A Multi-center, Randomized, Double-blind, Placebo-controlled Phase 3 Efficacy Study of a Heterologous Vaccine Regimen of Ad26.Mos4.HIV and Adjuvanted Clade C gp140 and Mosaic gp140 to Prevent HIV-1 Infection Among Cis-gender Men and Transgender Individuals Who Have Sex With Cis-gender Men and/or Transgender Individuals
Phase: PHASE3
Conditions: Healthy
Sponsor: Janssen Vaccines & Prevention B.V.

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved, Date: 28 February 2023
Janssen Vaccines & Prevention B.V.*
Clinical Protocol
A Multi-center, Randomized, Double-blind, Placebo-controlled Phase 3 Efficacy Study of a
Heterologous Vaccine Regimen of Ad26.Mos4.HIV and Adjuvanted Clade C gp140 and
Mosaic gp140 to Prevent HIV-1 Infection Among Cis-gender Men and Transgender
Individuals who Have Sex with Cis-gender Men and/or Transgender Individuals
MOSAICO
Protocol VAC89220HPX3002; Phase 3
AMENDMENT 7
JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
* Janssen Vaccines & Prevention B.V. is a Janssen pharmaceutical company of Johnson & Johnson and is
hereafter referred to as the sponsor of the study. The sponsor is identified on the Contact Information page
that accompanies the protocol.
US sites of this study will be conducted under US Food & Drug Administration IND regulations
(21 CFR Part 312).
IND:016263
EudraCT NUMBER:2018-003666-13
Additional study numbers:HVTN 706
Status: 
Approved
Date: 
28 February 2023
EDMS number: 
EDMS-ERI-164221409, 17.0
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.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved, Date: 28 February 2023
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 7 
28 February 2023
Amendment 6 
27 October 2021
Amendment 5 
19 May 2021
Amendment 4 
10 March 2021
Amendment 3 
02 July 2020
Amendment 2 
20 June 2019
Amendment 1 
09 May 2019
Original Protocol 
14 January 2019
Amendment 7 (28 February 2023)
Overall Rationale for the Amendment: Decision has been made to terminate the Mosaico study
(VAC89220HPX3002/HVTN 706) prematurely by meeting the stopping rules for non-efficacy. Based on
the non-efficacy results of the Mosaico study as well as the outcome of immune correlates analysis in the
Imbokodo study (VAC89220HPX2008/HVTN 705), the immunogenicity analyses as specified in the
secondary endpoint of the Mosaico study are no longer relevant. The sponsor will continue to evaluate
immunogenicity as described under the exploratory endpoints. Additional changes are listed below.
The changes made to the clinical protocol VAC89220HPX3002/HVTN 706 Amendment 7 are listed below,
including the rationale of each change and a list of all applicable sections.
Section number 
and Name
Description of Change 
Brief Rationale
SYNOPSIS
2.1 Objectives and Endpoints
9.3 Immunogenicity Evaluations
Secondary objective & endpoint
related to immunogenicity has
been moved to exploratory
objectives and endpoints. In
addition, the description of the
endpoint is more generalized.
Knowledge of previously specified
secondary immune outcomes of the
vaccine is not critical for
understanding the study outcomes.
SYNOPSIS
TIME AND EVENTS
SCHEDULE
9.1.7 Visits for Participants who
Become HIV-1 Infected During
the Study
9.3 Immunogenicity Evaluations
11.8 Immunogenicity Analysis
It has been clarified that assays for
humoral and cellular responses are
no longer required, but that they
may be performed, if appropriate.
In addition, the option to use
alternative assays is included.
Knowledge of the immunogenicity of
the vaccine in participants who
become HIV-1 infected is not critical
for understanding the study outcomes.
SYNOPSIS
11.2 Analysis Populations
11.5.1 Vaccine Efficacy Analysis
Addition of the Modified Intent-
to-Treat-3 (mITT-3) population
for efficacy analysis, and
potentially for immune correlates.
The mITT population was
specifically removed for the
analysis of vaccine
immunogenicity and immune
correlates.
During the COVID-19 pandemic,
many participants received their
vaccination out-of-window. The
mITT-3 population includes
participants in the FAS population
who had a negative HIV test 4 weeks
post 3rd vaccination visit (ie, at the
Month 7 Visit), who received all
planned vaccinations at the first three
vaccination visits, even if these visits
were out-of-window. This population
will be an additional population for
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved, Date: 28 February 2023
Section number
and Name
Description of Change 
Brief Rationale
efficacy analysis, and potentially for
immune correlates.
The mITT population includes
participants in the FAS population
(having received at least one
vaccination) who are HIV-1 negative
on the date of first vaccination. Since
immune responses are known to
increase substantially after multiple
vaccinations, it has no added value to
use this population for the analysis of
immunogenicity and immune
correlates.
TIME AND EVENTS
SCHEDULE
Clarified that the request for 
redraw is considered as the initial 
positive HIV test result. 
Changes were made to provide
confirmation that for the purposes of
the protocol, the request for redraw is
considered as the initial positive HIV
test. Due to the HIV testing algorithm
steps, a scheduled or exposure sample
that leads to a request for redraw is
very likely to be HIV positive. The
request for redraw is what triggers the
#.X visit of the time and events
schedule for participants who become
HIV-1 infected.
9.4 Safety Evaluations 
Clarified that sexually transmitted
infection (STIs) detected from
study samples are considered
medically attended adverse events
(MAAEs).
The protocol could be interpreted that
an STI diagnosed from a study
collected sample will not meet criteria
for a MAAE. However, even if the
STI is diagnosed from a study sample,
as soon as any follow-up (discussion
or treatment) is performed, the event
meets MAAE criteria.
Amendment 6 (27 October 2021)
Overall Rationale for the Amendment: Upon request of CBER, it is specified that a serum sampling for
a PF4 antibody ELISA test should be performed in case of a potential AESI of TTS, if possible, and that a
test for anti-PF4 will also be performed on a stored pre-vaccination sample, if possible. Additional changes
are listed below.
The changes made to the clinical protocol VAC89220HPX3002/HVTN 706 Amendment 6 are listed below,
including the rationale of each change and a list of all applicable sections.
Section number 
and Name
Description of Change 
Brief Rationale
TIME AND EVENTS SCHEDULE
9.4 Safety Evaluations
12.3.4.1 Thrombosis with
Thrombocytopenia Syndrome
Specified that a serum sampling for
a PF4 antibody ELISA test should
be performed in case of a potential
AESI of TTS, if possible, and that a
Upon request of CBER
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved, Date: 28 February 2023
test for anti-PF4 will also be
performed on a stored pre-
vaccination sample, if possible.
ABBREVIATIONS
1.1.2 Background on the Study
Vaccines
12.3.4.1 Thrombosis with
Thrombocytopenia Syndrome
REFERENCES
The qualitative statement of ‘very
rare’ incidences of TTS was
replaced by reporting ratios.
It was added that cases of venous
thrombosis have also occurred at
more common sites, eg, lower
extremities.
Onset of symptoms was changed
from 1 to 2 weeks to 1 to 4 weeks,
and sometimes even later after
vaccination (up to 42 days as per
the American Society of
Hematology).
Added that these events have also
occurred in men and in individuals
older than 60 years.
Changed statement that TTS ‘can
be fatal’ to ‘has been fatal in some
cases’.
Added that participants should also
be instructed to report any leg pain,
changes in mental status or the
occurrence of seizures.
Align wording on TTS with
changes in TTS wording in the
Ad26.Mos(4).HIV Investigator’s
Brochure Edition 8 Addendum 1,
dated 19 Oct 2021, that were made
on request of CBER.
Synopsis
3.1 Overview of Study Design
9.4 Safety Evaluations
12.3.1 All Adverse Events
12.3.4.1 Thrombosis with
Thrombocytopenia Syndrome
In the definition of TTS,
‘symptomatic thrombocytopenia’
was replaced by
‘thrombocytopenia’.
For consistency with the definitions
of thrombocytopenia of the CDC,
Brighton Collaboration and
Medicines and Healthcare products
Regulatory Agency, which do not
include symptomatology, the
adjective “symptomatic” is
removed.
REFERENCES  
The reference to the Brighton
Collaboration case definition of
thrombotic events and
thrombocytopenia was updated.
Update
12.3.4 Adverse Events of Special 
Interest 
Clarified that no specific AESI
form is present in the eCRF, but
rather is a checkbox to indicate if
an AE is a potential AESI.
Clarification
12.3.4.1 Thrombosis with 
Thrombocytopenia Syndrome 
Clarified that TTS is reported using
the SAE form and not a separate or
different AESI specific form.
Clarification
6 DOSAGE AND 
ADMINISTRATION  
9.1.2 Visit Windows 
Clarified that cases of out of
window study vaccination due to
adhering to the required timeframe
between a per protocol allowed
COVID-19 vaccination and the
study vaccination do not require
Clarification and recommendation
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved, Date: 28 February 2023
safety review team approval of
whether the participant can still be
vaccinated, although cases should
still be notified to the sponsor.
Added that in case of out of
window study vaccinations there
should be an interval of at least 28
days between subsequent study
vaccinations.
12.3.3 Pregnancy  
Clarified that any postnatal 
sequelae in an infant will be 
collected if possible.
Clarification upon ethics committee
request.
1.1.2 Background on the Study 
Vaccines 
REFERENCES  
The background section of the 
protocol has been updated with a
summary of the HPX2008/HVTN
705 results.
Update
TIME AND EVENTS SCHEDULE  
9.1.5 Post-vaccination Follow-up 
Phase 
10.2 Discontinuation of Study 
Vaccination/Withdrawal from the 
Study  
Specified that participants who 
received the first 3 vaccinations but 
discontinue study vaccination 
before receiving the 4th  vaccination, 
should continue with safety, 
immunogenicity and HIV diagnosis
assessments as planned. All other
participants who discontinue study
vaccination, should continue with
safety and HIV diagnosis
assessments as planned.
To minimize blood draws and
testing for participants not
contributing to the per-protocol
population to be used for the
primary efficacy analysis.
4.3 Prohibitions and Restrictions 
Clarified that for surgeries 
mentioned in exclusion criterion 3,
it will be per investigator’s
judgement whether the surgery
would interfere with protocol
assessments during the study. The
safety review team will be available
for consultation, where appropriate.
Clarification
Amendment 5 (19 May 2021)
Overall Rationale for the Amendment: This amendment has been created to provide information and
guidance for investigators on signs and symptoms and on medical management should very rare events of
thrombosis with thrombocytopenia syndrome (TTS) occur, as observed in another Ad26-based vaccine
program (Ad26.COV2.S, COVID-19 vaccine). The Ad26.Mos4.HIV vaccine uses the same Ad26 vector
as Ad26.COV2.S, but has different transgene inserts. To date, no cases of TTS have been reported in
Janssen’s Ad26.Mos4.HIV clinical studies nor in any other Ad26-based non-COVID-19 vaccine programs
from Janssen. Nonetheless, TTS will be followed in this protocol as adverse event of special interest (AESI)
that needs to be reported to the sponsor within 24 hours of awareness. Additional changes are listed below.
The changes made to the clinical protocol VAC89220HPX3002/HVTN 706 are listed below, including the
rationale of each change and a list of all applicable sections.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved, Date: 28 February 2023
Section number 
and Name
Description of Change 
Brief Rationale
Synopsis 
TIME AND EVENTS SCHEDULE  
ABBREVIATIONS  
1.1.2 Background on the Study 
Vaccines 
1.2.5 Overall Benefit/Risk
Assessment
2.1 Objectives and Endpoints
3.1 Overview of Study Design
4.2 Exclusion Criteria
9.1.4 Vaccination
9.1.5 Post-vaccination Follow-up
Phase
9.1.7 Visits for Participants who
Become HIV-1 Infected During the
Study
9.1.8 Early Withdrawal/Exit Visit
9.4 Safety Evaluations
10.2 Discontinuation of Study
Vaccination/Withdrawal from the
Study
11.6 Safety Analysis
11.6.2 Unsolicited Adverse Events,
AESIs, MAAEs and Serious
Adverse Events
12 ADVERSE EVENT
REPORTING
12.2 Special Reporting Situations
12.3.1 All Adverse Events
12.3.4 Adverse Events of Special
Interest
REFERENCES
Attachment 4: 
Thrombotic
Events to be Reported as Potential
AESIs
TTS is to be reported as an AESI, 
within 24 hours of awareness. A 
potential TTS/AESI is defined as 
thrombotic events or symptomatic 
thrombocytopenia. 
Following observation of very rare
events of TTS after vaccination
with Janssen’s Ad26-based
COVID-19 vaccine, TTS will be
followed as an AESI in this study.
4.2 Exclusion Criteria 
Clarification added that exclusion 
criterion 3 pertains to surgery that is
already planned before enrollment
Clarification
17.1 Protocol Clarification 
Communications 
Process for protocol clarification 
communications added 
Alignment with Janssen internal
Standard Operation Procedures.
Title page 
IND number added 
Clarification
Amendment 4 (10 March 2021)
Overall Rationale for the Amendment: This amendment is written to specify that it is allowed for
study participants to receive a COVID-19 vaccine that has been either licensed or authorized for
emergency use (eg, through Emergency Use Authorization [EUA], Emergency Use Listing [EUL]
procedure or similar program) and to still enroll or continue in the current study. The time intervals
that should be respected between COVID-19 vaccination and study vaccination are specified.
Additional changes are listed below.
The changes made to the clinical protocol VAC89220HPX3002/HVTN 706 are listed below, including the
rationale of each change and a list of all applicable sections.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved, Date: 28 February 2023
Section number
and Name
Description of Change 
Brief Rationale
ABBREVIATIONS
4.2 Exclusion Criteria
8 PRESTUDY AND
CONCOMITANT THERAPY
Exclusion criteria 5 and 8 have
been modified to make clear that
authorized COVID-19 vaccinations
are allowed in the study. The time
interval that should be respected
between study vaccination and
COVID-19 vaccination is specified.
To allow participants to receive a
COVID-19 vaccine that has been
either licensed or authorized for
emergency use (eg, EUA, EUL or
similar program)
TIME AND EVENTS SCHEDULE
8 PRESTUDY AND
CONCOMITANT THERAPY
9.1.5 Post-vaccination Follow-up
Phase
9.1.6 Post-M30 Follow-up Phase
9.1.7 Visits for Participants who
Become HIV-1 Infected During the
Study
9.1.8 Early Withdrawal/Exit Visit
Added that COVID-19 vaccination
is to be recorded as of any time
before screening until the end of the
study for a participant.
To record COVID-19 vaccination
in study participants
9.1.3 Screening Phase (Day -45 to 
Month 0) 
Added that for participants who are
rescreened, the STI testing
(syphilis, chlamydia and gonorrhea)
does not have to be repeated, unless
the test was performed more than 3
months prior to the planned first
vaccination or unless clinically
indicated.
To reduce burden for participants
and facilitate entry in this study.
4.1 Inclusion Criteria 
Clarified that being negative for
HIV infection means having a
negative test result for HIV
infection.
Based on feedback from
investigators, clarification was
added that a negative HIV test
needs to be available within 28 days
before vaccination
TIME AND EVENTS SCHEDULE
9.1.2 Visit Windows
Clarified that the contact between
investigator and participant after the
last day of the reactogenicity
period, can also be done sooner, if
indicated. The lower allowed
window (- 7 days) is specified.
Text added to Section 9.1.2 for
consistency with Time and Events
Schedule footnote v. The lower
allowed window is specified in both
places.
9.4 Safety Evaluations
SYNOPSIS
12.3.1 All Adverse Events
The sections describing the
collection and recording of AEs has
been amended to be aligned with
Section 9.1.3.
Changes were originally made in
protocol Amendment 3/Italy-
specific 1 (on request of AIFA) and
now also included in the global
protocol amendment.
1.2.4 Potential Risks
REFERENCES
Text regarding the hypothesis on
the mechanism for possible increase
of HIV-1 acquisition risk with an
Ad5-vectored vaccine has been
updated to include conclusions
from article of Curlin et al, 2020,
which refute the original hypothesis
on activation of vector-specific
CD4+ t cells at mucosal surfaces
after Ad5 vaccination.
Text updated based on availability
of new data.
TIME AND EVENTS SCHEDULE
9.2 Efficacy Evaluations
Added that a local HIV PCR test is
allowed in case of recent HIV
exposure.
Addition/correction, alignment with
SSP.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved, Date: 28 February 2023
Amendment 3 (2 July 2020)
Overall Rationale for the Amendment:The amendment is written to address comments from Health
Authorities, to allow for clarifications to be added, and for minor inconsistencies and errors to be
corrected. 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 participants
and site staff during the pandemic. These measures will not be described in the body of the protocol
but rather outlined in Appendix 18.
The changes made to the clinical protocol VAC89220HPX3002/HVTN 706 are listed below, including the
rationale of each change and a list of all applicable sections.
Section number 
and Name
Description of Change 
Brief Rationale
4.1 Inclusion Criteria 
Attachment 1: Definition of 
Individual of Childbearing Potential 
and List of Acceptable Highly 
Effective Contraceptive Methods 
Inclusion criterion 7, specifying
contraceptive measures to be taken
during the study, has been adjusted.
In inclusion criterion 7, it is now
indicated that the acceptable
effective contraceptive methods are
based on the Clinical Trial
Facilitation Group guidance and the
full list of acceptable contraceptive
measures is provided in
Attachment.
Changes were made upon request
of Health Authorities.
1.2.4 Potential Risks 
It has been clarified that for
Ad26.Mos.HIV, Ad26.Mos4.HIV,
Clade C gp140 and Mosaic gp140,
no preclinical developmental or
reprotoxicity studies have yet been
performed. Also, no clinical studies
in pregnant women have been
conducted to date. It has been
added that the sponsor is planning
to conduct a nonclinical
reprotoxicity study in parallel with
the HPX3002 study.
SYNOPSIS  
ABBREVIATIONS  
3.2 Study Design Rationale 
11.3 Sample Size Determination  
11.9 Analysis Timepoints 
The option for a potential interim
analysis has been deleted from the
protocol. One primary analysis (no
interim analysis) with timing
dependent on Target Number of
Infections (TNI) will be performed
as the single pre-specified approach
independent from presumptive
evidence external to the study.
Changes were made upon request
of EMA. EMA did not support the
timing of the statistical analysis to
be driven by evidence external to
the study and recommended to
simplify the statistical testing
strategy to a case-driven vaccine
efficacy trial design.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
9
Status: Approved, Date: 28 February 2023
Section number
and Name
Description of Change 
Brief Rationale
11.9 Independent Data and Safety
Monitoring Board
It has been clarified that the
unblinded, closed DSMB report
including evaluations of HIV
infections will be shared with FDA
Center for Biologics Evaluation and
Research (CBER)/Office of
Vaccines Research and Review
(OVRR). To ensure the blinding of
the study team, an independent
regulatory expert will act as an
intermediary between the DSMB
and CBER/OVR.
Changes were made upon request
of FDA.
TIME AND EVENTS SCHEDULE
9.2 Efficacy Evaluations
To avoid delays in initiation of
combined antiretroviral treatment,
local HIV PCR testing is allowed
only in case of suspected acute HIV
infection and when a request for
redraw is received from the central
laboratory for confirmation of an
HIV positive test.
Changes were made to avoid delays
in initiation of combined
antiretroviral treatment as
recommended by universal HIV
treatment guidelines
TIME AND EVENTS SCHEDULE
9.1.3 Screening Phase (Day -45 to
Month 0)
The term oral swab has been
replaced with oropharyngeal swab
and it has been clarified that (1)
urine sample, (2) rectal swab and
(3) oropharyngeal swab are all
required. If required by standard
local procedure, the collection of a
urethral swab will be considered
equivalent to a urine sample.
Clarifications with regard to the
required tests have been added.
SYNOPSIS
TIME AND EVENTS SCHEDULE
3.1 Overview of Study Design
9.1.3 Screening Phase (Day -45 to
Month 0)
9.4 Safety Evaluations
12.3.1 All Adverse Events
REFERENCES
Clarifications have been added to
the sections describing the
collection and recording of AEs and
medically significant events and the
language related to AE collection
has been aligned with updated
templates and guidance.
Changes were made to align with
updated internal templates and
guidance documents. In addition,
language has been aligned across
sections.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved, Date: 28 February 2023
Section number 
and Name
Description of Change 
Brief Rationale
4.1 Inclusion Criteria 
It has been clarified in inclusion 
criterion 3 that gender non- 
conforming individuals could have 
either receptive or insertive anal 
and/or vaginal condomless 
intercourse. 
In addition, it is added that the 
potential participants could in the 
last 6 months, apart from any 
stimulant, also have used any other 
drug and/or substance which in the 
local context may be associated 
with increased HIV transmission in 
order to be eligible for the study  
Addition of "insertive" anal
intercourse allows for inclusion of
gender non-conforming individuals
with male genitalia. Previously,
these individuals could enter the
study but only if they consider
themselves transgender individuals
whereas the very definition of
‘gender non-conforming individual’
should allow for their entry also per
the criterion 3.
In addition to stimulants, several
other drugs and/or substances could
lead to behavior associated with
increased risk of HIV. Therefore,
the inclusion criterion has been
extended to include participants at
increased risk of HIV infection due
to the use of drugs, other than
stimulants and/or substances
associated with increased HIV
transmission.
1.1.1 Background on the Disease 
and Treatment 
The background section of the 
protocol has been updated with the 
recent information on the stop of 
study HVTN702 due to lack of 
efficacy of the investigational HIV 
vaccine. 
Recently, study HVTN 702 or
Uhambo, a Phase 2b/3 conducted in
South Africa was stopped as the
vaccine regimen did not
demonstrate efficacy. The study
evaluated an investigational prime-
boost vaccine regimen (ie,
ALVAC-HIV [vCP2438] +
Bivalent Subtype C gp120/MF59)
which is a regimen adapted from
the one that was used and
demonstrated modest efficacy in an
earlier study conducted in Thailand
(study RV144). The vaccine
regimen was adapted to the HIV
subtype Clade C most common in
southern Africa.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Status: Approved, Date: 28 February 2023
Section number 
and Name
Description of Change 
Brief Rationale
4.2 Exclusion Criteria 
Exclusion criterion 3 has been 
amended to clarify that the criterion 
concerns surgery requiring 
hospitalization and to adjust the 
time window during which surgery 
requiring hospitalization (defined as 
inpatient stay for longer than 24
hours or overnight stay) will lead to
exclusion of the potential
participant from the study. Potential
participants who had surgery
requiring hospitalization within 4
weeks before screening, or will not
have fully recovered from surgery
requiring hospitalization or has
surgery requiring hospitalization
planned 28 days before or after
planned administration of the first
or subsequent study vaccination(s)
that would interfere with protocol
assessments (as per the
investigator’s judgement and after
HPX3002/HVTN 706 safety review
team consultation) will be excluded
from the study.
Clarifications have been made and
the time window during which
surgery requiring hospitalization is
disallowed has been aligned with
internal templates and guidance
documents.
16.1 Study-Specific Design 
Considerations 
It is clarified that potential 
participants, when they complete 
the test of understanding (TOU), 
will receive further information and 
counseling after each missed 
question, from their first attempt 
onwards, rather than after each 
failed attempt.
To increase the likelihood of
potential participants passing the
TOU, the study-personnel should
provide information and counseling
after each missed question and not
wait until the participant did not
achieve the passing score.
TIME AND EVENTS SCHEDULE  
9.1.3 Screening Phase (Day -45 to 
Month 0) 
9.1.4 Vaccination  
9.1.5 Post-vaccination Follow-up 
Phase 
9.1.6 Post-M30 Follow-up Phase 
Collection of gender identity on an 
annual basis during the conduct of 
the study has been added to the 
protocol 
Non-collection of gender identity
on a regular basis throughout the
study could lead to an
underestimation of transgender and
gender non-conforming participants
in the analyses because transition
during the study will be missed.
TIME AND EVENTS SCHEDULE  
9.1.7 Visits for Participants who 
Become HIV-1 Infected During the 
Study  
The completion of the social impact 
questionnaire has been removed 
from the visit #.X. In addition, for 
HIV infected participants, if, in the 
opinion of the investigator/site 
staff, the completion of the social 
impact questionnaire during Visit 
Inf1, Inf2 or the early withdrawal 
visit can cause undue burden to the 
participant, it can be omitted.
To decrease the burden on the HIV
infected participant, the social
impact questionnaire does not need
to be completed during the visit #.X
and may be omitted during the
other visits in case the
investigator/site staff is of the
opinion that it can cause undue
burden to the participant.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
12
Status: Approved, Date: 28 February 2023
Section number 
and Name
Description of Change 
Brief Rationale
SYNOPSIS  
TIME AND EVENTS SCHEDULE  
3.1 Overview of Study Design  
18 COVID-19 Appendix: Guidance 
on Study Conduct During the 
COVID-19 Pandemic
A COVID-19 Appendix has been 
added to provide guidance to 
investigators for managing study- 
related procedures during the 
COVID-19 pandemic. 
For safety reasons and restrictions
applied during the COVID-19
pandemic, participants may not be
able to come to the study site for
scheduled procedures.
Title page 
The Confidentiality Statement was 
revised and the statement 
‘CONFIDENTIAL –FOIA 
Exemptions Apply in U.S. was
added to the running footer
Changes were made to comply with
an update from Janssen’s Legal
department.
TIME AND EVENTS SCHEDULE  
4.1 Inclusion Criteria 
9.1.2 Visit Windows 
9.1.3 Screening Phase (Day -45 to 
Month 0) 
Language with regard to the 
screening HIV test has been aligned 
across the HPX3002 protocol: the 
test should be performed within 28
days, ie, negative test ≤28 days,
prior to first vaccination.
Inconsistencies and minor errors
have been corrected. Minor
clarifications have been added.
1.2.4 Potential Risks 
It has been clarified that in case any
significant new risks are identified,
the investigators (and not only the
principal investigator as per the
HPX3002 protocol amendment 2)
and participants will be informed.
4.1 Inclusion Criteria 
Participants of childbearing
potential must have a negative
serum β-human chorionic
gonadotropin (β-hCG) pregnancy
test at screening. The inclusion
criterion 8 has been corrected to
reflect this. This correction is in
line with the information on
pregnancy tests at screening in
other sections of the HPX3002
protocol.
12.1.3 Severity Criteria 
The definition of grade 3 (severe)
fever has been corrected, ie, ≥39.3
to <40.0°C OR ≥102.7°F to
<104.0°F. The ‘<’ was missing in
HPX3002 protocol amendment 2.
SYNOPSIS  
3.1 Overview of Study Design  
4.2 Exclusion Criteria 
The language related to the use of
PrEP has been adjusted to more
accurately reflect that, once the
participant is enrolled in the study
and received the first vaccination,
the use of PrEP will not lead to
exclusion from the study.
TIME AND EVENTS SCHEDULE  
9.1.2 Visit Windows 
9.1.6 Post-M30 Follow-up Phase 
It has been clarified that the post
Month 30 visits, scheduled every 3
months, will be scheduled relative
to the Month 30 visit.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Status: Approved, Date: 28 February 2023
Section number 
and Name
Description of Change 
Brief Rationale
11.3 Sample Size Determination  
It is clarified that only if the
primary H0 is rejected, VE(7-
30 months) will be tested as
secondary hypothesis, using a fixed
sequence testing strategy, without
adjustment for the Type-I error, and
using all available durability data
between Month 24 and Month 30.
11.4 Study Monitoring 
The abbreviation ‘VE’ stands for
‘vaccine efficacy’ but was wrongly
defined as ‘viral efficacy’ in Table
4. This has been corrected.
6 DOSAGE AND 
ADMINISTRATION  
The text has been reworded to
clarify that vaccine administration
occurs by IM injection, preferably
into the deltoid muscle.
Attachment 2: Test of 
Understanding 
Questions 6 and 8 in the TOU have
been reworded to improve clarity
ABBREVIATIONS  
The abbreviations for the Center for
Biologics Evaluation and Research
(CBER) and the Office of Vaccines
Research and Review (OVRR) have
been added.
Amendment 2 (20 June 2019)
Overall Rationale for the Amendment:The amendment is written to remove questionnaires from the
protocol, to allow for clarifications to be added, and for minor inconsistencies and errors to be
corrected. The changes made to the clinical protocol VAC89220HPX3002/HVTN 706 are listed below,
including the rationale of each change and a list of all applicable sections.
Section number 
and Name
Description of Change 
Brief Rationale
9.1.4 Vaccination  
9.1.5 Post-vaccination Follow-up Phase 
9.5 Participant Reported Outcomes 
9.5.1 Social Impact Measured Using 
Questionnaire 
9.5.2 Sexual Activity Questionnaire 
9.5.4 Other Participant Reported 
Outcomes 
Attachment 2: Sexual Activity 
Questionnaire 
Attachment 3: Questionnaire on the 
Use of PrEP  
Attachment 5: Social Impact 
Questionnaire
Questionnaires unrelated to the 
in/exclusion criteria, including 
questions with regard to 
absenteeism and vaccine 
acceptance, have been removed 
from the protocol and will be 
added to the Study Specific 
Procedures Binder. 
To allow for (local) adaptations to
the questionnaires, the sexual
activity questionnaire,
questionnaire on the use of PrEP
and the social impact
questionnaire and questions with
regard to absenteeism and vaccine
acceptance were moved from the
protocol to the Study Specific
Procedures Binder. The test of
understanding is retained in the
protocol since it is linked to the
inclusion criteria to the study.
TIME AND EVENTS SCHEDULE  
3.1 Overview of Study Design  
9.1.4 Vaccination  
The questionnaire on the use of 
and adherence (if applicable) to 
PrEP will be completed at the 
Day 1 visit. 
To allow for accurate collection
of information on the
participants’ prior use of PrEP, it
is clarified that each participant
will be asked to complete the
questionnaire on the use of PrEP
on Day 1. The questionnaire has
been updated accordingly.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved, Date: 28 February 2023
Section number
and Name
Description of Change 
Brief Rationale
6 DOSAGE AND
ADMINISTRATION
The instructions on the drug
administration has been clarified
to indicate that the deltoid muscle
is the preferred administration site
and reference to the Study
Specific Procedures Binder has
been added for instructions in
case an alternative site would be
needed.
Alternative injection sites may be
needed to allow for eg,
participants with heavy tattoos to
be included in the study.
SYNOPSIS  
TIME AND EVENTS SCHEDULE  
3.1 Overview of Study Design  
10 PARTICIPANT 
COMPLETION/DISCONTINUATION 
OF STUDY VACCINATION/
WITHDRAWAL FROM THE STUDY
It is clarified that after the end of
the study, participants may be
offered the possibility to enter a
long-term follow-up phase or
program.
In order to allow collection of
additional durability data, study
participants may be offered the
possibility to enter a long-term
follow-up phase or program.
4.2 Exclusion Criteria 
The missing time window during
which pregnancy and breast-
feeding is not allowed has been
added, ie, while enrolled in the
study or within 90 days after the
last dose of study vaccination
Inconsistencies and minor errors
have been corrected. Minor
clarifications have been added.
TIME AND EVENTS SCHEDULE  
Inconsistencies between the Time
and Events Schedule and the body
of the protocol with regard to the
completion of the questionnaire
on the use of and adherence (if
applicable) to PrEP at the
exit/withdrawal visit has been
corrected.
TIME AND EVENTS SCHEDULE  
9.1.5 Post-vaccination Follow-up Phase 
Reference to footnote ‘cc’ to the
Visit 2a, 3a, 4a and 7a was
corrected to footnote ‘v’ which
indicates that these are not site
visits but contacts between site
staff and participants to discuss
presence of any signs and
symptoms of reactogenicity.
TIME AND EVENTS SCHEDULE  
Inconsistencies in the use of
‘early withdrawal/exit’ versus
‘exit’ visit was corrected.
TIME AND EVENTS SCHEDULE  
9.1.5 Post-vaccination Follow-up Phase 
Inconsistencies between the Time
and Events Schedule and the body
of the protocol with regard to the
collection of unsolicited AEs has
been corrected.
SYNOPSIS  
3.1 Overview of Study Design  
It is clarified that once
participants received the first
vaccination, in the event they
change their minds, they will be
allowed to start PrEP according to
the site PrEP plan.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
15
Status: Approved, Date: 28 February 2023
Amendment 1 (09 May 2019)
Overall Rationale for the Amendment: The amendment is written in response to the feedback
received from Health Authorities, partners and the community. The changes made to the clinical
protocol VAC89220HPX3002/HVTN 706 are listed below, including the rationale of each change and a
list of all applicable sections.
Section number
and Name
Description of Change 
Brief Rationale
SYNOPSIS
TIME AND EVENTS SCHEDULE
1.2.5 Overall Benefit/Risk Assessment
2.1 Objectives and Endpoints
3.1 Overview of Study Design
9.1.1 Overview
9.1.4 Vaccination
9.4 Safety Evaluations
11.3 Sample Size Determination
11.6.2 Unsolicited Adverse Events,
MAAEs and Serious Adverse Events
12 ADVERSE EVENT REPORTING
12.3.1 All Adverse Events
Solicited signs and symptoms will be
entered in a diary for 7 days after each
vaccination by all participants instead
of a subset of participants at selected
sites. Solicited adverse events will be
recorded for all participants.
The recording of solicited
adverse events in all
participants was requested by
Health Authorities.
ABBREVIATIONS
9.4 Safety Evaluations
12.1.3 Severity Criteria
Tables including severity grading
scales for the solicited adverse events
have been added to the protocol. In
addition, it is clarified that for
solicited administration site adverse
events an adjusted version of the
DAIDS grading table will be used
while for solicited systemic adverse
events the unmodified DAIDS grading
table will be used. Also, for the
grading of adverse events not
identified in the table the general
DAIDS grading will be used. Finally,
it is clarified that the DAIDS addenda
grading tables for microbicides studies
will be used for the grading of genito-
urinary disorders, sexually transmitted
infections (STIs), uterine bleeding and
pregnancy complications although this
is not a microbicide study.
The severity grading scales
have been added upon request
from the Health Authorities.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
16
Status: Approved, Date: 28 February 2023
Section number
and Name
Description of Change 
Brief Rationale
TIME AND EVENTS SCHEDULE
9.1.1 Overview
9.1.2 Visit Windows
9.1.4 Vaccination
9.1.5 Post-vaccination Follow-up
Phase
9.4 Safety Evaluations
The post-reactogenicity contact
between the site staff and participants
has been added as separate visits in
the Time and Events Schedule and
additional detail was added. The site
staff and the participant will make
multiple efforts in good faith to be in
contact after the last day of the
reactogenicity period, or sooner if
indicated, to review reactogenicity
data. Participants who self-report any
postvaccination reaction greater than
mild is seen by a clinician within 48
hours after onset, unless the reaction is
improving and/or has resolved
completely. Participants should bring
their diary to the site at the next visit
to complete review of the diary and
document solicited adverse events into
the clinic note and subsequently into
the eCRF.
Given the diary will be used as
a source document for the
recording of solicited AEs, it
is of the utmost importance
that the information included
is as accurate and detailed as
possible. Therefore, the
contact with the site following
the reactogenicity period has
been more clearly defined in
the protocol. Follow-up of
diary entries close to the diary
completion date, will allow for
accurate corrections of and
additions to the diary. In
addition, during these contacts
the participant may receive
further instructions/education
on how to complete the diary.
The contact will also allow for
close follow-up of safety and
scheduling of additional safety
follow-up visits, as needed.
SYNOPSIS
TIME AND EVENTS SCHEDULE
ABBREVIATIONS
2.1 Objectives and Endpoints
3.1 Overview of Study Design
9.1.4 Vaccination
9.1.5 Post-vaccination Follow-up
Phase
9.1.6 Post-M30 Follow-up Phase
9.1.7 Visits for Participants who
Become HIV-1 Infected During the
Study
9.1.8 Early Withdrawal/Exit Visit
9.4 Safety Evaluations
11.6.2 Unsolicited Adverse Events,
MAAEs and Serious Adverse Events
12 ADVERSE EVENT REPORTING
12.3.1 All Adverse Events
Medically-attended adverse events
(MAAEs) will be recorded from
signing of the ICF onwards until the
end of the study.
In line with the Guidance for
Industry –Submitting Study
Datasets for Vaccines to the
Office of Vaccines Research
and Reviewa and upon request
of the Health Authorities, the
recording of MAAEs is added
to the protocol. Recording of
MAAEs will allow collection
of potential immune-mediated
medical conditions (PIMMCs)
and new onset of chronic
diseases and will allow for a
better characterization of the
safety profile of VAC89220
overall.
a US Food & Drug Administration. Guidance for Industry - Submitting Study Datasets for Vaccines to the Office of
Vaccines 
Research 
and 
Review 
– 
Technical 
Specifications 
Document. 
Available 
at:
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidance
s/General/UCM605147.pdf. Accessed: 17 April 2019.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
17
Status: Approved, Date: 28 February 2023
Section number
and Name
Description of Change 
Brief Rationale
ABBREVIATIONS
9.1.3 Screening Phase (Day -45 to
Month 0)
9.4 Safety Evaluations
11.1 Participant Information
11.6.2 Unsolicited Adverse Events,
MAAEs and Serious Adverse Events
Potentially immune-mediated medical
conditions (PIMMCs) reported as
MAAEs will be considered events of
interest. A list of PIMMCs defined for
this study is presented in Attachment 6
of the protocol. In addition, history
and family history of immune
disorders will be recorded in the
eCRF.
Upon request of the Health
Authorities, adverse events of
special interest for this study
are identified in the protocol.
No adverse events of special
interest were identified based
on the nonclinical and clinical
data from the vaccine
components to date. However,
based on regulatory feedback,
special attention will be put on
PIMMCs that are reported as
MAAEs. These events will be
collected and analyzed.
12.1.2 Attribution Definitions 
The definitions for ‘related’ and
‘unrelated’ adverse events have been
updated.
To allow for pooling of safety
data from the proof-of-concept
study HPX2008/HVTN 705
and the current study
VAC89220HPX3002/HVTN
706, the definitions of
‘related’ and ‘unrelated’
adverse events have been
aligned.
SYNOPSIS
TIME AND EVENTS SCHEDULE
2.1 Objectives and Endpoints
3.1 Overview of Study Design
9.1.4 Vaccination
9.1.5 Post-vaccination Follow-up
Phase
9.1.6 Post-M30 Follow-up Phase
9.1.7 Visits for Participants who
Become HIV-1 Infected During the
Study
9.1.8 Early Withdrawal/Exit Visit
9.5 Participant Reported Outcomes
9.5.4 Other Participant Reported
Outcomes
11.6.4 Other Parameters
In addition to the participant reported
outcomes (PRO) questionnaires
included in the initial protocol, other
PROs, including the level of
absenteeism, defined as health-related
productivity loss due to sick-leave,
and the level of vaccine regimen
acceptance have been added to the
protocol.
Apart from collecting data on
the social impact of the
vaccine study, it was
considered important to
collect additional information
on the possible effect of the
vaccinations and of HIV-1
infection in terms of work loss
and work productivity. In
addition, in order to get a
better understanding of the
acceptance of the 4-
vaccination course as a HIV
prevention tool, the
participants will be asked to
rate their experience with the
vaccination regimen.
SYNOPSIS
TIME AND EVENTS SCHEDULE
2.1 Objectives and Endpoints
3.1 Overview of Study Design
9.1.4 Vaccination
9.1.5 Post-vaccination Follow-up
Phase
9.1.6 Post-M30 Follow-up Phase
9.1.7 Visits for Participants who
Become HIV-1 Infected During the
Study
9.1.8 Early Withdrawal/Exit Visit
9.6 Health Care Resource Utilization
11.6.4 Other Parameters
15 STUDY-SPECIFIC MATERIALS
The collection of medical and non-
medical resource utilization/Health
Care Research Utilization (HCRU)
data, as such, was removed from the
protocol.
The collection of MAAEs,
absenteeism and follow-up
information on HIV infected
participants throughout the
study will provide sufficient
information on HCRU without
the need for additional
questionnaires.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
18
Status: Approved, Date: 28 February 2023
Section number
and Name
Description of Change 
Brief Rationale
SYNOPSIS
TIME AND EVENTS SCHEDULE
3.1 Overview of Study Design
9.1.4 Vaccination
9.1.5 Post-vaccination Follow-up
Phase
9.1.8 Early Withdrawal/Exit Visit
9.5 Participant Reported Outcomes
9.5.3 Questionnaire on the Use of
PrEP
Attachment 3: Questionnaire on the
Use of PrEP
The questionnaire on the use of pre-
exposure prophylaxis (PrEP) will be
completed by all participants instead
of the participants who self-report
they use PrEP only. The questionnaire
has been modified accordingly.
To avoid bias, protocol
assessments were aligned for
all participants as much as
possible.
Attachment 2: Sexual Activity
Questionnaire
Attachment 3: Questionnaire on the
Use of PrEP
The sexual activity questionnaire and
the questionnaire on the use of PrEP
have been updated.
Questionnaires were updated
taking the feedback from
partners and the community
into consideration.
Attachment 2: Sexual Activity
Questionnaire
Attachment 3: Questionnaire on the
Use of PrEP
It has been added to the protocol that
adaptations to the sexual activity
questionnaire and the questionnaire on
the use of PrEP are allowed for local
purposes, after IRB and protocol team
(cross-functional) approval.
Given the wide geographical
coverage of the study, it may
be needed to make minor
adaptations to the
questionnaires to account for
cultural and regulatory
differences.
Title Page
SYNOPSIS
2.1 Objectives and Endpoints
3.1 Overview of Study Design
4.1 Inclusion Criteria
Inclusion criterion 3 has been
modified to include more detail on the
target study population. Other sections
in the protocol have been adapted
accordingly.
In order to better characterize
the target study population:
- more detail has been added
in the inclusion criteria
with regard to the
population as such, ie, cis-
gender men and
transgender individuals
having sex with cis-gender
men and/or transgender
individuals and gender
non-conforming
individuals having
receptive anal and/or
vaginal condomless
intercourse, AND
- major criteria to determine
if a potential participant is
at increased risk for HIV-1
infection has been added
to the inclusion criteria.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
19
Status: Approved, Date: 28 February 2023
Section number
and Name
Description of Change 
Brief Rationale
SYNOPSIS
TIME AND EVENTS SCHEDULE
3.1 Overview of Study Design
4.2 Exclusion Criteria
8 PRESTUDY AND
CONCOMITANT THERAPY
The exclusion criteria have been
modified to exclude potential
participants who have used long
acting PrEP within 24 months prior to
Day 1. In addition, reference to ‘oral
PrEP’ has been replaced by ‘PrEP’
Given the availability of long
acting PrEP (eg, cabotegravir)
which is administered as an
intramuscular injection and
has a long pharmacokinetic
tail, the use of long acting
PrEP will be disallowed from
24 months prior to Day 1. As
the use of PrEP is allowed
once participants received the
first vaccination, including
injectable long-acting PrEP, if
available, reference to ‘oral
PrEP’ has been replaced by
‘PrEP’.
4.2 Exclusion Criteria 
The exclusion criteria have been
modified to exclude potential
participants who share needles during
injection of drugs and other
substances instead of potential
participants with active or recent use
of any illicit IV drug.
Drug substance use is linked
to risky sexual behaviors.
Given the target population of
men who have sex with men
(MSM) and transgender
individuals considered at
increased risk for HIV-1
infection and the fact that drug
use can add to sexual risk
behavior, potential
participants who use injection
drugs will be allowed in the
study. Due to the different
way of transmission,
individuals sharing needles
will be excluded from the
study.
4.2 Exclusion Criteria 
The window during which the use of
HIV-related mAb, whether licensed or
investigational, is disallowed has been
adjusted from within 24 months prior
to Day 1 to within 12 months prior to
Day 1.
The time window from 24
months to 12 months prior to
Day 1 for the use of HIV-
related mAb was adjusted
based on more accurate
estimates of mAb washout
times including Fc-modified
versions currently in
development. The original
estimate was too conservative
and could exclude participants
who have no biologically
meaningful level of antibody
left.
SYNOPSIS
TIME AND EVENTS SCHEDULE
9.1.6 Post-M30 Follow-up Phase
10.1 Completion
The definition of study completion has
been updated.
To allow for timely
completion of the study, the
study will be considered
completed once the last
participant has completed the
Month 30 visit or has
discontinued earlier. HIV
infected participants still in the
study at that time will be
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
20
Status: Approved, Date: 28 February 2023
Section number 
and Name
Description of Change 
Brief Rationale
informed that they should
return to the site for the Visit
#.X, if not completed yet, but
no further site visits will be
required.
3.2 Study Design Rationale 
The regimen selection rationale has 
been updated to reflect the most 
recently available data. 
Phase 1/2a data that recently
became available strengthen
the vaccine regimen selected
for the Phase 3 HPX3002
study. The protocol language
has been updated accordingly.
TIME AND EVENTS SCHEDULE  
9.3 Immunogenicity Evaluations 
It is clarified in the protocol that 
venous blood samples for 
determination of immune responses 
from participants who become HIV 
infected will, depending on the 
vaccine efficacy outcome, be used for 
the evaluation of immune markers that 
have a sieving effect on any 
breakthrough infections and for the 
evaluation of any immune markers 
that are associated with post-infection 
control of HIV in participants if 
differences between active and 
placebo recipients are observed, 
potentially including immune
responses to all vaccine antigens.
In the initial protocol it was
indicated that samples for the
determination of the immune
responses from participants
who become HIV infected
would be analyzed upon
discretion of the study
responsible immunologist.
The Health Authorities
requested clarification on the
criteria which will determine
the selection of samples for
analysis and analyses
performed.
SYNOPSIS  
TIME AND EVENTS SCHEDULE  
2.1 Objectives and Endpoints 
9.1.1 Overview  
9.1.4 Vaccination  
9.1.5 Post-vaccination Follow-up 
Phase 
9.1.7 Visits for Participants who 
Become HIV-1 Infected During the 
Study  
9.3 Immunogenicity Evaluations
It is clarified that venous blood 
samples for cellular immune response 
will be collected in participants at sites 
with access to sponsor approved 
PBMC processing facilities and will 
be analyzed in a subset. 
To gather as much data as
possible, blood samples for
cellular immune response will
be taken in participants at sites
with access to sponsor
approved processing facilities
and not a subset of
participants at all sites or all
participants at randomly
selected sites.
SYNOPSIS  
TIME AND EVENTS SCHEDULE  
1.2.4 Potential Risks 
9.1.4 Vaccination  
9.1.7 Visits for Participants who 
Become HIV-1 Infected During the 
Study  
9.3 Immunogenicity Evaluations 
The possibility to perform limited
genetic testing has been added to the
protocol. For these analyses, leftover
blood from samples for determination
of cellular response will be used. In
addition, a blood sample will be
collected from participants who
become HIV infected at the Visit #.X.
To allow for the exploration of
potential effect of host genetic
factors in the immune
response to the vaccine
regimen and/or vaccine
efficacy, the possibility for
limited genetic testing has
been added to the study
protocol.
SYNOPSIS
2.1 Objectives and Endpoints
The analysis of frequency and
magnitude of cellular and humoral
immune responses in participants that
become HIV-1 infected will not be
limited to Env-specific responses.
Health Authorities requested
to include the possibility of
the assessing immune
responses to Gag and Pol and
not to limit the assessment to
Env-specific responses.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
21
Status: Approved, Date: 28 February 2023
Section number
and Name
Description of Change 
Brief Rationale
SYNOPSIS
9.3 Immunogenicity Evaluations
Ad26 seropositivity and titer will be 
assessed at Baseline AND post- 
vaccination. 
Upon request from the Health
Authorities, assessment of
post-vaccination Ad26
seropositivity and titer was
added to the protocol.
SYNOPSIS
TIME AND EVENTS SCHEDULE
2.1 Objectives and Endpoints
9.1.5 Post-vaccination Follow-up
Phase
9.1.8 Early Withdrawal/Exit Visit
Venous blood samples for cellular 
immune response assays will be 
collected on Day 1 and Month 7. 
Blood samples from other time points 
will only be used to determine 
humoral immune responses. 
To decrease the burden on
participants, the time points
for venous blood collection to
assess cellular immune
responses have been limited to
Day 1 and Month 7.
SYNOPSIS
2.1 Objectives and Endpoints
The evaluation of vaccine efficacy 
(VE) by and adjusting for potential 
(baseline) confounders has been 
moved from the exploratory objectives 
to the secondary objectives. 
Given the importance of the
analysis of the VE by and
adjusting for potential
confounding factors, it was
felt more appropriate to have
this as a secondary objective.
TIME AND EVENTS SCHEDULE
8 PRESTUDY AND
CONCOMITANT THERAPY
9.1.5 Post-vaccination Follow-up
Phase
9.1.6 Post-M30 Follow-up Phase
In addition to the use of PrEP, 
hormonal therapy and hormone-based 
contraception, the use of post- 
exposure prophylaxis (PEP) will also 
be recorded at Visit 9 to Visit 13 and 
during the post-M30 follow-up phase. 
As the use of PEP could be a
potential confounder for VE, it
is considered important to
record the use of PEP not only
during the vaccination period
but also during the post-
vaccination and post-M30
follow-up phases.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
22
Status: Approved, Date: 28 February 2023
Section number
and Name
Description of Change 
Brief Rationale
SYNOPSIS
3.1 Overview of Study Design
11.1 Participant Information
Reference to male circumcision as a
prevention tool for HIV infection has
been deleted from the protocol. Male
circumcision will be recorded as part
of the demographic data.
There is no unanimous
position on the protective
effect of male circumcision
against HIV infection in the
MSM and transgender
populationa and the World
Health Organization
guidelinesb do not recommend
adult male circumcision as a
prevention tool for HIV
infection in this population.
Therefore, male circumcision
will not be recommended to
participants as an HIV-1
prevention tool. Data on male
circumcision will be collected
as part of the demographic
data.
TIME AND EVENTS SCHEDULE
9.1.6 Post-M30 Follow-up Phase
