A Pivotal Phase 2b/3 Multisite, Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Safety and Efficacy of ALVAC-HIV (vCP2438) and Bivalent Subtype C gp120/MF59 in Preventing HIV-1 Infection in Adults in South Africa
Phase: PHASE2
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
PROTOCOL 
HVTN 702 
A pivotal phase 2b/3 multi-site, randomized, double-
blind, placebo-controlled clinical trial to evaluate the 
safety and efficacy of ALVAC-HIV (vCP2438) and 
Bivalent Subtype C gp120/MF59 in preventing HIV-1 
infection in adults in South Africa 
DAIDS DOCUMENT ID 12059 
CLINICAL TRIAL SPONSORED BY 
Division of AIDS (DAIDS) 
National Institute of Allergy and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
Department of Health and Human Services (DHHS) 
Bethesda, Maryland, USA 
STUDY PRODUCT(S) PROVIDED BY 
Sanofi Pasteur 
Swiftwater, Pennsylvania, USA 
 
GlaxoSmithKline Biologicals, S.A. (GSK) 
Rixensart, Belgium 
May 20, 2020 
HVTN 702 
Version 4.0 
 
 

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On 23 January 2020, in reviewing cumulative unblinded data for HVTN 702, the 
NIAID HIV Vaccine Data Safety and Monitoring Board (DSMB) found that pre-
established criteria for vaccine non-efficacy had been met. Accordingly, the DSMB 
recommended halting vaccinations. The HVTN 702 Oversight Group (OG) concurred 
with this DSMB recommendation and vaccinations in HVTN 702 were stopped as of 
3 February 2020. The OG further determined that all HVTN 702 participants who 
have not yet completed their clinic visits schedules should be followed for safety for 
12 months after the last vaccination they received.  
Since no more participants will be vaccinated at Visit 11 (Month 18), Visit 12 (Month 
18.5), whose purpose was evaluation of safety and immunogenicity following the 
vaccination at Visit 11, has been removed from the schedule. The visit schedule for 
the 12-month follow-up period for all participants remains otherwise unchanged.  
HVTN 702 had an adaptive two-stage design. Stage 1 entailed following all 
participants for 24 months post-enrollment. Stage 2 was to be conducted if the 
vaccine was found to be efficacious at the end of Stage 1 and entailed following all 
participants for an additional 12 months to 36 months post-enrollment. Because the 
criteria for vaccine non-efficacy were met during Stage 1, Stage 2 of the trial will not 
occur.  
All participants have been unblinded to their treatment assignments. Follow-up will 
continue in an unblinded fashion. 
Procedures specified for remaining follow-up visits have been revised. Because all 
remaining participants are now at least 3 months post-vaccination, pregnancy tests 
and contraception assessments have been removed from the list of procedures. 
Because the primary assessment of vaccine efficacy has been completed, further 
laboratory testing for ARV is no longer needed. Because all study participants have 
been unblinded, the “Outside testing and belief questionnaire” is no longer needed. 
Remaining procedures, including HIV testing, physical examinations, STI 
testing/treatment, recording of concomitant medications, AE assessment, social 
impact assessment, and specimen collection for safety and selected endpoint 
evaluations remain unchanged.  
The revised study procedures are shown in new Section 9.4.1 and in new Appendix M 
and Appendix N. 
The visit schedule and procedures for HIV-infected participants (Schedule 2) remain 
unchanged (see Appendix G and Appendix I). 
New Appendix K contains an addendum to the sample consent form that updates 
study information and new Appendix L contains tables of procedures for the consent 
addendum. 

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Contents 
1 Ethical considerations ....................................................................................................6 
2 IRB/EC review considerations .......................................................................................8 
2.1 
Minimized risks to participants ......................................................................8 
2.2 
Reasonable risk/benefit balance .....................................................................9 
2.3 
Equitable subject selection .............................................................................9 
2.4 
Appropriate informed consent ........................................................................9 
2.5 
Adequate safety monitoring .........................................................................10 
2.6 
Protect privacy/confidentiality .....................................................................10 
3 Overview ......................................................................................................................11 
3.1 
Protocol Team ..............................................................................................15 
4 Background ..................................................................................................................17 
4.1 
Burden of HIV and rationale for HIV vaccine development .......................17 
4.2 
Rationale for trial concept ............................................................................17 
4.3 
ALVAC-HIV (vCP2438) .............................................................................29 
4.4 
Bivalent Subtype C gp120/MF59 .................................................................31 
4.5 
Trial design rationale ....................................................................................33 
4.6 
Combination prevention of HIV acquisition ................................................38 
4.7 
Nonclinical studies .......................................................................................39 
4.8 
Plans for future product development and testing ........................................42 
4.9 
Clinical studies .............................................................................................43 
4.10 Potential risks of study products and administration ...................................67 
5 Objectives and endpoints .............................................................................................68 
5.1 
Primary objectives and endpoints ................................................................68 
5.2 
Secondary objectives and endpoints ............................................................69 
5.3 
Exploratory objectives ..................................................................................70 
6 Statistical considerations ..............................................................................................72 
6.1 
Definitions of study cohorts for analysis ......................................................72 
6.2 
Objectives .....................................................................................................73 
6.3 
Study cohorts utilized for evaluations of study endpoints ...........................73 
6.4 
Accrual and sample size ...............................................................................74 
6.5 
Monitoring of trial ........................................................................................76 
6.6 
Assessment of PrEP use ...............................................................................83 
6.7 
Randomization of treatment assignments ....................................................84 
6.8 
Blinding ........................................................................................................84 
6.9 
Statistical analysis ........................................................................................85 
7 Selection and withdrawal of participants .....................................................................92 
7.1 
Inclusion criteria ...........................................................................................92 
7.2 
Exclusion criteria ..........................................................................................94 
7.3 
Participant departure from vaccination schedule or withdrawal ..................96 
8 Study product preparation and administration .............................................................99 
8.1 
Vaccine regimen ...........................................................................................99 
8.2 
Study product formulation ...........................................................................99 
8.3 
Preparation of study products .....................................................................100 

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8.4 
Administration ............................................................................................103 
8.5 
Acquisition of study products ....................................................................103 
8.6 
Pharmacy records .......................................................................................103 
8.7 
Final disposition of study products ............................................................104 
9 Clinical procedures ....................................................................................................105 
9.1 
Informed consent ........................................................................................105 
9.2 
Pre-enrollment procedures .........................................................................107 
9.3 
Enrollment and vaccination visits (pre-unblinding) ...................................108 
9.4 
Follow-up visits (pre-unblinding) ..............................................................110 
9.5 
Stool sampling ............................................................................................112 
9.6 
Procedures for HIV-infected participants ..................................................112 
9.7 
HIV counseling and testing ........................................................................113 
9.8 
Pregnancy prevention assessment ..............................................................115 
9.9 
Assessments of reactogenicity ...................................................................115 
9.10 Visit windows and missed visits ................................................................116 
9.11 Early termination visit ................................................................................117 
9.12 Pregnancy ...................................................................................................117 
10 HIV-1 infection assessment and clinical response.....................................................118 
10.1 HIV-1 symptom assessment .......................................................................118 
10.2 HIV-1 screening test (prior to randomization) ...........................................118 
10.3 HIV-1 testing postvaccination ....................................................................118 
10.4 Endpoint adjudication ................................................................................119 
10.5 HIV-1 infection during the study ...............................................................119 
10.6 Medical care for participants who become HIV-1–infected ......................120 
11 Laboratory ..................................................................................................................121 
11.1 HVTN CRS laboratory procedures ............................................................121 
11.2 Total blood volume ....................................................................................121 
11.3 Assay timepoints ........................................................................................121 
11.4 Endpoint assays: humoral ...........................................................................121 
11.5 Endpoint assays: cellular ............................................................................122 
11.6 Viral sequencing .........................................................................................122 
11.7 ARV detection ............................................................................................122 
11.8 Genotyping .................................................................................................123 
11.9 Laboratory Center assay portfolio ..............................................................123 
11.10 Exploratory studies .....................................................................................123 
11.11 Other use of stored specimens ....................................................................124 
11.12 Biohazard containment ...............................................................................124 
12 Safety monitoring and safety review .........................................................................125 
12.1 Safety monitoring and oversight ................................................................125 
12.2 Safety reporting ..........................................................................................126 
12.3 AEs requiring immediate PSRT notification and prompt PSRT AE review
 129 
12.4 Review of cumulative safety data ..............................................................131 
12.5 Study termination .......................................................................................132 
13 Protocol conduct ........................................................................................................133 

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13.1 Protocol governance ...................................................................................134 
13.2 Social impacts ............................................................................................135 
13.3 Compliance with NIH guidelines for research involving products containing 
recombinant DNA ......................................................................................135 
13.4 Specific regulatory considerations for Republic of South Africa ..............136 
13.5 Emergency communication with study participants ..................................136 
14 Version history ...........................................................................................................137 
15 Document references (other than literature citations) ................................................144 
16 Acronyms and abbreviations......................................................................................147 
17 Literature cited ...........................................................................................................151 
Appendix A Sample informed consent form ..................................................................163 
Appendix B Approved birth control methods (for sample informed consent form) ......185 
Appendix C Approved birth control methods for transgender men (for sample informed 
consent form) ..............................................................................................186 
Appendix D Sample consent form for use of samples and information in other studies 187 
Appendix E Tables of procedures (for sample informed consent form) ........................192 
Appendix F Schedule 1: Laboratory procedures for HIV-uninfected participants ........194 
Appendix G Schedule 2: Laboratory procedures for HIV-infected participants ............196 
Appendix H Schedule 1: Procedures at HVTN CRS for HIV-uninfected participants 
(continued on next page) ............................................................................198 
Appendix I Schedule 2: Procedures at HVTN CRS for HIV-infected participants ......200 
Appendix J Adverse events of special interest ..............................................................201 
Appendix K Sample addendum to informed consent form (post-unblinding) ...............202 
Appendix L Tables of procedures (for addendum to sample informed consent form) ..208 
Appendix M Schedule 3: Follow-up laboratory procedures for HIV-uninfected 
participants (post-unblinding) ....................................................................209 
Appendix N Schedule 3: Follow-up procedures at HVTN CRS for HIV-uninfected 
participants (post-unblinding) ....................................................................211 
Appendix O Protocol Signature Page .............................................................................212 
 
