site events not meeting the above case definitions should be reported
separately as unsolicited AEs.
Systemic AEs
Subjects will be instructed on how to record daily temperature 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 day. If more
than one measurement is made on any given day, the highest temperature of that day will be used
in the CRF.
Fever is defined as endogenous elevation of body temperature ≥38°C, as recorded in at least one
measurement.19
Subjects will also be instructed on how to note daily in the diary symptoms for 7 days
post-vaccination (day of vaccination and the subsequent 7 days) of the following events: fatigue,
headache, nausea, myalgia, and chills.
The severity of these solicited systemic AEs will be graded according to the criteria presented in
Section 12.1.3.
AESI
Confirmed HIV infection in a subject during the study is considered an AESI. All AESIs,
irrespective if considered serious or not by the investigator, shall be reported to the sponsor
immediately and aggregate analyses performed either at the end of study and possibly at interim
time points during the study.


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Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and a urine sample for urinalysis will be
collected. The investigator must review the laboratory results, document this review, and record
any clinically relevant changes occurring during the study in the AE section of the CRF. The
laboratory reports must be filed with the source documents.
In case a Grade 3 or Grade 4 laboratory abnormality, or any laboratory abnormality accompanied
by clinically relevant signs or symptoms occurs (from the baseline visit onwards), all attempts will
be made to perform a confirmatory test within 48 hours after the results have become available.
After that, laboratory tests will be repeated weekly until values are resolved or stable.
The following tests will be performed by the local laboratory  (*parameters only measured at
screening):
 
Hematology Panel
-hemoglobin  
-platelet count
-hematocrit
-red blood cell (RBC) count
-white blood cell (WBC) count with differential
A WBC evaluation may include any abnormal cells, which will then be reported by the laboratory.
A RBC evaluation may include abnormalities in the RBC count and/or RBC parameters and/or
RBC morphology, which will then be reported by the laboratory.
In addition, any other abnormal cells in a blood smear will also be reported.
 
Serum Chemistry Panel
-creatinine 
-creatine phosphokinase*
-glucose* 
-bilirubin*
-aspartate aminotransferase (AST) 
-FSH (post-menopausal women only)*
-alanine aminotransferase (ALT)
 
Urinalysis
Dipstick  
-protein
-specific gravity  
-blood
-pH  
-ketones
-glucose
Microscopic reflex testing will be carried out in the event of abnormal urinalysis tests,
except when the investigator considers the abnormal urinalysis result to be from menstrual
origin.
In the microscopic examination, observations other than the presence of WBC, RBC, and casts
may also be reported by the laboratory.


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Laboratory values will be graded according to a modified version of the Division of Acquired
Immunodeficiency Syndrome (DAIDS) grading table, Version 2.0 (Attachment 1), and, if
clinically significant, reported as AEs. Laboratory reference ranges will be applied according to
the subject’s sex at birth.
Additional clinical laboratory assessments to be performed are as follows:
 
Serum (at screening) and Urine (pre-dose at vaccinations and the early Exit visit) Pregnancy
Testing for women of childbearing potential only
 
Serology (hepatitis B surface antigen, HCV Ab; at screening)
 
HIV testing (at screening, vaccinations, Week 72, the early Exit visit, and at each visit of the
optional LTE phase)
 
Syphilis, chlamydia, gonorrhea, trichomonas [for female subjects; urine or vaginal swab may
be used] (at screening)
Vital Signs (oral or tympanic temperature, pulse/heart rate, blood pressure)
Vital sign measurements will be performed at time points specified in the Time and Events
Schedule.
Blood pressure and pulse/heart rate measurements will be assessed with a completely automated
device. Manual techniques will be used only if an automated device is not available.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of rest
in a quiet setting without distractions (eg, television, cell phones).
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.
Physical Examination
Full physical examination  will be carried out at screening and at the final main study visit
(Week 72). At all other main study visits, an abbreviated, symptom-directed exam will be
performed as indicated 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. Height will be measured at screening. Weight will be
measured at every main study visit.
Physical examinations will be performed by the investigator or designated medically-trained
clinician. Any screening or baseline abnormality should be documented in the medical history
page of the CRF. Any clinically relevant post-baseline abnormality or any clinically relevant
worsening versus baseline conditions should be documented in the AE pages of the CRF.


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9.4. 
Human Immunodeficiency Virus Testing and Vaccine Induced
Seropositivity
9.4.1. 
Human Immunodeficiency Testing
HIV testing will be performed as indicated in the Time and Events Schedule.
At screening and baseline, subjects will be tested for HIV infection, and must be negative to be
entered into the study. If possible, the site should select an assay that is US FDA-approved.
At all other main study visits that include HIV-testing, a study-specific HIV-testing algorithm
(detailed in the Laboratory Manual) will be followed. Information provided to the clinical staff of
the study site will not include the results of specific tests, but will state only the final interpretation
as “infected” or “uninfected”. This system allows timely HIV testing without compromising the
double-blind nature of the study. The algorithm used for HIV testing throughout the main study
aims to differentiate false-positive results (Vaccine Induced Seropositivity [VISP]) from true
positives (HIV infection).
During the optional LTE phase, the study-specific HIV-testing algorithm described above will be
followed as long as treatment assignment is blinded. Upon study unblinding, unblinded HIV and
VISP results will be reported.
If a false-positive HIV test result develops during the study, further VISP testing will be offered
via post-study follow-up (see Section 9.4.3).
9.4.2. 
Management of Subjects who Become HIV-infected During the Study
Test results performed to confirm the diagnosis will be forwarded to the study staff. Subjects who
become HIV infected during the study, including the optional LTE phase, will be (see
Section 12.3.3):
 
Excluded from further vaccinations.
 
Provided counseling and referred for medical treatment.
 
Informed about observational studies monitoring subjects with HIV infection.
 
Excluded from initiation ofthe optional LTE phase.
9.4.3. 
VISP
In general, HIV-uninfected subjects who participate in preventative HIV-vaccine studies may
develop HIV-specific antibodies as a result of an immune response to the candidate HIV vaccine,
referred to as VISP. These antibodies may be detected in common HIV-serologic tests, causing
the test to appear positive even in the absence of actual HIV infection. Vaccine Induced
Seropositivity may become evident during the study or after the study has been completed.
Should an HIV-Ab test give a positive result for a particular subject during the study, the central
lab will carry out a follow-up testing algorithm either to exclude or confirm HIV infection. Further
details of this algorithm are given in the Laboratory Manual.


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Subjects should not donate blood during the study. Blood donation options for those subjects who
wish to resume blood donation after the study will be explained at the final study follow-up visit.
In the case of VISP, if, either during the study or after the end of the study, a subject requires an
HIV test outside the study (eg, to obtain a travel visa or insurance, or for medical reasons), he/she
should contact the research center. The center can issue a written statement giving details on VISP
and on the testing algorithm to be followed. If requested by a subject, repeat HIV testing will be
available at the site at most every 3 months to confirm their HIV status. It is highly preferable that
this repeat HIV testing will be performed at the research center. More frequent testing is only
allowed after sponsor approval. Testing for a particular subject will be available as long as VISP
is present for this subject.
Depending on the local availability of a follow-up protocol, subjects could join into such a study
that specifically follows the course of VISP. Such a study may not be available at all sites.
However, if such a study is not available, the site will provide HIV testing on request as described
in the previous paragraph.
In addition to providing testing, subjects will always receive pre- and post-test counseling.
9.4.4. 
Social Impact
Subjects in preventive HIV-vaccine clinical studies may experience problems with personal
relationships, employment, education, health care, housing, health, disability or life insurance,
travel, and immigration. In relation to a subject’s family, friends, and/or colleagues, the social
impact could manifest in one or more ways, resulting in social conflicts and stigmatization:
1. The investigational vaccine is thought to be harmful to the subject’s health, including a belief
that it might cause HIV infection.
2. The subject is perceived as HIV infected or at high risk.
3. Repercussions from any VISP.
For these reasons, subjects will complete a social impact questionnaire (at the timepoints specified
in the Time and Events Schedule) to evaluate any potential consequences of the subject’s
participation. For more information, please refer to the Study Procedures Manual.
9.5. 
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory
requisition form.
See the Time and Events Schedule for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
Laboratory Manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated
in the Laboratory Manual.


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10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY
TREATMENT/WITHDRAWAL FROM THE STUDY
10.1. Completion
A subject who is not participating in the optional LTE phase will be considered to have completed
the study if he or she has completed the assessments at Week 72. A subject who is participating in
the optional LTE phase will be considered to have completed the main study if he or she has
completed the assessments at Week 72 and will be considered to have completed the optional LTE
phase if he or she has completed the assessments at the last visit of the optional LTE phase at Week
216 (for subjects who consent to be followed-up for approximately 3 years after Week 72) or Week
264 (for subjects who consent to be followed-up for approximately 4 years after week 72).
10.2. Discontinuation of Study Treatment
Subjects will be withdrawn from study vaccine administration for the reasons listed below. These
subjects must not receive any additional dose of study vaccine but should enter the follow-up phase
with assessments of safety and immunogenicity. The subject will be encouraged to complete the
post-vaccination follow-up visits of the last vaccination received and a 12 and 24 weeks follow-
up visit after the last vaccination received, specified as Week 60 and Week 72 in the Time and
Events Schedule. Additional unscheduled visits may be performed for safety/tolerability reasons,
if needed. In case the subject withdraws before receiving the first vaccination, the subject is not
required to attend follow-up visits. In case of questions, the investigator is encouraged to contact
the study responsible physician. Subjects who prematurely discontinue study treatment are not
eligible for the optional LTE phase.
 
Unblinding
 
Anaphylactic reaction following vaccination
 
Pregnancy
 
Any related SAE
 
Any related AE, worsening of health status or intercurrent illnesses that, in the opinion of the
investigator, requires discontinuation from study vaccine
 
Confirmed HIV infection
 
Chronic or recurrent use of immunosuppressants (after discussion with the sponsor)
 
Missing more than 1 study vaccination
 
Any event (eg, overdose, incorrect dosing) that, in the opinion  of the investigator (in
agreement with the sponsor), would require discontinuation of study vaccine
10.3. Contraindications to Vaccination
The following events constitute a contraindication to vaccination at that point in time. If any of
these events occur at the scheduled time for vaccination, the vaccination can be rescheduled (as
long as this is in agreement with the allowed windows, see Section 9.1.2):


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 
Acute illness at the time of vaccination. This does not include minor illnesses, such as diarrhea
or mild upper-respiratory tract infection.
 
Fever (oral temperature ≥38.0°C) at the time of vaccination.
10.4. Withdrawal From the Study
Each subject has the right to withdraw from the study at any time for any reason without affecting
the right to treatment by the investigator. The investigator should make an attempt to contact
subjects who did not return for scheduled visits or follow-up. Although the subject is not obliged
to give reason(s) 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:
 
Lost to follow-up
 
Withdrawal of consent
 
Death
 
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 to stop or cancel the study
If a subject is lost to follow-up, every reasonable effort (at least 2 documented attempts to contact
the subject by telephone and at least one documented written attempt) 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.
When a subject withdraws before completing the study, the reason for withdrawal is to be
documented in the CRF and in the source document. Study vaccine assigned to the withdrawn
subject may not be assigned to another subject. Subjects who are vaccinated and who withdraw
will not be replaced. If a subject withdraws early from the study, assessments for early withdrawal
should be obtained (see Section 9.1.7).
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.
The exit visit is only applicable to the main study until Week 72.
10.5. Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (see 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.