During the post-M30 follow-up phase,
a test for syphilis and for chlamydia
and gonorrhea should be performed
approximately every 6 months.
The testing for sexual
transmitted infections,
including syphilis, chlamydia
and gonorrhea, is considered
an essential part of the
prevention measures.
TIME AND EVENTS SCHEDULE
9.1.2 Visit Windows
9.1.7 Visits for Participants who
Become HIV-1 Infected During the
Study
9.1.2 Visit Windows
The target visit day and visit window
for Visit #.X has been deleted and it is
clarified that this visit should be
scheduled as soon as possible after the
initial positive HIV-1 test and could
be a scheduled or unscheduled visit.
To allow for a confirmatory
HIV test to be performed as
close as possible to the initial
test, the target visit day and
allowed visit window for the
confirmatory visit (Visit #.X)
has been deleted.
TIME AND EVENTS SCHEDULE
9.1.2 Visit Windows
The visit window for Visit 7
(vaccination 4) has been adjusted to -
14/+28 days to -14/+42 days. The visit
window for Visit Inf1 and Visit Inf2
(previously Visit 1’ and Visit 2’) has
been adjusted from +/- 14 days to +/-
28 days
To avoid participants missing
the last vaccination and/or
post-HIV-1 infection follow-
up visits, the visit windows of
these visits have been
extended.
1.1.2 Background on the Study
Vaccines
For the list of excipients of
Ad26.Mos4.HIV, Clade C gp140 and
Investigator Brochures were
updated in March and
a Goodreau SM, Carnegie NB, Vittinghoff E, et al. Can male circumcision have an impact on the HIV epidemic in
men who have sex with men?. PLoS ONE. 2014;9(7):e102960.
Pintye J, Baeten JM. Benefits of male circumcision for MSM: evidence for action. Lancet Glob Health.
2019;7(4):e388-e389.
Yuan T, Fitzpatrick T, Ko NY, et al. Circumcision to prevent HIV and other sexually transmitted infections in men
who have sex with men: a systematic review and meta-analysis of global data. Lancet Glob Health.
2019;7(4):e436-e447.
b World Health Organization. Guidelines: Prevention and treatment of HIV and other sexually transmitted infections
among men who have sex with men and transgender people: recommendations for a public health approach. 2011.
Available 
at: 
https://apps.who.int/iris/bitstream/handle/10665/44619/9789241501750 eng.pdf;jsessionid=
3F17E7A555BA3024CEAE319D5FA3A6BF?sequence=1. Accessed: 2 April 2019.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
23
Status: Approved, Date: 28 February 2023
Section number
and Name
Description of Change 
Brief Rationale
14.1 Physical Description of Study
product(s)
REFERENCES
Mosaic gp140 and details on data
from studies HPX2003 and HPX2004,
reference to the appropriate
Investigator’s Brochure (IB) has been
added.
February, respectively.
Excipients for the Clade C and
Mosaic gp140 HIV Bivalent
Vaccine, Recombinant are
described in this most recent
version only.
1.2.4 Potential Risks 
REFERENCES  
The section describing the risks
related to aluminum has been aligned
with updated template language.
Changes were made to align
with updated internal
templates and guidance
documents.
SYNOPSIS  
9.4 Safety Evaluations 
12.3.1 All Adverse Events 
Wording with regard to the reporting
of unsolicited adverse events and
special reporting situations that are not
related to study-related procedures or
non-investigational sponsor-products
has been aligned with updated internal
template language.
Throughout the protocol 
The term ‘prime/boost’ regimen has
been replaced by ‘heterologous’
regimen throughout the protocol in
line with updated internal guidance.
Throughout the protocol 
To align with CDISC terminology
‘solicited local adverse events’ was
replaced with ‘solicited administration
site adverse events’ throughout the
protocol.
Title Page 
The study name MOSAICO was
added to the Cover page.
Administrative change
17.11 Use of Information and 
Publication  
The time for the sponsor and partners
to review manuscripts and
presentations including information
from the study before submission is
adjusted from at least 60 days to at
least 21 days. However, at the request
of the sponsor and/or the partners,
such submission may be delayed up to
60 days.
Upon request of the partners,
4.2 Exclusion Criteria 
More information has been added on
how it is assessed if a potential
participant has a known allergy or
history of anaphylaxis or other serious
adverse reactions to vaccines.
Upon request of the Health
Authorities, partners and the
community, clarifications
were made, and specifications
added throughout the protocol.
4.2 Exclusion Criteria 
It is clarified that potential participants
who received any HIV-vaccine
candidate, irrespective if it is
prophylactic or therapeutic vaccine,
are excluded from the study. In
addition, it is clarified that potential
participants who have proof they
received only placebo vaccine can be
included in the study.
4.2 Exclusion Criteria 
It is specified that isolated seizure
with clear etiology or febrile seizures
during childhood are not exclusionary.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
24
Status: Approved, Date: 28 February 2023
Section number 
and Name
Description of Change 
Brief Rationale
4.1 Inclusion Criteria 
It is clarified that contraceptive
requirements specified in the inclusion
criteria only apply to participants
assigned female at births and who did
not have sexual reassignment surgery.
4.1 Inclusion Criteria 
It is specified that testosterone is not
considered an acceptable
contraceptive method.
SYNOPSIS  
3.1 Overview of Study Design  
4.2 Exclusion Criteria 
It is clarified that only potential
participants who choose to use PrEP,
are excluded from the study. Due to
the high effectiveness of PrEP, these
potential participants are not
considered to be at increased risk for
HIV-1 infection. In addition, it is
specified that PrEP use during the
study should be according to the site
PrEP plan.
9.3 Immunogenicity Evaluations 
It is clarified that the planned venous
blood collected per the Time and
Events schedule will be sufficient to
allow for exploratory immune
analyses in addition to the
prespecified ones.
TIME AND EVENTS SCHEDULE  
9.2 Efficacy Evaluations 
It is clarified that blood samples for
viral sequencing may be analyzed to
study the presence of transmitted drug
resistance, to assess whether VE
differs by genotypic characteristics of
HIV and whether there is evidence of
vaccine-induced immune pressure on
the viral genotype, depending on the
vaccine efficacy outcome.
16.2.3 Informed Consent 
It is clarified that the informed consent
form needs to be in a language that the
potential participant can read and/or
understand as potential participants
who are unable to read are allowed in
the study.
SYNOPSIS  
3.1 Overview of Study Design  
9.1.7 Visits for Participants who 
Become HIV-1 Infected During the 
Study  
It is clarified that participants who
become HIV-1 infected during the
study will be referred to a local clinic
for medical treatment and follow-up
on their HIV-1 infection as soon as
possible after the diagnosis of the
infection.
SYNOPSIS  
3.1 Overview of Study Design  
It is added to the protocol that all
efforts will be made to ensure that the
study population includes good
representation from the population at
the highest risk ofHIV infection in
terms of race, ethnicity, gender
identity and age.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
25
Status: Approved, Date: 28 February 2023
Section number 
and Name
Description of Change 
Brief Rationale
SYNOPSIS  
TIME AND EVENTS SCHEDULE  
3.1 Overview of Study Design  
It is clarified that blood will be
collected for antiretroviral (ARV)
detection in dried blood. In addition, it
has been added that additional ARV
detection can be done on stored blood
samples, if required, as described in
the Study Specific Procedures Binder.
SYNOPSIS  
ABBREVIATIONS  
1 INTRODUCTION  
The term ‘sponsor’ (eg, sponsor and
partners, HPX3002/HVTN 706 safety
review team etc) is been specified
throughout the protocol. In addition,
additional partners have been
specified.
Throughout the protocol 
To term ‘study intervention’ is
specified (eg, study product, study
vaccine etc) throughout the protocol to
avoid confusion as it may be
misinterpreted as the study product
plus study procedures.
SYNOPSIS  
3.1 Overview of Study Design  
‘Lubricants’ is added as standard of
prevention that may be provided by
the sponsor and its partners.
SYNOPSIS  
ABBREVIATIONS  
1.2.5 Overall Benefit/Risk Assessment 
3.1 Overview of Study Design  
It is clarified that the NIAID HIV
vaccine Data and Safety Monitoring
Board (DSMB; in the initial HPX3002
protocol referred to as an independent
Data Monitoring Committee [DMC])
will serve as an independent DSMB
for this study to monitor data on an
ongoing basis.
TIME AND EVENTS SCHEDULE  
9.1.3 Screening Phase (Day -45 to 
Month 0) 
It is clarified that for the assessment of
chlamydia/gonorrhea a rectal and oral
swab, and urine sample is needed
TIME AND EVENTS SCHEDULE  
9.1.7 Visits for Participants who 
Become HIV-1 Infected During the 
Study
9.4 Safety Evaluations
It is clarified that CD4+ cell counts
will be assessed through a locally
performed test.
10.1 Completion  
It is clarified that at the end of the
study participants may be offered the
possibility to enter a follow-up study
or program, but not necessarily all
participants will be offered this
possibility.
14.3 Preparation, Handling, and 
Storage 
It is specified that study vaccine must
be stored upright in a secured location
at controlled temperature.
SYNOPSIS  
In alignment with the body of the
protocol, it is added to the synopsis
that exploratory immunogenicity
assessments, currently not specified in
the protocol, may be performed.
Inconsistencies and minor
errors have been corrected.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
26
Status: Approved, Date: 28 February 2023
Section number 
and Name
Description of Change 
Brief Rationale
SYNOPSIS  
For clarity, the timing of the primary
analysis is added to the hypothesis in
the synopsis.
SYNOPSIS  
9.4 Safety Evaluations 
12.1.3 Severity Criteria 
15 STUDY-SPECIFIC MATERIALS  
Swelling and induration are terms that
are used interchangeable. Within the
protocol these terms were simplified
to swelling
4.1 Inclusion Criteria 
10.2 Discontinuation of Study 
Vaccination/Withdrawal from the 
Study  
Participants should be HIV-1 AND
HIV-2 negative <28 days prior to first
vaccination to be eligible for the
study. Vaccination will be
discontinued in participants who
become HIV-1 or HIV-2 infected.
9.1.3 Screening Phase (Day -45 to 
Month 0) 
9.1.4 Vaccination  
The allowed screening period has
been corrected and aligned to 45 days
with HIV test to be performed within
28 days.
4.1 Inclusion Criteria 
4.3 Prohibitions and Restrictions 
Per the prohibitions and restrictions
section participants will not be able to
donate eggs (ova, oocytes). The
inclusion criterion requiring
participants to agree not to donate
eggs is, therefore, redundant.
6 DOSAGE AND 
ADMINISTRATION  
9.1.2 Visit Windows 
Information on the action to be taken
in case a participant is not vaccinated
within the allowed time window, ie, to
be discussed and decided with the
HPX3002/HVTN 706 safety review
team on a case-by-case basis, was
made consistent across the protocol. In
addition, it has been reiterated that all
efforts should be made to follow the
vaccination schedule per the protocol
and that vaccinations should generally
not be administered outside of the
prespecified window.
9.4 Safety Evaluations 
Not all laboratory tests will be
analyzed by a central laboratory. The
type of laboratory (central or local)
that will perform the different tests has
been specified for all tests.
16.1 Study-Specific Design 
Considerations 
Total blood volumes taken during the
study have been corrected, also taking
into consideration changes in blood
draws for immunogenicity assays (see
above).
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
27
Status: Approved, Date: 28 February 2023
Section number 
and Name
Description of Change 
Brief Rationale
TIME AND EVENTS SCHEDULE  
8 PRESTUDY AND 
CONCOMITANT THERAPY  
9.1.3 Screening Phase (Day -45 to 
Month 0) 
9.1.4 Vaccination  
9.1.5 Post-vaccination Follow-up 
Phase 
9.1.6 Post-M30 Follow-up Phase 
9.1.8 Early Withdrawal/Exit Visit 
The protocol has been aligned with
regard to the collection of concomitant
medication. Concomitant therapies
such as analgesics/antipyretic
medications and non-steroidal anti-
inflammatory drugs, hormonal
therapy, hormone-based
contraception, systemic
corticosteroids, antihistaminics,
mAbs, or vaccinations must be
recorded from the first study
vaccination to 1 month after the last
study vaccination (not needed at
Month 30 and early exit visit). The use
of PrEP, PEP, hormonal therapy and
hormone-based contraception should
be recorded at additional time points
as specified in the Time and Events
Schedule. All other concomitant
therapies should also be recorded if
administered in conjunction with new
or worsening adverse events reported
per protocol requirements.
For participants who become HIV
infected, all ARVs and all
concomitant therapies administered in
conjunction with new or worsening
adverse events reported per protocol
requirements should be reported.
TIME AND EVENTS SCHEDULE  
The Time and Events Schedule has
been corrected to reflect that no blood
will be collected for dried blood spot
at screening.
Throughout the protocol 
The terms Visit 1’, Visit 2’ and Early 
Exit’ have been replaced with Visit 
Infected 1 (Inf1), Visit Inf2, and Early 
Exit Inf, respectively. 
To avoid confusion with Visit
1, Visit 2 and Exit visit of the
main Time and Events
Schedule, the Visit 1’ and
Visit 2’ of the Time and
Events schedule for
participants who become HIV
infected have been replaced
with Visit Inf1, Visit Inf2, and
Early Exit Inf, respectively.
Throughout the protocol 
HVTN study identifiers, HVTN 117,
HVTN 118, HVTN 705 and HVTN
706 were added to the Janssen study
names VAC89220HPX2004,
HPX2003, HPX2008 and HPX3002,
respectively
For clarity and completeness
HVTN study identifiers were
added.
Throughout the protocol 
Minor grammatical, formatting, or
spelling changes were made.
Minor errors were noted, and
minor textual changes were
made following the request of
partners and community.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
28
Status: Approved, Date: 28 February 2023
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................. 28
LIST OF ATTACHMENTS.......................................................................................................................... 30
LIST OF IN-TEXT TABLES AND FIGURES.............................................................................................. 31
SYNOPSIS.................................................................................................................................................. 32
TIME AND EVENTS SCHEDULE .............................................................................................................. 41
ABBREVIATIONS ...................................................................................................................................... 47
1. 
INTRODUCTION................................................................................................................................ 49
1.1. 
Background.................................................................................................................................... 49
1.1.1. 
Background on the Disease and Treatment............................................................................... 49
1.1.2. 
Background on the Study Vaccines............................................................................................ 50
1.2. 
Benefit/Risk Section....................................................................................................................... 53
1.2.1. 
Known Benefits........................................................................................................................... 53
1.2.2. 
Potential Benefits........................................................................................................................ 53
1.2.3. 
Known Risks............................................................................................................................... 54
1.2.4. 
Potential Risks............................................................................................................................ 54
1.2.5. 
Overall Benefit/Risk Assessment ............................................................................................... 56
1.3. 
Overall Rationale for the Study...................................................................................................... 57
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 58
2.1. 
Objectives and Endpoints .............................................................................................................. 58
2.2. 
Hypothesis ..................................................................................................................................... 59
3. 
STUDY DESIGN AND RATIONALE................................................................................................. 60
3.1. 
Overview of Study Design.............................................................................................................. 60
3.2. 
Study Design Rationale.................................................................................................................. 62
4. 
PARTICIPANT POPULATION .......................................................................................................... 63
4.1. 
Inclusion Criteria ............................................................................................................................ 64
4.2. 
Exclusion Criteria ........................................................................................................................... 66
4.3. 
Prohibitions and Restrictions ......................................................................................................... 69
5. 
STUDY VACCINE ALLOCATION AND BLINDING.......................................................................... 69
6. 
DOSAGE AND ADMINISTRATION .................................................................................................. 70
7. 
TREATMENT COMPLIANCE............................................................................................................ 71
8. 
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 71
9. 
STUDY EVALUATIONS.................................................................................................................... 73
9.1. 
Study Procedures........................................................................................................................... 73
9.1.1. 
Overview..................................................................................................................................... 73
9.1.2. 
Visit Windows ............................................................................................................................. 73
9.1.3. 
Screening Phase (Day -45 to Month 0)...................................................................................... 74
9.1.4. 
Vaccination ................................................................................................................................. 76
9.1.5. 
Post-vaccination Follow-up Phase ............................................................................................. 79
9.1.6. 
Post-M30 Follow-up Phase ........................................................................................................ 81
9.1.7. 
Visits for Participants who Become HIV-1 Infected During the Study........................................ 81
9.1.8. 
Early Withdrawal/Exit Visit.......................................................................................................... 82
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
29
Status: Approved, Date: 28 February 2023
9.2. 
Efficacy Evaluations....................................................................................................................... 82
9.3. 
Immunogenicity Evaluations .......................................................................................................... 84
9.4. 
Safety Evaluations ......................................................................................................................... 84
9.5. 
Participant Reported Outcomes..................................................................................................... 87
9.5.1. 
Social Impact Measured Using Questionnaire ........................................................................... 88
9.5.2. 
Sexual Activity Questionnaire..................................................................................................... 88
9.5.3. 
Questionnaire on the Use of PrEP ............................................................................................. 88
9.5.4. 
Other Participant Reported Outcomes ....................................................................................... 88
9.6. 
Sample Collection and Handling.................................................................................................... 89
10. PARTICIPANT COMPLETION/DISCONTINUATION OF STUDY VACCINATION/
WITHDRAWAL FROM THE STUDY................................................................................................. 89
10.1. 
Completion ..................................................................................................................................... 89
10.2. 
Discontinuation of Study Vaccination/Withdrawal from the Study................................................. 89
10.3. 
Contraindications to Vaccination.................................................................................................... 90
10.4. 
Withdrawal From the Use of Research Samples........................................................................... 91
11. STATISTICAL METHODS................................................................................................................. 91
11.1. 
Participant Information ................................................................................................................... 91
11.2. 
Analysis Populations...................................................................................................................... 91
11.3. 
Sample Size Determination ........................................................................................................... 92
11.4. 
Study Monitoring ............................................................................................................................ 96
11.5. 
Efficacy Analysis ............................................................................................................................ 97
11.5.1. 
Vaccine Efficacy Analysis........................................................................................................... 97
11.5.1.1. 
Primary Vaccine Efficacy Analysis: HIV-1 Infection ................................................................ 97
11.5.1.2. 
Secondary/Exploratory Vaccine Efficacy Analyses................................................................. 98
11.6. 
Safety Analysis............................................................................................................................... 98
11.6.1. 
Reactogenicity: Solicited Adverse Events .................................................................................. 99
11.6.2. 
Unsolicited Adverse Events, AESIs, MAAEs and Serious Adverse Events............................... 99
11.6.3. 
Other Safety Parameters............................................................................................................ 99
11.6.4. 
Other Parameters ..................................................................................................................... 100
11.7. 
Reasons for Vaccination Discontinuation and Early Study Termination...................................... 100
11.8. 
Immunogenicity Analysis.............................................................................................................. 100
11.9. 
Independent Data and Safety Monitoring Board.......................................................................... 101
11.10. Endpoint Adjudicator(s)................................................................................................................ 101
12. ADVERSE EVENT REPORTING .................................................................................................... 101
12.1. 
Definitions .................................................................................................................................... 102
12.1.1. 
Adverse Event Definitions and Classifications ......................................................................... 102
12.1.2. 
Attribution Definitions................................................................................................................ 103
12.1.3. 
Severity Criteria ........................................................................................................................ 104
12.2. 
Special Reporting Situations........................................................................................................ 106
12.3. 
Procedures................................................................................................................................... 106
12.3.1. 
All Adverse Events.................................................................................................................... 106
12.3.2. 
Serious Adverse Events ........................................................................................................... 108
12.3.3. 
Pregnancy................................................................................................................................. 109
12.3.4. 
Adverse Events of Special Interest........................................................................................... 109
12.3.4.1. 
Thrombosis with Thrombocytopenia Syndrome.................................................................... 109
12.4. 
Contacting Sponsor Regarding Safety......................................................................................... 110
13. PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 110
13.1. 
Procedures................................................................................................................................... 111
13.2. 
Contacting Sponsor Regarding Product Quality.......................................................................... 111
14. STUDY PRODUCT INFORMATION................................................................................................ 111
14.1. 
Physical Description of Study product(s)..................................................................................... 111
14.2. 
Packaging and Labeling............................................................................................................... 112
14.3. 
Preparation, Handling, and Storage............................................................................................. 112
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
30
Status: Approved, Date: 28 February 2023
14.4. 
Vaccine Accountability................................................................................................................. 113
15. STUDY-SPECIFIC MATERIALS..................................................................................................... 114
16. ETHICAL ASPECTS ....................................................................................................................... 115
16.1. 
Study-Specific Design Considerations......................................................................................... 115
16.2. 
Regulatory Ethics Compliance..................................................................................................... 116
16.2.1. 
Investigator Responsibilities ..................................................................................................... 116
16.2.2. 
Independent Ethics Committee or Institutional Review Board................................................. 116
16.2.3. 
Informed Consent ..................................................................................................................... 117
16.2.4. 
Privacy of Personal Data .......................................................................................................... 118
16.2.5. 
Long-Term Retention of Samples for Additional Future Research .......................................... 119
16.2.6. 
Country Selection ..................................................................................................................... 119
17. ADMINISTRATIVE REQUIREMENTS ............................................................................................ 119
17.1. 
Protocol Clarification Communications ........................................................................................ 119
17.2. 
Protocol Amendments.................................................................................................................. 119
17.3. 
Regulatory Documentation .......................................................................................................... 120
17.3.1. 
Regulatory Approval/Notification .............................................................................................. 120
17.3.2. 
Required Prestudy Documentation........................................................................................... 120
17.4. 
Participant Identification, Enrollment, and Screening Logs ......................................................... 121
17.5. 
Source Documentation................................................................................................................. 121
17.6. 
Case Report Form Completion .................................................................................................... 122
17.7. 
Data Quality Assurance/Quality Control ...................................................................................... 122
17.8. 
Record Retention ......................................................................................................................... 123
17.9. 
Monitoring .................................................................................................................................... 123
17.10. Study Completion/Termination..................................................................................................... 124
17.10.1. Study Completion/End of Study................................................................................................ 124
17.10.2. Study Termination..................................................................................................................... 124
17.11. On-Site Audits.............................................................................................................................. 124
17.12. Use of Information and Publication .............................................................................................. 125
18. COVID-19 APPENDIX: GUIDANCE ON STUDY CONDUCT DURING THE COVID-19
PANDEMIC...................................................................................................................................... 127
REFERENCES.......................................................................................................................................... 130
INVESTIGATOR AGREEMENT............................................................................................................... 138
LIST OF ATTACHMENTS
Attachment 1: 
Definition of Individual of Childbearing Potential and List of Acceptable Highly
Effective Contraceptive Methods............................................................................................ 133
Attachment 2: 
Test of Understanding.................................................................................................. 134
Attachment 3: 
List of Potentially Immune-mediated Medical Conditions............................................ 135
Attachment 4: 
Thrombotic Events to be Reported as Potential AESIs............................................... 137
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
31
Status: Approved, Date: 28 February 2023
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Objectives and Endpoints ......................................................................................................... 58
Table 2: 
Vaccination Schedule ............................................................................................................... 60
Table 3: 
Description of Study Products .................................................................................................. 71
Table 4: 
Summary of interim monitoring of VE....................................................................................... 97
Table 5: 
Grading of Solicited Administration Site Adverse Events....................................................... 104
Table 6: 
Grading of Solicited Systemic Adverse Events ...................................................................... 105
FIGURES
Figure 1: Primary Efficacy Testing –Schematic Overview...................................................................... 94
Figure 2: Impact of Assumed PrEP use and Adherence on Annual HIV-1 Incidence in the
Placebo Group.......................................................................................................................... 96
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
32
Status: Approved, Date: 28 February 2023
SYNOPSIS
A Multi-center, Randomized, Double-blind, Placebo-controlled Phase 3 Efficacy Study of a
Heterologous Vaccine Regimen of Ad26.Mos4.HIV and Adjuvanted Clade C gp140 and Mosaic
gp140 to Prevent HIV-1 Infection Among Cis-gender Men and Transgender Individuals who Have
Sex with Cis-gender Men and/or Transgender Individuals
The aim of this study is to demonstrate the efficacy of a heterologous human immunodeficiency virus type 1
(HIV-1) vaccine regimen consisting of Ad26.Mos4.HIV and a combination of aluminum
phosphate-adjuvanted Clade C glycoprotein (gp) 140 and Mosaic gp140 (Mos gp140).
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives 
Endpoints
Primary
1 
To evaluate the vaccine efficacy (VE) of a
heterologous vaccine regimen utilizing
Ad26.Mos4.HIV and aluminum phosphate-
adjuvanted Clade C gp140 and Mosaic gp140 for
the prevention of HIV-1 infection in HIV-1
seronegative cis-gender men and transgender
individuals having sex with cis-gender men and/or
transgender individuals.
1 
Confirmed HIV-1 infections diagnosed between
Month 7 and Month x (with 24≤x≤30) visits in
the per-protocol (PP) population.
Secondary
1 
To evaluate the safety and reactogenicity of a
heterologous vaccine regimen utilizing
Ad26.Mos4.HIV and aluminum phosphate-
adjuvanted Clade C gp140 and Mosaic gp140 for
the prevention of HIV-1 infection in HIV-1
seronegative cis-gender men and transgender
individuals having sex with cis-gender men and/or
transgender individuals.
1 
 Reactogenicity: Solicited administration site
and systemic adverse events for 7 days after
each vaccination
 Unsolicited adverse events for 28 days after
each vaccination
 Adverse events of special interest (AESIs) for
6 months after the last vaccination
 Medically-attended adverse events (MAAEs)
for the entire duration of the study
 Serious adverse events for the entire duration
of the study
 Discontinuations from the study or
vaccination due to adverse events
2 
To evaluate VE at other timepoints and in other
analysis populations.
2 
Confirmed HIV-1 infections over different time
intervals (eg, VE[0-x months], VE[13-x months])
and in different populations (eg, modified intent-
to-treat [mITT], mITT-2, mITT-3, full
immunization set [FIS])
3 
To evaluate VE by and adjusting for potential
(baseline) confounders.
3 
Potential confounders include but are not limited
to: demographic characteristics, baseline Ad26
seropositivity status and titer, sexual risk
behavior, and pre-exposure prophylaxis (PrEP)
use.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
33
Status: Approved, Date: 28 February 2023
Objectives 
Endpoints
Exploratory
1 
To evaluate whether VE differs by phenotypic 
characteristics of HIV, such as neutralization 
sensitivity, and whether there is evidence of 
vaccine-induced immune pressure on the viral 
phenotype. 
1 
Confirmed HIV-1 infection diagnosed after Day 1
through Month 30 and inferred transmitted viral
isolate(s) phenotype(s) from HIV-1–infected
mITT participants at the earliest available post-
infection timepoint, and possible subsequent
visits.
2 
To evaluate whether VE differs by genotypic 
characteristics of HIV, such as signature site 
mutations, and whether there is evidence of 
vaccine-induced immune pressure on the viral 
sequences. 
2 
Confirmed HIV-1 infection diagnosed after Day 1
through Month 30 and inferred transmitted viral
sequence(s) genotype(s) from HIV-1–infected
mITT participants at the earliest available post-
infection timepoint, and possible subsequent
visits, using sieve analysis methods.
3 
To evaluate vaccine effects on virologic and
immunologic outcomes among participants that
become HIV-1–infected during the study,
accounting for antiretroviral (ARV) use.
3 
HIV-1 viral load and CD4+ count over a 6-month
period after diagnosis.
The frequency and magnitude of HIV-1 cellular
(participants at sites with access to sponsor
approved PBMC processing facilities) and
humoral immune responses in participants that
become HIV-1–infected during the study.
4 
To evaluate immune correlate(s) of risk of HIV-1
infection and/or correlates of VE.
4 
Magnitude and/or frequency of immune
responses to vaccination in HIV-1 infected
vaccine recipients (cases) relative to a subset of
HIV-1 uninfected vaccine recipients (controls)
and placebo cases and controls, as relevant.
The association of immune response(s) that are
identified as being associated with VE in Study
VAC89220HPX2008 /HVTN 705 (further
referred to as HPX2008/HVTN 705a, in HIV-1
infected vaccine recipients (cases) relative to a
subset of HIV-1 uninfected vaccine recipients
(controls) and placebo cases and controls, as
relevant.
5 
To evaluate the occurrence of vaccine-induced
seropositivity/seroreactivity (VISP/R, further
referred to as VISP) following vaccination with
heterologous vaccine regimen utilizing
Ad26.Mos4.HIV and aluminum phosphate-
adjuvanted Clade C gp140 and Mosaic gp140.
5 
The frequency of confirmed VISP, determined
utilizing a pre-specified diagnostic algorithm to
distinguish HIV- 1 infection from VISP (refer to
the Study-Specific Procedures Binder for more
information) at different time points following
vaccination.
a VAC89220HPX2008/HVTN 705 proof-of-efficacy study: A multicenter, randomized, double-blind, placebo-
controlled phase 2b efficacy study of a heterologous prime/boost vaccine regimen of Ad26.Mos4.HIV and
aluminum phosphate-adjuvanted Clade C gp140 in preventing HIV-1 infection in women in sub-Saharan Africa.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
34
Status: Approved, Date: 28 February 2023
Objectives 
Endpoints
6 
To describe PROs. 
6 
Social impact and vaccine regimen acceptance,
sexual activity, absenteeism and PrEP use
collected through questionnaires completed by
study participants.
7 
To describe HCRU over the study period. 
7 
Collection of MAAEs, level of absenteeism and
follow-up of HIV infections throughout the study.
8 
To evaluate the immune responses elicited by the 
vaccine regimen. 
8 
The frequency and magnitude of HIV-1-specific
cellular and humoral immune responses.
Hypothesis
This study is designed to test the primary hypothesis of VE in the PP population:
Null hypothesis (H0): VE(7-x months) ≤20% versus the alternative hypothesis (H1): VE(7-x months)
>20%, with 24≤x≤30.
The timing of the primary analysis will be determined by when the Target Number of Infections (TNI) is
reached within a given follow-up period x (24≤x≤30).
If the lower bound of the 95% confidence interval (CI) for VE(7-x months) is >20% at the primary analysis,
the corresponding H0 will be rejected.
OVERVIEW OF STUDY DESIGN
This is a multi-center, randomized, parallel-group, placebo-controlled, double-blind, Phase 3 study to
demonstrate efficacy of a heterologous prophylactic HIV-1 vaccine regimen consisting of Ad26.Mos4.HIV
and a combination of aluminum phosphate-adjuvanted Clade C gp140 and Mosaic gp140. Safety,
reactogenicity and immunogenicity will also be evaluated. The study population will include healthy adults
considered to be at increased risk of acquiring HIV-1 infection. A target of 3,800 participants, consisting
of HIV-1-uninfected cis-gender men and transgender individuals having sex with cis-gender men and/or
transgender individuals, aged ≥18 to ≤60 years, will be randomized in a 1:1 ratio to the study vaccine or
placebo. Randomization will be stratified by site. Sample size re-assessment may be performed based on
blinded study data or external study data (eg, Phase 2b Study HPX2008/HVTN 705). The target number of
HIV-1 infections may be re-assessed based on external study data (eg, Phase 2b Study HPX2008/HVTN
705) only.
Participants will receive intramuscular (IM) doses of study vaccine or placebo at four time points as
indicated in the table below.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
35
Status: Approved, Date: 28 February 2023
Table: 
Vaccination Schedule
Group  
N 
Month 0 
Month 3 
Month 6 
Month 12
1 
1,900 Ad26.Mos4.HIV  Ad26.Mos4.HIV
Ad26.Mos4.HIV  
+ 
Clade C gp140, Mosaic 
gp140, adjuvanted 
Ad26.Mos4.HIV
+
Clade C gp140, Mosaic
gp140, adjuvanted
2 
1,900 
Placebo 
Placebo 
Placebo 
+ 
Placebo 
Placebo
+
Placebo
Total dose of Ad26.Mos4.HIV is 5x1010 viral particles (vp)/0.5 mL injection.
Clade C gp140, Mosaic gp140, adjuvanted: adjuvanted protein formulation with a dosage strength of 80 mcg
Clade C protein, 75 mcg Mosaic protein and 425 mcg aluminum (as aluminum phosphate adjuvant). Note:
previously the dose of Clade C gp140 and/or Mosaic gp140 was reported as mcg of glycoprotein: 125 mcg Clade
C gp140 and 125 mcg Mosaic gp140 glycoprotein correspond with 80 mcg and 75 mcg of protein, respectively.
The study comprises of ascreening period of 45 days, a 12-month vaccination period and a follow-up period
of at least 18 months after the fourth vaccination (until Month 30) in participants who remain HIV-1
negative or up to 6 months after diagnosis of HIV-1 infection in participants who become HIV-1 infected.
Participants who completed their Month 30 visit will be followed for HIV infection, MAAEs and serious
adverse events until the end of the study (ie, when the last participant completed the Month 30 visit or
discontinued earlier). At the end of the study, participants may be offered the possibility to enter a long-
term follow-up phase or program (to collect, amongst others, additional durability data).
After vaccination, participants will remain under observation at the study site for at least 30 minutes for
presence of any acute reactions. In addition, participants will record solicited signs and symptoms in a diary
for 7 days post-vaccination. Unsolicited adverse events will be recorded for all participants until 28 days
after each preceding vaccination. AESIs will be collected until 6 months after the last vaccination. Serious
adverse events, MAAEs, and adverse events leading to discontinuation will be collected for all participants
until the end of the study.
An HIV test will be performed approximately every 3 months. Upon discretion of the investigator,
additional HIV tests may be performed during unscheduled visits; participants should refrain from
performing any HIV testing outside of the study protocol. Blood samples will be collected at specific visits
for determination of humoral immune responses (all participants) and for determination of cellular immune
responses (participants at sites with access to sponsor approved PBMC processing facilities). At specific
clinic visits, participants will complete Participant Reported Outcomes (PRO) questionnaires, including a
social impact questionnaire, a sexual activity questionnaire, a questionnaire on the use of PrEP  and
questions with regard to the level of absenteeism and the vaccine regimen acceptance.
If a participant becomes HIV-1 infected during the study (confirmed HIV test), the participant will remain
in the study but no further scheduled vaccinations will be administered. The participant will be followed-up
until approximately 6 months after the diagnosis (see the Time and Events Schedule for Participants Who
Become HIV-1 Infected) and will be referred to a local clinic for medical treatment and follow-up on their
HIV-1 infection as soon as possible after the diagnosis of the infection.
The sponsor and its partners are committed to ensuring that all study participants receive access to the
highest standard of prevention, which may include, but is not limited to, HIV testing, risk reduction
counseling, provision of male condoms and lubricants, access to management of sexually transmitted
infections (STIs), and appropriate referrals for PrEP and post-exposure prophylaxis (PEP) according to
national and/or local guidelines. Note: potential participants choosing to use PrEP will not be eligible for
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
36
Status: Approved, Date: 28 February 2023
participation in the study as, due to the high effectiveness of PrEP, these individuals are not considered to
be at increased risk of HIV acquisition. However, once enrolled in the study and having received their first
vaccination, a participant who changes his/her mind regarding PrEP use is permitted to take PrEP according
to the site PrEP plan and will continue to receive further vaccinations. In case of PrEP use during the study,
safety monitoring for PrEP will be the responsibility of the prescribing physician. HIV testing should be
performed within the study to avoid unblinding due to VISP elicited by the vaccine. Participants should
refrain from HIV testing outside of the study protocol. As part of the study protocol, blood samples will be
collected for ARV detection in dried blood spot and stored at pre-specified sample collection days for
assessment of quantitative concentrations of tenofovir diphosphate. Additional ARV detection can be done
on stored blood samples if required as per the Study Specific Procedures Binder. The use of PrEP and
adherence to PrEP (if applicable) will be monitored by means of a questionnaire which will be completed
by all participants approximately every 3 months.
The NIAID HIV vaccine Data and Safety Monitoring Board (further referred to as DSMB) will serve as an
independent DSMB for this study and will monitor data on an ongoing basis to ensure the continuing safety
of the participants and will formally monitor the efficacy endpoint.
A COVID-19 Appendix provides guidance to investigators for managing study-related procedures during
the COVID-19 pandemic.
PARTICIPANT POPULATION
Screening for eligible participants will be performed within 45 days before the first administration of study
vaccine or placebo at Day 1.
Study participants must be healthy (on the basis of medical history, physical examination [including vital
sign measurement]), HIV-uninfected adult cis-gender men and transgender individuals having sex with cis-
gender men and/or transgender individuals, aged ≥18 to ≤60 years, who are considered to be at increased
risk for HIV infection. All efforts will be made to ensure that the study population includes good
representation from the population at highest risk of HIV infection in terms of race, ethnicity, gender and
age.
DOSAGE AND ADMINISTRATION
Each participant will receive doses of study vaccine or placebo at 4 time points according to randomization,
on Month 0 (Day 1), 3, 6, and 12, administered by IM injection into the deltoid. For visits with only one
injection (ie, at Month 0 [Day 1] and 3), preferably the deltoid of the non-dominant upper arm is used.
When 2 injections are to be given at one visit (ie, at Month 6 and 12), it is required to use a different deltoid
for each injection. Two injections in the same deltoid are allowed only if medically indicated.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
37
Status: Approved, Date: 28 February 2023
Table: 
Description of Study Products
Test articles 
Ad26.Mos4.HIV  
Clade C gp140, Mosaic
gp140, aluminum phosphate
Placebo
Description  
See Section Vaccine Information.
Dose/delivery 
(0.5 mL 
injection) 
5x1010 vp 
80 mcg Clade C protein*,
75 mcg Mosaic protein*,
adjuvanted with aluminum 
phosphate (425 mcg
aluminum)
0.9% saline
Frequency  
Month 0 (Day 1), 3, 6, and
12
Month 6 and 12 
Month 0 (Day 1) and 3
(1 injection), Month 6 and 12
(2 injections)
Route of
administration
IM in deltoid 
IM in deltoid 
IM in deltoid
Delivery
method
Refer to the Study-Specific Procedures Binder for details.
* 
80 mcg Clade C gp140 and 75 mcg Mosaic gp140 of protein correspond with 125 mcg and 125 mcg glycoprotein,
respectively.
EFFICACY EVALUATIONS
An HIV test will be performed approximately every 3 months. Upon discretion of the investigator,
additional HIV  tests may be performed during unscheduled visits; participants should refrain from
performing any HIV testing outside of the study protocol. Testing will be performed according to a sponsor-
approved HIV testing algorithm that differentiates VISP (see below) from true HIV infection. An endpoint
adjudication process will be in place to assess all serological and virological testing, in a blinded manner,
on each participant in the study who, prior to study unblinding, tests positive per the sponsor-approved HIV
testing.
IMMUNOGENICITY EVALUATIONS
Venous blood samples for determination of humoral immune responses will be collected from all
participants (and analyzed in a subset). Humoral immune responses may be assessed by the response
magnitude and frequency to the vaccine autologous Clade C gp140 and Mosaic gp140 proteins by total
immunoglobulin G (IgG) binding ELISA, or alternative assays. Baseline and post-vaccination Ad26
seropositivity and titer will be assessed in a subset of participants by vector neutralization assay.
Venous blood samples for determination of cellular immune responses will be collected from participants
at sites with access to sponsor approved PBMC processing facilities (and analyzed in a subset). Cellular
immune responses may be assessed by the response magnitude and frequency of peripheral blood
mononuclear cells generating interferon-γ ELISpot responses to cPTE Env peptide stimulation, or
alternative assays.
Additional exploratory immunogenicity assessments may be performed, which may include limited genetic
testing.
SAFETY EVALUATIONS
Solicited adverse events, unsolicited adverse events, AESIs, serious adverse events, MAAEs, and adverse
events leading to discontinuation will be reported for all participants.
All serious adverse events and adverse events and special reporting situations, that are related to study
procedures or that are related to non-investigational (concomitant) sponsor products will be reported
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
38
Status: Approved, Date: 28 February 2023
from the time a signed and dated informed consent form (ICF) is obtained until the end of the study/early
withdrawal. Clinically relevant medical events not meeting the above criteria and occurring between
signing of ICF and the moment of first vaccination will be collected on the Medical History CRF page as
pre-existing conditions. Solicited adverse events, collected through a diary, will be recorded daily for each
vaccination from the moment of vaccination until 7 days post-vaccination. All other unsolicited adverse
events and special reporting situations will be reported for each vaccination from the moment of vaccination
until 28 days post-vaccination. From the time of local approval of protocol amendment 5 onwards, TTS is
considered to be an AESI. Thrombotic events and/or thrombocytopenia (defined as platelet count below
the lower limit of normal (LLN) range for the testing lab) are considered to be potential AESIs. All AESIs,
including potential AESIs, will be reported to the sponsor from the moment of first vaccination until
6 months after the last vaccination. Each potential AESI will be reviewed to identify a TTS case. All serious
adverse events, MAAEs, and adverse events leading to discontinuation (regardless of the causal
relationship) are to be reported from the moment of first vaccination for the duration of the study.
After each vaccination, participants will remain under observation at the study site for at least 30 minutes
for presence of any acute reactions.
Occurrences of the following solicited administration  site and systemic signs and symptoms 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.
 