 

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1 
Ethical considerations 
Multiple candidate HIV vaccines will need to be studied simultaneously in 
different populations around the world before a successful HIV preventive 
vaccine is found. It is critical that universally accepted ethical guidelines are 
followed at all sites involved in the conduct of these clinical trials. The HIV 
Vaccine Trials Network (HVTN) has addressed ethical concerns in the following 
ways: 
x HVTN trials are designed and conducted to enhance the knowledge base 
necessary to find a preventive vaccine, using methods that are scientifically 
rigorous and valid, and in accordance with Good Clinical Practice (GCP) 
guidelines. 
x HVTN scientists and operational staff incorporate the philosophies underlying 
major codes (1-3), declarations, and other guidance documents relevant to 
human subjects research into the design and conduct of HIV vaccine clinical 
trials. 
x HVTN scientists and operational staff are committed to substantive 
community input—into the planning, conduct, and follow-up of its research—
to help ensure that locally appropriate cultural and linguistic needs of study 
populations are met. Community Advisory Boards (CAB) are required by 
DAIDS and supported at all HVTN research sites to ensure community input, 
in accordance with Good Participatory Practices (GPP) and all local and 
national guidelines. The HVTN leadership is aware of the Guidelines for 
Good Clinical Practice in the Conduct of Clinical Trials with Human 
Participants in South Africa Section 2.4 “Communication and Community 
Involvement” and the South African Medical Research Council’s Guidelines 
on Ethics for Medical Research: HIV Preventive Vaccine Research 
(particularly Section 5, Community Participation) and works to implement 
both guidelines generally and those sections specifically. 
x HVTN clinical trial staff counsel study participants routinely on how to 
reduce HIV risk. Participants who become HIV infected during the trial are 
provided counseling on notifying their partners and about HIV infection 
according to local guidelines. Staff members will also counsel them about 
reducing their risk of transmitting HIV to others. 
x The HVTN requires that all international HVTN sites lacking national plans 
for providing antiretroviral therapy (ART) develop plans for the care and 
treatment of participants who acquire HIV infection during a trial. Each plan 
is developed in consultation with representatives of host countries, 
communities from which potential trial participants will be drawn, sponsors, 
and the HVTN. Participants will be referred to agreed-upon programs for 
ART provision as soon as the participant is willing and able to attend. If a 

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program is not available at a site and ART is needed, a privately established 
fund will be used to pay for access to treatment to the fullest extent possible. 
x The HVTN is committed to ensuring that all trial participants receive access to 
the highest standard of prevention, which may include, but is not limited to, 
risk reduction counseling, provision of male and female condoms, diagnostic 
testing and access to treatment for sexually transmitted infections (STIs), 
information regarding male circumcision and referral to services that can 
provide male circumcision when indicated, and appropriate referrals to pre- 
and postexposure prophylaxis (PrEP and PEP) according to national and/or 
local guidelines. 
x The HVTN provides training so that all participating sites similarly ensure fair 
participant selection, protect the privacy of research participants, and obtain 
meaningful informed consent. During the study, participants will have their 
wellbeing monitored, and to the fullest extent possible, their privacy 
protected. Participants may withdraw from the study at any time. 
x Prior to implementation, HVTN trials are rigorously reviewed by scientists 
who are not involved in the conduct of the trials under consideration. 
x HVTN trials are reviewed by local and national regulatory bodies and are 
conducted in compliance with all applicable national and local regulations. 
x The HVTN designs its research to minimize risk and maximize benefit to both 
study participants and their local communities. For example, HVTN protocols 
provide enhancement of participants’ knowledge of HIV and HIV prevention, 
as well as counseling, guidance, and assistance with any social impacts that 
may result from research participation. HVTN protocols also include careful 
medical review of each research participant’s health conditions and reactions 
to study products while in the study. 
x HVTN research aims to benefit local communities by directly addressing the 
health and HIV prevention needs of those communities and by strengthening 
the capacity of the communities through training, support, shared knowledge, 
and equipment. Researchers involved in HVTN trials are able to conduct other 
critical research in their local research settings. 
x The HVTN recognizes the importance of institutional review and values the 
role of in country Institutional Review Boards (IRBs) and Ethics Committees 
(ECs) as custodians responsible for ensuring the ethical conduct of research in 
each setting. 

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2 
IRB/EC review considerations 
US Food and Drug Administration (FDA) and other US federal regulations 
require IRBs/ECs to ensure that certain requirements are satisfied on initial and 
continuing review of research (Title 45, Code of Federal Regulations (CFR), Part 
46.111(a) 1-7; 21 CFR 56.111(a) 1-7). Each HVTN Investigator welcomes 
IRB/EC questions or concerns regarding these research requirements. 
This trial is being conducted exclusively in South Africa, with funding from the 
US NIH. Due to this, the trial is subject to both US and South African regulations 
and guidelines on the protection of human research subjects and ethical research 
conduct. These research regulations and guidelines are based on ethical principles 
of respect for persons, beneficence and nonmaleficence, and justice. Where there 
is a conflict in regulations or guidelines, the regulation or guideline providing the 
maximum protection of human research subjects will be followed. 
In compliance with the Guidelines For Good Practice In The Conduct Of Clinical 
Trials In Human Participants In South Africa (“South African GCPs”), each 
research location in South Africa has a South African-based Principal Investigator 
(PI) who is qualified to conduct (and supervise the conduct of) the research; and 
the research addresses an important South African health need for an HIV vaccine 
in line with the national strategic plan for South Africa and the national South 
African HIV vaccine plan. In addition, the investigators take responsibility for the 
conduct of the study and the control of the study products, including obtaining all 
appropriate South African regulatory and ethical reviews of the research. Each 
participating site has a standard operating procedure for ensuring that participants 
have the necessary information to make a decision whether or not to consent to 
the research. The sections below address each of the review concerns by 
IRBs/ECs regarding how the research will be conducted. 
2.1 
Minimized risks to participants 
45 CFR 46.111 (a) 1 and 21 CFR 56.111 (a) 1: Risks to subjects are 
minimized. 
This protocol minimizes risks to participants by (a) correctly and promptly 
informing participants about risks so that they can join in partnership with the 
researcher in recognizing and reporting harms; (b) respecting local/national blood 
draw limits; (c) performing direct observation of participants postvaccination and 
collecting information regarding side effects for several days postvaccination; (d) 
having staff properly trained in administering study procedures that may cause 
physical harm or psychological distress, such as blood draws, vaccinations, HIV 
testing and counseling and HIV risk reduction counseling; (e) providing HIV risk 
reduction counseling and checking on contraception use (for women); and (f) 
providing safety monitoring. 

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2.2 
Reasonable risk/benefit balance 
45 CFR 46.111(a) 2 and 21 CFR 56.111(a) 2: Risks to subjects are 
reasonable in relation to anticipated benefits, if any, to subjects, and 
the importance of the knowledge that may reasonably be expected to 
result. 
In all public health research, the risk-benefit ratio may be difficult to assess 
because the benefits to a healthy participant are not as apparent as they would be 
in treatment protocols, where a study participant may be ill and may have 
exhausted all conventional treatment options. However, this protocol is designed 
to minimize the risks to participants while maximizing the potential value of the 
knowledge it is designed to generate. 
2.3 
Equitable subject selection 
45 CFR 46.111 (a) 3 and 21 CFR 56.111 (a) 3: Subject selection is 
equitable 
This protocol has specific inclusion and exclusion criteria for investigators to 
follow in admitting participants into the protocol. Participants are selected 
because of these criteria and not because of positions of vulnerability or privilege. 
Investigators are required to maintain screening and enrollment logs to document 
volunteers who screened into and out of the protocol and for what reasons. 
2.4 
Appropriate informed consent 
45 CFR 46.111 (a) 4 & 5 and 21 CFR 56.111 (a) 4 & 5: Informed 
consent is sought from each prospective subject or the subject’s 
legally authorized representative as required by 45 CFR 46.116 and 
21 CFR Part 50; informed consent is appropriately documented as 
required by 45 CFR 46.117 and 21 CFR 50.27 
The protocol specifies that informed consent must be obtained before any study 
procedures are initiated and assessed throughout the trial (Section 9.1). Each site 
is provided training in informed consent by the HVTN as part of its entering the 
HVTN. The HVTN requires a signed consent document for documentation, in 
addition to chart notes or a consent checklist. 

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2.5 
Adequate safety monitoring 
45 CFR 46.111 (a) 6 and 21 CFR 56.111 (a) 6: There is adequate 
provision for monitoring the data collected to ensure the safety of 
subjects. 
This protocol has extensive safety monitoring in place (Section 12). Safety is 
monitored daily by HVTN Core and routinely by the HVTN 702 Protocol Safety 
Review Team (PSRT). In addition, a Data and Safety Monitoring Board (DSMB) 
periodically reviews study data. 
2.6 
Protect privacy/confidentiality 
45 CFR 46.111 (a) 7 and 21 CFR 56.111 (a) 7: There are adequate 
provisions to protect the privacy of subjects and maintain the 
confidentiality of data. 
Privacy refers to an individual’s right to be free from unauthorized or 
unreasonable intrusion into his/her private life and the right to control access to 
individually identifiable information about him/her. The term “privacy” concerns 
research participants or potential research participants as individuals whereas the 
term “confidentiality” is used to refer to the treatment of information about those 
individuals. This protocol respects the privacy of participants by informing them 
about who will have access to their personal information and study data 
(Appendix A). The privacy of participants is protected by assigning unique 
identifiers in place of the participant’s name on study data and specimens. In 
addition, each staff member at each study site in this protocol signs a 
Confidentiality Agreement with the HVTN and each study site participating in the 
protocol is required to have a standard operating procedure on how the staff 
members will protect the confidentiality of study participants. 