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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 safety and immunogenicity data is
outlined below. Specific details will be provided in the Statistical Analysis Plan.
11.1. Subject Information
For all subjects, demographic characteristics (eg, age, height, weight, body mass index [BMI],
race, and gender), and other baseline characteristics (eg, medical history, concomitant diseases)
will be tabulated and summarized with descriptive statistics.
11.2. Analysis Populations
The safety population will consist of all subjects who received at least one dose of study vaccine,
and for whom any post-dose data is available.
The immunogenicity population will consist of all subjects who received at least one dose of study
vaccine, and who have data from at least one evaluable post-dose blood sample.
The per protocol immunogenicity population  will consist of all randomized and vaccinated
subjects for whom immunogenicity data are available, excluding subject samples with major
protocol deviations expecting to impact the immunogenicity outcomes (for example missed
vaccinations, natural infections, etc).
11.3. Sample Size Determination
The sample sizes in the main  study are regarded to be appropriate to assess the safety and
tolerability of the different vaccine regimens. Placebo recipients are included for blinding and
safety purposes and will provide control specimens for immunogenicity assays.
While mild to moderate vaccine reactions (local site and systemic responses) are expected, AEs
that preclude further vaccine administration or more serious ones that would limit product
development are not anticipated. With 110 individuals in the tetravalent Ad26.Mos4.HIV vaccine
regimen, the observation of 0 such reactions would be associated with a 95% confidence that the
true rate is <2.7%. For the combined active groups (n 165), there would be 95% confidence that
the true rate is <1.8% when 0 events are observed. The following table shows the probabilities of
observing at least one AE given true AE rates.
True AE Rate 
Probability ofObserving at Least one AE in n Subjects
n = 55 
n = 110 
n=165
0.1%  
5%  
10%  
15%
0.5%  
24%  
42%  
56%
1%  
42%  
67%  
81%
2.5%  
75%  
94% 
98.5%
5%  
94%  
99.6% 
>99.9%
10%  
99.7%  
>99.9%  
>99.9%


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The primary population for the safety analyses will consist of all subjects who received at
least 1 dose (Ad26.Mos.HIV, Ad26.Mos4.HIV, or placebo).
Anticipating a dropout rate of approximately 10%, the sample sizes will allow detection of
approximately 1.5-fold differences in Env-binding Ab titers between the groups with
Ad26.Mos4.HIV  (approximately  100 evaluable subjects) and their corresponding group with
Ad26.Mos.HIV only (approximately 50 evaluable subjects); with 80% probability, assuming a
1-sided 5% Type I error and a standard deviation of 0.4 on the log10 scale.
The immunogenicity population will consist of all subjects who received at least 1 dose and have
at least 1 measured post-dose blood sample collected.
11.4. Immunogenicity Analyses
Descriptive statistics (actual values and changes from reference with 95% confidence interval) will
be calculated for continuous parameters. Frequency tabulations will be calculated for discrete
parameters. Graphical representations of changes in immunologic parameters will be made as
applicable.
No formal hypothesis on immunogenicity will be tested. The analysis of immunogenicity will be
done on the (per protocol) immunogenicity population as defined in Section 11.2.
Differences between groups at a specific time point will be tested for exploratory purposes by a 2-
sample t-test if the data appear to be normally distributed. If not, the non-parametric Wilcoxon
rank sum test will be used. If portions of the measurements are censored below the assay
quantification limit, the Gehan-Wilcoxon test will be employed. All statistical tests will be 2-sided
and will be considered statistically significant if p<0.05.
Frequency tabulations will be calculated for discrete (qualitative) immunologic parameters.
Significant differences between groups will be determined by a 2-sided Fisher’s exact test.
11.5. Safety Analyses
No formal statistical testing of safety data is planned. Safety data will be analyzed descriptively.
Baseline for all safety parameters will be defined as the last evaluation done before the first dose
of study vaccine.
AEs
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). All reported AEs and events-related
diary information (solicited local at injection site and systemic, and unsolicited) with onset within
28 days after each vaccination (ie, treatment-emergent AEs, and AEs that have worsened since
baseline) will be included in the analysis. For each AE, the number and percentage of subjects who
experience at least one occurrence of the given event will be summarized by group and/or by
vaccine.


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Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those
subjects who die, who discontinue treatment due to an AE, or who experience a severe AE, an
SAE, or an AESI.
Summaries and listings may be provided separately for AEs with onset outside the above defined
timeframe and that were reported pre-dose at the moment of subsequent vaccinations.
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 solicited and
unsolicited AEs, separately for all and vaccination-related only, will be presented by System Organ
Class and preferred term.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Laboratory abnormalities will be
determined according to a modified version of the DAIDS grading table, Version 2.0 (Attachment
1), and in accordance with the normal ranges of the clinical laboratory. Laboratory abnormalities
will be tabulated per treatment group and/or per vaccine.
Vital Signs
The percentage of subjects with values beyond pre-specified limits (see Attachment 1) will be
summarized.
Physical Examination
Physical examination findings will not be tabulated separately. Clinically relevant findings will be
reported as AE and will be tabulated and listed as AEs. BMI will be calculated using the recording
of height at screening.
Social Impact Questionnaire
Data from the Social Impact Questionnaire will be summarized using descriptive statistics.
11.6. Analysis Time Points
An interim immunogenicity analysis will be performed once approximately 60 subjects have
completed the Week 16 visit and will be unblinded at the group level, but not at the subject level
(for details see Section 5).
The primary analysis will be performed in an unblinded fashion (for details see Section 5), once
all subjects have completed the Week 28 visit (ie, 4 weeks after the third injection) or discontinued
earlier. An additional analysis will be performed once all subjects have completed the Week 52
visit (ie, 4 weeks after the fourth injection) or discontinued earlier. The final analysis of the main
study will be performed once all subjects have completed their final main study visit at Week 72
or discontinued earlier. The final analysis of the LTE phase (optional and only for subjects
randomized to Group 2A) will be performed once all included subjects have completed the last


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visit of the optional LTE phase (Week 216 for subjects who consent to be followed-up for
approximately 3 years after Week 72 or Week 264 for subjects who consent to be followed-up for
approximately 4 years after Week 72), or discontinued earlier.
11.7. PSRT
A PSRT will review blinded safety data reports on a regular basis (at least 2 times per month)
starting from one week after first vaccination until the last subject has completed the Week 52
visit, and thereafter as needed.
After a sentinel group of 10 subjects received the first injection, further vaccinations will be paused
until a 3 day safety evaluation is performed. This evaluation will be performed by the PSRT and
the PI(s) of the subjects involved and will be based on the information received from the
investigator(s) by email/telephone.
If an administration of vaccine is considered, by PSRT review, to raise significant safety concerns,
all enrollment and vaccinations will be suspended until recommendations are issued (see
Section 11.9, Table 2). In specific cases a Data Review Committee (DRC) meeting will be
triggered.
The PSRT will include, but will not be limited to medical and safety representatives from the
sponsor, sites, DAIDS, BIDMC, HVTN, IAVI, and MHRP. The PSRT responsibilities, authorities,
and procedures will be documented in its charter.
11.8. DRC
A DRC will be established for this study, which will monitor data to ensure the safety and
well-being of the subjects enrolled. The DRC will review data as indicated below. The conclusions
of the DRC will be communicated to the investigators, the Institutional Review Board/Independent
Ethics Committee, and the national regulatory authorities, as appropriate.
The DRC will specifically review safety data (solicited and unsolicited AEs, SAEs, and available
laboratory assessments) at 3 time points:
 
Review blinded safety data (4 weeks of follow-up) after 15% of subjects have received their
first injection. The DRC will review these interim safety results and will allow administration
of the first dose of Ad26.Mos4.HIV/placebo (first injection) in the VAC89220HPX2003 study
only if no significant safety concerns are identified.
 
Review blinded safety data (4 weeks of follow-up) after 30% of subjects have received their
first injection.
 
Review blinded safety data (4 weeks of follow-up) after 30% of subjects have received their
third injection.
In addition, ad hoc review may be performed further to the occurrence of any AE/SAE leading to
a study holding situation as outlined in Section 11.9, or at request of the PSRT.


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The DRC will include medical experts in vaccines and at least one statistician. The DRC can
include members from both inside and outside Janssen, but will not include any study team
personnel or people otherwise directly involved in the study conduct, data management, or
statistical analysis for the study. The DRC responsibilities, authorities, and procedures will be
documented in its charter.
11.9. Study Holding Rules
If an administration of vaccine is considered, by the PSRT, to raise significant safety concerns, all
screening and vaccinations will be suspended until recommendations are issued. The AEs that may
lead to a safety pause or prompt PSRT AE review are summarized below in Table 2. These study
holding rules apply to related AEs that occur up to 4 weeks after vaccination and to SAEs occurring
up to 4 weeks after the last vaccination.
Table 2: 
AE Notification and Safety Pause/AE Review Rules1
(S)AE and 
Relationship2
Severity  
Site Principal Investigator Action 
PSRT/DRC Action3
SAE, related
Any 
grade 
Notify Study Responsible Physician or designee
AND fax SAE form to Global Medical Safety 
Office, immediately and no later than 24 h after 
becoming aware of the event
Immediate pause for PSRT
review of safety data
SAE, not 
related 
Grade 5
Notify Study Responsible Physician or designee
AND fax SAE form to Global Medical Safety 
Office, immediately and no later than 24 h after 
becoming aware of the event
PSRT review and
consideration of pause
AE4, related 
Grade 3 
or 
Grade 4 
Notify Study Responsible Physician immediately
and no later than 24 h after becoming aware of the
event
PSRT review and
consideration of pause
Three subjects 
with a similar 
related AE5 
Grade 3
or 
Grade 4
Not applicable
Immediate pause for DRC
review of safety data
The contact details of the medical team are in the Contact Information page(s). The Study Responsible
Physician (or designee) is responsible for the immediate notification of PSRT/DRC members and coordination
of a PSRT/DRC meeting.
1 
Applicable for AEs/SAEs occurring up to 4 weeks after the last vaccination. For a Grade 3/4 laboratory related
AE, the test must be repeated at least once, within 48 hours of the site becoming aware of the abnormal value.
PSRT evaluation for consideration of a pause will proceed without waiting for repeat testing. Start of DRC review
will require a confirmation of the laboratory test within 48 hours.
2 
Related: suspicion of relationship between the study vaccine and the AE. Not related: no suspicion of relationship
between the study vaccine and the AE. (Relationship as assessed by investigator)
3 
All sites will be notified immediately in case of a safety pause.
4 
For Grade 3 solicited related AEs, immediate PSRT review is mandatory only if the event persists for longer than
3 consecutive days, and the event doesn't get worse during this time. PSRT evaluation for consideration of a
pause will proceed for all other cases not specified in footnote 4.
5 
Applicable for the following related AEs:
- All Grade 4 AEs (regardless of duration)
- Grade 3 unsolicited AEs (regardless of duration)
- Grade 3 solicited AEs (only if persisting for longer than 3 consecutive days)
After each DRC review of a similar AE, the DRC will indicate the conditions under which they require further
notification and/or review of the subsequent similar AEs.


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Vaccinations for an individual subject may be suspended for safety concerns other than those
described in the table, at the discretion of the investigator if he/she feels the subject’s safety may
be threatened. The investigator may ask for a PSRT 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 in the
table, or before pause rules are met, if, in the judgment of the DRC, subject safety may be
threatened.
For events in the table above, the investigator notifies the sponsor’s study responsible physician
(or designee) immediately, and in all cases within 24 hours at the latest after the site observes, or
is notified of, the AE, and the study responsible physician (or contacted sponsor’s representative)
then notifies the PSRT immediately. If the case(s) is (are) deemed to fulfill the potential holding
rules, the PSRT will convene within one business day to review these AEs. The PSRT will review
and determine disposition, including whether the DRC needs to review the event(s).
If a study pause is triggered by the PSRT, all screening and vaccinations will be held until review
by the PSRT or DRC is complete. Resumption of screening and study treatment may be determined
by the PSRT or DRC (in consultation with the FDA, if required) following a cumulative review of
the available safety data as outlined in the charter. The clinical sites will be allowed to resume
activities upon receipt of a written notification from the sponsor. As needed, the appropriate
regulatory authorities will be informed in writing of the decision by the PSRT and/or DRC to
resume or discontinue study activities. The site is responsible for notifying their IEC/IRB
according to local standards and regulations. The sponsor is responsible for notifying the FDA.
12. 
AE 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.
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 AEs
Solicited AEs are predefined local (at the injection site) and systemic events for which the subject
is specifically questioned and which are noted by subjects in their diary (see Section 9.1.1).


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Unsolicited AEs
Unsolicited AEs are all AEs for which the subject is NOT specifically questioned in the subject
diary.
12.1. Definitions
12.1.1. 
AE Definitions and Classifications
AE
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 the treatment. 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 AEs starting with the signing of the ICF (see Section 12.3.1 for time of
last AE recording).
SAE
An SAE based on ICH and European 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.


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If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship
between the study vaccine and the event (eg, death from anaphylaxis), the event must be reported
as a serious and unexpected suspected adverse reaction by the sponsor to the Health Authorities
and by the investigator to the IEC/IRB according to regulatory and local requirements.
Unlisted (Unexpected) AE/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For Ad26.Mos4.HIV, Ad26.Mos.HIV, and Clade C gp140, the
expectedness of an AE will be determined by whether or not it is listed in the Investigator's
Brochure.
AE 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
definition listed in Section 12.1.2.
AESI
Confirmed HIV infection in a subject is considered an AESI. All AESIs, irrespective if considered
serious or not by the investigator, shall be reported to the sponsor immediately and aggregate
analyses performed either at the end of study and possible at interim time points during the study.
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.
Causality of AEs should be assessed by the investigator based on the following:
Related: 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, laboratory data, and fever will be coded for severity using a modified version of the
DAIDS grading table, Version 2.0 (Attachment 1).
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 DAIDS grading
table.