Administration site: erythema, swelling (measured using the ruler supplied) and pain/tenderness.
 
Systemic: fever (temperature measurement [measured at approximately the same time each day using
the thermometer supplied]), fatigue, headache, nausea, myalgia, chills, arthralgia, and vomiting.
PARTICIPANT REPORTED OUTCOMES
Social impact, vaccine regimen acceptance, sexual activity, absenteeism and PrEP use will be evaluated at
selected time points during the study, through questionnaires.
STATISTICAL METHODS
The primary analysis of VE will be based on the PP populationa. The primary population for the safety
analysis will be the full analysis set (FAS)b. For those with immunogenicity outcomes, analyses of vaccine
immunogenicity and immune correlates may be based on the mITT-3c population, PP population, at risk
immunogenicity cohort (IC-at risk)d, and the FISe, Other populations may be defined in the Statistical
Analysis Plan (SAP) for the purpose of exploratory (correlate) analyses.
The sample size calculations are based on the power of a 1-sided 0.025-level Wald test for comparing
cumulative incidences of HIV-1 infection by the Month x visit (24≤x≤30) between randomized groups, in
a PP population: participants in the FAS population who have a negative HIV test 4 weeks post 3rd vaccination visit
(ie, at the Month 7 visit), who received all planned vaccinations at the first 3 vaccination visits within the respective
visit windows.
b FAS: all randomized participants who receive at least one vaccine administration.
c mITT-3 population: participants in the FAS population who have a negative HIV test 4 weeks post 3rd vaccination
visit (ie, at the Month 7 Visit), who received all planned vaccinations at the first three vaccination visits. This will
be an additional population for efficacy analysis, and potentially for immune correlates.
d IC-at risk: participants in the FAS who are selected for measurement of immune response endpoints at the primary
immunogenicity timepoints and who are HIV-1 uninfected 4 weeks after the 3rd vaccination visit (ie, at the Month
7 visit).
e FIS: participants in the FAS who are HIV-1 uninfected 4 weeks after the 4th  vaccination visit (ie, at the
Month 13 visit) and who receive all planned vaccinations within the respective visit windows.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
39
Status: Approved, Date: 28 February 2023
the presence of the sequential monitoring of VE. Power is computed based on simulating 10,000 efficacy
studies using the R package seqDesign under the following assumptions:
 
10% annual dropout incidence in both groups;
 
5% of participants with at least one missed vaccination (excluded from PP population);
 
VE=20% in the first 7 months after first vaccination;
 
VE=65% from Month 7 onwards;
 
12-month uniform accrual with halved accrual during the first 3 months;
 
Visits approximately every 3 months for HIV-1 diagnostic tests;
 
2% annual HIV-1 incidence in the placebo group;
Under these assumptions, a study population of 3,800 participants (randomized 1,900:1,900 to
vaccine:placebo) is expected to yield a total of 78 HIV-1 infections in the PP population between the
Month 7 and Month 30 visits, considered to be the TNI needed to achieve approximately 90% power for
rejecting the primary H0, under an alternative VE of 65% and with a one-sided error rate of 2.5%.
Efficacy Analyses
The primary analysis of VE will evaluate the number of HIV-1 infections in the vaccine group compared
to the number of HIV-1 infections in the placebo group between Month 7 and Month x (with 24≤x≤30) in
the PP population. The timing of the primary analysis will be determined by when the TNI is reached within
a given follow-up period x (24≤x≤30). The H0 of VE, ie, VE(7-x months) ≤20% will be tested versus the
H1, ie, VE(7-x months) >20%. Vaccine efficacy is defined as 1-cumulative incidence ratio (vaccine versus
placebo) between Month 7 and Month x after first vaccination and is estimated by the transformation of the
Nelson-Aalen estimator for the cumulative hazard function. If the lower bound of the 95% CI for
VE(7-x months) is >20% (equivalently, the 1-sided p-value for testing H0: VE[7-x months] ≤20% is below
0.025), the H0 will be rejected in favor of the H1.
As a key secondary objective, the VE beyond Month 7 will be evaluated in all participants, regardless of
whether they received the first three vaccinations according to the protocol-specified schedule (modified
intent-to-treat-2 [mITT-2]a). Other secondary objectives will evaluate the VE over different time intervals
(eg, VE[0-x months], VE[13-x months]) and in different populations (eg, mITT, mITT-2, mITT-3, FIS).
Immunogenicity Analyses
No formal hypothesis on immunogenicity will be tested. Descriptive statistics (actual values and changes
from reference) may be calculated for continuous parameters. Frequency tabulations may be calculated for
discrete parameters. Graphical representations of changes in immunologic parameters may be made as
applicable.
Safety Analyses
No formal statistical testing of safety data is planned. Safety data will be analyzed descriptively.
a mITT-2 population: participants in the FAS who have a negative HIV test 4 weeks post 3rd vaccination visit (ie, at
the Month 7 Visit).
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
40
Status: Approved, Date: 28 February 2023
Analyses of PRO
Data from the PRO questionnaires will be summarized using descriptive statistics. In addition, data from
PRO questionnaires may be included as co-variates in the exploratory efficacy analysis.
Analyses of Health Economics Aspects (HCRU)
Health Care Resource Utilization will be described based on data collected through MAAEs and follow-up
of HIV infections and complemented by description of absenteeism. Data will be summarized using
descriptive statistics.
NCT03964415

NCT03964415

NCT03964415

NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
44
Status: Approved, Date: 28 February 2023
g
Targeted physical examination, including weight, vital signs, and a symptom directed evaluation by history and/or appropriate physical examination based on participant self reported
symptoms or complaints.
h
HIV testing should be performed per sponsor approved algorithm, as described in the Study Specific Procedures Binder. To avoid delays in initiation of combined antiretroviral treatment,
local HIV PCR testing is allowed only in case of suspected acute HIV infection, in case of recent HIV exposure, or in case a request for sample redraw is received from the central HIV
testing laboratory for confirmation of an HIV positive test. Upon discretion of the investigator, additional HIV tests may be performed during unscheduled visits; participants should
refrain from performing any HIV testing outside of the study protocol.
i
If a participant becomes HIV 1 infected during the study, no further scheduled vaccinations will be administered. The participant should follow further assessments as outlined in the
Time and Events schedule for participants who become HIV 1 infected.
j
The screening HIV test should be performed within 28 days prior to first vaccination.
k
HIV test 13 months post 1st vaccination will be collected but is only to be analyzed in case the test at 15 months is positive and the test at 12 months was negative.
l
The following concomitant therapies must be recorded from the first study vaccination to 1 month after the last study vaccination: analgesics/antipyretic medications and non steroidal
anti inflammatory drugs, hormonal therapy, hormone based contraception, systemic corticosteroids, antihistaminics, monoclonal antibodies (mAbs), or vaccinations must be recorded
from the first study vaccination to 1 month after the last study vaccination. Exception: COVID 19 vaccination must be recorded as of any time before screening until the end of the study.
All other concomitant therapies should also be recorded if administered in conjunction with new or worsening adverse events reported per protocol requirements. If applicable, HIV
prevention medication should be recorded.
m
The use of PrEP, PEP, hormonal therapy, hormone based contraception, and all COVID 19 vaccinations should be recorded. All other concomitant therapies should also be recorded if
administered in conjunction with new or worsening adverse events reported per protocol requirements.
n
Check clinical status again before first dose of study vaccine.
o
For participants of childbearing potential only.
p
A urine pregnancy test is to be performed every 3 to 6 months.
q
Participants who have been prematurely withdrawn from study vaccine administration will be encouraged to complete the visit schedule as planned with assessments per the Time and
Event Schedule, including assessments of safety and HIV diagnosis. Participants who received the first 3 vaccinations but discontinue study vaccination before receiving the 4th
vaccination, should continue the visit schedule as planned with assessments per the Time and Event Schedule including assessments of safety, immunogenicity and HIV diagnosis. They
will also be reminded not to have HIV testing outside of the study protocol as this could lead to misdiagnosis and unblinding.
r
Participants will remain under observation at the study site for at least 30 minutes for presence of any acute reactions.
s
All participants will record solicited signs and symptoms in a diary for 7 days post vaccination.
t
Unsolicited adverse events will be recorded for all participants until 28 days after each vaccination.
u
Applicable from the time of local approval of protocol amendment 5 onwards: AESIs (including potential AESIs) are to be reported to the sponsoruntil 6 months after the last vaccination
(see Section 12.3.4). In case of a potential AESI of TTS, a serum sample should be obtained to test for anti PF4 at the local laboratory or substitute local laboratory, if possible; repeat
testing may be requested for confirmation upon sponsor discretion. A test for anti PF4 will also be performed on a stored pre vaccination sample, if possible. Serious adverse events,
MAAEs, and adverse events leading to discontinuation will be recorded until the participant’s last study contact.
v
The site staff and the participant will make multiple efforts in good faith to be in contact after the last day of the reactogenicity period, or sooner if indicated, to discuss presence of any
signs and symptoms of reactogenicity. Participants who self report any post vaccination reaction greater than mild are seen by a clinician within 48 hours after onset, unless the reaction
is improving and/or has resolved completely.
w
The recall period of the questionnaire is the last month.
x
All participants will be asked about their level of absenteeism at each visit except for Visit 2a, 3a, 4a and 7a. At Visit 8, approximately 1 month post vaccination 4, participants will be
asked about the acceptance of the vaccine regimen.
y
(1) Urine sample, (2) rectal swab, and (3) oropharyngeal swab are all required. If required by standard local procedure, the collection of a urethral swab will be considered equivalent
to a urine sample.
z
Venous blood samples for determination of humoral immune responses will be collected from all participants (and analyzed in a subset)
aa
Blood samples will be collected for ARV detection in dried blood spot and stored at pre specified sample collection days for assessment of quantitative concentrations of tenofovir
diphosphate. Additional ARV detection can be done on stored blood samples if required, as per the Study Specific Procedures Binder.
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bb
The use of PrEP at baseline and the use ofPrEP and adherence to PrEP (if applicable) since their last visit will be assessed through a questionnaire. Safety monitoring for PrEP will be
the responsibility of the prescribing physician.
cc
At Visit 2 (Day 1) and Visit 5 (Month 7), venous blood samples for determination of cellular immune response will be collected from participants at sites with access to sponsor
approved PBMC processing facilities (and analyzed in a subset).
dd
Approximately every 6 months, blood samples for syphilis serology determination should be collected and a test for chlamydia/gonorrhea should be performed.
ee
Limited genetic testing may be performed onleftover blood from samples collected for the determination of cellular immune response. No separate blood sample is needed.
ff
Includes history and family history of immune disorders.
gg
Demographics (eg, sex assigned at birth, participant identified gender at screening, age, male circumcision, race) will be recorded at screening. Gender identity needs to be collected at
Visit 7 (Month 12), Visit 12 (Month 24), approximately Month 36 and from then onwards on an annual basis.
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Time and Events Schedule for Participants Who Become HIV-1 Infected
Visit #j 
#.X  
i 
Inf1 
Inf2 
Early Exit Infb
Time in months since diagnosisa 
M3 
M6
Visit Day  
D84 
D168
Target/allowable visit window 
±28d 
±28d
HIV test 