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3 
Overview 
Title 
A pivotal phase 2b/3 multi-site, randomized, double-blind, placebo-controlled 
clinical trial to evaluate the safety and efficacy of ALVAC-HIV (vCP2438) and 
Bivalent Subtype C gp120/MF59 in preventing HIV-1 infection in adults in South 
Africa 
Primary objective(s) 
Primary objective 1: 
To evaluate the vaccine efficacy (VE) of ALVAC-HIV (vCP2438) + Bivalent 
Subtype C gp120/MF59 for the prevention of HIV infection in HIV-seronegative 
South African adults over 24 months from enrollment 
Per the 23 January 2020 DSMB finding that monitoring boundaries for non-
efficacy have been met, Primary objective 1 has been superseded by Primary 
objective 3 below. 
Primary objective 2: 
To evaluate the safety and tolerability of ALVAC-HIV (vCP2438) + Bivalent 
Subtype C gp120/MF59 in adults in South Africa 
Primary objective 3:  
To evaluate the effect of ALVAC-HIV (vCP2438) +Bivalent Subtype C 
gp120/MF59 vaccination on HIV acquisition in HIV-seronegative African adults 
Study products and routes of administration 
x ALVAC-HIV (vCP2438) expresses the gene products ZM96 gp120 (clade C 
strain) linked to the sequences encoding the HIV-1 transmembrane anchor 
(TM) sequence of gp41 (28 amino acids clade B LAI strain) and gag and pro 
(clade B LAI strain). It is formulated as a lyophilized vaccine for injection at a 
dose > 106 cell culture infectious dose 50% (CCID50) and < 1 × 108 CCID50 
(nominal dose of 107 CCID50) and is reconstituted with 1 mL of sterile sodium 
chloride solution (NaCl 0.4%) administered by intramuscular (IM) injection as 
a single dose 
x Bivalent Subtype C gp120/MF59: subtype C TV1.C gp120 Env and 1086.C 
gp120 Env proteins, each at a dose of 100 mcg, mixed with MF59 adjuvant 
(an oil-in-water emulsion) and delivered as a 0.5 mL IM injection 
x ALVAC-HIV placebo: Sodium Chloride for injection, 0.9% delivered as a 1 
mL IM injection 

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x Bivalent subtype C gp120/MF59 placebo: Sodium Chloride for injection, 
0.9%, delivered as a 0.5 mL IM injection 
Table 3-1 Schema 
Group 
N* 
Primary vaccine regimen 
Boosters 
Month 0 
Month 1 
Month 3 
Month 6 
Month 12 
Month 18 
1 
2700 
ALVAC-
HIV 
(vCP2438) 
ALVAC-
HIV 
(vCP2438) 
ALVAC-HIV 
(vCP2438) + 
Bivalent 
Subtype C 
gp120/MF59 
ALVAC-HIV 
(vCP2438)+ 
Bivalent 
Subtype C 
gp120/MF59 
ALVAC-HIV 
(vCP2438) + 
Bivalent 
Subtype C 
gp120/MF59 
ALVAC-HIV 
(vCP2438) + 
Bivalent 
Subtype C 
gp120/MF59 
2 
2700 
Placebo 
Placebo 
Placebo + 
Placebo 
Placebo + 
Placebo 
Placebo + 
Placebo 
Placebo + 
Placebo 
Total  
5400 
 
 
 
 
 
 
* Due to the randomization scheme, the numbers of vaccine and placebo recipients 
may differ slightly. 
Participants 
5400 healthy, HIV-1–uninfected adults in South Africa who are aged 18 to 35 
years and who are at risk for HIV infection, with 2700 vaccinees and 2700 
placebo recipients. To preserve study power, no more than 35% and no fewer than 
30% of participants born male will be enrolled. 
Actual enrollment was 5407, 2706 of whom received vaccine and 2701 received 
placebo. These represented 5404 unique individuals, of whom 2704 received 
vaccine and 2700 received placebo. 
Design 
Multicenter, randomized, placebo-controlled, double-blind trial with interim 
safety and immunogenicity assessments and interim analyses of efficacy 
Duration per participant 
Minimum 24, maximum 42 months per participant (including 6 months follow-up 
should a participant be diagnosed with HIV infection at their last scheduled study 
visit). All HIV-1–uninfected study participants will be followed for at least 24 
months following enrollment unless an interim monitoring boundary is reached. If 
the vaccine efficacy analysis in Stage 1 (ie, months 0-24) supports continuation of 
the study through Stage 2 (ie, months 24-36), all HIV-1–uninfected study 
participants will be followed for 36 months of scheduled clinic visits. Participants 
who become HIV-1–infected during the study will be followed for approximately 
6 months after confirmation of diagnosis. 

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The NIAID DSMB determined on 23 January 2020 that the interim non-efficacy 
boundary had been reached. Accordingly, vaccinations were stopped on 3 
February 2020 and it was determined that participants should be unblinded and 
that follow up for HIV-uninfected participants should last 12 months following 
their last vaccination. At that time the last enrolled participant had passed the 
timepoint for the scheduled Month 6 vaccination; hence, the minimum scheduled 
study duration for this participant is 18 months. Some participants had already 
reached the 36-month maximum duration for HIV-1–uninfected participants. As 
indicated above, participants who become HIV-1 infected during the study will be 
followed for approximately 6 months after confirmation of diagnosis. 
Estimated total study duration 
Approximately 62 months. This includes 20 months projected for enrollment, up 
to 36 months follow-up for the last enrolled HIV-uninfected participant, and 6 
months follow-up should the last-enrolled participant be diagnosed with HIV 
infection at the last [ie, Month 36] scheduled clinic visit. 
Following cessation of vaccination and reduction of follow-up duration for HIV-
1–uninfected participants, the estimated total study duration is reduced to 
approximately 44 months. 
Study sponsor 
DAIDS, NIAID, NIH, DHHS (Bethesda, Maryland, USA) 
Study product providers 
x ALVAC-HIV (vCP2438): Sanofi-Pasteur (Swiftwater, Pennsylvania, USA ) 
x Bivalent Subtype C gp120/MF59: GlaxoSmithKline Biologicals, S.A. 
(Rixensart, Belgium) 
Core operations 
HVTN Vaccine Leadership Group/Core Operations Center, Fred Hutchinson 
Cancer Research Center (FHCRC) (Seattle, Washington, USA) 
Statistical and data management center (SDMC) 
Statistical Center for HIV/AIDS Research and Prevention (SCHARP), FHCRC 
(Seattle, Washington, USA) 
Endpoint assay laboratories 
x HIV Sero-Molecular Laboratory–National Institute for Communicable 
Diseases (HSML-NICD) (Johannesburg, South Africa) 

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x South Africa Immunology Laboratory–National Institute for Communicable 
Diseases (SAIL-NICD) (Johannesburg, South Africa) 
x Cape Town HVTN Immunology Laboratory (CHIL) (Cape Town, South 
Africa) 
x Duke University Medical Center (Durham, North Carolina, USA) 
x FHCRC/University of Washington (Seattle, Washington, USA) 
x University of Cape Town (Cape Town, South Africa) 
x University of Colorado, Denver (Aurora, Colorado, USA) 
x University of Washington Virology Specialist Laboratory (UW-VSL) (Seattle, 
Washington, USA) 
Study sites 
HVTN Clinical Research Sites (HVTN CRSs) to be specified in the Site 
Announcement Memo 
Safety monitoring 
HVTN 702 PSRT; NIAID DSMB 

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3.1 
Protocol Team 
Protocol leadership 
Chair 
Glenda Gray 
Perinatal HIV Research Unit 
(PHRU), Chris Hani Baragwanath 
Hospital, Soweto; President, South 
African Medical Research Council 
011-27-11-989 9702 
glenda.gray@mrc.ac.za 
Statisticians 
Yunda Huang 
SCHARP, FHCRC 
206-667-5780 
yunda@scharp.org 
Cochair 
Linda-Gail Bekker 
The Desmond Tutu HIV Centre, 
Cape Town, South Africa 
27-21-650-6959 
linda-gail.bekker@hiv-
research.org.za 
 
Holly Janes 
SCHARP, FHCRC 
206-667-6353 
hjanes@scharp.org 
 
Fatima Laher 
PHRU, Chris Hani Baragwanath 
Hospital, Soweto, South Africa 
27-11-989-9720 
laherf@phru.co.za 
 
Zoe Moodie 
SCHARP, FHCRC 
206-667-7077 
zoe@scharp.org 
 
Mookho Malahleha 
Setshaba Research Centre, 
Soshanguve, South Africa 
27-12-799-2422 
MMalahleha@setshaba.org.za 
Medical officer 
Mary Allen 
DAIDS, NIAID 
240-627-3036 
mallen@niaid.nih.gov  
Protocol Team 
leader 
Nicole Grunenberg 
HVTN Core, FHCRC 
206-667-2043 
ngrunenb@fredhutch.org 
Laboratory lead 
John Hural 
HVTN Laboratory Program, 
FHCRC 
206-667-1683 
jhural@fredhutch.com 
Other contributors  
Core medical 
monitor 
Nicole Grunenberg 
HVTN Core, FHCRC 
DAIDS protocol 
pharmacist 
Irene Rwakazina 
DAIDS, NIAID 
301-761-7269 
Regional medical 
liaison 
Simba Takuva 
HVTN Core, FHCRC 
Statistical research 
associates 
Doug Grove 
SCHARP, FHCRC 
Vaccine developer 
representatives 
Carlos DiazGranados 
Sanofi Pasteur 
 