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For AEs not identified in the grading table (eg, diagnosis of HIV infection), the following
guidelines will be applied:
Mild  
Grade 1 
Symptoms causing no or minimal interference with usual social and
functional activities
Moderate 
Grade 2 
Symptoms causing greater than minimal interference with usual social
and functional activities
Severe 
Grade 3 
Symptoms causing inability to perform usual social and functional
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
Fatal 
Grade 5 
For any AE where the outcome is death, the severity of the AE is
classified as Grade 5
12.2. Situations Requiring Special Notification
Safety events of interest on a sponsor study vaccine that require expedited notification  to the
sponsor or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study vaccine
 
Suspected abuse/misuse of a sponsor study vaccine
 
Accidental or occupational exposure to a sponsor study vaccine
 
Medication error involving a sponsor product (with or without subject exposure to the sponsor
study vaccine, eg, name confusion)
 
Exposure to a sponsor study vaccine from breastfeeding
Subject-specific situations requiring special notification should be recorded in the CRF. Any
situation requiring special notification that meets the criteria of an SAE should be recorded on the
SAE form. Additional reporting from the sites to IEC/IRB and HA should be performed according
to local regulations.
12.2.1. 
AESI
Confirmed HIV infection in a subject is considered an AESI. All AESIs, irrespective if considered
serious or not by the investigator, shall be reported to the sponsor immediately and aggregate
analyses performed either at the end of study and possible at interim time points during the study.
Data collection on AESI will be performed through a questionnaire. The questionnaire has to be
sent to the sponsor within 24 hours of awareness of the confirmed HIV infection in a subject.


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12.3. Procedures
12.3.1. 
All AEs
All AEs and situations requiring special notification (see Section 12.2) 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, pre-dose and for 28 days (including
relevant visit window, if applicable) after each subsequent dose of study vaccine. Unsolicited AEs
with the onset date outside the timeframe defined above (>28 days after previous study
vaccination), which are ongoing on the day of the subsequent vaccination, should be recorded on
the CRF AE page.
All SAEs and AEs leading to discontinuation from the study vaccination (regardless of the causal
relationship) and AESIs (ie, confirmed HIV infection) are to be reported for the duration of the
main study. During the optional LTE phase, only SAEs and AESIs are to be reported. The sponsor
will evaluate any safety information that is spontaneously reported by an investigator beyond the
time frame specified in the protocol.
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether they
are protocol-specific assessments.
The investigator will monitor and analyze study data including all AE and laboratory data as they
become available and will make determinations regarding the severity of the adverse experiences
and their relation to study vaccine. Adverse events will be deemed either related to study vaccine
or not related to study vaccine, according to Section 12.1.2. To ensure that all AEs are captured in
a timely manner, CRFs will be entered in real-time, and subjected to review to identify AEs which
may invoke study pausing rules.
The investigator or designee must review both collected solicited events and other AE CRFs to
insure prompt and complete identification of all events that require expedited reporting as SAEs,
invoke study pausing rules or are other serious and unexpected events.
All AEs, regardless of seriousness, severity, or presumed relationship to vaccine, must be recorded
using medical terminology in the source document and the CRF. Whenever possible, diagnoses
should be given when signs and symptoms are due to a common etiology (eg, cough, runny nose,
sneezing, sore throat, and head congestion should be reported as "upper respiratory infection").
Investigators must record in the CRF their opinion concerning the relationship of the AE to study
therapy. All measures required for AE management must be recorded in the source document and
reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or
sponsor where required) must report SUSARs to the appropriate IEC/IRB that approved the
protocol unless otherwise required and documented by the IEC/IRB. A SUSAR will be reported to


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regulatory authorities unblinded. Participating investigators and IEC/IRB will receive a blinded
SUSAR summary, unless otherwise specified.
For all studies with an outpatient phase, including open-label studies, the subject must be provided
with a "wallet (study) card" and instructed to carry this card with them for the duration of the study
indicating the following:
 
Study number
 
Statement, in the local language(s), that the 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. 
SAEs
All SAEs occurring during the study, including the optional LTE phase, 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 of their knowledge of the event. The initial and follow-up reports of an SAE should be
made by facsimile (fax) and/or email.
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
 
The event can be attributed to agents other than the 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:


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 
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 CRF).
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 vaccine, is considered an SAE.
12.3.3. 
HIV Infection
Human immunodeficiency virus testing will be carried out at times indicated in the Time and
Events Schedule. Subjects will be tested for HIV infection at screening and baseline, and must be
negative to be entered into the study. If possible, the site should select an assay that is US FDA-
approved. At all other main study visits that include HIV-testing, a study-specific HIV testing
algorithm (as described in the Laboratory Manual) will be followed. During the optional LTE
phase, the study-specific HIV-testing algorithm described above will be followed as long as
treatment assignment is blinded. Upon study unblinding, unblinded HIV and VISP results will be
reported.
Any subject with confirmed HIV infection must be discontinued from any further study vaccine
administration, but should remain in the study and be followed up for safety and immunogenicity
until the end of the study.
Confirmed HIV infection in a subject during the study is considered an AESI. All AESIs,
irrespective if considered serious or not by the investigator, shall be reported to the sponsor
immediately (see Section 12.2). An aggregate analysis will be performed either at the end of study
and possible at interim time points during the study.
Test results performed to confirm the diagnosis will be forwarded to the study staff. Subjects who
become HIV infected during the study, including the optional LTE phase, will be (see
Section 9.4.2):
 
Excluded from further vaccinations.
 
Provided counseling and referred for medical treatment.
 
Informed about observational studies monitoring subjects with HIV infection.
 
Excluded from initiation ofthe optional LTE phase
12.3.4. 
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported to
the sponsor by the study-site personnel within 24 hours of their knowledge of the event using the
appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and


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must be reported using the SAE Form. Any subject who becomes pregnant during the study must
promptly discontinue further vaccinations, but should continue participation in the study for
follow-up (see Section 10.2).
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 to be sent to the sponsor.
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,
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 (see Section 12.3.2). A sample of the suspected product
should be maintained for further investigation if requested by the sponsor.
13.2. Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.


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14. 
VACCINE INFORMATION
14.1. Physical Description of Study Vaccines
The Ad26.Mos4.HIV, Ad26.Mos.HIV, and Clade C gp140 supplied for this study are formulated
as:
Ad26.Mos4.HIV
Ad26.Mos4.HIV is a tetravalent vaccine containing the following 4 active pharmaceutical
ingredients pre-mixed in a 1:1:1:1 vp ratio:
 
Ad26.Mos1.Gag-Pol  recombinant, replication-incompetent Ad26 encoding for Mosaic 1
(Mos1) HIV-1 Gag and Pol proteins, manufactured in PER.C6® cells (JNJ-55471494-AAA).
 
Ad26.Mos2.Gag-Pol 
 recombinant, replication-incompetent Ad26 encoding Mosaic 2
(Mos2) HIV-1 Gag and Pol proteins, manufactured in PER.C6® cells (JNJ-55471520-AAA).
 
Ad26.Mos1.Env  recombinant, replication-incompetent Ad26 encoding Mos1 HIV-1 Env
protein, manufactured in PER.C6® cells (JNJ-55471468-AAA).
 
Ad26.Mos2S.Env 
 recombinant, replication-incompetent Ad26 encoding modified
(substitute, 
S) Mos2 
HIV-1 
Env protein, 
manufactured 
in 
PER.C6® 
cells
(JNJ-64219324-AAA).
The Ad26.Mos4.HIV vaccine is formulated as a tetravalent vaccine, as a clear to slightly
opalescent solution for IM injection. The vaccine will be supplied as a frozen liquid to be thawed
prior to use, and will be practically free from particles. The vaccine will be provided in individual
dosage vials at a concentration of 1x1011 vp/mL. Refer to the Investigator's Brochure for a list of
excipients.12
Ad26.Mos.HIV
Ad26.Mos.HIV is a trivalent vaccine containing the following 3 active pharmaceutical ingredients
pre-mixed in a 1:1:2 vp ratio:
 
Ad26.Mos1.Gag-Pol  recombinant, replication-incompetent Ad26 encoding Mos1 HIV-1
Gag and Pol proteins, manufactured in PER.C6® cells (JNJ-55471494-AAA).
 
Ad26.Mos2.Gag-Pol  recombinant, replication-incompetent Ad26 encoding Mos2 HIV-1
Gag and Pol proteins, manufactured in PER.C6® cells (JNJ-55471520-AAA).
 
Ad26.Mos1.Env  recombinant, replication-incompetent Ad26 encoding Mos1 HIV-1 Env
protein, manufactured in PER.C6® cells (JNJ-55471468-AAA).
The Ad26.Mos.HIV vaccine is formulated as a trivalent vaccine as a clear to slightly opalescent
solution for IM injection. The vaccine will be supplied as a frozen liquid to be thawed prior to use,
and will be essentially free from particles. The vaccine will be provided in individual dosage vials
at a concentration of 1x1011 vp/mL. Refer to the Investigator's Brochure for a list of excipients.12


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Ad26.Mos4.HIV and Ad26.Mos.HIV are classified as genetically modified organisms (GMOs).
Based on nonclinical biodistribution and shedding data with related vectors, the investigational
vaccine is not expected to pose any risk to the environment. Any local requirements related to GMOs
must be fulfilled by the investigator.
Clade C gp140
Clade C gp140 is a monovalent vaccine containing the following pharmaceutical ingredient:
 
Clade C gp140 Drug Substance is a trimeric, recombinant HIV-1 Env gp140 of Clade C,
produced on a PER.C6® cell line. Aluminum phosphate suspension is used as adjuvant
(JNJ-55471585-AAA: Clade C gp140 + aluminum phosphate adjuvant).
Clade C gp140 is formulated as a colorless to slightly yellowish/brownish solution for IM injection.
Clade C gp140 will be supplied as a frozen liquid to be thawed prior to use, and will be practically
free from particles. Clade C gp140 will be supplied at a nominal strength of either 1 mg/mL or 0.2
mg/mL. Refer to the Investigator’s Brochure for a list of excipients.13 The aluminum phosphate
adjuvant will be supplied as a formulated refrigerated liquid suspension with a nominal aluminum
content of 1.7 mg/mL. It will be mixed with Clade C gp140 at the site pharmacy prior to
administration.
Placebo
Placebo consisting of sterile 0.9% Saline for Injection will be supplied (as commercially available).
Study vaccines will be manufactured and provided under the responsibility of the sponsor.
14.2. Packaging and Labeling
All study vaccines were manufactured and packaged in accordance with Current Good
Manufacturing Practice (GMP). All study vaccines will be packaged and labeled under the
responsibility of the sponsor.
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 Site Investigational
Product Procedures Manual.
14.3. Preparation, Handling, and Storage
Refer to the Site Investigational Product Procedures Manual for guidance on study vaccine
preparation, handling, and storage.
Study vaccine must be stored in a secured location at controlled temperature with no access for
unauthorized personnel. The study freezer must be equipped with a continuous temperature
monitor and alarm. Study freezers should be equipped with back-up power systems. In the event
that study vaccine is exposed to temperatures outside the specified temperature ranges, all relevant
data will be sent to the sponsor to determine if the affected study vaccine can be used or will be


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replaced. The affected study vaccine must be quarantined and not used until further instruction
from the sponsor is received.
All injections should be administered in the deltoid. For visits with only one injection, preferably
the deltoid of the non-dominant upper arm is used. When 2 study vaccine injections are to be given
at one visit, it is required to use a different deltoid for each injection. Exceptions on injection site
are allowed only if medically indicated. No local or topical anesthetic will be used prior to the
injection. To account for the product with the shortest stability time, the maximum time allowed
between preparation and administration of the study vaccine will be 3 hours.
A site pharmacist will prepare all doses for administration and will provide it to the clinic. In order
to preserve blinding, the pharmacist will place an overlay on the syringes.
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 authorized
destruction unit and study vaccine supplies are destroyed on-site, this must also be documented on
the vaccine return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be
retained for accountability purposes.
Study vaccine should be dispensed under the supervision of the investigator or a qualified member
of the study-site personnel, or by a hospital/clinic pharmacist. Study vaccine will be supplied only
to subjects participating in the study. Study vaccine may not be relabeled or reassigned for use by
other subjects. The investigator agrees neither to dispense the study vaccine from, nor store it at,
any site other than the study sites agreed upon with the sponsor.
15. 
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:
 