HIV 1 viral load measurement 
 
 
 

CD4+ T cell counth 
 
 
 

Limited genetic testing 

Counseling on HIV testing/diagnosis 

Full physical examinationc 

Pregnancy testd 
 
 

Targeted physical examination 
 
 

Concomitant medication k 
 
 

AE/AESI/SAE recordinge 
 
 
 

Transmission risk reduction counseling 
 
 
 

Social impact questionnairel 
 
 

Absenteeism  
 
 
 

Immunogenicity assaysf 
 
 
 

Viral sequencingg 
 
 
 

#.X: interim visit for the purpose of drawing samples for confirmatory HIV testing
AE: adverse event; ARV: antiretroviral; D: Day; d: days; HIV 1: human immunodeficiency virus type 1; HCRU: Health Care
Resource Utilization; M: month; SAE: serious adverse event
The COVID 19 Appendix in Section 18 provides guidance to investigators for managing study related procedures during the
COVID 19 pandemic.
a 
Target dates for Visit Inf1 and Inf2 are relative to the participant’s diagnosis date, which is the date the initial positive HIV
test result.
b 
For those participants who are unable to continue in the study, an exit visit will be conducted as soon as possible.
c 
Including assessment of HIV/acquired immunodeficiency syndrome (AIDS) related conditions.
d 
For participants of childbearing potential only.
e 
Unsolicited adverse events until 28 days after preceding vaccination, AESIs until 6 months after the last vaccination, serious
adverse events and MAAEs until the last study contact. In case of a potential AESI of TTS, a serum sample should be
obtained to test for anti PF4 at the local laboratory or substitute local laboratory, if possible; repeat testing may be requested
for confirmation upon sponsor discretion. A test for anti PF4 will also be performed on a stored pre vaccination sample, if
possible.
f 
Venous blood samples for determination of humoral immune responses will be collected from all participants and for
determination of cellular immune responses from participants at sites with access to sponsor approved PBMC processing
facilities. Depending on the vaccine efficacy outcome, samples may be used for the evaluation of immune markers that have
a sieving effect on any breakthrough infections and for the evaluation of any immune markers that are associated with post
infection control of HIV in participants, potentially including immune responses to all vaccine antigens.
g 
Blood samples for viral sequencing will be collected for all participants and may be analyzed to assess whether VE differs by
phenotypic characteristics of HIV and whether there is evidence of vaccine induced immune pressure on the viral genotype,
depending on the vaccine efficacy outcome.
h 
Locally performed test.
i 
To be scheduled as soon as possible after the initial positive HIV test result (Note: the request for redraw is considered as the
initial positive HIV test result). This could be either a scheduled or unscheduled visit.
j 
Once the last subject has completed the Month 30 visit of the Time and Events Schedule for HIV 1 Negative Participants or
has discontinued earlier, the study is considered completed. HIV infected participants still in the study at that time will be
informed that they should return to the site for the Visit #.X, if not completed yet, but no further site visits will be required.
k 
All ARVs, all COVID 19 vaccinations, and all concomitant therapies administered in conjunction with new or worsening
adverse events reported per protocol requirements should be reported.
l
If, in the opinion of the investigator/site staff, the completion of the social impact questionnaire can cause undue burden to
the participant, it can be omitted.
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ABBREVIATIONS
Ad 
adenovirus
Ad26 
adenovirus serotype 26
Ad5 
adenovirus serotype 5
AE 
adverse event
AESI 
adverse event of special interest
AIDS  
acquired immunodeficiency syndrome
API 
active pharmaceutical ingredient
ART  
antiretroviral therapy
ARV  
antiretroviral
β-hCG  
β-human chorionic gonadotropin
CBER  
Center for Biologics Evaluation and Research
CDC  
Centers for Disease Control and Prevention
CI 
confidence interval
cPTE 
clinical potential T cell epitopes
CRF  
case report form
DAIDS  Division of Acquired Immunodeficiency Syndrome
DSMB  
Data and Safety Monitoring Board
DP  
drug product
DS  
drug substance
eDC 
electronic data capture
ELISA  
enzyme-linked immunosorbent assay
ELISPOT enzyme-linked immunospot
Env 
envelope
EUA  
Emergency Use Authorization
EUL 
Emergency Use Listing
FAS  
full analysis set
FDA  
Food and Drug Administration
FIH  
first-in-human
Gag 
group-specific antigen
gp 
glycoprotein
H0 
null hypothesis
H1 
alternative hypothesis
HCRU  
Health Care Resource Utilization
HITT  
heparin-induced thrombocytopenia and thrombosis
HIV  
human immunodeficiency virus
HVTN  
HIV Vaccine Trials Network
ICF  
informed consent form
ICH  
International Conference on Harmonisation
IEC  
Institutional Ethics Committee
Ig 
immunoglobulin
IM  
intramuscular
IRB  
Institutional Review Board
IWRS  
interactive web response system
LLN  
lower limit of normal
MAAE medically-attended adverse event
mAb 
monoclonal antibody
MedDRA Medical Dictionary for Regulatory Activities
mITT(-2) modified intent-to-treat(-2)
Mos 
Mosaic
MSM  
men who have sex with men
NeF  
Negative Regulatory Factor
NHP  
non-human primate
NIAID  
National Institute of Allergy and Infectious Diseases
NIH  
National Institutes of Health
OVRR  
Office of Vaccines Research and Review
PBMC  
peripheral blood mononuclear cell
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PEP  
post-exposure prophylaxis
PIMMC  potentially immune-mediated medical conditions
Pol 
polymerase
PP 
per-protocol
PQC  
product quality complaint
PrEP  
pre-exposure prophylaxis
PRO  
Participant Reported Outcome
SAE 
serious adverse event
SAP  
Statistical Analysis Plan
SHIV  
simian human immunodeficiency virus
STI 
sexually transmitted infection
SUSAR  suspected unexpected serious adverse reaction
TNI 
Target Number of Infections
TOU  
test of understanding
TTS  
thrombosis with thrombocytopenia syndrome
USFA  
usual social and functional activities
VE 
vaccine efficacy
Visit Infx Visit infected x
VISP  
vaccine-induced seropositivity
VISR  
vaccine-induced seroreactivity
vp 
viral particle
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1. 
INTRODUCTION
In the development of the prophylactic VAC89220 HIV-1 vaccine, the sponsor is currently
evaluating the following candidate components in clinical studies: Ad26.Mos4.HIV, (aluminum
phosphate-adjuvanted) Clade C gp140 and Mosaic gp140. For details see Section 14.1.
For the most comprehensive nonclinical and clinical information regarding the VAC89220 HIV-1
vaccine, see the latest version of the Investigator's Brochures and Addenda for Ad26.Mos4.HIV,
Clade C gp140 and Mosaic gp140.
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, ie, the HIV Vaccine Trials Network (HVTN), Division of AIDS (DAIDS; a
division of the National Institute of Allergy and Infectious Diseases [NIAID] which is part of the
National Institutes of Health [NIH]) are also involved in this study and are referred to in this
protocol as "partners".
1.1. 
Background
1.1.1. 
Background on the Disease and Treatment
Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that, if left untreated, can progress
to acquired immunodeficiency syndrome (AIDS), a condition in which the immune system is
severely compromised, leading to life-threatening conditions. The main modes of transmission of
HIV-1 in the world, although varying significantly by region, are heterosexual transmission,
male-to-male transmission and intravenous drug use.34 The global prevalence of HIV-1 in 2017 is
estimated at 36.9 million (range: 31.1 to 43.9 million), which is an increase from previous years,
mainly explained by broader access to life-saving antiretroviral therapy (ART) and a related longer
life of HIV-infected individuals. Approximately 53% of all people living with HIV have access to
ART. Despite an overall decline in HIV incidence and AIDS-related deaths, the number of new
infections and the cost and morbidity associated with lifelong ART remain high. Worldwide,
1.8 million (range: 1.4 to 2.4 million) people became newly infected with HIV-1 in 2017.35 HIV
infection therefore continues to be a serious and potentially life-threatening condition of major
global public health interest.
A number of specific approaches are being employed or evaluated to reduce the spread of HIV-1,
but no single prevention method or approach utilized to date suggests that it will be able to stop
the epidemic on its own. Several methods and interventions have proved highly efficacious in
reducing the risk of, and protecting against, HIV infection, including male and female condoms,
the use of ARV medicines as PrEP or as PEP, voluntary male medical circumcision, sexual activity
change interventions to reduce the number of sexual partners, STI testing and treatment, the use
of clean needles and syringes, opiate substitution therapy (eg, methadone) and the treatment of
people living with HIV to reduce viral load and prevent onward transmission (treatment as
prevention). Despite the availability of this widening array of efficacious HIV prevention tools
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and methods in recent years, new infections among adults globally have not decreased
sufficiently.33,36
An effective, universal prophylactic HIV-1 vaccine could play a pivotal role in the so-called ‘HIV
prevention toolbox’, where several HIV prevention methods will be necessary to play a significant
role in controlling the spread of the infection.33,38
Evidence for the potential to develop a prophylactic HIV-1 vaccine comes from study RV144
(sponsored by the United States Army Surgeon General, with vaccines manufactured by Sanofi
Pasteur and VaxGen). The study was conducted in more than 16,000 healthy adult Thai
participants who received recombinant canarypox vector encoding group-specific antigen (Gag),
polymerase (Pol), and Env proteins of HIV-1 (ALVAC-HIV [vCP1521]) vaccine followed by a
recombinant gp120 subunit vaccine (AIDSVAX B/E). The vaccine afforded a modest (31%)
reduction in the rate of HIV-1 acquisition.30 In contrast to the Thai study, two Phase 3 studies of
gp120 protein11,29 and three Phase 2b/3 studies using adenovirus serotype 5 (Ad5)-vectored Gag,
Pol, and Negative Regulatory Factor (Nef) HIV-1 antigens7,16,17, failed to demonstrate protection.
Recently, study HVTN 702 or Uhambo, a Phase 2b/3 evaluating the efficacy of an investigational
heterologous vaccine regimen (ie, ALVAC-HIV [vCP2438] + Bivalent Subtype C gp120/MF59)
based on the regimen evaluated in the RV144 clinical study but adapted to HIV-1 Clade C which
is most common in southern Africa, was stopped early because the vaccine was not efficacious.48,49
A successful global HIV-1 vaccine will need to protect against the diverse strains and clades
predominating in the target populations in different geographic regions. There is growing evidence
that potent humoral responses with multiple effector functions combined with robust T cell
responses will be necessary attributes of an effective HIV-1 vaccine. The HIV-1 genes expressed
in the cytoplasm (eg, Gag and Pol) are primarily targeted by cytotoxic cellular immune responses,
whereas the Env gp is a primary target of humoral responses.26
1.1.2. 
Background on the Study Vaccines
Nonclinical Studies
A summary of nonclinical study data available at the time of the initial protocol writing and
relevant to the current study is provided below. For more information, refer to the Investigator's
Brochure Editions 5 for Ad26.Mos4.HIV and Investigator's Brochure Editions 5 and Addendum 1
for and Clade C gp140 and Mosaic gp140.21,22,20
A regimen consisting of a 2 Ad26 vaccinations followed by two Ad26 + Clade C gp140
vaccinations was first tested in non-human primate (NHP) immunogenicity study 13-04, which
showed that several differently composed heterologous Ad26/Clade C gp140 immunization
schedules were immunogenic and induced comparable broad reactivity and neutralization capacity
of diverse tier 1 Env pseudotyped viruses and a robust cellular immune response. This regimen
was further evaluated in an NHP efficacy study (13-19/15-06), which assessed several different
components and combinations thereof in the Ad26
Clade C gp140 schedule developed in 13-04.
This latest study showed that a combination of vaccination with Ad26.Mos.HIV followed by
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Ad26.Mos.HIV together with Clade C gp140 protein in aluminum phosphate adjuvant led to the
highest level of protection observed so far with this vaccine concept. Eight/12 NHP (67%) had
complete protection after the full series of 6 intrarectal challenges with Simian HIV (SHIV)
SF162P3, an engineered virus consisting of the generic backbone of SIVmac239 with the envelope
gene and some accessory genes derived from HIV. Env-binding antibody responses and
Env-specific cellular immune responses were identified as important immunologic markers
associated with vaccine-mediated protection against SHIV-SF162P3 challenges.4
To expand the sequence coverage of our HIV-1 vaccine strategy, an additional component (the
novel Ad26.Mos2S.Env) was added to the trivalent vaccine to produce a tetravalent vaccine
(Ad26.Mos4.HIV). Immunogenicity and antigenicity of a selection of novel insert combinations
with the vectors under clinical development in Ad26.Mos.HIV were tested in rabbits (study
0095-14), which demonstrated that the proposed tetravalent adenovector combination shows
improved Clade C pseudovirus recognition in the absence of negative effects on Clade B
pseudovirus recognition and thus has the potential to substantially increase the breadth of humoral
immune responses of the full vaccine regimen.
In guinea pigs, it was shown that Clade C gp140 was able to induce neutralizing antibody responses
against a set of HIV-1 variants from different clades and with different neutralization sensitivities.
Furthermore, it was observed that the immunogenicity of Clade C gp140 was improved by an
aluminum-based adjuvant, and that these immunogenicity results were comparable in high and
low absorption formulations of aluminum phosphate and aluminum hydroxide, both in terms of
the binding antibody and neutralizing antibody responses induced.
Clade C gp140 was further evaluated as part of the heterologous adenovirus-based vector
(Ad26)/Clade C gp140 protein immunization schedules in a rhesus monkey SHIV challenge
model. The data confirmed the improved protective capacity of vaccine regimens including a
Clade C gp140 boost immunization.
Mosaic gp140 induced an increased breadth of immune responses when combined with Clade C
gp140 in guinea pigs, and in the context of Ad26 immunization in rabbits. Mosaic gp140 was
immunogenic in NHP and was able to boost Clade C gp140-specific immune responses.
Clinical Studies
A summary of clinical study data available at the time of initial protocol writing and relevant to
the current study is provided below. For more information on the clinical study results, refer to the
Investigator's Brochure Editions 5 for Ad26.Mos4.HIV, Clade C gp140 and Mosaic gp140.21,22
More information on the vaccine regimen selection for the current study is provided in Section 3.2.
Study VAC89220HPX2004/HVTN 117 (hereafter abbreviated to HPX2004/HVTN  117), a
randomized, parallel-group, placebo-controlled, double-blind Phase 1/2a study in 198 healthy
HIV-uninfected adult participants is the first-in-human (FIH) study for the tetravalent
Ad26.Mos4.HIV, evaluating the safety/tolerability and immunogenicity of heterologous vaccine
regimens with Ad26.Mos.HIV (trivalent) or Ad26.Mos4.HIV (tetravalent) and Clade C gp140 plus
adjuvant. In the Week 52 analysis (4 weeks post 3rd vaccination), all vaccine regimens were found
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to be well tolerated. The most frequently reported solicited adverse events post any dose were
injection site pain/tenderness, fatigue, headache, and myalgia. No deaths, no grade 4 AEs and few
SAEs, Grade 3 related AEs and AEs leading to discontinuation were reported. During the
vaccination period, no on-study HIV infections occurred. Overall, both vaccine regimens were
immunogenic with the highest humoral and cellular responses being observed in the tetravalent
group. Refer to the Investigator's Brochure Editions 6 for Ad26.Mos4.HIV, Clade C gp140 and
Mosaic gp140 for more information.46,47
Study VAC89220HPX2003/HVTN 118 (hereafter abbreviated to HPX2003/HVTN 118), a multi-
center, randomized, parallel-group, placebo-controlled, double-blind Phase 1/2a study in
152 healthy HIV-uninfected adult participants is the FIH study for Mosaic gp 140 comparing the
safety/tolerability and immunogenicity of different regimens of Ad26.Mos4.HIV together with
either adjuvanted Clade C gp140 or an adjuvanted combination of Mosaic and Clade C gp140. In
the Week 52 analysis (4 weeks post 4th vaccination), both vaccine regimens were found to be well
tolerated. The most frequently reported solicited adverse events post any dose were injection site
pain/tenderness, fatigue, headache, and myalgia. No deaths, no grade 4 AEs and few SAEs, Grade
3 related AEs and AEs leading to discontinuation were reported. During the vaccination period,
no on-study HIV infections occurred. Overall, both vaccine regimens were immunogenic and favor
the selection of the bivalent regimen. refer to the Investigator's Brochure Editions 6 for
Ad26.Mos4.HIV, Clade C gp140 and Mosaic gp140 for more information.46,47
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.23
Clinical Safety Experience With the Ad26.COV2.S Vaccine
Thrombosis in combination with thrombocytopenia (thrombosis with thrombocytopenia syndrome
[TTS]), in some cases accompanied by internal bleeding, has been observed following vaccination
with the Janssen COVID-19 (Ad26.COV2.S) vaccine. As of 31 August 2021, out of 33,584,049
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doses of Ad26.COV2.S administered post-marketing, the following spontaneous reported/solicited
reports of probable TTS cases were identified.a
 
A total of 104 post-marketing events that met the Brighton TTS Case Definition Criteria
Level 1 to 3.5 This corresponds to a reporting ratio of 3.1 per million doses overall.
 
A total of 67 post-marketing events that met the Centers for Disease Control and Prevention
(CDC) TTS Case Definition Criteria Tier 1 to 2.32 This corresponds to a reporting ratio 2 per
million doses overall.
Reports include severe cases of venous thrombosis at unusual sites such as cerebral venous sinus
thrombosis (CVST), splanchnic vein thrombosis and arterial thrombosis, in combination with
thrombocytopenia. Venous thrombosis cases have also been reported at more common sites, eg,
in the lower extremities. The onset of associated symptoms has usually been 1 to 4 weeks, but
sometimes even later following vaccination  (up to 42 days as per the American Society of
Hematology 20212). TTS cases have been reported mostly in women under 60 years of age
although some cases of TTS have also been reported in men and in individuals older than 60 years
of age. Thrombosis in combination with thrombocytopenia has been fatal in some cases. The exact
pathophysiology of TTS is unclear. This event has not been observed to date with any other
Janssen Ad26-based vaccines (including with Ad26.Mos4.HIV). Participants should be instructed
to seek immediate medical attention if they develop symptoms such as shortness of breath, chest
pain, leg pain or leg swelling, persistent abdominal pain, severe or persistent headaches, blurred
vision, skin bruising or petechiae beyond the site of vaccination, changes in mental status or the
occurrence of seizures.
Knowledge about TTS continues to evolve, and updates will be made as new data become
available.
1.2. 
Benefit/Risk Section
1.2.1. 
Known Benefits
The clinical benefits of combinations of Ad26.Mos4.HIV and Clade C/Mosaic gp140 have yet to
be established.
1.2.2. 
Potential Benefits
Participants may benefit from clinical testing, physical examination and high standard sexual
health services; others may benefit from the knowledge that they may aid in the development of
an HIV-1 vaccine. Currently, there are no effective prophylactic HIV vaccines and no efficacy can
be concluded from current data. The overall benefit and risk balance for individual participants
thus cannot be ascertained. Participants must be informed that this vaccine is currently being tested
a 
Probable TTS is defined as a thrombotic/thromboembolic event reported in combination with a low platelet count
(thrombocytopenia).
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to determine whether it is effective, and it should be assumed that it is not the case until clinical
study data demonstrate its effectiveness.
1.2.3. 
Known Risks
Adverse drug reactions and/or adverse reactions to immunization have not yet been fully
characterized. As of 8 January 2019, 2200 healthy adult participants have been enrolled in ongoing
Ad26.Mos.HIV and Ad26.Mos4.HIV studies, of which 236 participants, for whom the treatment
assignment is known, received at least one vaccination with Ad26.Mos4.HIV. At that cut-off date,
2250 healthy adult participants have been enrolled in ongoing Clade C gp140 and Clade C gp140
in combination with Mosaic gp140 studies, of which 93 participants, for whom the treatment
assignment is known, received 250 mcg glycoprotein Clade C gp140 + Mosaic gp140. The
available nonclinical and clinical data for the study vaccines support the conclusion that the
vaccines have an acceptable safety profile with no emerging significant safety concerns to date.
As with any experimental product, the safety profile of the vaccines or of the vaccine regimen
cannot be fully defined until more clinical data are available.
1.2.4. 
Potential Risks
The following potential risks for Ad26.Mos4.HIV and Clade C/Mosaic gp140 will be monitored
during the study and are specified in the protocol and/or the Study-Specific Procedures Binder:
Risks Related to Vaccination
In general, IM injection may cause local itching, warmth, pain, tenderness, erythema/redness,
induration/swelling, arm discomfort or bruising of the skin at vaccine administration sites.
Participants may exhibit general signs and symptoms associated with administration of a vaccine,
or injection with placebo, including fever, chills, rash, myalgia, nausea/vomiting, headache,
dizziness, arthralgia, general itching, and fatigue. These side effects will be monitored but are
generally short-term and do not require treatment.
Syncope can occur in association with administration of injectable vaccines. Syncope can be
accompanied by falls. Procedures should be in place to avoid falling injury. If syncope develops,
participants should be observed until the symptoms resolve. Fear of injection might lead to fainting
and fast breathing.
Participants may have an allergic reaction to the vaccination. An allergic reaction may cause a
rash, urticaria or even anaphylaxis. Severe reactions are rare. Participants with a known allergy, or
history of anaphylaxis or other serious adverse reactions to vaccines or vaccine products (including
any of the constituents of the study vaccine) will be excluded from the study.
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 hydroxide, aluminum phosphate, and aluminum potassium
sulphate have been used safely in vaccines for more than 70 years. A few studies reported an
association between vaccines containing aluminum  adjuvants and persistent nodules at the
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injection  site, at an estimated rate of 0.03% to 0.83%.39,40,41,42 Two studies examining infant
exposures to aluminum from both diet and vaccines concluded that aluminum adjuvants at the
levels included in vaccines are well below the calculated body burden.43,44 A 2017 review found
that current data do not support a causal relationship between aluminum-containing vaccines and
a variety of autoimmune disorders.45
Risks Related to Vaccine-induced Seropositivity
Risks related to vaccine-induced seropositivity (VISP) are discussed in Section 9.2.
Pregnancy and Contraception
No preclinical developmental or reprotoxicity  studies have yet been performed with
Ad26.Mos.HIV, Ad26.Mos4.HIV, Clade C gp140 or Mosaic gp140. However, a combined
embryo-fetal and pre- and postnatal development study has been conducted in rabbits with an
Ad26 vector in combination with another insert(Ad26ZEBOV, as part of a 2-dose vaccine regimen
with MVA-BN-Filo). In this study, there was no maternal or developmental toxicity observed
during premating and gestation period.
The sponsor is planning to conduct a combined embryo-fetal and pre- and postnatal development
study including Ad26.Mos4.HIV and a combination of aluminum phosphate-adjuvanted Clade C
gp140 and Mosaic gp140 in parallel with the Phase 3 HPX3002 study.
Since the effect of the study vaccines on a fetus or nursing baby is unknown, participants of
childbearing potential are required to agree to practice adequate contraception measures for sexual
intercourse from at least 21 days before the first vaccination until at least 90 days after the last
vaccination (see Section 4.1).
Risks from Blood Draws
As with all clinical studies requiring blood sampling, there are risks associated with venipuncture
and multiple blood sample collection. Blood drawing may cause pain, tenderness, bruising,
bleeding, dizziness, vaso-vagal response, syncope, and, rarely, infection at the site where the blood
is taken. The total blood volume to be collected is considered to be an acceptable amount of blood
over this time period from the population in this study (see Section 16.1).
Risks of genetic testing
The genetic testing could indicate risks for certain diseases, which could potentially lead to
discrimination of or other problems for the participant. However, the results are for exploratory
research purposes only and will not be provided to the participant.
Unknown Risks
There may be other risks that are not known. If any significant new risks are identified, the
investigators and participants will be informed.
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Participants may believe that this vaccine provides protection against acquiring HIV infection, and
therefore practice riskier sexual activity. Participants must be informed that this vaccine is
currently being tested to determine whether it is efficacious, and it should be assumed that it is not
the case until clinical study data demonstrate efficacy. The overall benefit and risk balance for
individual participants thus cannot be ascertained.
In previous HIV-efficacy studies utilizing Ad5, increased HIV-1 infection was observed in vaccine
recipients as compared with placebo recipients. The mechanism for this possible increase in HIV-1
acquisition risk remains unclear, but a longstanding hypothesis suggested that activation of vector-
specific CD4+ T cells at mucosal surfaces following Ad5 vaccination potentially results in
increased targets for HIV-1 infection. However, a recent study demonstrated no long-term changes
in the activation state of mucosal CD4+ or CD8+ T cells after Ad5-vectored vaccination, regardless
of baseline Ad5 serostatus.10 Ad26 is substantially different from Ad5 in seroprevalence and
immunology, biology, and protective efficacy in NHP.
1.2.5. 
Overall Benefit/Risk Assessment
Based on the available data and proposed safety measures, the overall benefit/risk assessment for
this clinical study is considered acceptable for the following reasons:
 Safety data from the ongoing clinical studies revealed no significant safety issues (see
Section 1.1.2).
 
Only participants who meet all inclusion criteria and none of the exclusion criteria (specified
in Section 4) will be allowed to participate in this study. The selection criteria include adequate
provisions to minimize the risk and protect the well-being of participants in the study.
 
Safety will be closely monitored throughout the study:
 
In general, safety evaluations will be performed at scheduled visits during the study, as
indicated in the Time and Events Schedule.
 
After each vaccination, participants will remain in the clinic for a certain period and will
be closely observed by study staff. Necessary emergency equipment and medications
must be available in the clinic to treat severe allergic reactions. Participants will use a
diary to document solicited administration site and systemic signs and symptoms. Details
are provided in Section 9.1.1.
 
The investigator or the designee will document unsolicited adverse events, SAEs,
MAAEs and (potential) adverse events of special interest (AESIs) as indicated in
Section 12.3.1.
 
Any clinically significant abnormalities (including those persisting at the end of the
study/early withdrawal) will be followed by the investigator until resolution or until a
clinically stable endpoint is reached.
 
Several safety measures are included in this protocol to minimize the potential risk to
participants, including the following:
 
The NIAID HIV Vaccine DSMB (further referred to as DSMB) will serve as an
independent DSMB for this study and will monitor data on an ongoing basis to ensure the
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continuing safety of the participants and will formally monitor the efficacy endpoints (see
Section 11.4). The sponsor’s HPX3002/HVTN 706 safety review  team may initiate
DSMB review for any single event or combination of multiple events which, in their
professional opinion, could jeopardize the safety of the participants or the reliability of
the data.
 
Participants will discontinue study vaccine for the reasons included in Section 10.2.
 
Contraindications to vaccination are included in Section 10.3.
 