Brittany Sanchez 
SCHARP, FHCRC 
 
Marguerite Koutsoukos  
GSK 
Social behavioral 
scientists 
Michele Andrasik 
HVTN Core, FHCRC 
 
Olivier Van Der Meeren 
GSK 
 
Millicent Atujuna 
The Desmond Tutu HIV Centre, 
University of Cape Town 
Laboratory program 
representative 
Lisa Sanders 
HVTN Laboratory Center, 
FHCRC 
Clinical safety specialist 
Megan Jones 
HVTN Core, FHCRC 
Regulatory affairs 
associate 
Elizabeth Briesemeister 
HVTN Core, FHCRC 
Clinical trials manager 
Shelly Ramirez 
HVTN Core, FHCRC 
Clinic coordinator 
Katlego Mapetla 
Setshaba CRS  
DAIDS Project Officer 
Michael Pensiero 
DAIDS, NIAID 
Community Advisory 
Board (CAB) 
members 
Praise Moyo 
Emavundleni CRS 
Protocol development 
manager 
Carter Bentley 
HVTN Core, FHCRC 

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Jim Tabane 
Setshaba CRS 
Community engagement 
unit representative 
Kagisho Baepanye  
HVTN Core, FHCRC 
 
Thembeka Maduna 
Soweto (PHRU) CRS 
Community 
educator/recruiter 
Phumla Madi 
PHRU – Kliptown CRS 
 
 
Technical editor 
Erik Schwab 
HVTN Core, FHCRC 
 
 
 
 
 
 
 
 
 
 
 
 

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4 
Background 
4.1 
Burden of HIV and rationale for HIV vaccine development 
Despite remarkable advances in antiretroviral use both to treat HIV and to prevent 
vertical and horizontal transmission of HIV (4-9), the HIV epidemic grows 
relentlessly worldwide. Over 2.1 million new infections occur each year, two 
thirds in women and 240,000 in children (10, 11). In heavily affected countries, 
HIV infection rates have at best stabilized; in southern Africa the annualized 
acquisition rates in persons in their first decade of sexual activity average 3-5% 
(12-14). With approximately 6.8 million people living with HIV as of 2014 (15), 
South Africa’s epidemic remains the largest in the world, and the vast majority of 
newly acquired infections occur during unprotected heterosexual intercourse. 
These figures clearly indicate that southern Africa is far from achieving the 
international health community’s stated goal of an “AIDS-free generation” (5). 
Treatment scale-up (16), medical male circumcision (17), and rolling out 
strategies to prevent mother-to-child transmission (4) may help control the HIV 
epidemic, but biomedical interventions that are not user dependent or time critical 
(eg, pericoital) and that do not rely on only one gender will be pivotal to curtail 
the ongoing HIV acquisition seen in young women and their partners. Due to cost, 
complexity of roll-out, adherence requirements, and the reservation of 
antiretroviral therapy for treatment, systemic or topical antiretroviral (ARV)–
based biomedical interventions (5-8) to prevent sexual acquisition of HIV in 
southern Africa may have limited impact at a population level, despite reported 
efficacy. These countries may benefit from alternatives that are sustainable, 
affordable, and implementable; therefore, an effective HIV vaccine remains an 
important tool for the long-term control and eventual elimination of HIV 
transmission and investment in HIV vaccine evaluation remains critical (18). 
4.2 
Rationale for trial concept 
4.2.1 
Rationale for the HVTN 702 phase 2b/3 HIV vaccine trial 
RV144 was a phase III randomized controlled clinical trial conducted by the US 
Military HIV Research Program and the Thailand Ministry of Health in 
approximately 16,000 HIV-1–uninfected adults between the ages of 18-30 years 
at varying degrees of HIV risk in Thailand (19). The clinical trial evaluated the 
heterologous prime-boost combination of 2 canarypox primes ALVAC-HIV 
(vCP1521), expressing clade E env and clade B gag and pro, followed by 2 
ALVAC-HIV + AIDSVAX clades B/E gp120 protein boosts. These products 
were designed to match HIV-1 strains commonly circulating in Thailand at the 
time. This vaccine regimen demonstrated 31.2% efficacy when compared with 
placebo (n = 51 vs. n = 74, respectively; p = 0.04) at 3.5 years (19). Although 
evaluation of vaccine efficacy at 12 months post vaccination was not included in 
the pre-specified analysis, substantially greater reduction in acquisition was 

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observed one year postvaccination (estimated 60.5%, 95% confidence interval 
[CI] 22%-80%), with the vaccine effect waning over time (Figure 4-1) to 31% 
cumulative through 3.5 years (20). 
 
Figure 4-1 Observed vaccine efficacy (cumulative over time) in the RV144 trial (figure 
produced by P. Gilbert with data published by Robb et al [20]) 
Following the announcement of these promising efficacy results (19) and the 
subsequent identification of immunological correlates of risk in that trial (21) 
(Section 4.2.2 below), an effort was undertaken by a public-private partnership 
(the Pox-Protein Public Private Partnership [P5]) to adapt the RV144 ALVAC-
HIV/gp120 vaccine design to more closely match the subtype C HIV strains 
predominant in southern Africa (22-33), the region most in need of an effective 
prophylactic HIV vaccine (34-38). The resulting vaccine regimen was designed to 
strike a balance between maintaining a close link to the RV144 vaccine regimen 
and the need to target the clade C HIV-1 virus while, at the same time, potentially 
improving the magnitude and durability of immune responses in ways that may 
translate into improvements in vaccine efficacy (Section 4.2.3). 
The trigger to initiate enrollment of HVTN 702 will be based on the safety and 
immunogenicity data from HVTN 100, a phase 1-2 trial of the same vaccine 
regimen. HVTN 100 data demonstrating that the vaccine regimen with 2 primes 
and 2 boosts, regardless of the 3rd boost, is safe and produces key immune 
responses comparable or superior to those induced by the RV144 vaccine regimen 
will be the impetus for evaluating the preventive efficacy of the regimen. 
HVTN 702 is a pivotal phase 2b/3 trial designed so that, if the vaccine regimen 
proves sufficiently efficacious, the data will support an application for marketing 
authorization in the Republic of South Africa (RSA). 

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4.2.2 
Correlates of risk (CoR) in RV144 
To better understand how the RV144 vaccine regimen reduced the risk of HIV 
infection, a large consortium of independent laboratories worked together 
systematically to ensure that maximal information could be derived from samples 
obtained from RV144 vaccinees who became infected compared with vaccinees 
who remained HIV uninfected at the end of the trial. A case control study was 
performed on 41 infected vaccine recipients, 205 uninfected vaccine recipients 
(5:1), and 40 placebo recipients (20 infected and 20 uninfected) within the RV144 
clinical trial to identify CoR (21). Among the 6 primary immunological variables 
selected for the correlates analysis (5 different antibody [Ab] responses and CD4+ 
T cell cytokine production) that were measured at the visit 2 weeks after the final 
vaccination (ie, at or near peak immunogenicity), 2 immune CoR of HIV 
acquisition were identified among vaccine recipients in the RV144 case control 
study. The first was the presence of immunoglobulin G (IgG) Ab that bound to a 
scaffolded gp70 V1V2 recombinant protein; this variable correlated inversely 
with infection rate (ie, higher IgG titers to V1V2→lower infection rate), a finding 
subsequently extended to scaffolded gp70 V1V2 proteins from multiple HIV-1 
subtypes, including clade C (39). The second was plasma Env-specific binding 
immunoglobulin A (IgA), which correlated directly with infection rate (ie, higher 
IgA Ab to Env→higher infection rate). The other 4 primary variables correlated 
inversely with infection rate only when the level of IgA binding was low. 
Notably, neither low levels of the V1V2 Ab nor high levels of Env-specific IgA 
was associated with a higher rate of infection than observed in the placebo group 
(21). 
Recently, several studies have further enhanced our understanding of the efficacy 
seen in RV144. Rolland and colleagues demonstrated a sieve effect in the vaccine 
recipients, showing that the vaccine induced better protection against viruses that 
matched the vaccine sequence at position 169 in the V2 loop of Env (40). These 
data further substantiate the importance of antibodies directed against this region 
in protecting against infection (21). Yates and colleagues noted that Env V1V2-
specific IgG3 was the immunoglobulin subclass showing the strongest negative 
correlation with risk of HIV acquisition in RV144 (41). Chung and colleagues 
demonstrated that the IgG3 subclass engaged Fc-mediated effector responses 
more effectively than other IgG subclasses, thereby providing a possible 
mechanism explaining the association of Env V1V2 IgG3 with a lower rate of 
HIV acquisition (42). In addition, while the original search for correlates of risk 
failed to demonstrate an association between CD4+ T-cell responses and infection 
risk, Lin et al (43) recently used a computational framework for unbiased 
combinatorial polyfunctionality analysis of antigen-specific T-cell subsets 
(COMPASS) to identify CD4+ T-cell subsets in RV144 vaccinees that correlated 
with reduced risk of infection. One subset of polyfunctional CD4+ T cells (ie, 
those expressing TNF-α, IFN-γ, IL-4, IL-2, and CD40L) was as significantly 
associated with reduced infection risk as IgG responses to the V1V2 region of 
Env. Notably, the two subsets identified by the COMPASS algorithm as 
significantly correlated with reduced infection risk both included T cells 
expressing IL-4 and CD40L, cytokine and functional markers important for CD4+ 
T cell and B cell interactions, leading the authors to suggest that the specific 