Investigator's Brochure for Ad26.Mos.HIV and Clade C gp140
 
Laboratory Manual, Study Procedures Manual
 
IWRS Manual


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 
Electronic Data Capturing (eDC) Manual/electronic CRF completion guidelines and
randomization instructions
 
Sample ICF
 
Subject diary
 
Test of Understanding
 
Social Impact Questionnaire
 
Ruler (to measure diameter of any erythema and induration/swelling), thermometer
 
Subject wallet cards
 
Recruitment tools, as applicable
16. 
ETHICAL ASPECTS
16.1. Study-specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the
study, subjects will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may be
withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and
potential AEs of the study, and provide their consent voluntarily will be enrolled.
From screening to the final main study visit at Week 72, the total blood volume to be collected
from each subject will be approximately 1,200 mL. The total blood volume to be collected during
the optional LTE phase (Group 2A only) will be approximately 470 mL over a 3-year period or
628 mL over a 4-year period. The total blood volume to be collected is considered to be within the
US Department of HHS OHRP, and US FDA guidelines of 550 mL in any 8-week period. Daily
volumes for humoral immunogenicity testing will be approximately 20 mL/visit and for cellular
immunogenicity testing approximately 50-102 mL/visit during the main study and 50 mL/visit
during the optional LTE phase.
Test of Understanding
The TOU is a short assessment of the subject’s understanding of key aspects of the study. The test
will help the study staff to determine how well subjects understand the study and their requirements
for participation.
The TOU must be completed by all subjects, as the first assessment after signing of the ICF. The
TOU is reviewed one-on-one with the subjects and a member of the study team. Subjects are
allowed to retake the test as many times as necessary to achieve the passing score (≥90%) required
for participation in the study. If a subject fails to achieve the passing score, further information
and counseling will be provided by the study team member.
Any subject not capable of understanding the key aspects of the study, and their requirements for
participation, should not be enrolled.


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Risks Related to Aluminum
Aluminum is one of the most common metals found in nature and is present in air, food, and water.
Aluminum salts, such as aluminum phosphate have been used safely in vaccines for more than 70
years. Aluminum-containing vaccines have been associated with severe local reactions, such as
redness, lumps under the skin, contact allergy or irritation, and swelling at the site of injection.
There have also been reports, especially in patients with impaired renal function, of systemic
accumulation of aluminum, which has been associated with nervous disorders and bone disease.
Nonetheless, aluminum intake from vaccines is far less than that received from the diet or
medications such as antacids.4,14
Risks Related to Vaccines
Subjects may exhibit general signs and symptoms associated with administration of a vaccine, or
vaccination with placebo, including fever, chills, rash, aches and pains, nausea, headache,
dizziness and fatigue. 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 are rare. Medications must be available in the
clinic to treat serious allergic reactions.
The effect of this vaccine on a fetus or nursing baby is unknown, as well as the effect on semen,
so female subjects of child bearing potential, and male subjects having sexual intercourse with
females, will be required to agree to use birth control for sexual intercourse beginning prior to the
first vaccination and through 3 months after the last vaccination. Women who are pregnant or
nursing will be excluded from the main study.
Risks related to VISP are discussed in Section 9.4.3.
Risks from Blood Draws
Blood drawing may cause pain, bruising, and, rarely, infection at the site where the blood is taken.
Risks from HLA Testing
Tests results can be used to provide information about how susceptible subjects are to certain
diseases. Used inappropriately, this information could be discriminatory (for example, by
insurance companies). Human Leukocyte Antigen typing can also be used to determine paternity.
However, the blood samples donated will not be used for this purpose; they will be used only to
provide study investigators information about the immune system. The results will be coded to
protect subject identity.
Unknown Risks
There may be other serious risks that are not known.


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Subjects may believe that this vaccine provides protection against acquiring HIV infection, and
therefore practice riskier behavior. They will receive extensive counseling throughout the study to
address this potential problem. It is not known if the study vaccines increase or decrease the chance
of becoming HIV infected when exposed, or if upon becoming HIV infected, the person’s disease
course progresses faster or slower to AIDS.
In previous HIV-efficacy studies utilizing Ad5, a trend towards increased HIV-1 infection was
observed in vaccine recipients as compared with placebo recipients. Adenovirus serotype 26 is
biologically substantially different than Ad5 and Ad26-based vaccines afford superior protective
efficacy compared with Ad5-based vaccines against SIVMAC251 challenges in rhesus monkeys.
Further, Ad26 did not increase the number or activation status of total or vector-specific CD4+
T-lymphocytes at mucosal surfaces in humans following vaccination in a randomized,
double-blind, placebo-controlled clinical study.
Potential Benefits
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 HIV vaccine.
16.2. Regulatory Ethics Compliance
16.2.1. 
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human subjects.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study subjects are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
16.2.2. 
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the subjects)
 
Investigator's Brochure (or equivalent information) and amendments/addenda
 
Sponsor-approved subject recruiting materials
 
Information on compensation for study-related injuries or payment to subjects for
participation in the study, if applicable


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 
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 vaccine
 
New information that may adversely affect the safety of the subjects or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the subjects
 
Report of deaths of subjects under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).


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At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion.
16.2.3. 
Informed Consent
Each subject must give written consent according to local requirements after the nature of the study
has been fully explained. The ICF must be signed before performance of any study-related activity.
The ICF that is 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 oflong-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, which includes permission to obtain
information about his or her survival status if applicable. 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 and subsequent disease-related treatment, if needed.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. After
this explanation and before entry into the study, consent should be appropriately recorded by means
of the subject's personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the subject.
If the subject is unable to read or write, an impartial witness should be present for the entire
informed consent process (which includes reading and explaining all written information) and
should personally date and sign the ICF after the oral consent of the subject is obtained.
For participation in the optional 3-year LTE phase of the study, an ICF appendix will be available.
Upon sponsor unblinding at the Week 28 analysis, subjects randomized to Group 2A who have
received all 4 vaccinations, will be asked to participate in the optional LTE phase and sign the ICF
appendix for the optional LTE phase at Week 72. Subjects who attend their Week 72 visit prior to
the sponsor's unblinding at the Week 28 analysis, will be enrolled in the optional LTE phase if
they consent and sign the ICF appendix for the optional LTE phase and meet the eligibility criteria
for the optional LTE phase. When the Week 28 sponsor unblinding subsequently occurs, subjects
that started the optional LTE phase but turn out not to be in Group 2A of the main study will be
withdrawn from the optional LTE phase. If signing the ICF appendix is not possible at Week 72,


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signing should be performed at an extra visit (Visit 17bis) as soon as possible after Week 72 and
at the latest before any assessment is done on the first visit of the optional LTE phase.
An optional 2-year extension of this 3-year optional LTE is introduced in protocol amendment 3.
Subjects will be informed of the option to participate in this 2-year extension at the next possible
visit after approval of this amendment. Subjects willing to participate will need to sign the ICF
appendix for the 2-year extension at Visit 23. Subjects not willing to participate in the 2-year
extension will have their final study visit at Visit 23. In protocol amendment 5, this 2-year
extension was shortened to 1 year. Subject willing to participate will have their final visit at Visit
25. Participants who already had their Visit 25 or Visit 26 will be contacted to perform an extra
unscheduled exit visit, to be performed within 6 weeks after local approval of protocol amendment
5.
16.2.4. 
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be limited
to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of
personal data and for the investigator/institution to allow direct access to his or her original medical
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and
regulatory inspection. This consent also addresses the transfer of the data to other entities and to
other countries.
The subject has the right to request through the investigator access to his or her personal data and
the right to request rectification of any data that are not correct or complete. Reasonable steps will
be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.
Exploratory DNA, immunogenicity, and social impact questionnaire research is not conducted
under standards appropriate for the return of data to subjects. In addition, the sponsor cannot make
decisions as to the significance of any findings resulting from exploratory research. Therefore,
exploratory research data will not be returned to subjects or investigators, unless required by law
or local regulations. Privacy and confidentiality of data generated in the future on stored samples
will be protected by the same standards applicable to all other clinical data.
16.2.5. 
Long-term Retention of Samples for Additional Future Research
Each study subject will be asked to consent voluntarily for their blood samples to be stored for
other research studies that may be done after this study is completed. Future testing may involve


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deoxyribonucleic acid(DNA)/RNAtests. For subjects unwilling to have their blood samples stored
for future use, they can consent to participate in this study only, without having their blood samples
stored for future testing (see Section 10.5). In this case, their blood samples will be destroyed after
all the tests specified for this study have been concluded.
All samples, for which consent has been obtained and for which additional material is available
after study-specified testing is complete, will be stored for future testing. All applicable approvals
will be sought before any such samples are used for analysis not specified in the protocol or a
protocol amendment approved by the IRB.
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 (see Section 10.5).
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 IRB/IEC (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 CRF 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.


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17.2.2. 
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of vaccine to the study
site:
 
Protocol and amendment(s), if any, signed and dated by the principal investigator
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, subject compensation programs. This approval must clearly identify the specific
protocol by title and number and must be signed (or sealed, where appropriate per local
regulations) by the chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study-site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
 
Documentation of investigator qualifications (eg, curriculum vitae)
 
Completed investigator financial disclosure form from the principal investigator, where
required
 
Signed and dated clinical trial agreement, which includes the financial agreement
 
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first 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


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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
informed consent; dates of visits; results of safety parameters as required by the protocol; record
of all AEs and follow-up of AEs; concomitant medication; vaccine receipt/dispensing/return
records; vaccine administration information; and date of study completion and reason for early
discontinuation of 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).
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. This data is electronically extracted for
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in the
CRF.
The subject’s diary used to collect information regarding solicited events after vaccination will be
considered source data.
17.5. Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.
All CRF 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 CRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an
electronic CRF, 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 CRF. Any such
worksheets will become part of the subject's source documents. Data must be entered into CRF in
English. The CRF 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.


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All subjective measurements (eg, questionnaires) will be completed by the same individual who
made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after the
initial entry into the CRF, this can be done in either of the following ways:
 
Investigator and study-site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
17.6. Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study-site personnel before the study, and periodic monitoring visits by the sponsor. Written
instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study-site personnel before
the start of the study.
The sponsor will review CRFs 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 CRF 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


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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 may use a combination of monitoring techniques: central, remote, or on-site
monitoring to monitor this study.
The sponsor will ensure on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits,
the monitor will compare the data entered into the CRF with the source documents (eg,
hospital/clinic/physician's office medical records); a sample may be reviewed. The nature and
location of all source documents will be identified to ensure that all sources of original data
required to complete the CRF are known to the sponsor and study-site personnel and are accessible
for verification by the sponsor study-site contact. If electronic records are maintained at the study
site, the method of verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the
relevant study-site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study-site personnel will be available to provide an update on the progress of the
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
17.9. Study Completion/Termination
17.9.1. 
Study Completion/End of Study
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


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studysite 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 vaccine development
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.Mos4.HIV,
Ad26.Mos.HIV, and Clade C gp140 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
and/or its partners. 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.Mos4.HIV, Ad26.Mos.HIV, and
Clade C gp140, 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.


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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 any analyses performed
after the Clinical Study Report has been issued will be reported in a separate report and will not
require a revision of the Clinical Study Report. Study subject identifiers will not be used in
publication of results. Any work created in connection with performance of the study and
contained in the data that can benefit from copyright protection (except any publication by the
investigator as provided for below) shall be the property of the sponsor as author and owner of
copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors guidelines, the sponsor with its partners shall have the right to publish such primary
(multicenter) data and information without approval from the investigator. The investigator has
the right to publish study site-specific data after the primary data are published. If an investigator
wishes to publish information from the study, a copy of the manuscript must be provided to the
sponsor for review at least 60 days before submission for publication or presentation. Expedited
reviews will be arranged for abstracts, poster presentations, or other materials. If requested by the
sponsor in writing, the investigator will withhold such publication for up to an additional 60 days
to allow for filing of a patent application. In the event that issues arise regarding scientific integrity
or regulatory compliance, the sponsor will review these issues with the investigator. The sponsor
will not mandate modifications to scientific content and does not have the right to suppress
information. For multicenter study designs and substudy approaches, secondary results generally
should not be published before the primary endpoints of a study have been published. Similarly,
investigators will recognize the integrity of a multicenter study by not submitting for publication
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months ofthe availability of the final data (tables,
listings, graphs), or the sponsor confirms there will be no multicenter study publication.
Authorship of publications resulting from this study will be based on the guidelines on authorship,
such as those described in the Uniform Requirements for Manuscripts Submitted to Biomedical
Journals, which state that the named authors must have made a significant contribution to the
design of the study or analysis and interpretation of the data, provided critical review of the paper,
and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law.