If acute illness (excluding minor illnesses such as diarrhea or mild upper-respiratory tract
infection) or fever (body temperature ≥38.0°C) occur at the scheduled time for
vaccination, vaccination will be temporarily contraindicated. However, the participant
may be vaccinated later, within the window allowed for the scheduled vaccination (see
Section 10.3).
1.3. 
Overall Rationale for the Study
The proposed Phase 3 clinical study VAC89220HPX3002/HVTN 706 (hereafter referred to as
HPX3002/HVTN 706) will aim to demonstrate the efficacy of a heterologous HIV-1 vaccine
regimen consisting of Ad26.Mos4.HIV and a combination of aluminum phosphate-adjuvanted
Clade C gp140 and Mosaic gp140.
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2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1. 
Objectives and Endpoints
An overview of the objectives and endpoints is provided in Table 1.
Table 1: 
Objectives and Endpoints
Objectives 
Endpoints
Primary
1 
To evaluate the VE of a heterologous vaccine 
regimen utilizing Ad26.Mos4.HIV and 
aluminum phosphate-adjuvanted Clade C gp140 
and Mosaic gp140 for the prevention of HIV-1
infection in HIV-1 seronegative cis-gender men
and transgender individuals having sex with cis-
gender men and/or transgender individuals.
1 
Confirmed HIV-1 infections diagnosed between
Month 7 and Month x (with 24≤x≤30) visits in the
PP population.
Secondary
1 
To evaluate the safety and reactogenicity of a 
heterologous vaccine regimen utilizing 
Ad26.Mos4.HIV and aluminum phosphate- 
adjuvanted Clade C gp140 and Mosaic gp140 for
the prevention of HIV-1 infection in HIV-1
seronegative cis-gender men and transgender
individuals having sex with cis-gender men 
and/or transgender individuals.
1 
 Reactogenicity: Solicited administration site
and systemic adverse events for 7 days after
each vaccination
 Unsolicited adverse events for 28 days after
each vaccination
 AESIs for 6 months after the last vaccination
 MAAEs for the entire duration of the study
 Serious adverse events for the entire duration
of the study
 Discontinuations from the study or vaccination
due to adverse events
2 
To evaluate VE at other timepoints and in other 
analysis populations. 
2 
Confirmed HIV-1 infections over different time
intervals (eg, VE[0-x months], VE[13-x months])
and in different populations (eg, mITT, mITT-2,
mITT-3, FIS).
3 
To evaluate VE by and adjusting for potential 
(baseline) confounders. 
3 
Potential confounders include but are not limited
to: demographic characteristics, baseline Ad26
seropositivity status and titer, sexual risk
behavior, and PrEP use.
Exploratory
1 
To evaluate whether VE differs by phenotypic
characteristics of HIV, such as neutralization
sensitivity, and whether there is evidence of
vaccine-induced immune pressure on the viral
phenotype.
1 
Confirmed HIV-1 infection diagnosed after Day 1
through Month 30 and inferred transmitted viral
isolate(s) phenotype(s) from HIV-1–infected
mITT participants at the earliest available post-
infection timepoint, and possible subsequent
visits.
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2 
To evaluate whether VE differs by genotypic
characteristics of HIV, such as signature site
mutations, and whether there is evidence of
vaccine-induced immune pressure on the viral
sequences.
2 
Confirmed HIV-1 infection diagnosed after Day 1
through Month 30 and inferred transmitted viral
sequence(s) genotype(s) from HIV-1–infected
mITT participants at the earliest available post-
infection timepoint, and possible subsequent
visits, using sieve analysis methods.
3 
To evaluate vaccine effects on virologic and
immunologic outcomes among participants that
become HIV-1–infected during the study,
accounting for ARV use.
3 
HIV-1 viral load and CD4+ count over a 6-month
period after diagnosis.
The frequency and magnitude of HIV-1 cellular
(participants at sites with access to sponsor
approved PBMC processing facilities) and
humoral immune responses in participants that
become HIV-1–infected during the study.
4 
To evaluate immune correlate(s) of risk of HIV-1
infection and/or correlates of VE.
4 
Magnitude and/or frequency of immune responses
to vaccination in HIV-1 infected vaccine
recipients (cases) relative to a subset of HIV-1
uninfected vaccine recipients (controls) and
placebo cases and controls, as relevant.
The association of immune response(s) that are
identified as being associated with VE in Study
VAC89220HPX2008/HVTN 705 (further referred
to as HPX2008/HVTN 705), in HIV-1 infected
vaccine recipients (cases) relative to a subset of
HIV-1 uninfected vaccine recipients (controls)
and placebo cases and controls, as relevant.
5 
To evaluate the occurrence of VISP following 
vaccination with heterologous vaccine regimen 
utilizing Ad26.Mos4.HIV and aluminum 
phosphate-adjuvanted Clade C gp140 and 
Mosaic gp140. 
5 
The frequency of confirmed VISP, determined
utilizing a pre-specified diagnostic algorithm to
distinguish HIV- 1 infection from VISP (refer to
the Study-Specific Procedures Binder for more
information) at different time points following
vaccination.
6 
To describe PROs. 
6 
Social impact and vaccine regimen acceptance,
sexual activity, absenteeism and PrEP use
collected through questionnaires completed by
study participants.
7 
To describe HCRU over the study period. 
7 
Collection of MAAEs, level of absenteeism and
follow-up of HIV infections throughout the study.
8 
To evaluate the immune responses elicited by the 
vaccine regimen. 
8 
The frequency and magnitude of HIV-1-specific
cellular and humoral immune responses.
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2. 
Hypothesis
This study is designed to test the primary hypothesis of VE in the PP population:
H0: VE(7-x months) ≤20% versus H1: VE(7-x months) >20%, with 24≤x≤30.
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If the lower bound of the 95% CI for VE(7-x months) is >20% at the primary analysis, the
corresponding H0 will be rejected.
3. 
STUDY DESIGN AND RATIONALE
3.1. 
Overview of Study Design
This is a multi-center, randomized, parallel-group, placebo-controlled, double-blind, Phase 3 study
to demonstrate efficacy of a heterologous prophylactic HIV-1 vaccine regimen consisting of
Ad26.Mos4.HIV and a combination of aluminum phosphate-adjuvanted Clade C gp140 and
Mosaic gp140. Safety, reactogenicity and immunogenicity will also be evaluated. The study
population will include healthy adults considered to be at increased risk of acquiring HIV-1
infection. A target of 3,800 participants, consisting of HIV-1-uninfected cis-gender men and
transgender individuals having sex with cis-gender men and/or transgender individuals, aged ≥18
to ≤60 years, will be randomized in a 1:1 ratio to the study vaccine or placebo. Randomization will
be stratified by site. All efforts will be made to ensure that the study population includes good
representation of the population at the highest risk of HIV infection in terms of race, ethnicity,
gender identity and age. Participants will receive IM doses of study vaccine or placebo at 4 time
points: Ad26.Mos4.HIV or placebo will be given at Months 0 (Day 1) and 3; Ad26.Mos4.HIV
together with a co-formulation of aluminum phosphate-adjuvanted Clade C gp140 and
Mosaic gp140, or placebo will be given at Months 6 and 12 (see Table 2). Sample size
re-assessment may be performed based on blinded study data or external study data (eg, Phase 2b
Study HPX2008/HVTN 705). The target number of HIV-1 infections may be re-assessed based on
external study data (eg, Phase 2b Study HPX2008/HVTN 705) only.
Table 2: 
Vaccination Schedule
Group  
N 
Month 0 
Month 3 
Month 6 
Month 12
1 
1,900 Ad26.Mos4.HIV  Ad26.Mos4.HIV
Ad26.Mos4.HIV  
+ 
Clade C gp140, Mosaic 
gp140, adjuvanted 
Ad26.Mos4.HIV
+
Clade C gp140, Mosaic
gp140, adjuvanted
2 
1,900 
Placebo 
Placebo 
Placebo 
+ 
Placebo 
Placebo
+
Placebo
Total dose of Ad26.Mos4.HIV is 5x1010 viral particles (vp)/0.5 mL injection.
Clade C gp140, Mosaic gp140, adjuvanted: adjuvanted protein formulation with a dosage strength of 80 mcg
Clade C protein, 75 mcg Mosaic protein and 425 mcg aluminum (as aluminum phosphate adjuvant). Note:
previously the dose of Clade C gp140 and/or Mosaic gp140 was reported as mcg of glycoprotein: 125 mcg Clade
C gp140 and 125 mcg Mosaic gp140 glycoprotein correspond with 80 mcg and 75 mcg of protein, respectively.
The study comprises of a screening period of 45 days, a 12-month vaccination period and a
follow-up period of at least 18 months after the fourth vaccination (until Month 30) in participants
who remain HIV-1 negative or up to 6 months after diagnosis of HIV-1 infection in participants
who become HIV-1 infected. Participants who completed their Month 30 visit will be followed for
HIV infection, MAAEs and serious adverse events until the end of the study (ie, when the last
participant completed the Month 30 visit or discontinued earlier). At the end of the study,
participants may be offered the possibility to enter a long-term follow-up phase or program (to
collect, amongst others, additional durability data).
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After vaccination, participants will remain under observation at the study site for at least
30 minutes for presence of any acute reactions. In addition, participants will record solicited signs
and symptoms in a diary for 7 days post-vaccination. Unsolicited adverse events will be recorded
for all participants until 28 days after each preceding vaccination. From the time of local approval
of protocol amendment 5 onwards, TTS is considered to be an AESI. Thrombotic events and/or
thrombocytopenia (defined as platelet count below the lower limit of normal (LLN) range for the
testing lab) are considered to be potential AESIs. All AESIs, including potential AESIs, will be
reported to the sponsor from the moment of first vaccination until 6 months after the last
vaccination. Each potential AESI will be reviewed to identify a TTS case. Serious adverse events,
MAAEs, and adverse events leading to discontinuation will be collected for all participants until
the end of the study. For details on reporting period of unsolicited adverse events, MAAEs, and
serious adverse events, see Section 9.4. In addition, physical examinations, which includes vital
sign measurements, and pregnancy testing will be performed.
An HIV test will be performed approximately every 3 months. Upon discretion of the investigator,
additional HIV tests may be performed during unscheduled visits; participants should refrain from
performing any HIV testing outside of the study protocol. Blood samples will be collected at
specific visits for determination of humoral immune responses (all participants) and for
determination of cellular immune responses (at selected sites). Participants will complete PRO
questionnaires, including a social impact questionnaire, a sexual activity questionnaire and a
questionnaire on the use of PrEP and questions with regard to the level of absenteeism and the
vaccine regimen acceptance. For details, see the Time and Events Schedule.
If a participant becomes HIV-infected during the study (confirmed HIV test), the participant will
remain in the study but no further scheduled vaccinations will be administered. Participants will
be followed-up until up to 6 months after the diagnosis and will be referred to a local clinic for
medical treatment and follow-up on their HIV-1 infection as soon as possible after the diagnosis
of the infection. Assessments during the 6-month study follow-up will be performed according to
the Time and Events Schedule for Participants Who Become HIV-1 Infected.
The sponsor and its partners are committed to ensuring that all study participants receive access to
the highest standard of prevention, which may include, but is not limited to, HIV testing, risk
reduction counseling, provision of male condoms and lubricants, access to management of STIs,
and appropriate referrals for PrEP and PEP according to national and/or local guidelines. Note:
potential participants choosing to use PrEP will not be eligible for participation in the study as,
due to the high effectiveness of PrEP, these individuals are not considered to be at increased risk
of HIV acquisition. However, once enrolled in the study and having received their first vaccination,
a participant who changes his/her mind regarding PrEP use is permitted to take PrEP according to
the site PrEP plan and will continue to receive further vaccinations. In case of PrEP use during the
study, safety monitoring for PrEP will be the responsibility of the prescribing physician. HIV
testing should be performed within the study to avoid unblinding due to VISP elicited by the
vaccine. Participants should refrain from HIV testing outside of the study protocol. As part of the
study protocol, blood samples will be collected for ARV detection in dried blood spot and stored
at pre-specified sample collection days for assessment of quantitative concentrations of tenofovir
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diphosphate. Additional ARV detection can be done on stored blood samples if required, as per
the Study Specific Procedures Binder. The use ofPrEP and adherence to PrEP (if applicable) will
be monitored by means of a questionnaire which will be completed by all participants on Day 1
and approximately every 3 months.
An independent DSMB will monitor data on an ongoing basis to ensure the continuing safety of
the participants and will formally monitor the efficacy endpoints (see Section 11.4). The DSMB
responsibilities, authorities, and procedures will be documented in its charter.
The COVID-19 Appendix in Section 18 provides guidance to investigators for managing study-
related procedures during the COVID-19 pandemic.
3.2. 
Study Design Rationale
Vaccines and Dose Selection Rationale
The sponsor and its partners has evaluated and are evaluating different candidate HIV-1 vaccine
components in different clinical studies, results of which formed the basis of the vaccine regimen
selection for the the Phase 3 study HPX3002/HVTN 706.
Based on immunologic responses observed in the Phase 1/2a study HIV-V-A004, a regimen of
vaccination with the Ad26.Mos.HIV vaccine at Months 0 (Day 1) and 3 and vaccination with the
Ad26.Mos.HIV vaccine and aluminum phosphate-adjuvanted Clade C gp140 at Months 6 and 12
has been selected over other regimens. The pre-clinical NHP study NHP 13-19/15-06 (in which
the vaccination regimens reflect to a large extent the regimens in the HIV-V-A004 clinical study)
indicated that this vaccination regimen showed the highest per exposure risk reduction (94%),
which was associated with 67% complete protection after a series of 6 weekly intrarectal SHIV
challenges.4
Based on the magnitude of immunologic responses observed in the Phase 1 study HIV-V-A003
and in the Phase 1/2a study HIV-V-A004, a 250-mcg glycoprotein dose of aluminum
phosphate-adjuvanted Clade C gp140 has been selected over a 50-mcg glycoprotein dose.
Based on interim (Month 7 [Week 28; 4 weeks post 3rd vaccination], approximately
60 participants) results of the Phase 1/2a study HPX2004/HVTN 117 showing better
immunogenicity for Clade C and other clades, the tetravalent Ad26.Mos4.HIV was selected for
evaluation in the Phase 2b proof-of-efficacy study HPX2008/HVTN 705. Consequently, a
heterologous regimen with the tetravalent Ad26.Mos4.HIV and a 250-mcg dose of aluminum
phosphate-adjuvanted Clade C gp140 is being evaluated in the ongoing Phase 2b study
HPX2008/HVTN 705. This study is being performed in female participants in sub-Saharan Africa
where circulating viruses are predominantly of subtype (Clade) C. The primary analysis results of
HPX2004/HVTN 117, including Month 7 data of all participants confirm the choice of the tetra-
over the trivalent Ad26 vaccine.21,22 Therefore, the Ad26.Mos4.HIV will be used for the proposed
Phase 3 efficacy study HPX3002/HVTN 706.
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Based on the primary analysis of HPX2003/HVTN 118 and HPX2004/HVTN 117, the
combination of aluminum phosphate-adjuvanted Clade C gp140 and Mosaic gp140 was selected
for inclusion in the 3rd and 4th vaccinations over the Clade C gp140 alone. In line with the bivalent
nature of the Env and Gag-Pol encoding Ad26 vectors, a bivalent mixture of gp140 proteins, which
have complementary sequences, is anticipated to provide better coverage of the circulating strains
of HIV-1 globally, than either component alone. The favorable safety profile of Clade C gp140
was maintained by replacing half of the Clade C gp140 dose with Mosaic gp140, while maintaining
the same total glycoprotein dose of 250 mcg (corresponding to a total protein dose of 155 mcg).
Peak immune responses post 3rd vaccination were highly comparable between the 2 regimens and
similar levels of Clade C-specific humoral and cellular responses were observed, demonstrating
that a region-specific vaccine is not needed. The immune responses induced by the combination
of Clade C gp140 and Mosaic gp140 show broad Env-specific binding and functional humoral
responses, as well as high frequencies of Env-specific T cell responses and improved Clade B Env
binding antibody responses without compromising Clade C Env binding antibody responses. In
addition, a combination  of Clade C and Mosaic gp140 is preferred due to the efficient
manufacturability of Mosaic gp140, which results in higher yields compared to Clade C gp140,
thereby contributing to a continuous vaccine supply.
This last step of the final regimen selection was based on the Month 7 (Week 28; 4 weeks post 3rd
vaccination) results of HPX2003/HVTN 118. The Month 13 (Week 52; 4 weeks post 4th
vaccination) analysis results of HPX2003/HVTN 118 strengthened the original choice of the
combination of aluminum phosphate-adjuvanted Clade C gp140 and Mosaic gp140 over the
Clade C gp140 alone.
Blinding, Control, Study Phase/Periods, Treatment Groups
A placebo control will be used to establish the frequency in clinical endpoints that may occur in
the absence of active vaccine. Randomization will be used to minimize bias in the assignment of
participants to treatment groups, to increase the likelihood that known and unknown participant
attributes (eg, demographic and baseline characteristics) are evenly balanced across treatment
groups, and to enhance the validity of statistical comparisons across treatment groups. In addition,
randomization will be stratified by site. Blinded vaccination will be used to reduce potential bias
during data collection and evaluation of clinical endpoints.
The independent DSMB will monitor data on a 6-monthly basis to ensure the continuing safety of
the participants enrolled in this study. The independent DSMB will review unblinded data.
4. 
PARTICIPANT POPULATION
Screening for eligible participants will be performed within 45 days before administration of the
first study vaccination.
The inclusion and exclusion criteria for enrolling participants 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 HPX3002/HVTN 706 safety review team
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representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
4.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. Each potential participant must pass the TOU (see Attachment 2), indicating understanding of
the purpose, procedures and potential risks and benefits of the study, after reading the ICF and
after the investigator or designee has provided detailed information on the study and has
answered the potential participant’s questions. Each participant must subsequently sign the
ICF, indicating the willingness to participate in the study.
2. Potential participant is ≥18 to ≤60 years old on the day of signing the ICF.
3. Criterion modified per Amendment 1
3.1 Criterion modified per Amendment 3
3.2 Individual is either:
 Cis-gender man having sex with cis-gender men and/or transgender individuals, OR
 Transgender woman having sex with cis-gender men and/or transgender individuals,
OR
 Transgender man having sex with cis-gender men and/or transgender women
(transgender man having sex exclusively with transgender men is excluded), OR
 Gender non-conforming individual having receptive or insertive anal and/or vaginal
condomless intercourse,
AND who is considered by the site staff to be at increased risk for HIV-1 infection. The
potential participants must in the last 6 months have had:
 Any condomless receptive anal or vaginal sex  (not included is condomless anal sex
within a mutually monogamous relationship ≥12 months if the partner is HIV negative
or living with HIV and virally suppressed), OR
 Rectal or urethral gonorrhea or chlamydia or incident syphilis, OR
 Any stimulant use or any other drug and/or substance which in the local context may
be associated with increased HIV transmission (eg, cocaine, amphetamine), OR
 5 or more sex partners
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Refer to the Study-Specific Procedures Binder for further guidance and screening tool on
the sexual risk evaluation.
4. Criterion modified per Amendment 1
4.1 Criterion modified per Amendment 3
4.2 Criterion modified per Amendment 4
4.3 Potential participant has a negative test result for HIV-1 and HIV-2 infection ≤28 days
prior to first vaccination.
5. Potential participant must be healthy based on medical history, physical examination, and vital
sign measurement performed at screening.
6. Potential participant is willing/able to adhere to the prohibitions and restrictions specified in
the protocol and study procedures.
7. Criterion modified per Amendment 1
7.1 Criterion modified per Amendment 3
7.2 Contraceptive use by participants assigned female at birth and who have not had sexual
reassignment surgery should be consistent with local regulations regarding the acceptable
methods of contraception for those participating in clinical studies.
Before randomization, participants who were assigned female at birth must be either (as
defined in Attachment 1):
a. Not of childbearing potential
b. Of childbearing potential and practicing an acceptable highly effective method of
contraception when engaging in receptive vaginal sexual intercourse and agrees to
remain on such a method of contraception from 21 days prior to the first vaccination
until 90 days after the last dose of study vaccine. Acceptable highly effective
contraceptive methods based on the Clinical Trial Facilitation Group guidance are
included in Attachment 1:
8. Criterion modified per Amendment 1
8.1 Criterion modified per Amendment 3
8.2 All participants of childbearing potential (as defined in Attachment 1) must:
a. Have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test at
screening
b. Have a negative urine β-hCG pregnancy test immediately prior to each study vaccine
administration
9. Criterion was deleted per Amendment 1
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
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4.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. Criterion modified Amendment 1
1.1 Potential participant shares needles during injection of drugs or any other substance.
2. Criterion modified Amendment 1
2.1 Potential participant has any clinically significant acute or chronic medical condition that
in the opinion of the investigator would preclude participation (including, but not limited
to: history of seizure disorders, bleeding/clotting disorder, autoimmune disease, active
malignancy, poorly controlled asthma, active tuberculosis or other systemic infections). In
case of questions, the investigator should contact the HPX3002/HVTN 706 safety review
team. An isolated seizure with clear etiology or febrile seizures during childhood are not
exclusionary.
3. Criterion modified Amendment 1
3.1 Criterion modified per Amendment 3
3.2 Criterion modified per Amendment 5
3.3 Potential participant has had surgery requiring hospitalization (defined as inpatient stay for
longer than 24 hours or overnight stay) within the 4 weeks before screening, or will not
have fully recovered from surgery requiring hospitalization, or has surgery (planned before
enrollment) requiring hospitalization planned 28 days before or after planned
administration of the first or subsequent study vaccination(s) that would interfere with
protocol assessments (as per the investigator’s judgement and after HPX3002/HVTN 706
safety review team consultation).
4. Potential participant has had a psychiatric condition or alcohol or drug abuse problems
(including hospitalization or periods of work disability) that in the opinion of the investigator
would interfere with protocol compliance and thus would preclude participation.
5. Criterion modified per Amendment 4
5.1 Potential participant received or plans to receive:
a. licensed live attenuated vaccines - within 28 days before or after planned
administration of the first or subsequent study vaccination[s]. For details regarding
COVID-19 vaccines, see bullet c and d below.
b. other licensed (not live) vaccines - within 14 days before or after planned
administration of the first or subsequent study vaccination[s]. For details regarding
COVID-19 vaccines, see bullet c and d below.
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c. Recombinant viral vectored COVID-19 vaccines or live attenuated COVID-19
vaccines, either licensed or authorized for emergency use (eg, Emergency Use
Authorization [EUA], Emergency Use Listing [EUL] or similar program) within 28
days before or after planned administration of the first or subsequent study
vaccination[s].
d. Other COVID-19 vaccines than the ones specified in bullet c (eg, mRNA vaccines,
protein-based vaccines) either licensed or authorized for emergency use (eg, EUA,
EUL or similar program) within 14 days before or after planned administration of
the first or subsequent study vaccination[s]
6. Criterion modified per Amendment 1
6.1 Criterion modified per Amendment 3
6.2 Potential participants choosing to use PrEP.
Notes:
 Once participants are enrolled and received theirfirst vaccination, and they change their
mind regarding PrEP usage, they will be allowed to take PrEP according to the site
PrEP plan and will continue to receive further vaccinations.
 The use of long acting PrEP is disallowed from 24 months prior to Day 1.
7. Criterion modified per Amendment 1
7.1 Potential participant has used investigational research agents within 28 days of
randomization. For experimental vaccines, see exclusion criterion  8. For HIV-related
monoclonal antibodies (mAbs), see exclusion criterion 9.
8. Criterion modified per Amendment 1
8.1 Criterion modified per Amendment 4
8.2 Potential participant is a recipient of a HIV-vaccine candidate at any time, or a recipient of
other experimental vaccine(s) within the last 12 months prior to Day 1. For participants
who received an experimental vaccine (except HIV vaccine) more than 12 months prior to
Day 1, documentation of the identity of the experimental vaccine must be provided to the
HPX3002/HVTN 706 safety review team, who will determine eligibility on a case-by-case
basis.
Exceptions: Participants can be included if the vaccine received (except HIV vaccine) was
subsequently licensed or authorized for emergency use (eg, EUA, EUL, or similar program)
(see exclusion criterion 5). Participants with proof of having received only placebo can also
be included. Participants who are currently still in an interventional study of such a
licensed/emergency use-authorized vaccine are to be excluded from the current study (see
exclusion criterion 10).
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Status: Approved, Date: 28 February 2023
9. Criterion modified per Amendment 1
9.1 Potential participant has received an HIV-related mAb, whether licensed or investigational,
within the last 12 months prior to Day 1. For participants who received an HIV-related
mAb more than 12 months prior to Day 1, documentation of the identity of the mAb must
be provided to the HPX3002/HVTN 706 safety review team, who will determine eligibility
on a case-by-case basis.
10. Criterion modified Amendment 1
10.1 Potential participant 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 HPX3002/HVTN 706 safety review team.
11. Potential participant has been in receipt of blood or Ig products in the past 3 months.
12. Criterion modified per Amendment 1
12.1 Potential participant has known allergy or history of anaphylaxis or other serious adverse
reactions to vaccines.
Note: Potential participants should inform the doctor/staff of prior history ofany allergic
reaction to any injection or vaccine. If the answer is yes, more in-depth questioning will
be conducted in an attempt to ascertain the specific vaccine, type of vaccine, excipients
used in such a vaccine, etc
13. Potential participant has a history of any chronic/recurrent conditions that require
regular/recurrent 
use 
of 
oral/parenteral 
corticosteroids 
or 
other
immunomodulators/immunosuppressors. Ocular, topical or inhaled steroids are allowed.
14. Potential participant is an employee of the investigator or study site, with direct involvement
in the proposed study or other studies under the direction of that investigator or study site or
an employee of the sponsor or its partners.
15. Criterion modified per Amendment 2
15.1 Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study
or within 90 days after the last dose of study vaccination.
16. Criterion added per Amendment 5
16.1 History of TTS or heparin-induced thrombocytopenia and thrombosis (HITT)
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
If a participant's clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before the first dose of study vaccine is given such
that he or she no longer meets all eligibility criteria, then the participant should be excluded from
participation in the study. Section 9.1.3 describes options for retesting. Section 17.5, Source
Documentation, describes the required documentation to support meeting the enrollment criteria.
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
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Status: Approved, Date: 28 February 2023
4.3. 
Prohibitions and Restrictions
Potential participants must be willing and able to adhere to the following prohibitions and
restrictions during the course of the study to be eligible for participation:
1. 
Refer to Section 8 PRESTUDY AND CONCOMITANT THERAPY  for details
regarding prohibited and restricted therapy during the study.
2. 
Criterion modified per Amendment 1:
2.1. Participants in the study will not be able to donate blood, blood products, eggs (ova,
oocytes) or sperm during the time of the study due to the potential confusion with
VISP at blood banks or sperm banks. Furthermore, participants may be excluded
from donating blood, eggs or sperm  in the future upon disclosure of their
participation in a viral-vectored vaccine study and the potential of a positive HIV
screening test result due to VISP.
3. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (Section 4.1 and Section 4.2, respectively). For the
surgeries mentioned in exclusion criterion 3, it will be per investigator’s judgement
whether the surgery would interfere with protocol assessments during the study. The
safety review team will be available for consultation, where appropriate.
5. 
STUDY VACCINE ALLOCATION AND BLINDING
Study Vaccine Allocation
Procedures for Randomization and Stratification
Participants will be randomly assigned to 1 of 2 treatment groups in a 1:1 ratio based on a
computer-generated randomization schedule prepared before the study by or under the supervision
of the sponsor. The randomization will be balanced by using permuted blocks and will be stratified
by study site. Based on this randomization code, the study vaccine/placebo will be packaged and
labeled for each participant.
Central randomization will be implemented in this study. The interactive web response system
(IWRS) will assign a unique treatment code, which will dictate the treatment assignment and
matching study vaccine/placebo vial for the participant. The requestor must use his or her own
user identification and personal identification number when contacting the IWRS and will then
give the relevant participant details to uniquely identify the participant.
Blinding
The study participants, 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 the end of the study (see Section 10.1). The sponsor and its partners will be blinded to study
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 28 February 2023
vaccine allocation until the primary analysis when the last participant has reached their Month x
visit (with 24≤x≤30).
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. Administration of study vaccine to the participants will be performed by a blinded
qualified healthcare provider from the study site.
The investigator will not be provided with randomization codes during the study. The codes will
be maintained within the IWRS, which has the functionality to allow the investigator to break the
blind for an individual participant.
Data that may potentially unblind the 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.
Participants who discontinue vaccination early will be reminded that no HIV testing should be
performed outside the study protocol to avoid unblinding.
Under normal circumstances, the blind should not be broken by the investigator until the end of
the study and the electronic data capture (eDC) database is finalized unless it is essential for the
timely management of the participant. In this case, the investigator may determine the identity of
the treatment by contacting the IWRS. While the responsibility to break the code in emergency
situations resides solely with the investigator, it is recommended that the investigator contacts the
HPX3002/HVTN 706 safety review team if possible to discuss the particular situation, before
breaking the blind. Telephone contact with the sponsor or its partners will be available 24 hours
per day, 7 days per week. In the event the blind is broken, the sponsor and its partners 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
participant's source documents in a secure manner.
Participants who have had their treatment assignment unblinded due to safety reasons should
continue to return for safety and immunogenicity evaluations and efficacy (see Section 10.2), but
will be withdrawn from further study vaccine administration.
6. 
DOSAGE AND ADMINISTRATION
Participants will be vaccinated at the study site according to the schedule detailed in Section 3.1.
For description of the vaccinations, see Section 14.1.
Each participant will receive doses of study vaccine or placebo at four time points according to
randomization, on Month 0 (Day 1), 3, 6, and 12, administered by IM injection, preferably into the
deltoid muscle. In case an alternative site is needed, please refer to the Study Specific Procedures
Binder. For visits with only one injection (ie, at Month 0 [Day 1] and 3), preferably the deltoid of
the non-dominant upper arm is used. When 2 injections are to be given at one visit (ie, at Month 6
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 28 February 2023
and 12), it is required to use a different deltoid for each injection. Two injections in the same
deltoid are allowed only if medically indicated.
For information on vaccination windows, see Section 9.1.2. Every effort should be made to follow
the vaccination schedule per the protocol. Vaccinations should generally not be administered
outside the predefined visit window(see Section 9.1.2). If a participantcannot be vaccinated within
the predefined window, the HPX3002/HVTN 706 safety review team can determine on a case-by-
case basis if the participant can still be vaccinated. Note that cases of out of window vaccination
due to per protocol allowed COVID-19 vaccination (see Section 8) should be notified to the
sponsor and do not need safety review team approval. There should be a time interval of at least
28 days between study vaccinations.
Table 3: 
Description of Study Products
Test articles 
Ad26.Mos4.HIV  
Clade C gp140, Mosaic
gp140, aluminum phosphate
Placebo
Description  
See Section 14.
Dose/delivery 
(0.5 mL 
injection) 
5x1010 vp 
80 mcg Clade C protein*,
75 mcg Mosaic protein*,
adjuvanted with aluminum 
phosphate (425 mcg
aluminum)
0.9% saline
Frequency  
Month 0 (Day 1), 3, 6, and
12
Month 6 and 12 
Month 0 (Day 1) and 3
(1 injection), Month 6 and 12
(2 injections)
Route of
administration
IM in deltoid 
IM in deltoid 
IM in deltoid
Delivery
method
Refer to the Study-Specific Procedures Binder for details.
Gp: glycoprotein; HIV: human immunodeficiency virus; IM: intramuscular; vp: viral particle
* 
80 mcg Clade C gp140 and 75 mcg Mosaic gp140 of protein correspond with 125 mcg and 125 mcg
glycoprotein, respectively.
7. 
TREATMENT COMPLIANCE
Study vaccines will be administered as an IM injection by blinded qualified study-site personnel
at the study site. Details of each administration will be recorded in the CRF (including date and
time of injection and deltoid used for injection). For blinding procedures, see Section 5.
8. 
PRESTUDY AND CONCOMITANT THERAPY
The following prestudy specific therapies administered up to 1 month before the first vaccination
must be recorded at screening: analgesic/antipyretic medications and non-steroidal
anti-inflammatory drugs, systemic corticosteroids, antihistaminics, mAbs, or vaccinations. Any
COVID-19 vaccination must also be recorded at screening, regardless of how long before
screening the vaccination took place.
The following concomitant therapies must be recorded from the first dose of study vaccine to
1 month after the last study vaccination: analgesic/antipyretic medications and non-steroidal
anti-inflammatory drugs, hormonal therapy, hormone-based contraception, systemic
corticosteroids, antihistaminics, mAbs, or vaccinations. Exception: Any COVID-19 vaccination
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Status: Approved, Date: 28 February 2023
must be recorded until the end of the study. In addition, any HIV prevention medication should be
recorded. The use of PrEP, PEP, hormonal therapy and hormone-based contraception should be
recorded at each visit, except for the follow-up contact Visits 2a, 3a, 4a and 7a). All other
concomitant therapies should also be recorded if administered in conjunction with new or
worsening adverse events reported per protocol requirements outlined in Section 12.3.1. If a
participant becomes HIV-1 infected during the study, use of ARVs should also be recorded.
Use of any experimental medication (including experimental vaccines other than the study
vaccines) during the study is not allowed.
The use of long acting PrEP is disallowed from 24 months prior to Day 1 until after the first
vaccination.
Vaccination with licensed live attenuated vaccines (for details on COVID-19 vaccines, see below)
within 28 days before or after planned administration of the first or subsequent study vaccination(s)
is prohibited. Other licensed vaccines (eg, tetanus, hepatitis A, hepatitis B, rabies, for details on
COVID-19 vaccines, see below) should be given at least 14 days before or after administration of
first or subsequent study vaccination(s) in order to avoid potential confusion of adverse reactions
and potential immune interference. If a vaccine is indicated in a post-exposure setting (eg, rabies
or tetanus), it must take priority over the study vaccine.
Vaccination with COVID-19 vaccines that have been either licensed or authorized for emergency
use (eg, EUA, EUL, or similar program) must take priority over the study vaccine. The interval
between study vaccination and administration of a recombinant viral vectored COVID-19 vaccine
or a live attenuated COVID-19 vaccine should be at least 28 days. The interval between study
vaccination and administration of other types of COVID-19 vaccines (eg, mRNA vaccines,
protein-based vaccines) should be at least 14 days.
Treatment with HIV-related mAbs, whether licensed or investigational, during the study is
disallowed.
Chronic or recurrent use of immunomodulators/suppressors, eg, cancer chemotherapeutic agents
or systemic corticosteroids, is prohibited (after discussion with the HPX3002/HVTN 706 safety
review team) starting from 1 month before the planned administration of the first dose of study
vaccine until 1 month after the last vaccination. If participants require these medications, they will
be withdrawn from the study vaccine administration (See Section 10.2). Note: Ocular, topical or
inhaled steroids are allowed.
For participants who become HIV infected, all ARVs and all concomitant therapies administered
in conjunction with new or worsening adverse events reported per protocol requirements should
be reported.
The HPX3002/HVTN 706 safety review team must be notified in advance (or as soon as possible
thereafter) of any instances in which prohibited therapies are administered.
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
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9. 
STUDY EVALUATIONS
9.1. 
Study Procedures
9.1.1. 
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy (HIV testing;
refer to the Study-Specific Procedures Binder for more information) immunogenicity and safety
measurements applicable to this study.
Evaluation of the safety/tolerability of the vaccine regimens will include physical examinations by
clinical staff, vital signs assessments and signs and symptoms following vaccinations. Additional
unscheduled study visits may be required if in the investigator’s opinion, further clinical or
laboratory evaluation is needed.
Participants will be provided with a thermometer (to measure body temperature), ruler (to measure
local administration site reactions), and participant diary to record body temperature and solicited
administration site and systemic signs and symptoms.
The diary includes instructions on how to capture the data and grading scales to assess severity of
the signs and symptoms. The study staff is responsible for providing appropriate training to the
participant to avoid missing or incorrect data (refer to Study-Specific Procedures Binder). If a
participant misses a vaccination, the diary covering the period after the missed vaccination does
not have to be filled in.
Venous blood samples will be collected for humoral immunogenicity testing (all participants;
analyzed in a subset) and for cellular immunogenicity testing (participants at sites with access to
sponsor approved PBMC processing facilities; analyzed in a subset).
To determine VE, venous blood samples will be collected for HIV testing. HIV testing should be
performed per the sponsor-approved algorithm as described in the Study Specific Procedures
Binder.
9.1.2. 
Visit Windows
The maximum screening period is 45 days, except for HIV testing which needs to be performed
within 28 days prior to first vaccination.
The timings of the visits will be determined relative to the actual day of the first vaccination. For
the study visits, following windows will be allowed:
Visit 2a: 
(Day 9) 
± 7 days#
Visit 3: Month 3 (Day 84) ± 14 days
Visit 3a: 
(Day 92)* ± 7 days#
Visit 4: Month 6 (Day 168) -14/+28 days
Visit 4a: 
(Day 176)* ±7 days#
Visit 5: Month 7 (Day 196)* -14/+28 days
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 28 February 2023
Visit 6: Month 9 (Day 273) -14/+28 days
Visit 7: Month 12 (Day 364) -14/+42 days
Visit 7a: 
(Day 372)* ±7 days#
Visit 8: Month 13 (Day 394)* -14/+28 days
Visit 9: Month 15 (Day 455) -14/+28 days
Visit 10: Month 18 (Day 546) -14/+28 days
Visit 11: Month 21 (Day 637) -14/+28 days
Visit 12: Month 24 (Day 728) -14/+28 days
Visit 13: Month 27 (Day 819) -14/+28 days
Visit 14: Month 30 (Day 910) -14/+28 days
* 
If a participant is not vaccinated on the given day of vaccination, ie, Visit 3 (Day 84), Visit 4
(Day 168) and Visit 7 (Day 364), the timings of the study site Visits 5 and 8 and follow-up contact
Visits 3a, 4a and 7a, will be scheduled relative to the actual day of vaccination.
# 
The site staff and the participant will make multiple efforts in good faith to be in contact after
the last day of the reactogenicity period, or sooner if indicated, to discuss presence of any signs
and symptoms of reactogenicity. Participants who self-report any post-vaccination reaction greater
than mild are seen by a clinician within 48 hours after onset, unless the reaction is improving
and/or has resolved completely.
Every effort should be made to follow the vaccination schedule per the protocol. Vaccinations
should generally not be administered outside the prespecified window. If a participant cannot be
vaccinated within the predefined window, the HPX3002/HVTN 706 safety review team can
determine on a case-by-case basis if the participant can still be vaccinated. Note that cases of out
of window vaccination due to per protocol allowed COVID-19 vaccination (see Section 8) should
be notified to the sponsor and do not need safety review team approval. There should be a time
interval of at least 28 days between study vaccinations.
The allowed time window for the follow-up visits scheduled every 3 months post Month 30 is ±
28 days. Visits post Month 30 will be scheduled relative to the Month 30 visit.
For participants who become HIV-1 infected, the timings of the follow-up visits will be determined
relative to the date of diagnosis, which is the date of the initial positive HIV test result. Following
time windows will be allowed:
Visit #.X  
as soon as possible after the initial positive HIV test result.
This could be either a scheduled or unscheduled visit.
Visit Inf1: Month 3(Day 84) ± 28 days
Visit Inf2: Month 6(Day 168) ± 28 days
9.1.3. 
Screening Phase (Day -45 to Month 0)
Only healthy volunteers negative for HIV infection  and complying with the inclusion and
exclusion criteria specified in Section 4, Participant Population, will be included into the study.
The investigator or designee will provide detailed information on the study to the potential
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 28 February 2023
participants and will obtain written informed consent prior to each participant’s enrollment in the
study. All the procedures described in the Time and Events Schedule, except for the TOU, will
only take place after written informed consent has been obtained.
Screening may be conducted in part via a protocol team (cross-functional) and Institutional Review
Board (IRB)/Institutional Ethics Committee (IEC)-pre-approved non-study-specific screening
consent process, but only if the relevant pre-screening tests match the per protocol screening tests
and are within 45 days (28 days for HIV test) prior to first vaccination. However, no study-specific
procedures, other than screening assessments, will be performed until the potential participant has
signed the study-specific ICF. The study-specific ICF date will be entered into the CRF. The
non-study-specific ICF will be considered source data.
Each potential participant must pass the TOU (see Section 16.1 and Attachment 2), indicating that
he or she understands the purpose of, and procedures required for the study, after reading the
informed consent and after the investigator or designee has provided detailed information on the
study and has answered the potential participant’s questions. Each participant must subsequently
sign the ICF, indicating that he or she is willing to participate in the study.
The following evaluations will be performed to determine eligibility requirements as specified in
the inclusion and exclusion criteria:
 