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polyfunctional T-cell subsets they identified may contribute T-cell help for 
production of the antibody detected as a correlate in the primary analysis, though 
this specific functional association has yet to be demonstrated. In sum, these CoR 
studies point to the importance of Ab responses, directed against a specific region 
of Env, in mediating the differing rates of HIV acquisition observed in RV144 
and also suggest an important role for CD4+ T cell help in generating those Ab 
responses. They lay the groundwork for immunogenicity analyses planned for 
HVTN 100 and for future HIV vaccine clinical trials. 
4.2.3 
Rationale for the proposed vaccine regimen for South Africa 
This clinical trial will be conducted in South Africa, where clade C is the 
predominant circulating HIV subtype (33), and will evaluate the efficacy, safety, 
and immunogenicity of the regionally adapted ALVAC/protein vaccine regimen. 
The regimen will comprise 2 administrations of ALVAC-HIV (vCP2438) 
containing clade C ZM96 gp120 env along with clade B (LAI) gag, pro and gp41 
env TM at Months 0 and 1, followed by 3 administrations of the same ALVAC-
HIV along with Bivalent Subtype C gp120/MF59 (comprising recombinant 
TV1.C and 1086.C gp120 Env proteins mixed with MF59 adjuvant), at Months 3, 
6, and 12. 
The vaccine regimen in this trial maintains a close link to the RV144 vaccine 
regimen while targeting the clade C HIV strains circulating in southern Africa, the 
region of the world where deployment of the vaccine is envisioned. In addition, 
the vaccine design and vaccination schedule have been altered in ways that aim at 
improving the magnitude and duration of vaccine-elicited immune responses 
beyond those observed in RV144. These changes have been made under the 
scientific assumption that improvements or extensions of immune responses will 
translate into improvements in vaccine efficacy. 
The gag, pro, and gp41 env components of ALVAC-HIV (vCP2438) are the same 
as in ALVAC-HIV (vCP1521), the ALVAC-HIV used in the RV144 trial. 
Adaptations of the RV144 vaccine regimen to South Africa include use of the 
96ZM651 gp120 env insert (subtype C) rather than the TH023 gp120 env insert 
(subtype E) used in RV144, and inclusion of 2 subtype C gp120 Env proteins 
(TV1.C and 1086.C) in boost vaccinations (rather than the subtype B and E 
proteins used in RV144). 
The TV1.C and 1086.C gp120 Env proteins comprising Bivalent Subtype C 
gp120 were selected from among a long list of candidate clade C gp120 proteins 
according to a predefined algorithm incorporating, among other factors, genetic 
relatedness to regional HIV strains, CCR5 binding, capacity in animal studies to 
elicit key epitope-specific Ab, percent monomer expression (associated with 
receptor and co-receptor binding and induction of neutralizing antibodies [nAb]), 
expression/secretion levels in stable cell lines, stability, and immunogenicity in 
animal models (including evidence of recognition of key epitopes identified in the 
RV144 correlates studies) (44, 45). Use of gp120 monomers rather than trimers 
was prioritized to support comparisons with the RV144 results (46). 

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MF59 was selected as the protein adjuvant for multiple reasons, including its 
established safety record and previous experience with this adjuvant in similar 
prime-boost HIV vaccine regimens (47, 48). Based on related human experience, 
it is expected that MF59 will provide significant antigen dose sparing compared to 
proteins adjuvanted with alum, while potentially improving the magnitude and 
subsequent durability of the immune responses elicited by the RV144 regimen. In 
addition, MF59 has the capacity to provide a more balanced Th1/Th2 response 
than alum (49). MF59 was originally approved in Europe to enhance the 
immunogenicity of seasonal influenza vaccine among the elderly (50). MF59-
adjuvanted influenza vaccine is now licensed in more than 20 countries with more 
than 100 million doses having been distributed. Recently, influenza vaccine 
formulated with MF59 has been shown to be safe in young children and to 
significantly enhance immune responses and efficacy in this group (51). MF59 is 
also used in a prepandemic H5N1 influenza vaccine (Aflunov) licensed in the 
European Union (EU) for use in adults, and in two pandemic H1N1 influenza 
vaccines (Focetria and Celtura), licensed in EU and other countries for use in 
adults and children (52). 
If the immune responses elicited by the proposed vaccine regimen are similar to 
those associated with the level of protection seen in RV144 at 6.5 months after the 
first vaccination, close to the peak of observed vaccine efficacy, then it is believed 
that there will be sufficient feasibility to demonstrate that the vaccine efficacy will 
be close to 50% at 24 months after first vaccination. Given the observed vaccine 
efficacy in RV144 (Figure 4-1), Figure 4-2, Figure 4-3, and Figure 4-4 show 
graphically how the additional booster vaccination (Section 4.5.3) and potentially 
enhanced immune responses elicited by the revised vaccine regimen may translate 
into improved vaccine efficacy and durability. 
Figure 4-2 presents the observed vaccine efficacy for study RV144. The vaccine 
efficacy observed 12 months after the last vaccination in RV144 (18 months after 
the first vaccination) was 44%. 
 
Figure 4-2 Observed vaccine efficacy over time in the RV144 trial 
Figure 4-3 plots the same data from RV144 as Figure 4-2 but assumes that peak 
60% efficacy is maintained for 6 more months due to the planned booster 

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vaccination at month 12. This assumes that the booster vaccination induces 
immune responses associated with the same level of protection as the month 6 
vaccination. The vaccine efficacy decay curves are identical in Figure 4-2 and 
Figure 4-3, but the decay starts 6 months later in Figure 4-3. 
 
Figure 4-3 Expected vaccine efficacy for a regimen with efficacy comparable to that 
observed in RV144 but with a booster vaccination added at month 12 
As seen in Figure 4-3, if this vaccine regimen is associated with the same peak 
level of protection as was observed in RV144 and the booster vaccination can 
maintain the peak level of protection for 6 months more, the vaccine efficacy to 
month 24 is projected to be 44%, which is higher than that observed for RV144. 
Study RV305, a follow-up study to RV144 also conducted by the USMHRP, 
demonstrated enhanced immune responses with an additional booster vaccination 
of the ALVAC/protein regimen used in the RV144 study. Geometric mean (GM) 
titers of IgG responses to gD+ gp120 A244 antigen and to gp70 V1V2CaseA2 
and gp70 V1V2 92TH023 scaffolds 2 weeks after the booster vaccination were 
several-fold higher than the immune responses observed at the month 6.5 
timepoint (53). If this improvement in immune responses is associated with 
improved protection and can be replicated after the booster vaccination given at 
month 12, then the vaccine efficacy observed between months 12 and 18 may be 
higher than the vaccine efficacy observed between months 6 and 12 in RV144. 
Figure 4-4 presents a graphical representation of this scenario, and assumes that 
the improved immune responses resulting from the booster vaccination are 
capable of improving protection by 10% between months 12 and 18. 
 

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Figure 4-4 Expected vaccine efficacy for a regimen with protective efficacy comparable to 
that observed in RV144 over the first 12 months, and 10% improved protection from a 
booster vaccination at month 12. 
In Figure 4-4, the vaccine efficacy decay curve is identical as the one observed in 
RV144, but it starts 6 months later and at a higher level. For this scenario the 
vaccine efficacy is projected to be 54% at 24 months and 46% at 36 months, 
which is substantially higher than what was observed in RV144. 
4.2.4 
Rationale for booster vaccination at Month 18  
The immune responses induced by the clade C ALVAC/Bivalent gp120 vaccine 
regimen in HVTN 100 met predetermined criteria for going forward with HVTN 
702, including IgG binding antibody response rates and magnitudes to vaccine-
matched Env antigens, CD4+ T-cell response rate to the ALVAC ZM96 Env 
insert, and V1V2 response rate. The predetermined criteria are described in Table 
4-16 and the results are summarized in Section 4.9.6.4 (Figure 4-15, Table 4-17, 
and Table 4-18). In particular, the V1V2 IgG binding antibody response rate 
criterion was met for the 1086.C V1V2 protein antigen, while the response rate 
for any clade C V1V2 antigen was 84%, well above the 63% response rate that 
served as the basis for the efficacy projections in Section 4.2.3.  
Recently, HVTN 100 immunogenicity data from Month 12 (6 months post the 4th 
vaccination), Month 12.5 (2 weeks post the Month 12 booster vaccination), and 
Month 18 (6 months post the 5th vaccination) have become available. This data 
shows that overall, IgG responses decrease by 6 months following the 4th 
vaccination, rebound following the 5th vaccination to levels similar to post 4th 
vaccination peaks, and by 6 months post 5th vaccination, decline again but to 
levels higher than to those at 6 months post 4th vaccination. The IgG responses to 
V1V2 antigens are substantially lower at the Month 12 and 18 durability 
timepoints than are the responses to gp120 antigens (Figure 4-5 and Figure 4-6). 

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Figure 4-5 IgG antibody responses to vaccine-matched gp120 antigens at visit 10 (month 
6.5, 2 weeks post 4th vaccination), at visit 12 (month 12, 6 months post 4th vaccination), at 
visit 13 (month 12.5, 2 weeks post 5th vaccination), and at visit 15 (month 18, 6 months post 
5th vaccination). MFI – Blank = negative control adjusted mean fluorescent intensity. 

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Figure 4-6 IgG antibody responses to vaccine-matched gp70 V1V2 antigens at visit 10 
(month 6.5, 2 weeks post 4th vaccination), at visit 12 (month 12, 6 months post 4th 
vaccination), at visit 13 (month 12.5, 2 weeks post 5th vaccination), and at visit 15 (month 18, 
6 months post 5th vaccination). MFI – Blank = negative control adjusted mean fluorescent 
intensity. 