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18. 
COVID-19 APPENDIX: GUIDANCE ON STUDY CONDUCT DURING THE
COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on
the conduct of this clinical study due to, for example, self-isolation/quarantine by subjects and
study-site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for study
related subject management in the event of disruption to the conduct of the study. This guidance
does not supersede any local or government requirements or the clinical judgement of the
investigator to protect the health and well-being of subjects and site staff and to maintain oversight
of delegated trial activities.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent
possible as a remote visit, a home visit, or delayed until such time that on-site visits can be
resumed.g At each contact, subjects will be interviewed to collect safety data. Key endpoint
assessments should be performed if required and as feasible. Subjects will also be questioned
regarding general health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments. Modifications to
protocol-required assessments may be permitted via COVID-19 Appendix after consultation with
the subject, investigator, and the sponsor. Missed assessments/visits will be captured in the clinical
trial management system for protocol deviations. Discontinuations of study interventions and
withdrawal from the study should be documented with the prefix “COVID-19-related” in the case
report form (CRF). Any deviations to study procedures occurring due to the COVID-19 pandemic
need to be properly captured in the clinical trial management system (or CRF), with the prefix
“COVID-19-related” (including actual visit date) and will be summarized in the clinical study
report.
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to applicable
guidance documents and regulations. If a subject has tested positive for severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), the investigator should contact the sponsor’s responsible
medical officer to discuss plans for study intervention and follow-up. Modifications made to the
study conduct as a result of the COVID-19 pandemic should be summarized in the clinical study
report.
g An on-site visit is defined as a visit during which the subject and the qualified site staff are both present in person at
the study site.
A remote visit is defined as a visit during which there is no direct in-person physical presence between the subject and
the qualified site staff (telephone or video call).
A home visit is defined as a visit during which the subject and the qualified site staff are both present at the subjects’
home.


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GUIDANCE SPECIFIC TO THIS PROTOCOL:
The following emergency provisions are meant to ensure subject safety on study while site
capabilities are compromised by COVID-19-related restrictions. When restrictions are lifted, sites
should revert to the original protocol conduct as soon as feasible and in accordance with local
guidance and regulations and in agreement with the institutions and the investigator’s assessment
of the safety of site staff and study subjects.
Study Visits and Assessments
 
Subjects may have remote visits for reactogenicity and safety assessments until such time that
on-site visits can be resumed. The actual visit date should be captured in the eCRF according
to the eCRF completion guidelines.
Sample Management
 If a site is experiencing a disruption in shipment of specimens from their Site Processing Lab
to the centralized HIV diagnostic testing laboratory(ies) due to the COVID-19
pandemic-related challenges, the Site Processing Lab should hold that specimen at the proper
temperature for later per-protocol testing.
Informed Consent
 Consenting and re-consenting of subjects for the measures taken (including also remote
consenting by phone or video consultation) will be performed as applicable and according to
local guidance for informed consent applicable during the COVID-19 pandemic. The process
is to be documented in the source documents.
Source Data Verification/Monitoring
 
In case on-site monitoring visits are not possible, the site monitor may contact the investigator
to arrange monitoring visits and activities remotely (in accordance with site and local
requirements). Additional on-site monitoring visits may be needed in the future to catch up on
source data verification.
Site Audits
 
During the COVID-19 pandemic and at the impacted sites, study site GCP audits with direct
impact/engagement from the investigator and study site personnel may not be conducted in
order to comply with national, local, and/or organizational social distancing restrictions.
Additional quality assurance activities such as remote audits or focused review of
study-related documents may take place with limited impact/engagement if possible.


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immunization 
safety 
data. 
http://www.sciencedirect.com/science/article/pii/
S0264410X07004835. Accessed 11 June 2015.
17. Kohl KS, Walop W, Gidudu J, et al. The Brighton Collaboration Local Reaction Working Group for Induration
at or near Injection Site. Induration at or near injection site: Case definition and guidelines for collection, analysis
and 
presentation 
of 
immunization 
safety 
data. 
http://www.sciencedirect.com/science/article/pii/
S0264410X07005038. Accessed 11 June 2015.
18. Kovacs J, Nkolola J, Peng H, et al. HIV-1 envelope trimer elicits more potent neutralizing antibody responses
than monomeric gp120. Proc Natl Acad Sci USA. 2012; 109: 12111-12116.
19. Marcy SM, Kohl KS, Dagan R, et al. The Brighton Collaboration Fever Working Group. Fever as an adverse
event following immunization: case definition and guidelines of data collection, analysis, and presentation.
http://www.sciencedirect.com/science/article/pii/S0264410X03006601. Accessed 11 June 2015.


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20. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-
1 infection in Thailand. N Engl J Med. 2009; 361: 2209-2220.
21. Vella S. Addressing barriers to the end of AIDS by 2030. The Lancet. 2015;2:e360-e361.
22. Investigator's Brochure: Ad26.Mos.HIV - Ad26.Mos4.HIV. Edition 7. Janssen Vaccines & Prevention B.V.
(February 2020).
23. Investigator's Brochure: Clade C gp140 - Mosaic gp140. Edition 7. Janssen Vaccines & Prevention B.V.
(February 2020).


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Attachment 1: Division of Aids Table for Grading the Severity of Adult and Pediatric AEs –Including
Modifications
The Division of AIDS Table for Grading the Severity of Adult and Pediatric AEs (Version 2.0,
November 2014), or ‘DAIDS grading table’, is a descriptive terminology to be utilized for AE
reporting in this study. A grading (severity) scale is provided for each AE term. Modifications
made by the sponsor are footnoted.
General Instructions
Estimating Severity Grade for Parameters Not Identified in the Grading Table
If the need arises to grade a clinical AE that is not identified in the DAIDS grading table, use the
category ‘Estimating Severity Grade’ located at the top of the table on the following page. In
addition, all deaths related to an AE are to be classified as Grade 5.
Grading Adult and Pediatric AEs
The DAIDS grading table includes parameters for grading both adult and pediatric AEs. When a
single set of parameters is not appropriate for grading specific types of AEs for both adult and
pediatric populations, separate sets of parameters for adult and/or pediatric populations (with
specified respective age ranges) are provided. If there is no distinction in the table between adult
and pediatric values for a type of AE, then the single set of parameters listed is to be used for
grading the severity of both adult and pediatric events of that type.
Determining Severity Grade
If the severity of an AE could fall under either 1 of 2 grades (eg, the severity of an AE could be
either Grade 2 or Grade 3), select the higher of the 2 grades for the AE.
Laboratory normal ranges should be taken into consideration to assign gradings to a laboratory
value.
Definitions
Basic Self-care Functions 
Adult Activities such as bathing, dressing, toileting, transfer or
movement, continence, and feeding.
Young Children Activities that are age and culturally
appropriate, such as feeding one’s self with culturally
appropriate eating implements.
Usual Social & Functional 
Activities 
Activities which adults and children perform on a routine basis
and those which are part ofregular activities of daily living, for
example:
Adults Adaptive tasks and desirable activities, such as going to
work, shopping, cooking, use of transportation, or pursuing a
hobby.
Young Children Activities that are age and culturally
appropriate, such as social interactions, play activities, or
learning tasks.












































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Attachment 2: HIV-risk Assessment
The following are intended as guidelines for the investigator to help identify potential vaccine trial
participants at “low risk” for HIV infection in the US and Switzerland. Outside these countries, in addition
to minimum requirements specified by the first two criteria defined below (“Have oral, vaginal or anal
intercourse with an HIV-infected partner, or a partner who uses injection drugs” and “Give or receive
money, drugs, gifts or services in exchange for oral, vaginal or anal sex”), low risk criteria as defined by
local standards would be applicable.
HVTN Low Risk Guidelines
August 1, 2013
The following are intended as guidelines for the investigator to help identify potential vaccine trial
participants at “low risk” for HIV infection in the US and Switzerland. These guidelines are based on
behaviors within the last 6-12 months prior to enrollment; however, it may be appropriate to consider a
person’s behavior over a longer period of time than specified to assess the person’s likelihood of
maintaining low risk behavior. Some volunteers may not be appropriate for enrollment even if they meet
these guidelines. These guidelines should be supplemented and interpreted with local epidemiologic
information about HIV prevalence in your area and community networks. The investigator may review the
risk level of any volunteer with the site PI and/or the Protocol Safety Review Team.
A volunteer may be appropriate for inclusion if he/she meets these guidelines:
1. 
SEXUAL BEHAVIORS
In the last 12 months did not:
 
Have oral, vaginal, or anal intercourse with an HIV-infected partner, or a partner who uses injection
drugs
 
Give or receive money, drugs, gifts, or services in exchange for oral, vaginal, or anal sex
AND
In the last 6 months has abstained from penile/anal or penile/vaginal intercourse, OR
In the last 6 months:
 
Had 4 or fewer partners of the opposite birth sex for vaginal and/or anal intercourse, OR
Is an MSM (person born male with partner(s) born male) who, in the last 12 months:
 
Had 2 or fewer MSM partners for anal intercourse and had no unprotected anal sex with MSM, OR
 
Had unprotected anal intercourse with only 1 MSM partner, within a monogamous relationship lasting
at least 12 months (during which neither partner had any other partners). If the monogamous
relationship ended, the volunteer may then have had protected anal intercourse with 1 other MSM
partner (total 2 or fewer partners in the last 12 months).


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Is a transgender person, regardless of the point on the transition spectrum, having sex with men (born male)
and/or other transgender persons, who in the last 12 months:
 
Had 2 or fewer partners for anal or vaginal intercourse, and had no unprotected anal or vaginal sex,
OR
 
Had unprotected anal or vaginal intercourse sex with 1 partner only within a monogamous relationship
lasting at least 12 months (during which neither partner had any other partners). If the monogamous
relationship ended, may then have had protected anal or vaginal sex with 1 other partner (total 2 or
fewer partners in the last 12 months).
AND
Uses or intends to use condoms in situations which may include penile/anal or penile/vaginal intercourse
with new partners of unknown HIV status, occasional partners, partners outside a primary relationship,
and/or partners known to have other partners.
2. 
NON-SEXUAL BEHAVIORS
In the last 12 months did not:
 
Inject drugs or other substances without a prescription
 
Use cocaine, methamphetamine, or excessive alcohol, which in the investigator’s judgment, rendered
the participant at greater than low risk for acquiring HIV infection
The investigator’s judgment should consider local epidemiologic information about HIV prevalence in the
area and community networks.
A volunteer is NOT appropriate for inclusion if he/she:
Acquired an STI (ie, new infection) in the last 12 months:
 
Syphilis
 
Gonorrhea
 
Non-gonococcal urethritis
 
HSV-2
 
Chlamydia
 
Pelvic inflammatory disease (PID)
 
Trichomonas
 
Mucopurulent cervicitis
 
Epididymitis
 
Proctitis
 
Lymphogranuloma venereum
 
Chancroid
 
Hepatitis B




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Attachment 4: Social Impact Questionnaire
Vaccine Research Center (VRC) Social Impact Case Report Form j
j Adaptations to the social impact questionnaire are allowed for local purposes, after IRB and sponsor approval.