Demographics (eg, sex assigned at birth, participant-identified gender at screening, age, male
circumcision, race) and Medical history (Note in addition to medical history to determine
eligibility requirements, history and family history of immune disorders will be recorded)
 
Full physical examination, including height, weight, vital signs, and clinical assessments of
head, ears, eyes, nose, and throat; neck; lymph nodes; heart; chest; abdomen; extremities;
neurological function; and skin
 
Review of prestudy medications as specified in Section 8
 
Counseling on avoidance of HIV infection
 
Review of inclusion/exclusion criteria
 
HIV testing (including pre- and post-HIV-test counseling). The screening HIV test should be
performed within 28 days prior to first vaccination
 
Participants of childbearing potential: serum -hCG pregnancy testing
General eligibility for this clinical study will be dependent on results of the medical assessment.
After medical history and physical examination data have been reviewed for completeness and
adherence to inclusion/exclusion criteria, the potential participant can be deemed to be eligible for
the study. Eligible participants will be contacted and scheduled for vaccination (Visit 2) within 45
days from signing ICF.
At screening, blood samples for syphilis serology determination will be collected and the presence
of chlamydia/gonorrhea will be tested using (1) a urine sample, (2) a rectal swab, and (3) an
oropharyngeal swab. If required by standard local procedure, the collection of a urethral swab will
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 28 February 2023
be considered equivalent to a urine sample. However, potential participants with STIs will not be
excluded from the study.
Potential participants with vital signs not meeting eligibility criteria on the screening visit may
have one repeat testing during the screening period if the abnormality is not clinically significant
and may be a testing aberrancy. The screening visit may be split into multiple days/visits.
All serious adverse events and adverse events and special reporting situations, that are related to
study procedures or that are related to non-investigational sponsor products will be recorded on
the CRF, from the time a signed and dated ICF is obtained until the end of the study/early
withdrawal, together with information about concomitant medications as specified in Section 8.
If a potential participant is a screen failure, but at some point in the future is expected to meet the
participant eligibility criteria, the potential participant may be rescreened on one occasion only.
Potential participants who are rescreened will be assigned a new participant number, undergo the
informed consent process, and then restart a new screening phase. In case a potential participant is
rescreened, there is no need to repeat the STI tests (syphilis, chlamydia and gonorrhea), unless the
STI test results were performed more than 3 months prior to the planned first vaccination or unless
clinically indicated. Previous STI test results can be used provided these are not older than 3
months. If the previous STI test was performed more than 3 months prior to the first vaccination
or if clinically indicated, the STI testing needs to be repeated.
9.1.4. 
Vaccination
Visit 2/Randomization/Vaccination 1
After re-check of inclusion/exclusion criteria (including concomitant medication), a targeted,
symptom-directed physical examination (including weight measurement and vital sign
measurement), and a urine pregnancy test (for participants of childbearing potential), eligible
participants 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, if applicable, will be repeated and the
Month 0 (Day 1) visit rescheduled, provided that the rescheduled visit is within 45 days of the
initial screening assessment.
Blood samples for HIV testing and humoral (pre-dose; all participants) and cellular (pre-dose; at
sites with access to sponsor approved PBMC processing facilities) immunogenicity assays will be
collected.
Participants will be provided with a thermometer, ruler, and participantdiary to measure and record
solicited signs and symptoms. Solicited adverse events will be recorded daily for 7 days post-
vaccination. Pre-and post-dose unsolicited adverse events will be recorded for 28 days post-
vaccination in all participants. AESIs will be recorded from first vaccination onwards until 6
months after the last vaccination. Serious adverse events, MAAEs and adverse events leading to
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
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vaccine or study discontinuation will be collected for all participants, together with information
about concomitant medications as specified in Section 8.
Study vaccine will be prepared by the unblinded site pharmacist, who will place an overlay on the
syringes (to preserve blinding) and will send it to the clinic. Administration of study vaccine to the
participant will be performed by a blinded qualified healthcare provider from the study site.
After each vaccination, participants will remain under observation at the study site for at least
30 minutes for presence of any acute reactions (see Section 9.4), and vital signs measurement will
be repeated.
A sexual activity questionnaire and a questionnaire on the use of PrEP  will be completed. In
addition, the level of absenteeism since screening will be collected.
Counseling related to avoidance of HIV infection will be provided to all participants.
Visit 3/Vaccination 2
Procedures for Visit 3 will include the following:
 A targeted physical examination as described for Visit 2
 Completion ofthe social impact questionnaire
 Collection level of absenteeism since Visit 2
 An HIV test (pre-dose)
 Recording of concomitant medication, adverse events, includingAESIs, serious adverse events
and MAAEs as described for Visit 2
 Distribution of diary
 HIV risk reduction counseling
 Completion of a questionnaire on the use of and, if applicable, adherence to PrEP
 Blood for dried blood spots will be collected for participants who have their visit on
pre-specified calendar days (may differ per site)
 A urine pregnancy test must be performed before vaccination for participants of childbearing
potential, and results must be available and negative prior to vaccination.
 Review of solicited signs and symptoms recorded in the diary will be completed and solicited
adverse events will be documented.
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 28 February 2023
Visit 4/Vaccination 3
Procedures for Visit 4 will include the following:
 A targeted physical examination as described for Visit 2
 Collection level of absenteeism since Visit 3
 An HIV test (pre-dose)
 Recording of concomitant medication, adverse events, includingAESIs, serious adverse events
and MAAEs as described for Visit 2
 Distribution of diary
 Syphilis serology and chlamydia/gonorrhea test as described for Visit 1
 HIV risk reduction counseling
 Completion of a questionnaire on the use of and, if applicable, adherence to PrEP
 Blood for dried blood spots will be collected for participants who have their visit on
pre-specified calendar days (may differ per site)
 A urine pregnancy test must be performed before vaccination for participants ofchildbearing
potential, and results must be available and negative prior to vaccination.
 Review of solicited signs and symptoms recorded in the diary will be completed and solicited
adverse events will be documented.
Visit 7/Vaccination 4
Procedures for Visit 7 will include the following:
 A targeted physical examination as described for Visit 2
 An HIV test (pre-dose)
 Recording of concomitant medication, adverse events, including AESIs, serious adverse events
and MAAEs as described for Visit 2
 Distribution of diary
 Syphilis serology and chlamydia/gonorrhea test as described for Visit1
 HIV risk reduction counseling
 Completion of the sexual activity questionnaire and social impact questionnaire
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 28 February 2023
 Collection level of absenteeism since their last visit
 Completion of a questionnaire on the use of and, if applicable, adherence to PrEP.
 Blood for dried blood spots will be collected for participants who have their visit on
pre-specified calendar days (may differ per site).
 A urine pregnancy test must be performed before vaccination for participants of childbearing
potential, and results must be available and negative prior to vaccination.
 Recording of gender identity
9.1.5. 
Post-vaccination Follow-up Phase
Participants who have been prematurely withdrawn from study vaccine administration will be
encouraged to complete the visit schedule as planned with assessments per the Time and Event
Schedule, including assessments of safety and HIV diagnosis. Participants who received the first
3 vaccinations but discontinue study vaccination before receiving the 4th vaccination, should
continue the visit schedule as planned with assessments per the Time and Event Schedule including
assessments of safety, immunogenicity and HIV diagnosis. They will also be reminded not to have
HIV testing outside of the study protocol as this could lead to misdiagnosis and unblinding.
Visits 2a, 3a, 4a and 7a
The site staff and the participant will make multiple efforts in good faith to be in contact after the
last day of the reactogenicity period, or sooner if indicated, to discuss the presence of any signs
and symptoms of reactogenicity. Clinic staff will follow new or unresolved reactogenicity
symptoms present at the last day of the reactogenicity assessment period to resolution. Participants
are instructed to contact the clinic for events that arise during the period between vaccination and
the next scheduled visit. In general, a participant who self-reports any postvaccination reaction
greater than mild is seen by a clinician within 48 hours after onset, unless the reaction is improving
and/or has resolved completely.
Visits 5 and 6/Post-Vaccination 3 Follow-up
Visit 5 is a clinic visit which will include a targeted, symptom-directed physical examination
(including weight measurement and vital signs measurement) and HIV testing. Unsolicited AEs
(if applicable), AESIs, SAEs, MAAEs and adverse events leading to study discontinuation will be
recorded for all participants, together with information about concomitant medications as
described in Section 8. Review of solicited signs and symptoms recorded in the diary will be
completed and solicited adverse events will be documented. Counseling related to avoidance of
HIV infection will be provided to all participants. A sexual activity questionnaire will be
completed. The level of absenteeism since their last visit will be recorded. Samples for humoral
(all participants) and cellular (at sites with access to sponsor approved PBMC processing facilities)
immunogenicity assays will be collected.
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 28 February 2023
Visit 6 is a clinic visit which will include a targeted physical examination, HIV testing, recording
of AESIs, serious adverse events, MAAEs and adverse events leading to study discontinuation,
recording of concomitant medication, and HIV risk reduction counseling as described above for
Visit 5. The level of absenteeism since their last visit will be recorded. Participants will complete
a questionnaire on the use of and, if applicable, adherence to PrEP and blood for dried blood spots
will be collected for participants who have their visit on pre-specified calendar days (may differ
per site).
Visits 8 to 14/Post-Vaccination 4 Follow-up
Visit 8 is a clinic visit which will include a targeted, symptom-directed physical examination
(including weight measurement) and vital signs measurement. Review of solicited signs and
symptoms recorded in the diary will be completed and solicited adverse events will be
documented. AESIs, serious adverse events, MAAEs and adverse events leading to study
discontinuation and concomitant medications (see Section 8) will be recorded for all participants.
Counseling related to avoidance of HIV infection will be provided to all participants. A sample for
HIV testing will be collected but will only be analyzed in case the test at Month 15 (Visit 9) is
positive and the test at Month 12 (Visit 7) is negative. Blood samples for humoral (all participants)
immunogenicity assays will be collected. A urine pregnancy test (participants of childbearing
potential) will be performed. The level of absenteeism since their last visit will be recorded. In
addition, participants will be questioned about the vaccine regimen acceptance (see Section 9.5).
Visit 9 to 14 are clinic visits that will include a targeted physical examination (full physical
examination at Visit 14), recording of serious adverse events, MAAEs and adverse events leading
to study discontinuation and HIV reduction counseling as described above for Visit 8. AESIs are
to be collected up to Visit 10 (6 months after the last vaccination). Samples for HIV testing will
be collected at each visit. The level of absenteeism since their last visit will be recorded. The use
of PrEP, PEP, hormonal therapy, hormone-based contraception, and all COVID-19 vaccinations
should be recorded at each visit. All other concomitant therapies should also be recorded if
administered in conjunction with new or worsening adverse events reported per protocol
requirements. Participants will complete a questionnaire on the use of and, if applicable adherence
to PrEP and blood for dried blood spots will be collected for participants who have their visit on
pre-specified calendar days (may differ per site).
In addition:
 If applicable, unsolicited AEs will be recorded at Visit 8
 A urine pregnancy test should be performed every 3 to 6 months
 Blood samples for syphilis serology determination will be collected and tests for
chlamydia/gonorrhea will be performed at Visit 10, 12 and 14.
 Blood samples for humoral (all participants) immunogenicity assays will be collected at Visit
10, 12 and 14.
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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 A sexual activity questionnaire will be completed at Visit 12.
 A social impact questionnaire will be completed at Visit 14.
 Gender identity will be recorded at Visit 12.
9.1.6. 
Post-M30 Follow-up Phase
Participants who complete their Month 30 visit will return to the site every 3 months for an HIV
test until the last participant has completed the Month 30 visit or discontinued earlier. Visits post
Month 30 will be scheduled relative to the Month 30 visit. At approximately Month 36 and from
then onwards approximately on an annual basis, gender identity should be recorded. Upon
discretion of the investigator, additional HIV tests may be performed during unscheduled visits;
participants should refrain from performing any HIV testing outside of the study protocol. Serious
adverse events, MAAEs and adverse events leading to study discontinuation will be recorded. The
use of PrEP, PEP, hormonal therapy, hormone-based contraception, all COVID-19 vaccinations,
and all other concomitant therapies administered in conjunction with new or worsening adverse
events reported per protocol requirements will be recorded. A urine pregnancy test is to be
performed every 3 to 6 months. The level of absenteeism since their last visit will be recorded.
Approximately every 6 months, blood samples for syphilis serology determination should be
collected and tests for chlamydia/gonorrhea should be performed.
9.1.7. 
Visits for Participants who Become HIV-1 Infected During the Study
If a participant has a positive HIV test during the study, the participants will have a visit (Visit
#.X, scheduled or unscheduled visit as soon as possible after the initial positive test) to perform a
confirmatory HIV test, viral load measurement, and CD4+ cell count (tested locally). In addition,
a blood sample for limited genetic testing will be collected. Counseling on HIV testing and
diagnosis and transmission reduction will be provided, and a targeted physical examination will
be performed. In addition, the level of absenteeism since their last visit will be recorded. Blood
samples for immunogenicity assays (humoral immune response from all participants and cellular
response from participants at sites with access to sponsor approved PBMC processing facilities)
and viral sequencing will be collected and may be analyzed when required. Solicited and
unsolicited adverse events will be recorded, if visit is within the 7 and 28 days post-vaccination
window, respectively. AESIs will be recorded until 6 months after last vaccination. Serious
adverse events, MAAEs and events leading to study discontinuation will be recorded for all
participants until the end of the study.
The study staff will receive a report confirming the HIV-1 diagnosis. Participants with a negative
HIV test may continue study vaccinations as planned. The participant with confirmed HIV-1 will
remain in the study but no further scheduled vaccinations will be administered. These participants
will be referred to a local clinic for medical treatment and follow-up on their HIV-1 infection as
soon as possible after the diagnosis of the infection and will have 2 additional follow-up visits
(Visit Inf1 and Visit Inf2 approximately at Month 3 and Month 6 after the initial positive HIV test
result, respectively). At these visits, procedures will be the same as for Visit #.X, except that no
HIV test will be performed, no blood sample for limited genetic testing will be collected,
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 28 February 2023
concomitant medication (all ARVs, all COVID-19 vaccinations, and all concomitant therapies
administered in conjunction with new or worsening adverse events reported per protocol
requirements should be reported.) will be recorded, at the Visit Inf2, a full physical examination,
including assessment of HIV/AIDS-related conditions will be performed and a social impact
questionnaire will be completed at Visits Inf1 and Inf2 . However, if, in the opinion of the
investigator/site staff, the completion of the social impact questionnaire can cause undue burden
to the participant, it can be omitted. Clear documentation on the rationale should be taken up in
the source document. A urine pregnancy test (participants of childbearing potential) will be
performed at each visit.
Once the last subject has completed the Month 30 visit of the Time and Events Schedule for HIV-1
Negative Participants or has discontinued earlier, the study is considered completed. HIV infected
participants still in the study at that time will be informed that they should return to the site for the
Visit #.X, if not completed yet, but no further site visits will be required.
9.1.8. 
Early Withdrawal/Exit Visit
In the event of early withdrawal from the study, an exit visit will be conducted as soon as possible.
The following procedures will be performed: a targeted symptom-directed physical examination
(including weight and vital signs measurement), recording of any adverse events (solicited and
unsolicited adverse events or AESIs, ifapplicable, and MAAEs and serious adverse events for all
participants), blood sampling for immunogenicity (humoral immune response), and HIV testing.
The use of PrEP, PEP, hormonal therapy, hormone-based contraception, and all COVID-19
vaccinations should be recorded. All other concomitant therapies should also be recorded if
administered in conjunction with new or worsening adverse events reported per protocol
requirements. A sexual activity questionnaire and social impact questionnaire will be completed.
In addition, the level of absenteeism since their last visit will be recorded. HIV risk reduction
counseling will be provided to all participants and participants will complete a questionnaire on
the use of and, if applicable, adherence to PrEP. A urine pregnancy test (participants of
childbearing potential) will be performed.
In the event of withdrawal from participants who become HIV-1 infected during the follow-up, an
exit visit will be conducted as soon as possible. Procedures will be similar as for Visit Inf1
specified in Section 9.1.7.
9.2. 
Efficacy Evaluations
An HIV test will be performed approximately every 3 months (see Time and Events schedule). To
avoid delays in initiation of combined antiretroviral treatment, local HIV PCR testing is allowed
only in case of suspected acute HIV infection, in case of recent HIV exposure, or in case a request
for sample redraw is received from the central HIV testing laboratory for confirmation of an HIV
positive test. Upon discretion of the investigator, additional HIV tests may be performed during
unscheduled visits; participants should refrain from performing any HIV testing outside of the
study protocol. Testing will be performed according to a sponsor-approved HIV-1-testing
algorithm that differentiates VISP  (see below) from true HIV-1 infection. An endpoint
adjudication process will be in place to assess all serological and virological testing, in a blinded
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 28 February 2023
manner, on each participant in the study who, prior to study unblinding, tests positive per the
sponsor-approved HIV testing.
If a participant has a confirmed positive HIV test during the study, the participant will remain in
the study but no further scheduled vaccinations will be administered. The study staff will receive
a report confirming the diagnosis. Confirmed HIV-1 infection should not be recorded as (serious)
adverse event. The participants will be provided counseling, will be referred for medical treatment
and, if applicable, will be informed about observational studies monitoring participants with HIV
infection. Further assessments, including HIV-1 viral load measurements, CD4+ T cell count, and
viral sequencing (samples taken in all participants and analyzed to assess whether VE differs by
genotypic characteristics of HIV and whether there is evidence of vaccine-induced immune
pressure on the viral genotype, depending on the vaccine efficacy outcome) will then be performed
according to the Time and Events Schedule for Participants Who Become HIV-1 Infected.
VISP
In general, HIV-uninfected participants in preventative HIV-vaccine studies may develop
HIV-specific antibodies as a result of an immune response to the candidate HIV-1 vaccine, referred
to as VISP (also known as VISR). 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.
In a preliminary analysis from study HIV-V-A004, using commercially available 4th  generation
ELISA test kits, VISP developed in a high percentage of the participants starting after the 1st
vaccination and increasing to >90% at all subsequent vaccination time points. The full duration of
VISP is not yet clear but VISP persisted to Week 96 (96%) and Week 120 (92%). The collection
of VISP data is continuing during the long-term extension of the HIV-V-A004 study and in specific
other Janssen-sponsored clinical studies to clarify the exact incidence of VISP and its duration.
Study participants have to be made aware of the risk of VISP. Study sites must ensure that study
participants understand the social risk of a positive test if it is conducted by an insurance company,
employer, government agency, blood bank, or other institution that is unaware of the
characteristics of the HIV vaccines or that the participant is or has been enrolled in an HIV-1
vaccine study.
The current study will utilize a diagnostic algorithm to distinguish HIV-1 infection from VISP.
More information is provided in the Study-Specific Procedures Binder. Should an HIV-Ab test
give a positive result for a particular participant 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 Study-Specific Procedures Binder.
To avoid possible unblinding as a result of positive HIV testing due to VISP, participants should
not donate blood, blood products or sperm during the study. Participants should also refrain from
performing any HIV testing outside of the study protocol as this could lead to misdiagnosis and
unblinding. Blood donation options for those participants who wish to resume blood donation after
the study will be explained at the final study follow-up visit.
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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In the case of VISP, if, either during the study or after the end of the study, a participant requires
an HIV test outside the study (eg, to obtain a travel visa or insurance, or for medical reasons), they
should contact the site. The sponsor or its designee can issue a written statement giving details on
VISP and on the testing algorithm to be followed. If requested by a participant, HIV testing will
be available to confirm their HIV status upon discretion of the investigator. Preferably, the
frequency of HIV testing should not exceed once every 3 months. It is highly preferable that this
repeat HIV testing will be performed through the site. After the study, testing for a particular
participant will be available as long as VISP is present for this participant.
In addition to providing testing, participants will always receive pre- and post-test HIV counseling.
In participants who become HIV-infected, samples for viral sequencing will be collected. These
samples will only be analyzed upon discretion of the study responsible virologist.
9.3. 
Immunogenicity Evaluations
Venous blood samples for determination of humoral responses to vaccination will be collected
from all participants (and analyzed in a subset) at the time points indicated in the Time and Events
Schedules. Humoral immune response may be assessed by the response magnitude and frequency
to the vaccine autologous Clade C gp140 and Mosaic gp140 proteins by total IgG binding ELISA,
or alternative assays. At baseline and post-vaccination, Ad26 seropositivity status and titer will be
assessed in a subset of participants by vector neutralization assay.
Venous blood samples for determination of cellular immune responses to vaccination will be
collected from a subset of participants at sites with access to sponsor approved PBMC processing
facilities (and analyzed in a subset) at the time points indicated in the Time and Events Schedules.
Cellular immune responses may be assessed by the response magnitude and frequency of
peripheral blood mononuclear cells generating interferon-γ ELISpot responses to cPTE Env
peptide stimulation, or alternative assays.
Depending on the vaccine efficacy outcome, samples may be used for the evaluation of immune
markers that have a sieving effect on any breakthrough infections and for the evaluation of any
immune markers that are associated with post-infection control of HIV, potentially including
immune responses to all vaccine antigens. These additional tests may include limited genetic
testing.
The collected blood per the Time and Events Schedules, will be sufficient to allow for exploratory
immune analyses. Additional exploratory immunogenicity assessments may be performed for the
purposes of more fully characterizing the immune responses elicited by vaccination and/or, if any
vaccine-associated change in HIV acquisition is identified, identifying immunologic responses
which are associated with vaccination and the rate of HIV acquisition.
Note:Participant samples with high levels of biotin can interfere with immunoassays utilizing
interaction of biotin with streptavidin.
9.4. 
Safety Evaluations
Details regarding the independent DSMB are provided in Section 11.9.
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Any clinically significant abnormalities that are considered related to vaccination persisting at the
end of the study/early withdrawal will be followed by the investigator until resolution or until a
clinically stable condition is reached (see Section 12.3.2).
All adverse events and laboratory data will be graded for severity according to the criteria
presented in Section 12.1.3.
Adverse Events
All serious adverse events and adverse events and special reporting situations, that are related to
study procedures or that are related to non-investigational concomitant sponsor products will be
reported from the time a signed and dated ICF is obtained until the end of the study/early
withdrawal. Clinically relevant medical events not meeting the above criteria and occurring
between signing of ICF and the moment of first vaccination will be collected on the Medical
History CRF page as pre-existing conditions.
Solicited adverse events, collected through a diary, will be recorded daily for each vaccination
from the moment of vaccination until 7 days post-vaccination.
All other unsolicited adverse events and special reporting situations will be reported for each
vaccination from the moment of vaccination until 28 days post-vaccination. Unsolicited adverse
events with the onset date outside the timeframe defined above (>28 days after previous study
vaccination), which are ongoing on the day of the subsequent vaccination, should be recorded as
such.
From the time of local approval of protocol amendment 5 onwards, TTS is considered to be an
AESI (see Section 12.3.4). Thrombotic events and/or thrombocytopenia (defined as platelet count
below the LLN range for the testing lab) are considered to be potential AESIs. All AESIs, including
potential AESIs, will be reported to the sponsor from the moment of first vaccination until 6
months after the last vaccination. Each potential AESI will be reviewed to identify a TTS case.
All serious adverse events, MAAEs, and adverse events leading to discontinuation (regardless of
causal relationship) are to be reported from the moment of first vaccination for the duration of the
study, which may include contact for safety follow-up. The HPX3002/HVTN 706 safety review
team will review the safety information during the conduct of the study. The sponsor will evaluate
any safety information that is spontaneously reported by an investigator beyond the time frame
specified in the protocol.
All AEs will be followed until resolution or until clinically stable.
Medically-attended adverse events (MAAEs) are defined as adverse events with medically
attended visits including hospital, emergency room, urgent care clinic, or other visits to or from
medical personnel for any reason. Potentially immune-mediated medical conditions (PIMMCs)
and new onset of chronic diseases will be collected as part of the MAAEs. Adverse events
identified during a routine study visit will not be considered MAAEs. STIs (including
HIV-2 infection) are associated with an increased likelihood to acquire HIV infection. Note that
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 28 February 2023
an STI identified from study visit testing, for which a participant receives subsequent medical
intervention, fulfils the criteria of an MAAE.
Based on regulatory  feedback, special attention will be put on PIMMC  that are reported as
MAAEs. These events will be collected and analyzed. A list of PIMMCs defined for this study is
presented in Attachment 3.
For solicited adverse events, the following applies.
Solicited Adverse Events
Solicited adverse events are used to assess the reactogenicity of the study vaccine and are
predefined local (at the administration site) and systemic events for which the participant is
specifically questioned, and which are noted by participants in their diary.
After each vaccination, participants will remain under observation at the study site for at least
30 minutes for presence of any acute reactions. In addition, participants will record solicited signs
and symptoms in a diary for 7 days post-vaccination. These participants will be provided with a
diary and instructions on how to complete the diary (Section 9.1.1). The study staff will transcribe
the information provided by the participant into the relevant sections of the CRF. After review and
verbal discussion of the initial paper diary entries with the participant, the investigator will
complete his/her own assessment in the relevant sections of the CRF. Once a solicited sign or
symptom from a diary is considered to be of severity Grade 1 or above, it will be recorded as a
solicited adverse event. For grading of solicited adverse events, see Section 12.1.3. For solicited
adverse events, the investigators will document them in the clinic note, followed by entry into the
CRF.
Solicited Administration Site Adverse Events
Participants will be asked to note in the diary occurrences of pain/tenderness, erythema and
swelling at the study vaccine administration site daily for 7 days post-vaccination (day of
vaccination and the subsequent 7 days). The extent (largest diameter) of any erythema, and
swelling should be measured (using the ruler supplied) and recorded daily.12,25
Solicited Systemic Adverse Events
Participants will be instructed on how to record daily temperature using a thermometer provided
for home use. Participants should record the temperature in the diary in the evening of the day of
vaccination, and then daily for the next 7 days approximately at the same time each day. If more
than 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.27
Participants will also be instructed on how to note daily in the diary signs and symptoms for 7 days
post-vaccination (day of vaccination and the subsequent 7 days) of the following events: fatigue,
headache, nausea, myalgia, chills, arthralgia, and vomiting.
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Clinical Laboratory Tests
No blood samples for safety laboratory testing will be collected. However, clinical laboratory
assessments to be performed are as follows:
 
Serum (at screening; local laboratory) and Urine (at time points indicated in the Time and
Events Schedule) pregnancy testing for participants of childbearing potential only.
 
HIV testing (see Section  9.2 and Study-Specific Procedures Binder; screening test: local
laboratory, other HIV testing: central laboratory)
 
Syphilis, chlamydia, and gonorrhea (local laboratory)
 
Dried blood spot test (central laboratory)
 
In case of HIV infection: HIV viral load (central laboratory) and CD4+ cell count (local
laboratory)
 
In case of a potential AESI of TTS (see Section 12.3.4.1), a serum sample should be obtained
to test for anti-PF4 at the local laboratory or substitute local laboratory, if possible; repeat
testing may be requested for confirmation upon sponsor discretion. A test for anti-PF4 will
also be performed on a stored pre-vaccination sample, if possible.
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).
Physical Examination
Full physical examination, including vital sign measurements, will be carried out at screening,
Month 30 and 6 months after HIV-1 diagnosis, as applicable. At all other study visits, a targeted,
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 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.
9.5. 
Participant Reported Outcomes
Social impact, sexual activity, absenteeism, vaccination regimen acceptance, and PrEP use will be
evaluated over the study period, until the end of follow up, through questionnaires completed under
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confidentiality by the study participants. Replies to questionnaires will be assessed in the following
groups:
1. In vaccine and placebo recipients,
2. In participants who become HIV-1 infected in comparison to non-infected participants,
3. In VISP positive and negative study participants,
4. In participants who are using PrEP or not during the course of the study, if applicable.
For the full questionnaires, refer to the Study Specific Procedures Binder.
9.5.1. 
Social Impact Measured Using Questionnaire
Participants in prophylactic HIV-vaccine clinical studies may experience problems with personal
relationships, employment, education, health care, housing, health, disability or life insurance,
travel, and immigration.1 In relation to a participant’s family, friends, and/or colleagues, the social
impact could manifest in one or more ways, resulting in social conflicts and stigmatization, for
example:
1. The investigational vaccine is thought to be harmful to the participant’s health, including a
belief that it might cause HIV infection.
2. The participant is perceived as HIV-infected or at high risk.
3. Repercussions from VISP.
For these reasons, participants will complete a social impact questionnaire at the time points
specified in the Time and Events Schedule, to evaluate any potential consequences of the
participant’s enrollment in the study.
9.5.2. 
Sexual Activity Questionnaire
In order to collect information to assess the level of risk of HIV infection throughout the study,
participants will complete a sexual activity questionnaire, at the time points specified in the Time
and Events Schedule. The recall period for this questionnaire is the last month.
9.5.3. 
Questionnaire on the Use of PrEP
Information with regard to the use of and, if applicable, adherence to PrEP will be collected for all
participants by means of a questionnaire. The questionnaire will be completed at the time points
specified in the Time and Events Schedule.
9.5.4. 
Other Participant Reported Outcomes
At each visit (except for Visit 2a and Visit 3a), participants will be questioned on their level of
absenteeism, defined as health-related productivity loss due to sick-leave, since their last visit at
which absenteeism was recorded.
In addition, at Visit 8, 1 month post-vaccination 4, participants will be asked how they perceived
their experience with this HIV vaccination.
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
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9.6. 
Sample Collection and Handling
The actual dates and time of sample collection must be recorded in the laboratory requisition form.
Refer to 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 Study-
Specific Procedures Binder 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 Study-Specific Procedures Binder.
10. 
PARTICIPANT COMPLETION/DISCONTINUATION OF STUDY
VACCINATION/ WITHDRAWAL FROM THE STUDY
10.1. Completion
The study will be considered completed when the last participant completed the Month 30 visit or
discontinued earlier. Participants will continue the study until the last participant has completed
the Month 30 visit or discontinued earlier.
At the end of the study, participants may be offered the possibility to enter a follow-up phase or
program.
10.2. Discontinuation of Study Vaccination/Withdrawal from the Study
Discontinuation of Study Vaccination
Participants will be withdrawn from study vaccine administration for the reasons listed below.
These participants must not receive any additional dose of study vaccine but should continue the
visit schedule as planned with assessments per the Time and Event Schedule including assessments
of safety and HIV diagnosis. Participants who received the first 3 vaccinations but discontinue
study vaccination before receiving the 4th  vaccination, should continue the visit schedule as
planned with assessments per the Time and Event Schedule including assessments of safety,
immunogenicity and HIV diagnosis. Additional unscheduled visits may be performed for
safety/reactogenicity reasons, if needed. In case of questions, the investigator is encouraged to
contact the HPX3002/HVTN 706 safety review team.
 