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The response rate to the gp70 CaseA2 V1V2 antigen at Month 12 and Month 18 
is also low (12.5% and 15%, respectively, Figure 4-7), whereas binding antibody 
response magnitude to this antigen was the primary correlate of risk identified in 
the RV144 trial. 
 
Figure 4-7 IgG antibody responses to gp70 CaseA2 V1V2 antigen at visit 10 (month 6.5, 2 
weeks post 4th vaccination), at visit 12 (month 12, 6 months post 4th vaccination), at visit 13 
(month 12.5, 2 weeks post 5th vaccination), and at visit 15 (month 18, 6 months post 5th 
vaccination). MFI – Blank = negative control adjusted mean fluorescent intensity. 
In addition, the breadth of IgG responses was assessed against a panel of 16 clade 
C V1V2 antigens and the area under the magnitude-breadth curve (AUC) was 
calculated (54). The overall AUC analyses showed that following the 5th 
vaccination, responses at peak (2 weeks) and durability (6 months) timepoints 
were greater than compared to those timepoints following the 4th vaccination 
(Figure 4-8, panel A and B). 

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Figure 4-8 V1V2 Magnitude- breadth curves of IgG binding antibody responses to 16 
different clade C V1V2 antigens among per-protocol HVTN 100 vaccine recipients at visit 10 
(month 6.5, 2 weeks post 4th vaccination) versus visit 13 (month 12.5, 2 weeks post 5th 
vaccination) in panel A and at visit 12 (month 12, 6 months post 4th vaccination) versus visit 
15 (6 months post 5th vaccination) in panel B. Solid curves are average breadth across 
individuals with breadth defined by the proportion of antigens in the panel with log10 (MFI – 
blank) greater than the threshold on the x-axis. 
The Env-specific CD4+ T-cell response rate declined 6 months after the 4th 
vaccination but was restored after boosting at month 12. Response rates declined 
less within 6 months following the 5th vaccination than within 6 months following 
the 4th vaccination (Figure 4-9). 
A 
B 

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Figure 4-9 CD4+ T cells expressing IFN-γ and/or IL-2 in response to stimulation with vaccine-
matched Env antigens at visit 10 (month 6.5, 2 weeks post 4th vaccination), at visit 12 (month 
12, 6 months post 4th vaccination), at visit 13 (month 12.5, 2 weeks post 5th vaccination), and 
at visit 15 (month 18, 6 months post 5th vaccination) 
The boost given at month 12 was intended to enhance the durability of the 
immune responses. The data from the month 12 boost shows a steep decline in 
IgG binding antibody responses to V1V2 antigens by 6 months following each 
vaccination, yet also overall enhancement of these key immune responses at peak 
and durability timepoints following the last boost. Therefore, HVTN 702 is 
amended to add an additional booster vaccination at month 18 in an effort to 
increase V1V2 responses and correspondingly to optimize vaccine efficacy by 
month 24. Based on models projecting vaccine-matched and heterologous clade C 
V1V2 antibody response rates and magnitudes, working with observed HVTN 
100 data at Months 6.5, 12, 12.5, and 18, the addition of a month 18 boost in 
HVTN 702 is expected to generate 0.26 - 0.41 higher expected log MFI V1V2 
responses between Month 6.5-24, as compared to the regimen with no boost at 
Month 18 (Figure 4-10). While the role of V1V2 binding antibody response in 
predicting VE in HVTN 702 is not yet determined, the addition of a Month 18 
boost will likely improve the opportunity for this regimen to demonstrate, for the 
first time, the capacity of an HIV vaccine to prevent HIV infection in South 
Africans. 
 

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Figure 4-10 Predicted average immune response profiles for C.1086C_V1_V2 Tags, gp70-
TV1.21 V1V2, and clade C V1V2 antigens. The area under the average immune response 
profile (AUC) is calculated using the trapezoidal rule, and divided by 17.5 (month 24 minus 
month 6.5); the resultant scaled AUC approximates the expected immune response at time 
of HIV exposure. 
4.3 
ALVAC-HIV (vCP2438) 
ALVAC-HIV (vCP2438) is a preparation of live, attenuated recombinant 
canarypox-derived virus expressing products from the HIV-1 env gp120 (clade 
C), env gp41 TM (clade B), gag (clade B), and protease (clade B) coding 
sequences and cultured in primary chicken embryo fibroblasts (CEFs). 
4.3.1 
Constructs 
The original strain of canarypox virus (Rentschler strain) was attenuated by serial 
passages on CEFs. The attenuated virus was plaque isolated and designated as 
ALVAC. Details of the manufacturing process are provided in the Investigator’s 
Brochure (IB). 
The construct is summarized in Table 4-1. The inserted HIV-1 gene sequences 
are: 
C.1086.C_V1_V2_Tags 
gp70-TV1.21 V1V2 
Clade C V1V2 antigens 

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x The region of the env gene encoding the extracellular Env gp120 moiety 
of the 96ZM651 strain of HIV-1 linked to the sequence encoding the HIV-
1 TM anchor sequence of gp41 (28 amino acids) from HIV-1 strain LAI. 
The env gene sequence is under the control of the vaccinia virus H6 
promoter. 
x The gag gene encoding the entire Gag protein and a portion of the pol 
sequences of the LAI strain of HIV-1 sufficient to encode the protease 
function. The gag/protease gene sequences are under the control of the 
same vaccinia virus I3L promoter. 
Table 4-1 ALVAC-HIV (vCP2438) construct summary table 
Inserted gene 
Strain 
Promoter 
Insertion Locus 
env (gp120 + gp41 TM) 
96ZM651 (gp120) 
LAI (gp41 TM) 
H6 (vaccinia) 
C6 
gag + pro 
LAI 
I3L (vaccinia) 
C6 
4.3.2 
Formulation characteristics 
ALVAC-HIV (vCP2438) is formulated as a lyophilized vaccine for injection and 
is reconstituted with 1.0 mL of sterile sodium chloride solution (NaCl 0.4%) for 
injection as a single dose. The composition of one dose of ALVAC-HIV 
(vCP2438) is provided in Table 4-2. 
Table 4-2 Composition of ALVAC-HIV (vCP2438) 
Ingredient 
Amount in one dose 
Function 
ALVAC-HIV (vCP2438) 
≥ 1 × 106 CCID50 and 
< 1 × 108 CCID50 
Immunogen 
Tris-HCl 
0.3 mg 
Buffer 
Lactose-monohydrate 
26.325 mg 
Component of lactoglutamate stabilizer 
L-Glutamic acid 
0.278 mg 
Component of lactoglutamate stabilizer 
NaH2PO4.2H2O 
0.15 mg 
Component of lactoglutamate stabilizer 
K2HPO4 
0.55 mg 
Component of lactoglutamate stabilizer 
KOH 
0.1 mg 
Component of lactoglutamate stabilizer 
Sucrose 
50 mg 
Component of freeze-drying stabilizer 
Sodium glutamate monohydrate 
5.5325 mg 
Component of freeze-drying stabilizer 
HCl 
1.8 mg 
Component of freeze-drying stabilizer 
Non-essential amino acids 
1.628 mg 
Component of freeze-drying stabilizer 
Essential amino acids 
4.46 mg 
Component of freeze-drying stabilizer 
4.3.3 
Manufacturing 
ALVAC-HIV (vCP2438) Bulk Drug Substance is manufactured by IDT 
Biologika GmbH, Am Pharmapark, Dessau-Rosslau, Germany, under contract to 

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Sanofi Pasteur. ALVAC-HIV (vCP2438) Drug Product is manufactured at the 
Sanofi Pasteur SA, facility located in Marcy l’Etoile, France. The diluent used for 
reconstitution is manufactured at the Sanofi Pasteur Inc. facility located in 
Swiftwater, Pennsylvania (USA). 
ALVAC-HIV (vCP2438) is produced by inoculating the viral seed lot into 
cultured primary CEFs derived from eggs produced by specific pathogen-free 
(SPF) flocks. 
The manufacturing process for ALVAC-HIV (vCP2438) is similar to that for 
ALVAC-HIV (vCP1521) used in RV144. 
4.4 
Bivalent Subtype C gp120/MF59 
4.4.1 
Constructs 
Bivalent Subtype C gp120/MF59, manufactured by Rentschler Biotechnologie 
(Laupheim, Germany), consists of two subtype C recombinant monomeric 
proteins, TV1.C gp120 and 1086.C gp120. These recombinant gp120s represent 
the receptor binding domain of the HIV envelope glycoprotein. Each gp120 is 
modified from its wild type full-length form (gp160) by replacement of the native 
signal sequence and deletion of the entire gp41 C-terminal portion of the 
glycoprotein containing the TM and cytoplasmic domains. The combination of 
the 2 subtype C gp120 proteins and the MF59 adjuvant is referred to as Bivalent 
Subtype C gp120/MF59. 
4.4.2 
Manufacturing and formulation 
Each protein is expressed in Chinese hamster ovary (CHO) cells under conditions 
favorable for secretion of monomeric protein. Following fermentation, each 
protein is extensively purified from culture supernatants, including further 
enrichment for monomer. 
Following clone selection, a fed batch cell culture at 250L scale is employed for 
cell propagation. Once the cells reach optimum cell density, the culture is 
harvested and purified using standard methods. The conditioned media is 
concentrated by ultrafiltration. The manufacturing process utilizes a weak cation 
exchange chromatography step, CM-Fractogel, which provides purification as 
well as viral reduction. Concentration (by ultrafiltration) is then used, followed by 
exchange into the formulation buffer. 
After these process steps, both subtype C gp120 protein processes include viral 
reduction filtration (nanofiltration) followed by 0.22 μm filtration and bulk fill. 
Following formulation and vialing, both TV1.C and 1086.C drug substances are 
stored frozen at not more than -61°C. For both drug substances, the formulation 
contains 0.8 mg/mL Env antigen, sodium citrate, and sodium chloride, pH 6.5 for 
TV1.C and pH 7.0 for 1086.C. 