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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: 
electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not
be required.
LAST PAGE
PPD


Signature
User 
Date 
Reason
 
29-Oct-2021 
13:47:24
(GMT)
Document Approval
PPD

SAP_001.pdf: 
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1
Approved, Date: 2 May 2022
Janssen Vaccines & Prevention B.V.
Statistical Analysis Plan
A randomized, parallel-group, placebo-controlled, double-blind Phase 1/2a study in 
healthy HIV uninfected adults to assess the safety/tolerability and immunogenicity of 2 
different prime/boost regimens; priming with trivalent Ad26.Mos.HIV and boosting with 
trivalent Ad26.Mos.HIV and Clade C gp140 plus adjuvant OR priming with tetravalent
Ad26.Mos4.HIV and boosting with tetravalent Ad26.Mos4.HIV and Clade C gp140 plus 
adjuvant
Protocol VAC89220HPX2004; Phase 1/2a
JNJ-55471468, JNJ-55471494, JNJ-55471520, JNJ-55471585, JNJ-64219324
*Janssen Vaccines & Prevention B.V. is a Janssen pharmaceutical company of Johnson & Johnson.
Status:
Approved  - V1.1
Date:
2 May 2022
Prepared by:
Janssen Infectious Diseases BVBA
Document No.:
EDMS-ERI-175658987
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.
NCT02788045


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................................ 4
DEFINITION OF TERMS .............................................................................................................................. 5
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Trial Objectives ................................................................................................................................ 6
1.2.
Trial Design ...................................................................................................................................... 6
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 6
1.4.
Sample Size Justification ................................................................................................................. 6
1.5.
Randomization and Blinding ............................................................................................................ 6
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 6
2.1.
Analysis Windows ............................................................................................................................ 6
2.2.
Pooling Algorithm for Analysis Centers............................................................................................ 8
2.3.
Analysis Sets.................................................................................................................................... 8
2.3.1.
Full Analysis Set ........................................................................................................................... 8
2.3.2.
Per-Protocol Immunogenicity Analysis Set................................................................................... 8
2.3.3.
LTE Analysis Set .......................................................................................................................... 9
2.4.
Definition of Subgroups.................................................................................................................... 9
3.
INTERIM ANALYSIS AND DATA REVIEW COMMITTEE ................................................................. 9
4.
SUBJECT INFORMATION.................................................................................................................. 9
4.1.
Demographics and Baseline Characteristics ................................................................................. 10
4.2.
Disposition Information................................................................................................................... 10
4.3.
Concomitant Medications............................................................................................................... 10
4.4.
Exposure ........................................................................................................................................ 11
4.5.
Protocol Deviations ........................................................................................................................ 11
4.6.
Medical History............................................................................................................................... 11
5.
SAFETY............................................................................................................................................. 11
5.1.
Adverse Events .............................................................................................................................. 12
5.1.1.
Definitions ................................................................................................................................... 12
5.1.2.
Analysis of Adverse Events ........................................................................................................ 12
5.1.3.
Transforming On-site Assessments and Diaries of Solicited Adverse Events into an 
Analysis Format.......................................................................................................................... 13
5.1.4.
Handling of Missing Data for Adverse Events ............................................................................ 15
5.1.5.
Solicited Local (Injection Site) Reactions ................................................................................... 15
5.1.6.
Solicited Systemic Adverse Events ............................................................................................ 15
5.2.
Clinical Laboratory Tests................................................................................................................ 16
5.2.1.
Analysis methodology................................................................................................................. 16
5.3.
Vital Signs ...................................................................................................................................... 17
5.3.1.
Definitions ................................................................................................................................... 17
5.3.2.
Analysis methodology................................................................................................................. 17
6.
IMMUNOGENICITY ........................................................................................................................... 17
6.1.
Analysis specifications ................................................................................................................... 17
6.2.
Immune Response Parameters ..................................................................................................... 17
6.3.
Immune Response Analysis .......................................................................................................... 18
6.4.
Handling of Missing and/or Invalid Immune Response Data......................................................... 20
6.5.
Immune response assays: details.................................................................................................. 22


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7.
SOCIAL IMPACT QUESTIONNAIRE................................................................................................ 26
APPENDIX 1: LABORATORY, VITAL SIGNS AND ABNORMALITY GRADINGS ................................. 27


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AMENDMENT HISTORY
V1.0 19 March 2019
First version 
V2.0 2 May 2022
Updated version to include long term extension data up 
to week 264 
ABBREVIATIONS
ADCP
antibody dependent cellular phagocytosis
AE
adverse event
BAMA
binding antibody multiplex assay
BIDMC
Beth Israel Deaconess Medical Center
BMI
body mass index
CI
confidence interval
CRF
case report form 
CTP
clinical trial protocol
DAIDS
Division of AIDS 
DP
drug product
DPS
data presentation specification 
ELISA
enzyme-linked immunosorbent assay
ELISPOT
Enzyme-Linked ImmunoSpot
ENV
Envelope
FHCRC
Fred Hutchinson Cancer Research Center
GM
geometric mean
GMR
geometric mean ratio
HIV
human immunodeficiency virus
ICS
intracellular cytokine staining
IG
immunogenicity 
LLOQ
lower limit of quantification
LOD
limit of detection
LTE
long term extension
PReP
Pre-Exposure Prophylaxis
SAE
serious adverse event
SDTM
study data tabulation model
ULN
upper limit of normal
VRC
Vaccine Research Center
RBC
red blood cell
WBC
white blood cell


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DEFINITION OF TERMS
Randomization
5:1:10:2 ratio
Study vaccine
-
Ad26.Mos4.HIV (Ad26.Mos.1.Env + Ad26.Mos.2.Env +Ad26.Mos1.Gag-Pol + 
Ad26.Mos2.Gag-Pol): Total dose is 5x1010 viral particles (vp) per 0.5 mL injection
-
Ad26.Mos.HIV (Ad26.Mos.1.Env + Ad26.Mos1.Gag-Pol + Ad26.Mos2.Gag-Pol): 
Total dose is 5x1010 viral particles (vp) per 0.5 mL injection
-
gp140 DP: gp140 DP with 250 mcg total protein, mixed with aluminum phosphate 
adjuvant (0.425 mg aluminum) at the pharmacy, per 0.5 mL injection
-
Placebo: 0.9% saline, 0.5 mL injection
Vaccination 
compliance
Each vaccine administered (if applicable) according to planned schedule
Vaccine regimen
Group 
Planned N
Day 1, Week 12
Week 24, Week 48
1A
55
Ad26.Mos.HIV
Ad26.Mos.HIV + gp140
1B
11
Placebo
Placebo + Placebo
2A
110
Ad26.Mos4.HIV
Ad26.Mos4.HIV + gp140
2B
22
Placebo
Placebo + Placebo


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1.
INTRODUCTION
This statistical analysis plan (SAP) was initially written to describe the analyses of the main part 
of the study (up to Week 72). This updated version covers also the reporting of data collected till 
the end of the long-term extension (LTE) which lasted up to Week 264 (final analysis at end of 
study) for the group 2A receiving the full vaccination regimen ‘Ad26.Mos4.HIV/Ad26.Mos4.HIV 
+ gp140’. At the time this SAP was written the Week 72 statistical analysis was already performed 
and will not be rerun. The below described analyses will be performed on fully unblinded data.  
1.1.
Trial Objectives
See CTP, Section 2.1.
1.2.
Trial Design
See CTP, Section 3.1.
1.3.
Statistical Hypotheses for Trial Objectives
No formal statistical hypothesis will be tested. 
1.4.
Sample Size Justification
See CTP, Section 11.2.
1.5.
Randomization and Blinding
See CTP, Section 5.
2.
GENERAL ANALYSIS DEFINITIONS
A baseline (or reference) value will be defined as the value of the last available assessment 
performed prior to the first dose (active vaccine or placebo).
2.1.
Analysis Windows
The phases and periods in the study will be constructed as follows:
Table 3: Phase and Period Definitions
Phase
Phase 
number
Period
Period 
number
Interval
From
To
Screening
1
00:00 of the date of 
signing the informed 
consent forma
One minute prior to Dose 1 on Day 1
Regimen
2
Post-
Dose 1
1
Date and time of Dose 1 
(Day 1)
Minimum of: 
a)
Maximum (28 days after first 
vaccination at 23.59, scheduled 
visit 4 weeks after first 
vaccination at 23:59)
b)
23:59 at the date of last contact 
(for early discontinuation)


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Table 3: Phase and Period Definitions
Phase
Phase 
number
Period
Period 
number
Interval
From
To
Follow-
Up 1
3
1 minute after end of Post-
Dose 1 period
Minimum of: 
a)
One minute prior to date and 
time of the next vaccination
b)
23:59 at the date of last contact 
(for early discontinuation)
Regimen
2
Post-
Dose 2
2
Date and time of Dose 2 
(Day 85)
Minimum of: 
a)
Maximum (28 days after 
second vaccination at 23.59, 
scheduled visit 4 weeks after 
second vaccination at 23:59)
b)
23:59 at the date of last contact 
(for early discontinuation)
c)
One minute prior to post-dose 3
Follow-
Up 2
4
1 minute after end of Post-
Dose 2 period
Minimum of: 
a)
One minute prior to date and 
time of the next vaccination
b)
23:59 at the date of last contact 
(for early discontinuation)
Regimen
2
Post-
Dose 3
3
Minimum of Date and 
Time of the two Dose 3 
Injections (Day 169)
Minimum of: 
a)
Maximum (28 days after the 
third vaccination at 23.59, 
scheduled visit 4 weeks after 
third vaccination at 23:59)
b)
23:59 at the date of last contact 
(for early discontinuation)
Follow-
Up 3
5
1 minute after end of Post-
Dose 3 period
Minimum of: 
a)
One minute prior to date and 
time of the next vaccination
b)
23:59 at the date of database cut-
offc in case of interim
c)
23:59 at the date of last contact 
(for early discontinuation)
Regimen
2
Post-
Dose 4
4
Minimum of Date and 
Time of the two Dose 4 
Injections (Day 337)
Minimum of: 
a)
Maximum (28 days after fourth
vaccination at 23.59, scheduled 
visit 4 weeks after fourth 
vaccination at 23:59)
b)
23:59 at the date of database cut-
offc in case of interim
c)
23:59 at the date of last contact 
(for early discontinuation)
Follow-
Up 4
6
1 minute after end of Post-
Dose 4 period
Minimum of: 
a)
Last available visit for 
completers
b)
23:59 at the date of last contact 
(for early discontinuation)c


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NOTE:
a  The start time of screening phase is 00:00. In case an earlier date is available (e.g. for lab or vital signs then use the very first date in order to 
include all data)
b In case a dose is not administered, the observations end up in the previous Follow-Up phase
c This timepoint is intended to be at the end of the main study i e  Week 72  LTE data will be reported separately
For the immunogenicity analyses no phases will be constructed. 
The periods/phases will be used primarily for safety and concomitant medication allocation.  The 
post-dose periods (and the regimen phase) are considered active periods/phase, the screening and 
follow-up phases are considered non-active phases. There will be no phase defined for the LTE 
part of the study.
For descriptive statistics over time, assessments (regardless of the investigated parameter) will be 
allocated to an analysis visit based on the visit number as captured in the database.
For subjects that received a first dose, but did not receive a 2nd dose while still continuing their 
planned visit schedule, the measurements after the planned but not administered 2nd dose will not 
be included in graphs and tables showing descriptive statistics over time. Those measurements will 
be shown in listings but it will be indicated that these are not used in the analysis.  Moreover, the 
vaccinations done after a missed one will not be shifted to the previous one but will be considered 
as planned: in the example above if the 2nd is missed, the 3rd vaccination will still be reported as 
post-dose 3. 
2.2.
Pooling Algorithm for Analysis Centers
Not planned, subgroups analyses by country are described in section 2.4. 
2.3.
Analysis Sets
2.3.1.
Full Analysis Set
The Full Analysis Set (FA) will consist of all subjects who were randomized and who received at 
least one dose of study vaccine. This will be the primary population for all analyses (except 
immunogenicity, see below) described in this document.
2.3.2.
Per-Protocol Immunogenicity Analysis Set
The per protocol immunogenicity (PPI) population consist of all subjects who have received at 
least the first three vaccinations, according to the protocol-specified vaccination schedule (+/- 2 
weeks), have at least one measured post-dose blood sample collected and were not diagnosed with 
HIV during the study. Samples taken after Week 48 from subjects in the PPI population who 
missed the 4th vaccination or did not receive the 4th vaccination in the protocol-specified time 
window (+/- 2 weeks) will be excluded from the analysis.
The analysis of the immune responses will be performed on the per protocol immunogenicity 
population.


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2.3.3.
LTE Analysis Set
The Long Term Extension (LTE) population consists of all subjects in the Per-Protocol 
Immunogenicity Analysis Set, randomized in group 2A receiving the full vaccination regimen 
‘Ad26.Mos4.HIV/Ad26.Mos4.HIV + gp140’ who had at least one visit in the long term extension 
part of the study. 
2.4.
Definition of Subgroups
The following subgroups will be investigated for the most relevant immunogenicity assays (more 
details in section 6.3):

Country (Rwanda, USA)

Ad26 VNA at baseline (<LLOQ, >=LLOQ)a

Sex (Female, Male)

Race (Caucasian, Black or African American, Asian, Otherb)

BMI [<18.5; 18.5-<25; 25-<30; ≥30]a
3.
INTERIM ANALYSIS AND DATA REVIEW COMMITTEE
A Data Review Committee (DRC) was planned to specifically review the safety data at three 
specific time points to ensure safety of the subjects:

Review blinded safety data (2 weeks of follow up) after 15% of subjects had received their 
first injection to decide whether further dosing can continue;

Review blinded safety data (2 weeks of follow up) after 30% of subjects had received their 
first injection to decide whether further dosing can continue;

Review blinded safety data (2 weeks of follow up) after 30% of subjects had received their 
third injection to decide whether further dosing can continue.
These analyses are described in a separate DRC Charter. 
4.
SUBJECT INFORMATION
Subject information will be analyzed based on the FA analysis set unless otherwise specified.
Continuous variables will be summarized using the following statistics, as appropriate: number of 
observations, arithmetic mean (mean), 95% confidence interval (CI) for the mean, standard 
deviation (SD), standard error (SE), median, quartiles (Q1 and Q3), minimum and maximum. The 
minimum and maximum will be presented to the same number of decimal places as the original 
data. The mean and median will be rounded to one more decimal place than the original data, while 
the SD, SE and 95% CI to two more decimal places.
                                                
a Baseline Ad26 VNA and BMI will also investigated as continuous variables.
b Subgroup “Other” should contain all remaining categories: Other, Multiple, American Indian or Alaska Native, etc.