Unblinding due to safety reasons
 
Pregnancy
 
Confirmed HIV-1 or HIV-2 infection
 
Any related adverse event, worsening of health  status or intercurrent illnesses that, in the
opinion of the investigator, required discontinuation from study vaccine
 
Anaphylactic reaction following vaccination
 
Serious adverse event or other potentially life-threatening (Grade 4) event that is determined
to be related to study vaccine
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 28 February 2023
 
Chronic or recurrent use of systemic immunomodulators/suppressants, eg, cancer
chemotherapeutic agents (after discussion with the HPX3002/HVTN 706 safety review team)
 
Use of HIV-related mAbs
 
From the time of local approval of protocol amendment 5 onwards: participant previously
experienced TTS or HITT.
Withdrawal From the Study
Each participant 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 participants who did not return for scheduled visits or follow-up. Although the participant
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 participant’s rights.
A participant 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 or IRB/IEC to stop or cancel the study
If a participant is lost to follow-up, every reasonable effort must be made by the study-site
personnel to contact the participant and determine the reason for discontinuation/withdrawal. The
measures taken to follow-up must be documented.
When a participant 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
participant may not be assigned to another participant. Participants who are vaccinated and
withdraw will not be replaced. If a participant withdraws early from the study, assessments for
early withdrawal should be obtained (see Section 9.1.8).
Participants 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.
10.3. Contraindications to Vaccination
The following events constitute a temporary contraindication to study vaccination. 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):
 
Acute illness at the time of vaccination. This does not include minor illnesses, such as diarrhea
or mild upper-respiratory tract infection.
 
Fever (body temperature ≥38.0°C) at the planned time of vaccination.
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 28 February 2023
If the vaccination visit cannot be rescheduled within the allowed window or the contraindications
to vaccination persist, the HPX3002/HVTN 706 safety review team should be contacted for further
guidance.
10.4. Withdrawal From the Use of Research Samples
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Section 16.2.5,
Long-Term Retention of Samples for Additional Future Research). 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 ICF.
11. 
STATISTICAL METHODS
Statistical analysis will be done by the sponsor and its partners or under the authority of the
sponsor. A general description of the statistical methods is outlined below. Specific details will be
provided in the SAP.
11.1. Participant Information
For all participants, descriptive statistics of demographic (eg, sex assigned at birth, participant-
identified gender at screening, age, height, weight, male circumcision, body mass index [BMI],
and race) and other baseline characteristics (eg, medical history, including history and family
history of immune disorders, concomitant diseases, Ad26 baseline serostatus) will be provided by
vaccination group.
11.2. Analysis Populations
The following study populations or analysis sets are used for addressing the study objectives. This
terminology is used throughout this protocol and SAP. The following sets and populations will
include all vaccinated participants with respect to the vaccine actually administered.
1. Full Analysis Set (FAS): all randomized participants who receive at least one vaccine
administration. This will be the primary population for the safety analysis.
2. Modified Intent-to-Treat (mITT) Population: participants in the FAS who are HIV-1 negative
on the date of first vaccination.
3. Modified Intent-to-Treat-2 (mITT-2) Population: participants in the FAS who have a negative
HIV test 4 weeks post 3rd vaccination visit (ie, at the Month 7 Visit).
4. Per-Protocol (PP) Population: participants in the FAS population who have a negative HIV
test 4 weeks post 3rd vaccination visit (ie, at the Month 7 Visit), who received all planned
vaccinations at the first three vaccination visits within the respective visit windows. This will
be the primary population for the efficacy analysis.
5. Modified Intent-to-Treat-3 (mITT-3): participants in the FAS population who have a negative
HIV test 4 weeks post 3rd vaccination visit (ie, at the Month 7 Visit), who received all planned
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vaccinations at the first three vaccination visits, irrespective whether within or outside the
respective visit windows. This will be an additional population for efficacy analysis, and
potentially for immune correlates.
6. Full Immunization Set (FIS): participants in the FAS who are HIV-1 uninfected 4 weeks after
the 4th  vaccination visit (ie, at the Month 13 Visit) and who receive all planned vaccinations
within the respective visit windows.
7. At risk Immunogenicity Cohort (IC-at risk): participants in the FAS who are selected for
measurement of immune response endpoints at the primary immunogenicity timepoints and
who are HIV-1 uninfected 4 weeks after the 3rd vaccination visit (ie, at the Month 7 Visit).
The analyses of safety will be performed on the FAS. The primary analysis of VE will be based
on the PP population. Secondary analyses of VE will be based on the mITT, mITT-2, and mITT-3
population, and the FIS. For those with immunogenicity outcomes, analyses of vaccine
immunogenicity and immune correlates may be based onPP, mITT-3, IC-at risk and the FIS. Other
populations may be defined in the SAP for the purpose of exploratory (correlate) analyses.
11.3. Sample Size Determination
This study is designed to test the primary hypothesis of VE in the PP population:
H0: VE(7-x months) ≤20% versus the H1: VE(7-x months) >20%, with 24≤x≤30 (See
Section 11.5.1.1).
If the lower bound of the 95% CI for VE(7-x months) is >20% at the primary analysis, the
corresponding H0 will be rejected.
The sample size calculations are based on the power of a 1-sided 0.025-level Wald test for
comparing cumulative incidences of HIV-1 infection by the Month x visit (24≤x≤30) between
randomized groups, in the presence of the sequential monitoring of VE. Power is computed based
on simulating 10,000 efficacy trials using the R package seqDesign14,24 under the following
assumptions:
 10% annual dropout incidence in both groups;
 5% of participants with at least one missed vaccination (excluded from PP population);
 VE 20% in the first 7 months after first vaccination;
 VE 65% from Month 7 onwards;
 12-month uniform accrual with halved accrual during the first 3 months;
 Visits approximately every 3 months for HIV-1 diagnostic tests;
 2% annual HIV-1 incidence in the placebo group;
Under these assumptions, a study of 3,800 participants (randomized 1,900:1,900 to
vaccine:placebo) is expected to yield a total of 78 HIV-1 infections in the PP population between
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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the Month 7 and Month 30 visits, considered to be the TNI needed to achieve approximately 90%
power for rejecting the primary H0, under an alternative VE of 65% and with a one-sided error
rate of 2.5%.
The timing of unblinding and conducting the primary analysis and the definition of the primary
efficacy endpoint will be determined by when the TNI is reached within a given follow-up period x
(24≤x≤30) for each participant. In practice, when the last participant has reached his/her Month 24
visit (or discontinued earlier), it will be assessed whether the TNI has been obtained within the
period of Month 7-Month 24. Ifat that time the number of HIV-1 infections between Month 7 and
Month 24 is greater than or equal to the TNI, the primary analysis may be conducted using VE(7-
24 months) as the primary efficacy endpoint. Only ifthis primary H0 is rejected, VE(7-30 months)
will be tested as secondary hypothesis, using a fixed sequence testing strategy, without adjustment
for the Type-I error, and using all available durability data between Month 24 and Month 30. If
the number of infections between Month 7 and Month 24 is less than the TNI, the study will
continue for 3 months until the last participant has reached their Month 27 visit. The same
procedure is repeated as described above, using all available HIV-1 infections between Month 7
and Month 27 and with VE(7-27 months) as the primary efficacy endpoint. If the number of
infections between Month 7 and Month 27 is less than the TNI, the study will continue for
3 months until the last participant has reached his final study visit at Month 30. At that point, the
primary analysis will be conducted regardless of whether the TNI has been reached, using
VE(7-30 months) as only efficacy endpoint.
The statistical strategy is schematically presented in Figure 1.
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
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Status: Approved, Date: 28 February 2023
Figure 1: 
Primary Efficacy Testing –Schematic Overview
H0: null hypothesis; M: month; TNI: Target Number of Infections; VE: vaccine efficacy
Note that investigators and participants will remain blinded with regards to their treatment
assignment, at least until the last participant has reached the Month 30 visit or discontinued earlier.
Both the study’s sample size as well as the TNI may be adjusted during the study, but prior to
unblinding, to ensure sufficient power at the time of the primary analysis. Whereas adjustment of
the sample size may be based on internal (but sponsor-blinded) study data (through monitoring of
the pooled HIV-1 incidence) as well as on external study data (eg, Phase 2b HPX2008/HVTN
705), any adjustment of the TNI will solely be driven by data external to this study (eg, Phase 2b
HPX2008/HVTN 705). Full details on the possible sample-size reassessment will be described in the
DSMB Charter and the SAP.
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 28 February 2023
To cope with the dynamic environment of the development, approval and uptake of other
prophylactic methods, such as PrEP (which would result in lower than expected annual incidence
rates and thus lower study power), an estimated annual incidence rate in the control group of 2%
was used to size this study.
Under the study assumptions as described above, the study will also have approximately 80%
power for the secondary efficacy endpoint VE(0-x months), assessing VE in the mITT population
and accounting for all HIV-1 infections starting from Month 0 (Day 1).
Rationale for the HIV-1 Incidence Assumptions
This study will recruit a large population of highest-risk MSM and transgender individuals who
have sex with men from many regions. In 2011, 62% of estimated new HIV diagnoses in the United
States were attributed to male-to-male sexual contact; 39% of these MSM were black or African
American.9 Lifetime risk was 1 in 68 for males and 1 in 253 for females. Lifetime risk for men
was 1 in 22 for blacks, 1 in 51 for Hispanic/Latinos, and 1 in 140 for whites. By risk group, the
highest risk was among MSM (1 in 6) and the lowest was among male heterosexuals (1 in 524).
Most of the states with the highest lifetime risk were in the South.19 Recent data from clinical
studies show placebo incidence rates in high risk MSM of 6.6% in the Ipergay study (France,
Canada)28, 3.9% in the iPrEX study for high risk MSM (USA, Brazil, Peru, Ecuador, South Africa
and Thailand)15, HVTN 505 yielded annual incidence rates of 2.3% in circumcised MSM and TG
(USA)18. To help identify the study participants pre-trial assessments and data will be collected
regarding incidence in potential sites.
The assumption of 2% annual HIV-1 incidence in the placebo group accommodates background
PrEP use by assuming incidence is decreased by the person-years at risk during which PrEP is
used, the efficacy of PrEP during PrEP use and the adherence to PrEP use. Figure 2 shows the
impact of assumed PrEP use and adherence on annual HIV-1 incidence in the placebo group when
the initial incidence (in the absence of PrEP) is 3% or 4% and the efficacy of PrEP is assumed to
be 90%.
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
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Status: Approved, Date: 28 February 2023
Eventually, the monitoring rules as agreed with the independent DSMB  and described in the
DSMB charter will take priority over the ones presented below.
Table 4: 
Summary of interim monitoring of VE
Monitoring 
Outcome 
Hypotheses 
Testing 
Approach
Size 
Monitoring Plan 
Timing of analyses
Potential 
Harm  
H0: VE(0-30) ≥0%  
vs. 
H 1: VE(0-30) <0%  
Exact 1-sided 
binomial test 
of the 
proportion of 
infections 
assigned to the
vaccine group
1-sided 
alpha=0.05 
Near-constant 1- 
sided p-value cut- 
off controlling 
FWER at 
alpha=0.05 
After every mITT
infection starting at
the 10 th total until
the 
first 
non-
efficacy analysis
Non- 
Efficacy  
H0: VE(0-30) ≥50%  
vs. 
H1: VE(0-30) <50%  
and 
H0: VE(7-30) ≥50%  
vs. 
H1: VE(7-30) <50%
Wald Test 
1-sided 
alpha=0.025 
Unadjusted 95% 
CIs for VE(0-30) 
and 
VE(7-30): 
lower 
bounds 
<0% and upper 
bounds <50%
6-monthly starting
at 
40 
mITT
infections and then
through the primary
analysis
CI: confidence interval; FWER: family-wise error rate; H0: null hypothesis; H1: alternative hypothesis; mITT:
modified intent-to-treat; VE: vaccine efficacy; vs.: versus
11.5. Efficacy Analysis
The primary efficacy analysis will be performed when all participants have reached the Month x
(with 24≤x≤30) visit or discontinued earlier and the TNI has been reached in the study. Refer to
Figure 1 for more information on the timing and strategy of statistical testing.
11.5.1. 
Vaccine Efficacy Analysis
The primary analysis of VE will evaluate the number of HIV-1 infections in the vaccine group
compared to the number of HIV-1 infections in the placebo group between Month 7 and Month x
(with 24≤x≤30) in the PP population. The H0 of VE will be tested VE(7-x months) ≤20% versus
the H1 VE(7-x months) >20%. Vaccine efficacy is defined as 1-cumulative incidence ratio
(vaccine versus placebo) between Month 7 and Month x after first vaccination and is estimated by
the transformation of the Nelson-Aalen estimator for the cumulative hazard function. If the lower
bound of the 95% CI for VE(7-x months) is >20% (equivalently, the 1-sided p-value for testing
H0: VE[7-x months] ≤20% is below 0.025), the H0 will be rejected in favor of the H1.
11.5.1.1. 
Primary Vaccine Efficacy Analysis: HIV-1 Infection
The primary analysis will be done in the PP population, where participants who become HIV-1
infected or who drop out before Month 7 or who have not received all of the first three vaccinations
within the specified time window, will be excluded from the analysis. The date of HIV-1 diagnosis
will be the draw date of the first sample that leads to a positive test result by the study protocol’s
diagnostic algorithm. Dropouts will be censored at the time of their last HIV-1 negative test. To
evaluate the primary VE endpoint, the number of HIV-1 infections in the vaccine group will be
compared to the number of HIV-1 infections in the placebo group between Month 7 and x months
since the first vaccination (with 24≤x≤30). The vaccine effect will be assessed using a ratio of
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JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
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cumulative incidences of HIV-1 infection between Month 7 and x (vaccine versus placebo),
estimated using the transformed Nelson-Aalen cumulative hazard function estimator and tested via
a Wald test.
11.5.1.2. 
Secondary/Exploratory Vaccine Efficacy Analyses
As a key secondary objective, the VE beyond Month 7 will be evaluated in all participants,
regardless of whether they received the first three vaccinations according to the protocol-specified
schedule (mITT-2 population, see Section 11.2 for definition). Other secondary objectives will
evaluate the VE over different time intervals (eg, VE[0-x months], VE[13-x months]) and in
different populations (eg, mITT, mITT-2, mITT-3, FIS), using similar methods as described above.
Cox proportional hazards model will also be used for estimating VE(7-x months), measured by
one minus the hazard ratio (vaccine versus placebo) and for testing whether the VE(7-x months)
differs from 20%.
To account for potentially confounding factors, subgroup and covariate-adjusted analyses will be
performed. These subgroups/covariates will include PrEP use, baseline Ad26 seropositivity status
and titers, presence of risk factors for HIV infection, and other baseline demographic factors.
Efforts will be made to estimate vaccine efficacy in complete absence of PrEP use in a
counterfactual framework.
In addition, an exploratory analysis that employs Bayesian methods will be conducted to evaluate
VE.13 The prior to be used for this analysis will be a robust, meta-analytic one based on
pre-specified weighting of the external Phase 2b data (study HPX2008/HVTN 705) as informative
prior and a non-informative prior.31 Details of pre-specified weights and priors will be specified in
the SAP.
If VE is established, an attempt will be made to identify correlates of increased risk of HIV-1
infection as well as correlates of VE, best individual-level classifiers of HIV infection and to assess
mediators of vaccine efficacy. To this extent, appropriate statistical methodology will be applied
or developed, and will be described in a (separate) SAP for correlate identification. If significant
VE is observed, a pre-specified case-control study of immune responses elicited by vaccination in
active vaccine recipients will be performed to identify vaccine-induced correlates of protection
and/or risk. Both single parameter and combinations of multiple immunologic parameter models
will be explored. The presence of time-dependent correlates of protection will be examined in
addition to single time point immune responses, including the peak immune response after the
primary vaccination series, or the time point most closely preceding the diagnosis of HIV-1
infection. To further ascribe immune correlates of protection and/or specifically of VE, placebo
case and control samples will also be included in a secondary stage of analysis.
11.6. Safety Analysis
No formal statistical testing of safety data is planned. Safety data will be analyzed descriptively.
All safety analyses will be tabulated by vaccination group (active vaccine, placebo) and based on
the FAS.
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Tabulations will be presented by time of occurrence relative to the preceding vaccination (7 days
for solicited adverse events and 28 days for unsolicited adverse events, 6 months after last
vaccination for AESIs).
Baseline for all safety parameters will be defined as the last evaluation done before the first dose
of study vaccine.
11.6.1. 
Reactogenicity: Solicited Adverse Events
The number and percentage of participants experiencing each type of solicited adverse event will
be tabulated by severity and vaccination group, and the percentages will be displayed graphically
by group. For a given solicited adverse event, each participant’s adverse event will be counted
once under the maximum severity for each vaccination dose.
11.6.2. 
Unsolicited Adverse Events, AESIs, MAAEs and Serious Adverse
Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using
the Medical Dictionary for Regulatory Activities (MedDRA). Tables will show, by vaccination
group, the number and percentage of participants experiencing an adverse event within a system
organ class or within a preferred term category by severity and by relationship to study vaccine.
All reported adverse events and events-related diary information with onset or worsening within
28 days after each vaccination (ie, treatment-emergent adverse events) will be included in the
analysis. For each adverse event, the percentage of participants who experience at least
1 occurrence of the given event will be summarized by vaccine group. A participant with multiple
adverse events within a category will be counted once under the maximum severity and by causal
relationship to study vaccine. Formal statistical testing comparing groups is not planned since
interpretation of differences must rely heavily upon clinical judgement. Parallel analyses will
include all AESIs, serious adverse events and adverse events leading to participant withdrawal or
early discontinuation of study vaccine(s).
For this study events of interest are PIMMCs. PIMMCs that are recorded as MAAEs will be
collected and analyzed.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue treatment due to an adverse event, or who experience a
serious adverse event or an AESI.
Summaries and listings may be provided separately for adverse events with onset outside the above
defined timeframe and that were reported pre-dose at the moment of subsequent vaccinations.
11.6.3. 
Other Safety Parameters
Vital Signs
The percentage of participants with values beyond pre-specified limits will be summarized.
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Physical Examination
Physical examination findings will not be tabulated separately. Clinically relevant findings will be
reported as adverse event and will be tabulated and listed as adverse events. BMI will be calculated
using the recording of height at screening.
11.6.4. 
Other Parameters
Participant Reported Outcomes
Data from the social impact questionnaire, sexual activity questionnaire, the questionnaire on the
use of PrEP and the level of absenteeism and vaccine regimen acceptance will be summarized
using descriptive statistics:
1. In vaccine and placebo recipients,
2. In participants who become HIV-1 infected in comparison to non-infected participants,
3. In VISP positive and negative study participants,
4. In participants who are using PrEP or not during the course of the study, if applicable.
In addition, data may be included as co-variates in the exploratory efficacy analysis.
Health Economics Aspects (HCRU)
Health Care Resource Utilization will be described based on data collected through MAAEs and
follow-up of HIV infections, and complemented by description of absenteeism.
1. Data will be summarized using descriptive statistics:In vaccine and placebo recipients,
2. In participants who become HIV-1 infected in comparison to non-infected participants,
3. In VISP positive and negative study participants,
4. In participants who are using PrEP or not during the course of the study, if applicable.
11.7. Reasons for Vaccination Discontinuation and Early Study Termination
The number and percentage of participants who discontinue vaccination and who terminate the
study early will be tabulated by vaccination group. The reason for discontinuation will be included.
11.8. Immunogenicity Analysis
Data from quantitative assays may be summarized (tabulated/graphically presented per timepoint
available) by vaccination group: N, geometric means and corresponding 95% CIs, percentage
positive responses/responders (if available).
Qualitative endpoints may be summarized by tabulating the frequency of positive responses for
each assay by group at each timepoint that an assessment is performed.
Descriptive statistics (actual values and changes from reference) may be calculated for continuous
parameters. Frequency tabulations may be calculated for discrete parameters. Graphical
representations of changes in immunologic parameters may be made as applicable.
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No formal hypothesis on immunogenicity will be tested. The analysis of immunogenicity may be
done on the immunogenicity populations as defined above.
11.9. Independent Data and Safety Monitoring Board
The NIAID HIV vaccine DSMB  will serve as an independent DSMB for this study and will
monitor data on a 6-monthly basis to ensure the continuing safety of the participants enrolled in
this study. The independent DSMB  will review unblinded data as indicated below. After the
review, the independent DSMB  will make recommendations to the sponsor about potential
modifications to the study. The independent DSMB will also monitor the study progression.
An independent statistical support group, appointed by the sponsor, and not involved in the study,
will be unblinded to treatment assignment and provide all necessary data to the independent
DSMB. The independent DSMB will consist of at least four clinical and vaccine experts, at least
one independent statistician, one ethicist, and one community representative. All independent
DSMB responsibilities, authorities, and procedures (data to be provided, meeting frequency, type
of meetings) will be specified in the DSMB Charter and the details on the analyses will be provided
in the SAP. An independent DSMB  meeting will start with an open (blinded to treatment
assignment with attendance of sponsor study representatives) followed by a closed (unblinded to
treatment assignment) session. No sponsor representative will be involved in the closed sessions.
The unblinded, closed DSMB report including evaluations of HIV infections will be shared with
the FDA Center for Biologics Evaluation and Research (CBER)/Office of Vaccines Research and
Review (OVRR). To ensure the blinding of the study team, an independent regulatory expert will
act as an intermediary between the DSMB and CBER/OVRR. Further details are described in the
DSMB charter.
In case of serious safety issues, the independent DSMB  will be informed immediately by the
sponsor.
11.10. Endpoint Adjudicator(s)
The diagnostic criteria for HIV-1 infection outside the setting of a vaccine trial are well accepted.
However, definitive diagnosis of HIV-1 infection in the context of having received an HIV vaccine
that is even partially effective may be more difficult. Specifically, if the immune responses elicited
by vaccination are capable of completely suppressing viral replication, or if vaccination alters the
normal serological response upon exposure to HIV-1, standard diagnostic tests may be more
difficult to assess.
Therefore, an endpoint adjudicator(s) and/or designees will assess all serological and virological
testing, in a blinded manner, on each participant in the study who, prior to study unblinding tests
positive per the sponsor-approved HIV testing algorithm.
12. 
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
are crucial for the protection of participants, investigators, and the sponsor, and are mandated by
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in
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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 Adverse Events, AESIs, MAAEs and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events, AESIs, MAAEs or serious
adverse events. Open-ended and nonleading verbal questioning of the participant is the preferred
method to inquire about adverse event occurrence.
Solicited Adverse Events
Solicited adverse events are predefined administration site and systemic events for which
participants are specifically questioned and which are noted in their diary (see Section 9.1.1).
Unsolicited Adverse Events
Unsolicited adverse events are all adverse events for which the participant is specifically not
questioned in the participant diary.
AESIs
For details, see Section 12.3.4.
Medically-attended Adverse Events
Medically-attended adverse events (MAAEs) are adverse events with medically attended visits
including hospital, emergency room, urgent care clinic, or other visits to or from medical personnel
for any reason.
12.1. Definitions
12.1.1. 
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study participant administered
a medicinal (investigational or non-investigational) product. An adverse event does not necessarily
have a causal relationship with the medicinal product. An adverse event 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: For time period of sponsor’s adverse event collection, see Section 12.3.1.
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Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal
Products for Human Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is
also appropriate in other situations, such as important medical events that may not be immediately
life-threatening or result in death or hospitalization but may jeopardize the participant or may
require intervention to prevent one of the other outcomes listed in the definition above. These
should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal
relationship between the study product and the event (eg, death from anaphylaxis), the event must
be reported as a serious and unexpected suspected adverse reaction even if it is a component of the
study endpoint.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable
product reference safety information. For Ad26.Mos4.HIV, Clade C gp140, and Mosaic gp140,
the expectedness of an adverse event will be determined by whether or not it is listed in the
respective Investigator's Brochures.
Adverse Event Associated With the Use of the Vaccine
An adverse event is considered associated with the use of the vaccine if the attribution is related
by the definitions listed in Section 12.1.2.
12.1.2. 
Attribution Definitions
Causality of adverse events should be assessed by the investigator based on the following:
Related: there is a reasonable possibility* that the adverse event may be related to the study agent.
This suggests that the adverse event is more likely to be related than not related to the study
product(s).
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Unrelated: there is not a reasonable possibility* that the adverse event is related to the study agent.
The choice suggests that the adverse event is more likely to be related to another cause rather than
the study products.
* There is evidence to suggest a causal relationship between the study product and the adverse
event.
By definition, all solicited adverse events at the administration site will be considered related to
the study vaccine administration.
12.1.3. 
Severity Criteria
For severity grading of solicited administration site adverse events the following applies
(differences with the DAIDS table are indicated in strikethrough and bold/underlined):
Table 5: 
Grading of Solicited Administration Site Adverse Events
Grade 1: MILD  
Grade 2: 
MODERATE  
Grade 3: SEVERE 
Grade 4:
POTENTIALLY
LIFE-
THREATENING
InjectionAdministration- 
related Site Pain or 
Tenderness 
(proximal to the 
injection site) 
Pain or tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater 
than minimal 
limitation of use of 
limb 
Pain or tenderness 
causing inability 
to perform USFAa 
Pain or tenderness
causing inability to
perform basic self-
care function OR
hospitalization
indicated
InjectionAdministration- 
related Site Erythema or 
Redness 
AND  
InjectionAdministration 
-related Site Induration or 
Swelling 
2.5 to <5 cm in 
diameter OR 6.25 
to <25 cm2 surface 
area AND 
Symptoms causing 
no or minimal 
interference with 
USFA  
≥5 to <10 cm in 
diameter OR ≥25 
to <100 cm2 
surface area OR 
Symptoms causing 
greater than 
minimal 
interference with 
USFA  
≥10 cm in 
diameter OR ≥100 
cm2 surface area 
OR secondary 
infection OR 
phlebitis OR 
sterile abscess OR 
drainage OR
Symptoms causing
inability to
perform USFA
Potentially life-
threatening
consequences (eg,
abscess, exfoliative
dermatitis, necrosis
involving dermis or
deeper tissue)
a 
USFA: usual social and functional activities. Adaptive tasks and desirable activities, such as going to work,
shopping, cooking, use of transportation, pursuing a hobby, etc
All adverse events, including solicited systemic adverse events, and laboratory data, if applicable,
will be coded for severity using the Division of Acquired Immunodeficiency Syndrome (DAIDS)
Table for Grading the Severity of Adult and Pediatric Adverse Events, version 2.1, July 2017 and
its addenda (the DAIDS addenda grading tables for microbicides studies will be used for the
grading of genito-urinary disorders, STIs, uterine bleeding and pregnancy complications although
this is not a microbicide study). Laboratory reference ranges will be applied according to the
participant’s sex at birth. Details for solicited systemic adverse events are provided in Table 6. For
the full DAIDS grading table, refer to the Study Specific Procedures Binder.
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Table 6: 
Grading of Solicited Systemic Adverse Events
Grade 1: MILD
Grade 2:
MODERATE 
Grade 3: SEVERE
Grade 4:
POTENTIALLY
LIFE-
THREATENING
Fever (non-axillary
temperatures only)
38.0 to <38.6°C OR
100.4 to <101.5°F
≥38.6 to <39.3°C 
OR ≥101.5 to 
<102.7°F  
≥39.3 to <40.0°C
OR ≥102.7°F to
<104.0°F
≥40.0°C OR
≥104.0°F
Fatigue or Malaise 
Symptoms causing
no or minimal
interference with
USFAa
Symptoms causing 
greater than minimal 
interference with 
USFA
Symptoms causing
inability to perform
USFA
Incapacitating
symptoms of fatigue
or malaise causing
inability to perform
BSCFb
Myalgia 
(generalized) 
Muscle pain
causing no or
minimal
interference with
USFA
Muscle pain causing
greater than minimal
interference with
USFA
Muscle pain
causing inability to
perform USFA
Disabling muscle
pain causing
inability to perform
BSCF
Headache 
Symptoms causing
no or minimal
interference with
USFA
Symptoms causing 
greater than minimal 
interference with 
USFA  
Symptoms causing 
inability to perform 
USFA  
Symptoms causing
inability to perform
BSCF OR
hospitalization
indicated OR
headache with
significant
impairment of
alertness or other
neurologic function
Nausea 
Transient (<24 
hours) or 
intermittent AND 
no or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 48 
hours 
Persistent nausea 
resulting in minimal 
oral intake for >48 
hours OR
rehydration
indicated (eg, IV
fluids)
Life-threatening
consequences (eg,
hypotensive shock)
Vomiting 
Transient or 
intermittent AND 
no or minimal 
interference with 
oral intake 
Frequent episodes 
with no or mild 
dehydration  
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR
aggressive
rehydration
indicated (eg, IV
fluids)
Life-threatening
consequences (eg,
hypotensive shock)
Chills 
Symptoms causing 
no or minimal 
interference with 
USFA  
Symptoms causing 
greater than minimal 
interference with 
USFA
Symptoms causing 
inability to perform
USFA
NA
Arthralgia 
Joint pain causing 
no or minimal 
interference with 
USFA  
Joint pain causing 
greater than minimal 
interference with 
USFA
Joint pain causing 
inability to perform 
USFA  
Disabling joint pain
causing inability to
perform BSCF
a 
Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing
a hobby, etc.
b Basic self-care functions. Activities such as bathing, dressing, toileting, transfer/movement, continence, and
feeding.
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The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant.
12.2. Special Reporting Situations
Safety events of interest on a sponsor study vaccine that may require expedited reporting or safety
evaluation include, but are not limited to:
 
Overdose of a sponsor study vaccine
 
Suspected abuse/misuse of a sponsor study vaccine
 
Accidental or occupational exposure to a sponsor study vaccine
 
Medication error involving a sponsor product (with or without participant/patient exposure to
the sponsor study product, eg, name confusion)
 
AESIs
Participant-specific special reporting situations should be recorded in the CRF. Any special
reporting situation that meets the criteria of a serious adverse event should be recorded on the
serious adverse event page of the CRF.
12.3. Procedures
12.3.1. 
All Adverse Events
Solicited adverse events, unsolicited adverse events, AESIs, serious adverse events and adverse
events leading to vaccine discontinuation will be reported for all participants.
All serious adverse events and adverse events and special reporting situations, that are related to
study procedures or that are related to non-investigational sponsor products will be reported from
the time a signed and dated ICF is obtained until the end of the study/withdrawal. Clinically
relevant medical events not meeting the above criteria and occurring between signing of ICF and
the moment of first vaccination will be collected on the Medical History CRF page as pre-existing
conditions.
Solicited adverse events, collected through a diary, will be recorded daily for each vaccination
from the moment of vaccination until 7 days post-vaccination.
All other unsolicited adverse events and special reporting situations will be reported for each
vaccination from the moment of vaccination until 28 days post-vaccination. Unsolicited adverse
events with the onset date outside the timeframe defined above (>28 days after previous study
vaccination), which are ongoing on the day of the subsequent vaccination, should be recorded as
such.
From the time of local approval of protocol amendment 5 onwards, TTS is considered to be an
AESI. Thrombotic events and/or thrombocytopenia (defined as platelet count below the LLN range
for the testing lab) are considered to be potential AESIs. All AESIs, including potential AESIs,
will be reported to the sponsor from the moment of first vaccination until 6 months after the last
vaccination. Each potential AESI will be reviewed to identify a TTS case.
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All serious adverse events, MAAEs, and adverse events leading to discontinuation (regardless of
the causal relationship) are to be reported from the moment of first vaccination for the duration of
the study. The HPX3002/HVTN 706 safety review team will review the safety information during
the conduct of the study. The sponsor will evaluate any safety information that is spontaneously
reported by an investigator beyond the time frame specified in the protocol.
All AEs will be followed until resolution or until clinically stable.
All events that meet the definition of a serious adverse event will be reported as serious adverse
events, regardless of whether they are protocol-specific assessments.
The investigator will monitor and analyze study data including all adverse event 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.
The investigator or designee must review both collected solicited events and other adverse event
CRFs to ensure prompt and complete identification of all events that require expedited reporting
as serious adverse events or as other serious and unexpected events.
All per-protocol collected adverse events, regardless of seriousness, severity, or presumed
relationship to study product, 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 adverse event to study therapy. All measures required for
adverse event management must be recorded in the source document and reported according to
sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events 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 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 participant must be
provided with a "wallet (study) card" and instructed to carry this card with them for the duration
of the study indicating the following:
 
Study number
 
Statement, in the local language(s), that the participant is participating in a clinical study
 
Investigator's name and 24-hour contact telephone number
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 
Local sponsor's name and 24-hour contact telephone number (for medical staff only)
 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
12.3.2. 
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious
Adverse Event Form, which must be completed and signed by a physician from the study site, and
transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious adverse
event should be made by email (facsimile [fax] is acceptable if email is not an option for the site).
All serious adverse events that have not resolved by the end of the study, or that have not resolved
upon discontinuation of the participant 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 study product or to factors unrelated to
study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs
during the course of a participant’s participation in a study must be reported as a serious adverse
event, except hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or adverse event (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 serious adverse events. Any adverse event that results in a prolongation of the
originally planned hospitalization is to be reported as a new serious adverse event.
The cause of death of a participant in a study during the entire study period, whether or not the
event is expected or associated with the study product, is considered a serious adverse event.
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12.3.3. 
Pregnancy
All initial reports of pregnancy in participants or partners of participants must be reported to the
sponsor by the study-site personnel within 24 hours of their knowledge of the event using the
appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious
adverse events and must be reported using the Serious Adverse Event Form. Any participant who
becomes pregnant during the study must discontinue further vaccination.
Follow-up information regarding the outcome of the pregnancy will be required. Any postnatal
sequelae in the infant will be collected, if possible.
12.3.4. 
Adverse Events of Special Interest
Adverse Events of Special Interest (AESIs) (including potential AESIs) are significant AEs that
are judged to be of special interest because of clinical importance, known or suspected class
effects, or based on nonclinical signals. AESIs (including potential AESIs) will be carefully
monitored during the study by the sponsor.
AESIs (including potential AESIs) must be reported to the sponsor within 24 hours of awareness
irrespective of seriousness (ie, serious and nonserious AEs) or causality following the procedure
described above for SAEs.
AESIs (including potential AESIs) must be reported using the AESI checkbox in the eCRF using
the eCRF completion guidelines.
Specific requirements for the AESI are described below.
12.3.4.1. 
Thrombosis with Thrombocytopenia Syndrome
As described in Section 1.1.2, TTS has been observed following vaccination with Janssen COVID
vaccine and is considered to be an AESI in this study. TTS is a syndrome characterized by a
combination of both a thrombotic event and thrombocytopenia.2,5
Because this syndrome is rare and not completely understood, all cases of thrombosis and/or
thrombocytopenia will be considered a potential case of TTS and should be reported to the sponsor
within 24 hours of awareness using the SAE form (even in cases that are not considered ‘serious’).
Each potential AESI will be reviewed to identify a TTS case. A Charter will describe the roles and
responsibilities of the Committee appointed to perform this review. A potential TTS case is defined
as:
 
Thrombotic events: suspected deep vessel venous or arterial thrombotic events as detailed in
Attachment 4,
and/or
 
Thrombocytopenia, defined as platelet count below LLN for the testing lab
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Symptoms, signs, or conditions suggestive of a thrombotic event or thrombocytopenia should be
recorded and reported as a potential AESI even if the final or definitive diagnosis has not yet been
determined, and alternative diagnoses have not yet been eliminated or shown to be less likely.
Follow-up information and final diagnoses, if applicable, should be submitted to the sponsor as
soon as they become available.
In the event of thrombocytopenia, study site personnel should report the absolute value for the
platelet count and the reference range for the laboratory test used.
For either a thrombotic event or thrombocytopenia, a serum sample should be obtained to test for
anti-PF4 at the local laboratory or substitute local laboratory, if possible; repeat testing may be
requested for confirmation upon sponsor discretion. A test for anti-PF4 will also be performed on
a stored pre-vaccination sample, if possible.
AESIs (including potential AESIs) will require enhanced data collection and evaluation. Every
effort should be made to report as much information as possible about the event to the sponsor in
a reasonable timeframe.
If an event meets the criteria for an SAE (Section 12.1.1), it should be reported using the same
process as for other SAEs.
Treatment and Follow-up Recommendation
The medical management of thrombotic events with thrombocytopenia is different from the
management of isolated thromboembolic diseases. Study site personnel and/or treating physicians
should follow available guidelines for treatment of thrombotic thrombocytopenia (eg, American
Society of Hematology 20212; British Society of Haematology 20216; CDC 20218). The use of
heparin may be harmful and alternative treatments may be needed. Consultation with a
hematologist is strongly recommended.
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 participants,
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.
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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 a serious adverse event, the study-site personnel must report the
PQC to the sponsor according to the serious adverse event reporting timelines (refer to
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be maintained
for further investigation if requested by the sponsor.
13.2. Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.
14. 
STUDY PRODUCT INFORMATION
14.1. Physical Description of Study product(s)
The candidate components of the VAC89220 HIV-1 vaccine supplied for this study are formulated
as follows:
Ad26.Mos4.HIV
Ad26.Mos4.HIV is a tetravalent vaccine composed of four pre-mixed recombinant, replication-
incompetent serotype 26 adenoviruses, in a 1:1:1:1 vp ratio:
 
Ad26.Mos1.Gag-Pol: serotype 26 adenovirus encoding for Mosaic 1 HIV-1 Gag and Pol
proteins, manufactured in PER.C6® cells (JNJ-55471494).
 