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The composition per dose of each subtype C gp120 vaccine protein is provided in 
Table 4-3. 
Table 4-3 Qualitative composition of Subtype C gp120 drug substances vials 
Ingredient 
Function 
gp120 protein 
Sodium Citrate, Dihydrate 
Citric Acid, Monohydrate 
Sodium Chloride 
Water for injections 
active 
buffer 
buffer 
tonicity modifying agent 
solvent 
Additional information is provided in the Bivalent Subtype C gp120/MF59 IB. 
4.4.3 
MF59 adjuvant 
The Novartis MF59 adjuvant is an oil-in-water emulsion with a squalene internal 
oil phase and a citrate buffer external aqueous phase. Two non-ionic surfactants, 
sorbitan trioleate and polysorbate 80, serve to stabilize the emulsion. The bulk 
formula is shown in Table 4-4. 
Table 4-4 Composition of MF59 per liter 
Name of Ingredients 
Quantity 
 per Litre* 
Function 
Reference to Standards 
Squalene 
39.0 g 
oil phase 
In-house specification 
Polysorbate 80 
4.7 g 
surfactant 
USP/NF 
Sorbitan Trioleate 
4.7 g 
surfactant 
USP/NF 
Sodium Citrate, dihydrate 
2.65 g 
buffer 
USP/NF 
Citric Acid, monohydrate 
0.17 g 
buffer 
USP/NF 
Water for Injection 
q.s. 1 L 
aqueous phase 
Ph.Eur. and USP/NF 
Nitrogen 
overlay 
inert gas 
USP/NF 
*An overage of up to 10% is included to compensate for manufacturing losses. 
The full dose of MF59 utilized in the marketed Fluad vaccine (containing 9.75 mg 
of squalene) will be utilized for formulation with subtype C recombinant envelope 
gp120 proteins (described above). 
The MF59 (full name: MF59C.1) manufacturing process consists of five 
manufacturing steps: raw materials dispensing and blending, premixing, 
emulsification, sizing filtration, and filling. 
The MF59 bulk resulting at the end of the process is filled into the vials with an 
overlay of nitrogen and stored protected from light at 2-8° C. 
Additional information is provided in the Bivalent Subtype C gp120/MF59 IB. 

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4.4.4 
Bivalent Subtype C gp120/MF59 for injection 
A final dose of 100mcg of each recombinant Env protein will be mixed with 
MF59 adjuvant. The composition of one dose of the resulting vaccine is shown in 
Table 4-5. 
Table 4-5 Composition of 0.5 mL dose of Bivalent Subtype C gp120/MF59 for injection 
Ingredient  
Amount in one dose  
Function  
Drug Substances  
TV1.C gp120 protein 
1086.C gp120 protein  
100 mcg 
100 mcg  
active 
active  
Adjuvant (MF59)  
Squalene  
9.75 mg  
oil phase  
Polysorbate 80  
1.175 mg  
surfactant  
Sorbitan Trioleate  
1.175 mg  
surfactant  
Excipients  
Sodium Citrate, Dihydrate 
Citric Acid, Monohydrate 
Sodium Chloride 
Water for injections  
1.39 mg 
0.051 mg 
4.38 mg 
qs to 0.5 mL 
buffer 
buffer 
tonicity modifying agent 
solvent  
4.5 
Trial design rationale 
Based on data supporting the hypothesis (tested in the HVTN 100 phase 1-2 trial) 
that 2 doses of ALVAC-HIV (vCP2438) followed by 2 doses of ALVAC-HIV 
(vCP2438) + Bivalent Subtype C gp120/MF59 would generate in a South African 
study population key immune responses at least comparable to those induced by 
the RV144 vaccine regimen, the current trial will assess whether this vaccine 
regimen can demonstrate efficacy in prevention of HIV-1 infection in HIV-
seronegative adults in South Africa. The study is designed with sufficient power 
to provide conclusive evidence of vaccine efficacy to be used to support a 
potential Marketing Authorisation Application in the Republic of South Africa. 
4.5.1 
Dose (amount and number) 
ALVAC-HIV (vCP2438): Viral titer ≥ 1 × 106 CCID50 and < 1 × 108 CCID50 
(nominal dose of 107 CCID50) lyophilized vaccine to be reconstituted for IM 
injection. 
This study will utilize doses of ALVAC-HIV that are within the same range as 
was used for the RV144 study and for HVTN 097 (Section 4.9.5). The ALVAC-
HIV (vCP1521) dose targeted for study RV144 was > 106 CCID50. The actual 
ALVAC-HIV titers from the 12 vaccine lots used in the RV144 study ranged 
from 107.06 CCID50 to 107.41 CCID50. The measured titer of the vaccine lot used in 
HVTN 097 was 107.72 CCID50 (ie, 2-4.5–fold higher than the dose used in RV144); 

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however, a dose effect on immunogenicity was not observed in a dose ranging 
study of an ALVAC HIV vaccine (HVTN 039). 
Titers of the ALVAC-HIV (vCP205) construct used in studies ranged from 105.6 
CCID50 to 106.85 CCID50. A dose response analysis was conducted with samples 
collected on Days 98 and 182 in the AIDS Vaccine Evaluation Group (AVEG) 
022, 022A, 027, 032, 033, 034 and 034A studies. In summary, these data indicate 
that while there is not a positive dose-response relationship between ALVAC-
HIV and cytotoxic T lymphocyte (CTL) responses, use of the lower titer is not 
optimal for induction of nAb responses. Therefore, many clinical studies in 
humans have targeted an ALVAC dose > 106 CCID50. 
HVTN 039 is the only study that has compared the safety and immunogenicity of 
ALVAC-HIV (vCP1452) given at the standard dose (107.25 CCID50) to a dose 5.6 
times higher (108 CCID50), and placebo. The high-dose ALVAC-HIV (vCP1452) 
resulted in unacceptable levels of reactogenicity, without evidence of enhanced 
immunogenicity. Although extrapolation of these findings to other ALVAC-HIV 
vaccines requires caution, the study suggested that an ALVAC-HIV dose < 108 
CCID50 is desirable. 
The desired improvements in overall and protective immune responses will rely 
on the use of a more potent protein adjuvant and adjustment of the vaccination 
schedule. 
For the Bivalent Subtype C gp120/MF59 vaccine component, 100 mcg each of 
the two gp120 subtype C proteins (TV1.C and 1086.C ) will be admixed with the 
oil-in-water emulsion MF59 (9.75 mg squalene) by the Pharmacist at each CRS 
prior to IM administration. The 200 mcg total dose Bivalent Subtype C gp120 
proteins was selected based on previous clinical experience. Limited dose range 
studies performed with Novartis (formerly Chiron) subtype B SF2 gp120 and 
subtype E gp120 protein candidates indicated that 50 mcg and 100 mcg, totalling 
150 mcg, doses with MF59 adjuvant were immunogenic and well tolerated (55). 
4.5.2 
Assumptions regarding HIV-1 incidence 
HIV-1 incidence estimates from previous clinical trials among at-risk study 
populations in South Africa include the following: 
x The Orange Farm male circumcision study (2002-2005), in which HIV-1 
incidence among the untreated male population, 18-24 years of age was 
estimated at 2.1 per 100 person-years (56). 
x The HVTN 503 (Phambili) HIV vaccine study (2007), in which HIV-1 
incidence among placebo recipients, 18-35 years of age was estimated at 3.7 
per 100 person-years (5.86 for females and 1.93 for males) (57). 

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x The CAPRISA 004 vaginal microbicide study (2007-2010), in which HIV-1 
incidence was estimated at 9.1-11.2 per 100 person-years among female 
placebo recipients, 18-40 years of age (58). 
x The FACTS 001 vaginal microbicide study (2011-2014), in which HIV-1 
incidence was estimated at 4.0 per 100 person-years in women age 18-30 (59). 
Additional estimates of HIV-1 incidence among at-risk study populations in 
Southern Africa come from: 
x The VOICE study of vaginal microbicide and systemic prophylactic 
antiretroviral drugs (2009-2013), in which overall HIV-1 incidence was 5.7% 
and incidence in the 3 placebo arms of the trial varied from 4.2 to 6.8 per 100 
person-years, while the annual incidence in single women in South Africa 
aged 25 or younger was up to 10% (60). 
x The Fem-PrEP study of oral Truvada (2009-2012), in which HIV-1 incidence 
was estimated at 5.0 per 100 person-years overall and ranged from 3.4–6 per 
100 person years in South African female placebo recipients aged 18-35 (61). 
x HPTN 043 (2009-2011), a study of community mobilization, mobile testing, 
same-day results, and post-test support in sub-Saharan Africa and Thailand, in 
which HIV-1 incidence estimates were 1.2 and 2.4 per 100 person-years for 
African male and female participants, respectively (Thai sites were excluded 
from these incidence estimates) (62). 
x The MIRA study of diaphragm, lubricant gel, and condoms in sexually active 
women in South Africa (2003-2007), in which HIV-1 incidence was estimated 
at 3.9-4.1 per 100 person-years, and was 7 per 100 person years in Durban and 
3.3 per 100 persons years in Johannesburg female placebo recipients aged 18-
49 (63). 
Based on the above data, the overall estimate of background HIV-1 incidence is 
4.0 per 100 person-years, and this level of incidence is expected for the duration 
of our study. Self-reported risk and presumably incidence decreases during 
entrance into HIV prevention studies as a result of risk reduction counseling 
provided to study participants. While incidence of HIV infection may be expected 
to decrease over time in trial populations due to extensive counseling and/or the 
increasing availability of alternative HIV prevention modalities, the established 
incidence of 4% per year in other prevention studies conducted recently in the 
area represents an average over the entire study period, which indicates that even 
if incidence declines, the power calculations do not underestimate sample size. In 
addition, some recent HIV prevention trials in Southern Africa have had steady or 
slightly increasing HIV incidence over the first 18 months (eg, HPTN 035) (64). 
Recent developments in HIV prevention may have an impact on background HIV 
incidence. Oral Pre-exposure Prophylaxis (PrEP) using the combination 
antiretroviral drugs emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) 