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4.1.
Demographics and Baseline Characteristics
The following demographic and baseline characteristics will be summarized.

Sex (Female/Male) 

Age (years)

Race

Ethnicity

Region

Country

Height (cm)

Weight (kg)

BMI (kg/m2), calculated from the recording of baseline height and weight. 
4.2.
Disposition Information
Number and percentage of subjects that were 1) screened, 2) screening failures, 3) subjects meeting 
eligibility criteria but not randomized, 4) randomized and vaccinated, 5) randomized not 
vaccinated and 6) vaccinated but not randomized will be tabulated. 
Number and percentage of subjects that completed and those who discontinued together with the 
reason(s) for discontinuation will be tabulated. This will be done for completion/vaccine
discontinuation from further vaccination and from the trial at Week 72 and at the end of LTE.  
Number and percentage of subjects at each planned LTE visit will also be tabulated.
4.3.
Concomitant Medications
The analysis of concomitant medications will be using the WHO drug dictionary as provided in 
the clinical database.
Based on their start and stop date, concomitant therapies will be reported in each period during 
which they were applied.
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.  

In case of a completely missing start date, the concomitant therapy will be considered as 
having started before the trial. 


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
In case of a completely missing end date, the concomitant therapy will be considered as 
ongoing at the end of the trial/cut-off date.
Concomitant therapies will be tabulated. There will be special attention to Acetaminophen, 
NSAIDS or Antihistamines to identify medication that can mask local or systemic solicited events 
in the 8 days after the vaccinations and to systemic glucocorticosteroids during the whole study 
duration for possible influence on the immunogenicity results. Systemic glucocorticosteroids will 
be flagged in the overall CM listing. Subjects taking PrEP during the study will be listed. After 
Week 72 only specific CM were to be collected (CTP Section 8) thus the reporting for the LTE 
will be limited to those as required by CTP.
4.4.
Exposure
Number and percentage of subjects by number of received vaccinations will be tabulated.
Tabulation of vaccine administered within and outside the protocol-specified time windows (-1/+3 
weeks of the planned vaccination and additional 2 weeks) will be provided as well.
4.5.
Protocol Deviations
All major protocol deviations will be listed.
4.6.
Medical History
Medical history data will be listed.
5.
SAFETY
The safety and tolerability endpoints are:

Unsolicited AEs 28 days following each vaccination 

Solicited local and systemic AEs (reactogenicity), collected daily from day of vaccination for 
7 days post-vaccination (day of vaccination and the subsequent 7 days).
The safety and tolerability analysis will be performed on the FA set. Specifically, the analysis for 
solicited adverse events will be done on those subjects in the FA set for whom reactogenicity 
assessments are available in the database (either via on-site assessments or via the diary pages of 
the CRF). 
Safety data will be tabulated per period by regimen.  Only the active periods will be shown in the 
tables (AE, Lab, VS), except for SAEs. In addition, for a selection of tables (AE, Lab), tabulations 
per subject by vaccine and per dose by vaccine will be provided.
In the ‘per subject by vaccine’ analysis, the safety will be presented per periods (post-dose 1, 2, 3, 
4) by vaccine rather than by regimen.  A ‘post any dose’ period (= regimen phase in section 2.1) 
will be added, that summarizes the safety after all administered doses of a vaccine. The post-any-
dose period allows determining how many subjects reported events after administration of a certain 
vaccine regardless the number of doses.  Each subject is counted only once.  In case a subject has 
the same event after more than one dose, it is counted only once (and in case of showing attributes, 


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the worst corresponding attribute is shown) in the post-any dose period. The denominator is the 
number of subjects that received the considered vaccine in the considered period.
In the ‘per dose by vaccine’ analysis, the safety will also be presented by vaccine.  This table 
allows determining the incidence of events per administered dose of a certain vaccine. For 
example, if a subject has the same event at least once after dose 1 and at least once after dose 2 of 
the same vaccine, it is counted 2 times (so the numerator is the sum of post-dose 1, 2, 3 and 4 
events in the “per subject by vaccine” table). In case of showing attributes, the worst corresponding 
attribute of each period are shown. The denominator is the total number of doses administered of 
the considered vaccine over all subjects.
At the 3th and 4th vaccination timepoint two vaccines should be administered at two different 
injection sites (left/right deltoid).  The local solicited events should be linked to the medication
injected in that specific injection site. However for some subjects the link between local AE and 
injection site might be unavailable, so the AE will be attributed to both medications received by 
the subject (e.g. if a subject receiving Ad26 + gp140 HD with AE “Erythema”: Erythema will be 
counted for Ad26 and for gp140 HD). Systemic solicited and unsolicited AE will be reported under 
both the administered medications. 
5.1.
Adverse Events
The analysis of AEs will be based on the MedDRA coded terms as provided in the clinical 
database. 
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 within the 28-day period following each vaccination will be presented in the 
safety tables except for SAE and AESI (AE of special interest), 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 of the CTP.
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 is defined as number of days from the start of the event until 


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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 vaccination 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 and AESI.
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.
Transforming On-site Assessments and Diaries of Solicited Adverse 
Events into an Analysis Format
Solicited events are always allocated to the respective Post Dose period.
When creating the analysis dataset for solicited AEs (dataset ADAESOL), solicited AEs (recorded 
by day) need to be converted into the format of 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 (both local and systemic). 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 1 day between 2 (or more) occurrences of the particular 
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 a corresponding day (eg, day of vaccination) of diary data, the on-site 
assessment should be recorded as a separate record in the database. The following example 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
Serious
N
Outcome
Recovered/Resolved
The data should be converted and stored in the AE dataset as follows:
Subject 
No.
AE
Start 
Date
Stop 
Date
Severity
Relatedness
Serious
Outcome
AEID
0001
Headache
01JAN16
01JAN16
2
Doubtful
1


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0001
Headache
01JAN16
02JAN16
1
Probable
N
Recovered/Resolved
1
0001
Headache
04JAN16
05JAN16
3
Probable
N
Recovered/Resolved
1
0001
Headache
06JAN16
06JAN16
1
Probable
N
Recovered/Resolved
1
If a solicited AE ends after Day 8:

The stop date of the event is the “Date of last day of symptom” as recorded in the eCRF and 
the “maximum severity” after Day 8 as recorded in the CRF. A separate record is created for 
this, in case this severity deviates from the previous record.
Note: To complete the start and end-date based on diary data, the date will be calculated based on 
the actual day that the AE occurred relative to vaccination and not on the reported date. For
example, if the vaccination is on 01-JAN-2016, and the AE starts on Day 3, the start date will be 
set to the 03-JAN-2016, independent of the reported actual date.
For the calculation of duration, the first and last day is used, irrespective of whether interruptions
occurred in between by missing reporting days or Grade 0 events. In the above example, the 4
records contribute to the same AE, therefore AEID is set to the same value and the duration of the 
AE is set to 6 for all records. 
Step 1: Allocation of events to the periods:
Adverse events in the SDTM database are allocated to periods based on their start date/time. If the 
start date/time of an event falls between (or on) the start and stop date/time of a period, the AE is 
attributed to that period (treatment-emergent principle).

In case of partial start or stop dates (i.e. time and/or day and/or month and/or year missing), 
the events are allocated to the periods using the available partial information on start and end 
date; no imputation will be done. If, for instance, the AE start date only month and year are 
available, these data are compared to the month and year information of the periods. This rule 
may lead to multiplication of the event as a consequence of its assignment to multiple periods.

In case of a completely missing 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 


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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.
5.1.4.
Handling of Missing Data for Adverse Events
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 (i.e. in case severity is missing it is not considered an event).
5.1.5.
Solicited Local (Injection Site) Reactions
The analysis of local solicited adverse events will include:
1. Pain/Tenderness
2. Erythema
3. Induration/Swelling
5.1.6.
Solicited Systemic Adverse Events 
The analysis of systemic solicited adverse events will include:
1. Fever (defined as body temperature of 38.0°C or higher)
2. Headache
3. Fatigue
4. Myalgia
5. Nausea
6. Chills


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5.2.
Clinical Laboratory Tests
Any clinically relevant lab value measured from signing of the ICF onwards must be recorded on 
the adverse event page of the CRF and are analyzed as AE. The data will be summarized by the 
type of laboratory test.
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 preceding or exceeding the cut-off value with one 
unit. (<x: subtract 1 unit from x, >x: add 1 unit to x)
Toxicity grades will be determined according to the DAIDS Grading list (see also APPENDIX 1). 
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 
phase separately, including all post-baseline measurements of that phase.

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 be
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
Definition emergent: An abnormality (toxicity grade or abnormality based on normal ranges) will 
be considered emergent in a particular phase if it is worse than the baseline (baseline = prior very 
first vaccination). If the baseline is missing, the abnormality is always considered as emergent.  A 
shift from ‘abnormally low’ at baseline to ‘abnormally high’ post baseline (or vice versa) is also 
emergent.
5.2.1.
Analysis methodology
Laboratory data will be analyzed based on the full analysis set.  Unless specified otherwise, 
percentages are calculated versus the number of subjects in the analysis set with non-missing data 
for the parameter, period (if applicable) and treatment group under evaluation. 
Tabulations of the worst graded abnormalities per period following vaccination will be provided. 
Grade 3 and 4 toxicities developed following vaccination will be listed. Tabulations of the worst 
emerging abnormalities (below/ above) will be performed for tests that have no grading.


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5.3.
Vital Signs
5.3.1.
Definitions
Vital sign measurements will be performed at the time points indicated in the Time and Events 
Schedule (see CTP). Following parameters will be summarized: 

Temperature (°C)

Blood Pressure: systolic/diastolic (mmHg)

Pulse rate (bpm)
For definition of emergent refer to section 5.2.
5.3.2.
Analysis methodology
Any clinically relevant vital signs occurring from signing of the ICF onwards must be recorded on 
the adverse event page of the CRF and are analyzed as AEs. Tabulations of the parameters per 
period following vaccination will be provided. All findings will be listed by subject and by time 
point. Tabulations of the worst emerging abnormalities will be performed for parameters if
applicable (see grading on APPENDIX 1).
Physical examination data will only be listed.
6.
IMMUNOGENICITY
6.1.
Analysis specifications
The analysis of immunogenicity will be done on the PPI analysis set (Section 2.3). 
6.2.
Immune Response Parameters
Humoral and cellular immune responses as measured by the following immune assays will be 
analyzed:
Humoral response

Env ELISA IgG-t gp140

ELISA IgG 1-4

TZM-BL

ADCP gp140

BAMA 

Ad26 VNA
Cellular response

ELISpot

ICS


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6.3.
Immune Response Analysis
No formal hypothesis on immunogenicity will be tested however at week 28 the differences 
between the 2 active groups (Ad26.Mos4.HIV + gp140/ Ad26.Mos.HIV + gp140) will be explored by means 
of a GMR including 95%CI and by a 2-sample t -test on the log data if those are normally 
distributed or by a Wilcoxon rank sum test otherwise. Those analyses will be performed on the 
following assays: 

ELISA: Clade C (C97ZA.012), Mos1

ADCP: Clade C (C97ZA.012), Mos1

ELISpot: Env peptide pool PTE, Gag peptide pool PTE, Pol peptide pool PTE
Humoral response
For all the humoral assays the immune response values will be log10-transformed before any 
further handling. The log10-transformed values will be used throughout the analysis. In the graphs, 
original values will be displayed on the log10 scale.  
For each assay and at each time point geometric mean of actual values, geometric mean increases 
and percentage of responders, all with corresponding 95% CIs will be provided in the tables. Also, 
mean fold change from highest post-baseline value to week 72 will be reported. The definition of 
responders is defined in section 6.4 for each assay. Graphical presentations will be provided 
displaying dots for the subject values and including the geometric mean and the percentage of 
responders. If available, baseline values will be summarized pooling all the groups and will be 
displayed on the left of each graph. Data from post-baseline timepoints will be plotted next to each 
other for each group, a symbol will identify the geometric mean (or the median) of each group and 
timepoint.
In the graphs the actual values will be shown and the LLOQ cut-off will be visualized, the values 
below LLOQ or below LOD will be visualized with the value imputed as described in section 6.3.
Graphs by subgroups listed in section 2.4 will be done for Elisa Clade C (C97ZA.012), ADCP 
Clade C (C97ZA.012). 
Durability will be shown as a line plots displaying the GM/median for each vaccine regimen.  
Magnitude-breadth (MB) plot for the ELISA assay will be provided at each timepoint to explore 
the magnitude and breadth of each individual serum sample assayed (antibody titers of 5 Clades). 
MB curves will show, for each possible titer threshold, the proportion of antibody titers greater 
than this threshold. The group-specific curve obtained as the average MB across all subjects in that 
group will be displayed. The AUC-MB is calculated as the average of the titers over the panel of 
antigens.
For BAMA the median will be reported instead of the geometric mean. Cumulative number of 
responses across the IgG/antigen classes will be tabulated.