Ad26.Mos2.Gag-Pol: serotype 26 adenovirus encoding for Mosaic 2 HIV-1 Gag and Pol
proteins, manufactured in PER.C6® cells (JNJ-55471520).
 
Ad26.Mos1.Env: serotype 26 adenovirus encoding for Mosaic 1 HIV-1 Env protein,
manufactured in PER.C6® cells (JNJ-55471468).
 
Ad26.Mos2S.Env: serotype 26 adenovirus encoding for Mosaic 2S HIV-1 Env protein,
manufactured in PER.C6® cells (JNJ-64219324).
The Ad26.Mos4.HIV vaccine is supplied as a colorless to slightly yellowish/brownish, clear to
slightly opalescent solution, practically free from particles. The recommended storage condition
of the Ad26.Mos4.HIV vaccine is 2°C to 8°C at the clinical site. The vaccine will be provided in
individual dosage vials at a concentration of 1x1011 vp/mL, for IM injection. Refer to the most
recent version of the Investigator's Brochure for a list of excipients.
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Clade C and Mosaic gp140 HIV Bivalent Vaccine, Recombinant
The Clade C and Mosaic gp140 HIV bivalent vaccine, recombinant (JNJ-65184340) contains
following active pharmaceutical ingredients:
 Clade C gp140 drug substance (DS) is a trimeric, recombinant HIV-1 Env gp140 of Clade C,
produced on a PER.C6® cell line.
 Mosaic gp140 DS is a trimeric, recombinant HIV-1 Env gp140 engineered to contain motifs
of multiple HIV-1 variants produced on a PER.6® cell line.
 Aluminum phosphate adjuvant.
The bivalent drug product (DP) is a vaccine with a dosage strength of 80 mcg Clade C protein and
75 mcg Mosaic protein and 425 mcg aluminum (as aluminum phosphate adjuvant) based on
0.5 mL delivery volume. Note: previously the dose of Clade C gp140 and/or Mosaic gp140 was
reported as mcg of glycoprotein: 125 mcg Clade C gp140 and 125 mcg Mosaic gp140 glycoprotein
corresponds with 80 mcg and 75 mcg of protein, respectively. The DP white to off-white
suspension for IM injection (or essential free of foreign particles). The DP is to be stored at 2 to
8°C. Refer to the most recent version of the Investigator’s Brochure for a list of excipients.
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. All study vaccines will be packaged and labeled, and all placebo
repackaged and relabeled 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 Study-Specific
Procedures Binder.
14.3. Preparation, Handling, and Storage
See the Study-Specific Procedures Binder for guidance on study product preparation, handling, and
storage.
Study vaccine must be stored upright in a secured location at controlled temperature with no access
for unauthorized personnel. 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 replaced. The affected study vaccine must be
quarantined and not used until further instruction from the sponsor is received.
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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. Administration of study
vaccine to the participants will be performed by a blinded qualified healthcare provider from the
study site.
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 participant must be
documented on the intervention accountability form. All study vaccine will be stored and disposed
of according to the sponsor's instructions. Study-site personnel must not combine contents of the
study product containers.
Study product 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 Investigational Product Destruction Form. When the study site
is an authorized destruction unit and study product supplies are destroyed on-site, this must also
be documented on the Investigational Product Destruction Form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be
retained for vaccine accountability purposes.
Study vaccine should be dispensed under the supervision of the investigator or a qualified member
of the study-site personnel, or by a hospital/clinic pharmacist. Study vaccine will be supplied only
to participants in the study. Study vaccine may not be relabeled or reassigned for use by other
participants. The investigator agrees neither to dispense the study product from, nor store it at, any
site other than the study sites agreed upon with the sponsor.
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15. 
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:
 
Investigator's Brochures for Ad26.Mos.HIV and Clade C gp140 and Mosaic gp140
 
Study-Specific Procedures Binder*
 
Sample ICF
 
Participant diary
 
TOU
 
Social Impact Questionnaire
 
Sexual Activity Questionnaire
 
Questionnaire on the use of PrEP
 
Ruler (to measure diameter of any erythema and swelling)
 
Thermometer
 
Participant wallet cards
 
Recruitment tools, as applicable
* 
The Study-Specific Procedures Binder consists of:
 
Study Procedures Manual
 
Guidance documents for identification of risk behavior
 
Guidance document for PrEP
 
Laboratory Manual
 
IWRS Manual
 
eDC Guidelines
 
etc
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16. 
ETHICAL ASPECTS
16.1. Study-Specific Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during
the study, participants will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may be
withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Only potential participants who are fully able to understand the risks,
benefits, and potential adverse events of the study, and provide their consent voluntarily will be
enrolled.
From screening to the final study visit, the total blood volume to be collected from each participant
will be approximately 590 mL (maximum). In case a participant becomes HIV-1 infected, from
visit #.X to the final study visit, additionally approximately 420 mL (maximum) will be taken. The
total blood volume to be collected is within the US Department of Health and Human Services
Office for Human Research Protections, and US Food and Drug Administration (FDA) guidelines
of 550 mL in any 8-week period.
Janssen scientists and operational staff are committed to adhering to all local and national guidance
as well as Good Participatory Practice37, which dictates broad and meaningful stakeholder
engagement (including but not limited to Community Advisory Boards) for input into the planning,
conduct, and follow-up of research to address all pertinent stakeholder issues including the local
cultural and linguistic needs of the communities where the research occurs.
Test of Understanding
The TOU (see Attachment 2) is a short assessment of the potential participant’s understanding of
key aspects of the study. The test will help the study staff to determine how well potential
participants understand the study and their requirements for participation.
Each potential participant must pass the TOU, indicating that he or she understands the purpose
of, and procedures required for the study, after reading the informed consent and after the
investigator or designee has provided detailed information on the study and has answered the
potential participant’s questions. Each participant must subsequently sign the ICF, indicating that
he or she is willing to participate in the study.
Potential participants are allowed to retake the test twice to achieve the passing score (≥90%)
required for participation in the study. Further information and counseling will be provided by the
study team member after each missed question.
Any potential participant not capable of understanding the key aspects of the study, and their
requirements for participation, should not be enrolled.
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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 human participants. Compliance with
this standard provides public assurance that the rights, safety, and well-being of study participants
are protected, consistent with the principles that originated in the Declaration of Helsinki, and that
the study data are credible.
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 participants)
 
Investigator's Brochure (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
 
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
participants, data or study conduct, unless required locally), the ICF, applicable recruiting
materials, and participant compensation programs, and the sponsor/partners have received a copy
of this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to participants
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 
If applicable, new or revised participant recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the 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 adverse events that are serious, unlisted/unexpected, and associated with the study
product
 
New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or studyconduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion.
16.2.3. 
Informed Consent
Each participant must give written consent according to local requirements after the nature of the
study has been fully explained. The ICF(s) must be signed before performance of any study-related
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing
IEC/IRB and be in a language that the potential participant can read and/or 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, andsponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site
personnel must explain to potential participants the aims, methods, reasonably anticipated benefits,
and potential hazards of the study, and any discomfort participation in the study may entail.
Participants will be informed that their participation is voluntary and that they may withdraw
consent to participate at any time. They will be informed that choosing not to participate will not
affect the care the participant will receive. Finally, they will be told that the investigator will
maintain a participant identification register for the purposes of long-term follow-up if needed and
that their records may be accessed by health authorities and authorized sponsor and its partners
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personnel without violating the confidentiality of the participant, to the extent permitted by the
applicable law(s) or regulations. By signing the ICF  the participant is authorizing such access,
which includes permission to obtain information about their HIV status. It also denotes that the
participant agrees to allow his or her study clinician to recontact the participant for the purpose of
obtaining consent for additional safety evaluations, and subsequent disease-related treatments, if
needed.
The participant will be given sufficient time to read the ICF and the opportunity to ask questions.
After this explanation and before entry into the study, consent should be appropriately recorded by
means of the participant's personally dated signature. After having obtained the consent, a copy of
the ICF must be given to the participant.
If the participant is unable to read or write, an impartial witness should be present for the entire
informed consent process (which includes reading and explaining all written information) and
should personally date and sign the ICF after the oral consent of the participant is obtained.
16.2.4. 
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor and its partners personnel whose responsibilities require access to personal data agree to
keep the identity of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of
personal data and for the investigator/institutionto allow direct access to his or her original medical
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and
regulatory inspection. This consent also addresses the transfer of the data to other entities and to
other countries.
The participant has the right to request through the investigator access to his or her personal data
and the right to request rectification of any data that are not correct or complete. Reasonable steps
will be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.
Exploratory research is not conducted under standards appropriate for the return of data to
participants. Exploratory research data will not be returned to participants or investigators, unless
required by law or local regulations. Privacy and confidentiality of data generated in the future on
stored samples will be protected by the same standards applicable to all other clinical data.
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16.2.5. 
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand vaccines, to understand
differential vaccine responders, and to develop tests/assays related to vaccines, and may include
DNA/RNA testing. The research may begin at any time during the study or the post-study storage
period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Participants may withdraw their consent for their samples to be
stored for research (refer to Section  10.4, Withdrawal From the Use of Samples in Future
Research).
16.2.6. 
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help
ensure access to the developed product if the need for the product persists, unless explicitly
addressed as a specific ethical consideration in Section 16.1, Study-Specific Design
Considerations.
17. 
ADMINISTRATIVE REQUIREMENTS
17.1. Protocol Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification
communication (PCC) may be prepared. The PCC Document will be communicated to the
Investigational Site, Site Monitors, Local Trial Managers (LTMs), Clinical Trial Managers
(CTMs), and/or Contract Research Organizations (CROs) who will ensure that the PCC
explanations are followed by the investigators.
The PCC Document may be shared by the sites with Independent Ethics Committees/Institutional
Review Boards (IECs/IRBs) per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the
PCC Document must be included in any future protocol amendments.
17.2. Protocol Amendments
Neither the investigator nor the sponsor or its partners will modify this protocol without a formal
amendment by the sponsor. All protocol amendments must be issued by the sponsor and signed
and dated by the investigator. Protocol amendments must not be implemented without prior
IEC/IRB approval, or when the relevant competent authority has raised any grounds for non-
acceptance, except when necessary to eliminate immediate hazards to the participants, in which
case the amendment must be promptly submitted to the IEC/IRB and relevant competent authority.
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the
IEC/IRB (where required) only needs to be notified.
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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 protocol
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 protocol representative 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.
17.3. Regulatory Documentation
17.3.1. 
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
17.3.2. 
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study product to the
study site:
 
Protocol and amendment(s), if any, signed and dated by the principal investigator
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, participant compensation programs. This approval must clearly identify the
specific protocol by title and number and must be signed (or sealed, where appropriate per
local regulations) by the chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study-site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
 
Documentation of investigator qualifications (eg, curriculum vitae)
 
Completed investigator financial disclosure form from the principal investigator, where
required
 
Signed and dated Clinical Trial Agreement, which includes the financial agreement
 
Any other documentation required by local regulations
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The following documents must be provided to the sponsor before enrollment of the first
participant:
 
Completed investigator financial disclosure forms from all subinvestigators
 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable
 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
17.4. Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor/partner study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not randomized
into the study, the date seen and age at initial informed consent will be used.
The investigator must also complete a participant screening log, which reports on all participants
who were seen to determine eligibility for inclusion in the study.
17.5. 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:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all adverse events and follow-up of adverse events; concomitant medication;
intervention receipt/dispensing/return records; study product administration information; and date
of study completion and reason for early discontinuation of study product 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 electronic source 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/partner. If the electronic source system is utilized, references made
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to the CRF in the protocol include the electronic source system but information collected through
the electronic source system may not be limited to that found in the CRF. Data in this system may
be considered source documentation.
Participant- and investigator-completed scales and assessments designated by the sponsor/partner
will be recorded and will be considered source data. The participant’s diary used to collect
information regarding solicited signs and symptoms after vaccination will be considered source
data.
17.6. Case Report Form Completion
Case report forms are prepared and provided by the sponsor/partner for each participant 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/partner.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into
CRF in English. The CRF must be completed as soon as possible after a participant visit and the
forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other 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.
17.7. 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, 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.
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The sponsor will review CRF 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.
17.8. 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 participant, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institutionmust permit access to such reports.
17.9. Monitoring
The sponsor will use a combination of monitoring techniques (central, remote, or on-site
monitoring) to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study-site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the
monitor will compare 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.
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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.
17.10. Study Completion/Termination
17.10.1. 
Study Completion/End of Study
The study is considered completed with the last visit for the last participant in the study. The final
data from the study site will be sent to the sponsor and its partners (or designee) after completion
of the final participant visit at that study site, in the time frame specified in the Clinical Trial
Agreement.
17.10.2. 
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
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 participants by the investigator
 
Discontinuation of further study product development
17.11. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Participant privacy must, however, be
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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.
17.12. Use of Information and Publication
If applicable, study results will be communicated to the study participants through the study sites
and/or community representatives prior to general public disclosure (eg, at a conference).
All information, including but not limited to information regarding VAC89220  or the sponsor's
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including exploratory research data, generated as a result of
this study, are considered confidential and remain the sole property of the sponsor. The investigator
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 VAC89220, and thus may be disclosed
as required to other clinical investigators or regulatory agencies. To permit the information derived
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of exploratory
analyses performed after the Clinical Study Report has been issued will be reported in a separate
report and will not require a revision of the Clinical Study Report. Study participant identifiers
will not be used in publication of results. Any work created in connection with performance of the
study and contained in the data that can benefit from copyright protection (except any publication
by the investigator as provided for below) shall be the property of the sponsor as author and owner
of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors guidelines, the sponsor shall have the right to publish such primary (multi-center) data and
information without approval from the investigator. The investigator has the right to publish study-
site-specific data after the primary data are published. If an investigator wishes to publish
information from the study, a copy of the manuscript must be provided to the sponsor and its
partners for review at least 21 days before submission for publication or presentation. At the
request of the sponsor and/or partners, such submission may be delayed up to 60 days. Expedited
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reviews will be arranged for abstracts, poster presentations, or other materials. If requested by the
sponsor in writing, the investigator will withhold such publication for up to an additional 60 days
to allow for filing of a patent application. In the event that issues arise regarding scientific integrity
or regulatory compliance, the sponsor will review these issues with the investigator. The sponsor
will not mandate modifications to scientific content and does not have the right to suppress
information. For multi-center study designs and substudy approaches, secondary results generally
should not be published before the primary endpoints of a study have been published. Similarly,
investigators will recognize the integrity of a multi-center study by not submitting for publication
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 18 months after study end date, or the sponsor
confirms there will be no multi-center study publication. Authorship of publications resulting from
this study will be based on the guidelines on authorship, such as those described in the International
Committee of Medical Journal Editors Recommendations for the Conduct, Reporting, Editing and
Publication of Scholarly Work in Medical Journals, which state that the named authors must have
made a significant contribution to the conception or design of the work; or the acquisition, analysis,
or interpretation of the data for the work; and drafted the work or revised it critically for important
intellectual content; and given final approval of the version to be published; and agreed to be
accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity
of any part of the work are appropriately investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by applicable 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 participants and
study-site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being reassigned to critical tasks, and may lead to a pause (after agreement between
the sponsor and the study site).
In alignment with recent health authority guidance, the sponsor is providing options for study
related participant management in the event of disruption to the conduct of the study. This guidance
does not supersede any local or government requirements or the clinical judgement of the
investigator to protect the health and well-being of participants and site staff 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.a At each contact, participants will be interviewed to collect safety data. Key endpoint
assessments should be performed if required and as feasible. Participants will also be questioned
regarding general health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments. Modifications to
protocol-required assessments may be permitted via COVID-19 Appendix after consultation with
the participant, investigator, and the sponsor. Missed assessments/visits will be captured in the
clinical trial management system for protocol deviations. Discontinuations of study interventions
and withdrawal from the study should be documented with the prefix “COVID-19-related” in the
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 participant has tested positive for 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.
a An on-site visit is defined as a visit during which the participant and the qualified and blinded 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 participant
and the qualified and blinded site staff (telephone or video call).
A home visit is defined as a visit during which the participant and the qualified and blinded site staff are both present
at the participants’ home.
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GUIDANCE SPECIFIC TO THIS PROTOCOL:
The following emergency provisions are meant to ensure participant 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 participants. The sponsor has developed a specific process
allowing activity to resume on a site-by-site basis when deemed safe to do so based on a risk
assessment.
Screening
 
During COVID-19-related pauses, all screening activities and enrollment of new participants
are stopped to safeguard well-being of individuals. Participants who are in screening at this
time, will be classified as screen failures, which will be captured in the CRF using the pre-fix
'COVID-19-related'. When screening activities can be resumed, these participants will be
allowed to be rescreened. Although protocol Section 9.1.3 states that potential participants
who fail screening can be rescreened only once, the COVID-19-related screen failure will not
be counted in this respect.
Vaccination Visits
 
During COVID-19-related pauses, study vaccine administration is put on hold. At the next
possible on-site visit, the study vaccine may be administered. Vaccination outside of the
window can be assessed on a case-by-case basis following approval and recommendations
from the safety review team and will be documented as ‘COVID-19-related’.
Other Study Visits and Assessments
 
When site visits are not possible, sites should collect the assessments via remote visits or via
home visits (if possible and if the participant allows and provides consent to it). For
participants having received one or more vaccinations, post-vaccination visits can be
conducted remotely with the main objective to collect safety and reactogenicity data, if
possible. The actual visit date and the type of visit (ie, remote or home visit) should be
captured in the eCRF according to the eCRF completion guidelines.
 
Procedures that can’t be performed in case of remote visits (eg, blood/urine sampling,
swabbing), including missed assessments related to efficacy endpoints (in-study HIV testing
and sampling for immunogenicity testing), should be documented as protocol deviations and
labelled as “missed due to COVID-19”. The protocol deviations need to be captured in the
source document.
 
Reactogenicity assessment should be discussed during the remote visits. Diary reconciliation
by the investigator will be done at the next possible on-site visit or at a home visit if possible
and agreed by the participant. At the end of the study, all diaries should be on site for final
reconciliation and filed in participants’ folders.
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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 and the Clinical Research Site should collect an
additional specimen for HIV-1 PCR RNA testing at a local laboratory. The site should collect
the specimen appropriate to local lab requirements for this purpose. Locally performed rapid
test, enzyme immunoassay (EIA), or chemiluminescence microparticle immunoassay (CMIA)
should NOT be used due to potential risk of unblinding to clinical staff. Local HIV-1 PCR
RNA testing will be used only for clinical management of the participants and will not replace
the in-study HIV diagnostics testing for protocol endpoints. The local testing result should be
recorded in the source document. Sites should continue to collect all specimens that are
required per the Specimen Collection Table SSP (including specimens for HIV diagnostics
testing).
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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pediatric vaccines? A prospective cohort study. Eur J Pediatr. 2014;173(10): 1297–1307.
41. Bergfors E, Trollfors B, Inerot A. Unexpectedly high incidence of persistent itching nodules and delayed
hypersensitivity to aluminium in children after the use of adsorbed vaccines from a single manufacturer.
Vaccine. 2003;22(1):64-69.
42. Netterlid E, Bruze M, Hindsén M, Isaksson M, Olin P. Persistent itching nodules after the fourth dose of
diphtheria-tetanus toxoid vaccines without evidence of delayed hypersensitivity to aluminium. Vaccine.
2004;22(27-28):3698-3706.
43. Keith LS, Jones DE, Chou CH. Aluminum toxicokinetics regarding infant diet and vaccinations. Vaccine.
2002;20 Suppl 3:S13-17.
44. Mitkus RJ, King DB, Hess MA, Forshee RA, Walderhaug MO. Updated aluminum pharmacokinetics
following infant exposures through diet and vaccination. Vaccine. 2011;29(51):9538-9543.
45. Ameratunga R, Gillis D, Gold M, Linneberg A, Elwood JM. Evidence Refuting the Existence of
Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants (ASIA). J Allergy Clin Immunol Pract.
2017;5(6):1551-1555.e1.
46. Investigator's Brochure: Ad26.Mos.HIV - Ad26.Mos4.HIV. Edition 6. Janssen Vaccines & Prevention B.V.
(7 March 2019).
47. Investigator's Brochure: Clade C gp140 - Mosaic gp140. Edition 6. Janssen Vaccines & Prevention B.V.
(7 February 2019).
48. National Institute of Allergy and Infectious Diseases (NIH). Experimental HIV vaccine regimen ineffective in
preventing HIV. February 3, 2020, News release. Available at https://www.niaid.nih.gov/news-
events/experimental-hiv-vaccine-regimen-ineffective-preventing-hiv. Accessed: 24 February 2020.
49. UNAIDS. HVTN 702 clinical trial of an HIV vaccine stopped. Press statement Geneva, 4 February 2020.
Available at:
https://www.unaids.org/en/resources/presscentre/pressreleaseandstatementarchive/2020/february/20200204 va
ccine. Accessed 24 February 2020.
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
133
Status: Approved, Date: 28 February 2023
Attachment 1: Definition of Individual of Childbearing Potential and List of Acceptable Highly Effective
Contraceptive Methods
Definition of Individual of Childbearing Potential
Individual of Childbearing Potential
A participant is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Individual Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause.
 
permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal
occlusion/ligation procedures, and bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal participant
experiences menarche) or the risk of pregnancy changes (eg, a participant who is not
heterosexually active becomes active), a participant must begin a highly effective method of
contraception, as described throughout the inclusion criteria.
List of Highly Effective Contraceptive Methods
Highly effective contraceptive methods, based on the CTFG guidance, for this study include:
1. 
Combined (estrogen and progestogen containing) hormonal contraception associated with
inhibition of ovulation (oral, intravaginal, transdermal)a
2. 
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral,
injectible, implantable)a,b
3. 
Intrauterine device (IUD)a,b
4. 
Intrauterine hormone-releasing system (IUS)a,b
5. 
Bilateral tubal occlusiona,b
6. 
Vasectomized partnerb,c
7. 
Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary
mode of action
a Contraception methods that in the context of the CTFG guidance are considered highly effective.
b Contraception methods that in the context of the CTFG guidance are considered to have low user dependency.
c Vasectomised partner is a highly effective birth control method provided that the partner is the sole sexual partner
of the WOCP study participant and that the vasectomised partner has received medical assessment of the surgical
success.
NCT03964415

NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
135
Status: Approved, Date: 28 February 2023
Attachment 3: List of Potentially Immune-mediated Medical Conditions
The list below contains relevant examples but might not be an exhaustive list.
Gastrointestinal disorders 
Blood disorders
Celiac disease 
Crohn disease 
Ulcerative colitis 
Ulcerative proctitis 
Antiphospholipid syndrome
Autoimmune aplastic anemia
Autoimmune hemolytic anemia
Autoimmune neutropenia
Autoimmune pancytopenia
Autoimmune thrombocytopenia
Pernicious anemia
Liver disorders 
Metabolic disorders
Autoimmune cholangitis 
Autoimmune hepatitis 
Primary biliary cirrhosis 
Primary sclerosing cholangitis 
Addison’s disease
Autoimmune thyroiditis (including Hashimoto
thyroiditis)
Diabetes mellitus type I
Grave’s or Basedow’s disease
Musculoskeletal disorders 
Neuroinflammatory disorders
Antisynthetase syndrome 
Idiopathic inflammatory myopathies, including 
dermatomyositis 
Mixed connective tissue disorder 
Polymyalgia rheumatica 
Polymyositis 
Psoriatic arthropathy  
Relapsing polychondritis 
Rheumatoid arthritis, and associated conditions 
including juvenile chronic arthritis and Still’s disease 
Spondyloarthritis, including ankylosing spondylitis, 
reactive arthritis (Reiter’s Syndrome) and 
undifferentiated spondyloarthritis 
Systemic lupus erythematous and associated conditions 
Systemic scleroderma (Systemic sclerosis), including 
diffuse systemic form and CREST syndrome 
Acute disseminated encephalomyelitis, including site-
specific variants (eg, non-infectious encephalitis,
encephalomyelitis, myelitis, myeloradiculoneuritis)
Cranial nerve disorders, including paralyses/paresis
(eg, Bell’s palsy)
Guillain-Barré syndrome, including Miller Fisher
syndrome and other variants
Immune-mediated peripheral neuropathies and
plexopathies, including chronic inflammatory
demyelinating polyneuropathy, multifocal motor
neuropathy and polyneuropathies associated with
monoclonal gammopathy
Multiple sclerosis
Myasthenia gravis, including Lambert-Eaton
myasthenic syndrome
Narcolepsy
Optic neuritis
Skin disorders 
Vasculitides
Alopeci areata 
Autoimmune bullous skin diseases, including 
pemphigus, pemphigoid, and dermatitis herpetiformis 
Cutaneous lupus erythematosus 
Erythema nodosum  
Lichen planus 
Localized scleroderma (Morphea) 
Psoriasis 
Sweet’s syndrome 
Vitiligo 
Large vessel vasculitis including giant cell arteritis
such as Takayasu’s arteritis and temporal arteritis
Medium sized and/or small vessels vasculitis including
polyarteritis nodosa, Kawasaki’s disease, microscopic
polyangiitis, Wegener’s granulomatosis, Churg-Strauss
syndrome (allergic granulomatous angiitis), Buerger’s
disease (thromboangiitis obliterans), necrotizing
vasculitis and antineutrophil cytoplasmic antibody
(ANCA) positive vasculitis (type unspecified),
Henoch-Schonlein purpura, Behcet’s syndrome,
leukocytoclastic vasculitis
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
136
Status: Approved, Date: 28 February 2023
Others
Autoimmune glomerulonephritis (including IgA
nephropathy, glomerulonephritis rapidly progressive,
membranous glomerulonephritis,
membranoproliferative glomerulonephritis, and
mesangioproliferative glomerulonephritis)
Autoimmune myocarditis/cardiomyopathy
Goodpasture syndrome
Idiopathic pulmonary fibrosis
Ocular autoimmune diseases (including autoimmune
uveitis and autoimmune retinopathy)
Raynaud’s phenomenon
Sarcoidosis
Sjörgen’s syndrome
Stevens-Johnson syndrome
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
137
Status: Approved, Date: 28 February 2023
Attachment 4: Thrombotic Events to be Reported as Potential AESIs
At the time of protocol amendment 5 writing, the list of thrombotic events to be reported to the
sponsor as potential AESIs is provided below. Further guidance may become available on
thrombotic events of interest.
 
MedDRA PTs for large vessel thrombosis and embolism
 
Aortic embolus, aortic thrombosis, aseptic cavernous sinus thrombosis, brain stem
embolism, brain stem thrombosis, carotid arterial embolus, carotid artery thrombosis,
cavernous sinus thrombosis, cerebral artery thrombosis, cerebral venous sinus
thrombosis, cerebral venous thrombosis, superior sagittal sinus thrombosis, transverse
sinus thrombosis, mesenteric artery embolism, mesenteric artery thrombosis, mesenteric
vein thrombosis, splenic artery thrombosis, splenic embolism, splenic thrombosis,
thrombosis mesenteric vessel, visceral venous thrombosis, hepatic artery embolism,
hepatic artery thrombosis, hepatic vein embolism, hepatic vein thrombosis, portal vein
embolism, portal vein thrombosis, portosplenomesenteric venous thrombosis, splenic
vein thrombosis, spontaneous heparin-induced thrombocytopenia syndrome, femoral
artery embolism, iliac artery embolism, jugular vein embolism, jugular vein thrombosis,
subclavian artery embolism, subclavian vein thrombosis, obstetrical pulmonary
embolism, pulmonary artery thrombosis, pulmonary thrombosis, pulmonary venous
thrombosis, renal artery thrombosis, renal embolism, renal vein embolism, renal vein
thrombosis, brachiocephalic vein thrombosis, vena cava embolism, vena cava
thrombosis, truncus coeliacus thrombosis
 
MedDRA PTs for more common thrombotic events
 
Axillary vein thrombosis, deep vein thrombosis, pulmonary embolism, MedDRA PTs for
acute myocardial infarction*, MedDRA PTs for stroke*
Source: Shimabukuro T. CDC COVID-19 Vaccine Task Force. Thrombosis with thrombocytopenia syndrome (TTS)
following Janssen COVID-19 vaccine. Advisory Committee on Immunization Practices (ACIP). April 23, 2021.
https://www.cdc.gov/vaccines/acip/meetings/slides-2021-04-23.html.
*Vaccine Adverse Event Reporting System (VAERS) Standard Operating Procedures for COVID-19 (as of 29 January
2021) https://www.cdc.gov/vaccinesafety/pdf/VAERS-v2-SOP.pdf
NCT03964415

JNJ-55471494, JNJ-55471520, JNJ-55471468, JNJ-64219324, JNJ-65184340
Clinical Protocol VAC89220HPX3002 Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
138
Status: Approved, Date: 28 February 2023
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): 
 by delegation
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.
PPD
NCT03964415

Signature
User 
Date 
Reason
 
28-Feb-2023
17:06:36
(GMT)
Document Approval
PPD
NCT03964415