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Magnitude-breadth (MB) plots for the BAMA assay will be provided at week 28 to explore the 
magnitude (MFI of IgG3 and of IgG breath binding antibodies) and breadth of each individual 
serum sample assayed. MB curves will show, for each possible MFI threshold, the fraction of 
antigens with MFI greater than this threshold.
Weights will be applied to take into account the correlation among the antigens (more details will 
be specified in the DPS).
The group-specific curve obtained as the average MB across all subjects in that group will be 
displayed. The AUC-MB is calculated as the average of the MFI over the panel of antigens.
Cellular response
For ELISpot and for each peptide: n, median, quartile range, min, max of actual values, percentage 
of responders above a predefined threshold (see section 6.4) and corresponding 95% CI will be 
tabulated. 
Graphical presentations will be provided displaying dots for the subject values and including the 
median and the percentage of responders. In the graphs the actual values will be shown and the 
LLOQ cut-off will be visualized, the values below LLOQ will be visualized with the value imputed 
as LLOQ/2. 
In the graphs, original values will be displayed on the log10 scale. Graphs by subgroups listed in 
section 2.4 will be done for ELISpot Env peptide pool PTE, Gag peptide pool PTE and Pol peptide 
pool PTE.
ICS 
T cells: CD4+, CD8+
Antigen: Combined pools and separated pools 
Cytokine counts: Marginal, Boolean AND (co-expression) counts, Boolean OR (and/or)
For CD4+ and CD8+ and for each antigen (combined and separated pools): n, median, quartile 
range, min, max, percentage of responders (see section 6.4) and corresponding 95% CI will be 
tabulated for each available cytokine background adjusted percentages listed below. 
Cytokine  (ISSCAT)
Description
CD154+
Marginal
GzB+
Marginal
ICOS+
Marginal
IFNg+
Marginal
IL2+
Marginal
IL17a+
Marginal
IL4+
Marginal
TNFa+
Marginal
IFNg+/IL2+
Boolean AND (co-expression)


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Cytokine  (ISSCAT)
Description
IFNg+/IL2+/TNFa+
Boolean AND (co-expression)
IFNg+/TNFa+
Boolean AND (co-expression)
IL2+/TNFa+
Boolean AND (co-expression)
IFNg+ or IL2+
Boolean OR (and/or)
IFNg+ or IL2+ or TNFa+
Boolean OR (and/or)
Graphical presentations will be provided displaying dots for the subject values and including the 
median and the percentage of responders. In the graphs the actual values will be shown and the 
LLOQ cut-off will be visualized, the values below LLOQ will be visualized with the value imputed 
as LLOQ/2. 
In the graphs, original values will be displayed on the log10 scale.  
The technical details for the calculation of the cytokine background adjusted percentages to be 
displayed in the above described outputs will be outlined in the DPS.
Additional timepoints and tests within one of the above listed assays may be investigated for 
exploratory purposes. These data and data from timepoints belonging to the long-term extension 
part of the study will be analyzed using the approaches described above.
6.4.
Handling of Missing and/or Invalid Immune Response Data  
Analysis will be carried out on the available data, no imputation will be done for missing samples.
BAMA and ICS unreliable values should be excluded from the analysis: those records will be 
flagged in the SDTM dataset.
LLOQs by assay/test are listed in section 6.5. Values below LLOQ or LOD will be handled as 
follows:  

Calculation of Geomean (humoral response except ADCP) and median (cellular response): 

values < LLOQ are imputed =LLOQ/2

values = LOD are imputed =LLOQ/2
For ADCP only: 

values < LOD are imputed =LOD/2

Calculation of fold increases from baseline: 

values <LLOQ are imputed =LLOQ

values =LOD are imputed = LLOQ  
For ADCP only: 

values < LOD are imputed =LOD                          


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Values above the upper limit of quantification (ULOQ) will be handled as follows: 

Calculation of geomean and median: 

Values>ULOQ are imputed=ULOQ. 

Calculation of fold increases from baseline: 

Values >ULOQ are imputed with ULOQ


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6.5.
Immune response assays: details 
The details for each immune response assay are listed in following table.
Assay
Test 
Lab
LLOQa
LODa
ULOQa
Unit
Responder 
definition (R)
Fold increase (FI) 
calculation
VNA
Ad26 VNA
Janssen Vaccines 
and Prevention
17
NA
NA
IC90
>LLOQ
NA
Env ELISA 
IgG-t gp140
Clade A (92UG037.1)
Clade B (1990a)
Clade C (Con C)
Clade C (C97ZA.012)
Mos1
Janssen Vaccines
and Prevention
625
156.25
625
156.25
78.125
0
1600000
800000
1600000
400000
400000
EU/ml
1) if baseline 
<LLOQ or missing, 
R>LLOQ 
2) if baseline 
>=LLOQ, R=3-fold 
increase from 
baseline 
1) if baseline >LLOQ, 
FI=Value post-
baseline/Value wk0
2) if baseline<LLOQ, 
FI=value post-
baseline/LLOQ
Env ELISA 
IgG1,3
Clade C (C97ZA.012) IgG1
Clade C (C97ZA.012) IgG3
BIDMC
12.3
12.4
4
NA
EC50
Env ADCP 
gp140
Clade A (92UG037.1)
Clade B (1990a)
Clade C (Con C)
Clade C (C97ZA.012)
Mos1
Ragon
NA
5.16
6.43
6.49
4.32
4.28
NA
PS 
1) if baseline <LOD
or missing, R>LOD 
2) if baseline 
>=LOD, R=3-fold 
increase from 
baseline
1) if baseline >LOD, 
FI=Value post-
baseline/Value wk0
2) if baseline<LOD, 
FI=value post-
baseline/LOD
TZM-bl
Clade C (MW965.26) 
Clade C (C97ZA.012)
Duke U
20
20
NA
NA
ID50
>LLOQ
NA
                                                
a In case final LLOQ and ULOQ values present in the dataset differ from those listed in this table, those provided from the lab should be used. 


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Assay
Test 
Lab
LLOQa
LODa
ULOQa
Unit
Responder 
definition (R)
Fold increase (FI) 
calculation
BAMA 
IgG3
HIV ENV Con S gp140 CFI 
(Clade M) HIV ENV Con 6 
gp120/B (Clade M) 
HIV ENV gp41  
HIV ENV 1086C_D7gp120  
(Clade C) 
HIV ENV 1086C gp140 (Clade 
C) 
HIV ENV 1086C_V1V2 (Clade 
C) 
HIV ENV gp70_B.Case A_V1V2 
(Clade B) 
Duke U
100a
NA
NA
MFI
BAMA interpretation
flag = 1
1) if baseline >LLOQ, 
FI=Value post 
baseline/Value wk0
2) if baseline<LLOQ, 
FI=value post 
baseline/LLOQ
BAMA 
Breadth
HIV ENV gp120 
Clade A (51802) IgG-t Ab
Clade AE (254008) IgG-t Ab
Clade AE (A244) IgG-t Ab
Clade B (B.6240) IgG-t Ab
Clade B (BORI) IgG-t Ab
Clade B (TT31P) IgG-t Ab
Clade BC (CNE20) IgG-t Ab
Clade BC(BJOX002) IgG-t Ab
Clade C(1086C_D7) IgG-t Ab
B Clade M (Con 6) IgG-t Ab
HIV ENV gp140
Clade B (SC42261) IgG-t Ab
Clade C (CH505TF) IgG-t Ab
C Clade A (9004S) IgG-t Ab
C Clade B (RHPA) IgG-t Ab
C Clade B (WITO)IgG-t Ab
C Clade C (1086C) IgG-t Ab
C Clade C (BF1266) IgG-t Ab
CF Clade AE (conAE) IgG-t Ab
                                                
a This is not LLOQ but “positive” threshold as provided by the lab


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Assay
Test 
Lab
LLOQa
LODa
ULOQa
Unit
Responder 
definition (R)
Fold increase (FI) 
calculation
CFI Clade M(Con S) IgG-t Ab
HIV ENV gp41
IgG-t Ab
HIV ENV gp70 
Clade A (191084)IgG-t Ab
Clade AE (C2101) IgG-t Ab
Clade AE (CM244) IgG-t Ab
Clade B (62357.14) IgG-t Ab
Clade B (CaseA) IgG-t Ab
Clade B (RHPA4259) IgG-t Ab
Clade B (TT31P) IgG-t Ab
Clade B(700010058) IgG-t Ab
Clade BC (BJOX) IgG-t Ab
Clade C (96ZM651) IgG-t Ab
Clade C (BF1266) IgG-t Ab
Clade C (CAP210) IgG-t Ab
Clade C(Ce1086) IgG-t Ab
Clade C(TV1.21)IgG-t Ab
Clade C (001428)IgG-t Ab
Clade C (7060101641)IgG-t Ab
ELISpot
Env peptide pool Mos1
Pol peptide pool Mos1
Gag peptide pool Mos1
Env peptide pool Mos2
Pol peptide pool Mos2
Gag peptide pool Mos2
Env peptide pool PTEa (Env 
peptide pool 1 PTE,
Env peptide pool 2 PTE, Env 
peptide pool 3 PTE)
BIDMC
55
0
NA
SFC/106
PBMC 
1) if baseline 
<threshold or 
missing, 
R>threshold 
2) if baseline 
>=threshold,
R=3-fold 
increase from 
baseline
73b
112
87
70
63
55
100
NA
                                                
a ENV pep pool (PTE) will be provided split in pool 1,2,3: for the purpose of the statistical analysis they will be reported only as sum of the 3: HIV ENV pep pool. The ADAM should 
however contain also the 3 separated pools.
b Threshold for ELISpot test is based on the 95 percentile from the baseline values of about 350 subjects on that test in the HIV-V-A004 study


JNJ-55471468, JNJ-55471494, JNJ-55471520, JNJ-55471585, JNJ-64219324  
Statistical Analysis Plan 2004
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Approved, Date: 2 May 2022
Assay
Test 
Lab
LLOQa
LODa
ULOQa
Unit
Responder 
definition (R)
Fold increase (FI) 
calculation
Pol peptide pool PTE
Gag peptide pool PTE
105
181
ICS (CD4+, 
CD8+)
Combined pools
HIV Gag pep pool 
HIV Pol pep pool (Mos1)
HIV Env pep pool (Mos1)
HIV Env pep pool clade C (ZA) 
HIV Env pep pool (Mos1 ZA) 
HIV Env Pol Gag pep pool  
Separated pools
HIV Pol RT pep pool (Mos1)
HIV Gag pep pool (Mos1)
HIV Pol RNAseInt pep pool 1 
(Mos1)
HIV Env gp120 pep pool 1 
(Mos1)
HIV Env gp41 pep pool 1 (Mos1) 
HIV Env gp120 pep pool clade C 
(ZA)
HIV Env gp41 pep pool clade C
(ZA)
FHCRC
NA
NA
NA
% of 
CD4+/C
D8+ T 
cells
ICS interpretation
flag=1
NA
NA: not applicable: PS: phagocytic score; SFC: spot forming cells, PBMC: peripheral blood mononuclear cell, MFI: median fluorescent intensities


JNJ-55471468, JNJ-55471494, JNJ-55471520, JNJ-55471585, JNJ-64219324  
Statistical Analysis Plan 2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Approved, Date: 2 May 2022
7.
SOCIAL IMPACT QUESTIONNAIRE
Data from the Vaccine Research Center (VRC) Social Impact Questionnaire will be listed and 
summarized using descriptive statistics.