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has proven to be an efficacious user-controlled prevention intervention. While the 
MCC has approved FTC/TDF for use as PrEP, this combination antiretroviral 
agent is not yet available for this use in the public sector in South Africa. It is 
available by prescription, in demonstration projects, and in the private sector. 
Participation in this trial is not precluded by oral PrEP use. In addition, medical 
male circumcision will be advocated as part of risk reduction counseling at all 
sites. The START (Strategic Timing of AntiRetroviral Treatment) study has 
confirmed that immediate referral for ART is beneficial to participants who are 
newly diagnosed with HIV (65) and HPTN 052 demonstrated the value of 
treatment in reducing secondary transmission in discordant couples (66). An 
initiative to implement universal test and treat was announced in the Republic in 
September 2016. Additional modes of HIV prevention (eg, topical microbicides, 
injectable ARVs, etc.) are currently being studied in efficacy trials and may 
become available while HVTN 702 is underway. Study participants will be 
informed of such developments and uptake will be tracked in order to estimate 
their impact on HVTN 702.  
4.5.3 
Schedule 
Safety and immunogenicity will be assessed for ALVAC-HIV (vCP2438) 
(months 0, 1, 3, 6, 12, 18) and for Bivalent Subtype C gp120/MF59 (months 3, 6, 
12, 18). 
The vaccine administration schedule encompasses the schedule used in RV144 
but with additional boosts at months 12 and 18 in response to the apparent wane 
in efficacy from 12 to 36 months observed in RV144. 
Addition of a booster vaccination at month 12 is supported by immunogenicity 
data from nonhuman primate (NHP) studies performed with another pox-protein 
regimen. Both neutralizing and binding Ab levels dropped after completion of the 
primary immunization, while the re-boost at week 49 was able to bring back the 
Ab responses to the higher level (67). In addition, administration of a late 
ALVAC-HIV/AIDSVAX boost (in RV 305) approximately 7-9 years after the 
final vaccination in RV144 demonstrated that immune responses were restored or 
improved compared to the responses observed at the year 3.5 primary timepoint in 
the RV144 trial (53). The addition of a boost at month 18 is supported by 
durability data from HVTN 100 (Section 4.2.4) 
The selected dose schedule is therefore a 6-dose schedule; a 4-dose primary 
vaccination schedule with ALVAC-HIV administered at 0, 1, 3 and 6 months plus 
protein boost administered at 3 and 6 months (replicating the RV144 schedule); 
and additional booster vaccinations with both ALVAC-HIV (vCP2438) and 
Bivalent Subtype C gp120/MF59 administered at 12 and 18 months. 
4.5.4 
Prime-boost regimen 
The prime-boost strategy consists of ALVAC-HIV (vCP2438) primes with 
ALVAC-HIV (vCP2438) plus Bivalent Subtype C gp120/MF59 boosts. 

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The concept of priming with one HIV vaccine followed by boosting with another 
heterologous HIV vaccine emerged in the 1990s as a strategy to enhance vaccine 
immunogenicity and, potentially, vaccine efficacy. While Env glycoproteins elicit 
strong humoral responses, they have not been associated with potent cellular 
immunity or efficacy when administered alone. On the other hand, although viral 
vector constructs, including ALVAC, often elicit both Ab and cell-mediated 
responses, it was observed that the level of Ab could be increased significantly by 
subsequent administration of Env glycoproteins. In addition, prime-boost vaccine 
regimens were explored as means of increasing the breadth of HIV strains to 
which vaccination might induce responses. Response breadth and the capacity to 
induce both potent CTL and potent Ab responses is a combination believed to be 
important in conferring protective immunity against HIV infection (68, 69). These 
desirable immune response characteristics were often observed in early phase 
clinical trials using a variety of prime-boost vaccine regimens (69-79). 
Among the many prime-boost vaccine regimens tested during this period were 
canarypox-derived (ALVAC) vector primes containing differing arrays of 
recombinant HIV genes and HIV Env glycoprotein boosts. By 1998, early phase 
clinical trials of ALVAC-protein regimens had shown: 
x These regimens with glycoproteins adjuvanted with alum or MF59 were well 
tolerated in several hundred HIV-uninfected, healthy volunteers; 
x HIV-specific immune responses were not dampened in vaccinia-experienced 
individuals; 
x The prime-boost regimens induced large repertoires of HIV-specific Ab, 
neutralizing activity against some laboratory HIV isolates, Ab capable of 
inducing antibody-dependent cellular cytotoxicity (ADCC), and HIV-specific 
CTL activity against a broad range of targets (69, 80). 
In NHP studies, heterologous prime-boost ALVAC-protein regimens afforded 
better protection against viral challenge than did sequential injections of ALVAC-
HIV vaccines alone, suggesting a potential connection between the characteristic 
responses elicited by the heterologous ALVAC-protein prime-boost regimens and 
protection from HIV infection (81). 
On the basis of results from nonclinical challenge studies and early-phase clinical 
trials, ALVAC-HIV (vCP1521) and HIV gp120 Env became the first 
heterologous prime-boost vaccine regimen to enter efficacy testing in humans in 
the RV144 trial in Thailand. Comparison of the immunogenicity observed in the 
RV144 trial to that from the VAX003 efficacy study previously conducted in 
Thailand, showed that the nAb response after two doses of gp120 protein 
following priming with ALVAC-HIV (vCP1521) [19] exceeded the nAb response 
seen after two inoculations with the same bivalent gp120 protein without 
preceding ALVAC-HIV (vCP1521) (in VAX003) [55], pointing to a priming 
effect by ALVAC-HIV (vCP1521) that benefited the immune response in the 
RV144 study (82). Hence, one of the primary advantages to prime-boost regimens 

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posited by nonclinical studies and supported in early phase clinical trials, was 
borne out in comparison of immunogenicity results from 2 large later-phase 
clinical trials conducted in the same country. 
Furthermore, recent data suggest that priming by ALVAC-HIV (vCP1521) may 
favourably influence the quality of Ab responses. The IgG3 HIV-1 Env responses 
induced by the ALVAC-protein prime-boost regimen were significantly higher 
than those induced by the homologous gp120 prime-boost regimen, indicating 
that ALVAC priming before a protein boost modifies the IgG subclass profile in a 
manner that may substantially change the HIV-1 inhibitory functions of the 
vaccine-elicited IgG responses (41, 42). IgG1 and IgG3 are the most functional of 
the IgG subclasses in that they have been associated with HIV-1 neutralization, 
complement fixation, phagocytosis, ADCC, and antibody dependent cellular viral 
inhibition (ADCVI) (83). 
4.5.5 
Choice of control 
The control for ALVAC-HIV (vCP2438) and for Bivalent Subtype C 
gp120/MF59 is sodium chloride for injection, 0.9%. 
4.6 
Combination prevention of HIV acquisition 
HVTN 702 embraces the highest South African Standards of Prevention for all 
participants. Participants will be provided with a comprehensive HIV prevention 
package consistent with all DAIDS-sponsored HIV prevention clinical trials. This 
package includes evidence-based behavioral risk reduction counseling (84), 
advocacy and referral for medical male circumcision as appropriate, free condoms 
and lubricant (where available), regular testing for sexually transmitted infections 
(STIs), counseling and referral for postexposure prophylaxis (PEP) when 
indicated, and, where appropriate, access to oral drugs for pre-exposure 
prophylaxis (PrEP, see below). Participants will be informed as new prevention 
modalities are proven effective and become available. These activities can be 
expected to reduce HIV acquisition below historical levels. The contribution of 
these efforts will be monitored. Further details on these efforts are provided in the 
HVTN 702 Study Specific Procedures (SSP) and the HVTN 702 website. 
4.6.1 
PrEP in South Africa 
South Africa recently registered FTC/TDF for prevention and is developing 
guidelines for its use. These guidelines stipulate that PrEP must be delivered in 
the service delivery setting with the main guiding principle of informed and 
voluntary choice and equitable access. FTC/TDF for HIV prevention is not yet on 
the Essential Drug List in South Africa, which is a pre-requisite for use in the 
public sector through which the vast majority of South Africans secure health 
care. However, the South African government through the National Department 
of Health (NDOH) intends to conduct demonstration projects, in conjunction with 

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key donors, in key populations such as sex workers and men who have sex with 
men (MSM), as well as in geographic locations that have a high burden of HIV.  
The World Health Organization has issued updated PrEP guidelines (85) and an 
investment case evaluating these guidelines has been undertaken by the South 
African government (86). While the investment case for universal test and treat is 
clear, and this will be rolled out as a priority, the investment case for PrEP is less 
certain and is being evaluated.  
For these reasons, the protocol team plans to work collaboratively with national 
regulatory authorities and other government agencies to develop mechanisms for 
PrEP access that are supportive of and consistent with national priorities and 
strategic objectives. 
Given the potential of FTC/TDF to prevent HIV acquisition, it could be argued 
that substantial uptake of PrEP could prevent the HVTN 702 trial from detecting 
any benefit of vaccine administration beyond the universal prevention package. 
This possibility is addressed in the sample size and power calculations (see 
Section 6.4.1) and in plans for trial monitoring by the DSMB (see Sections 6.5.5 
and 6.5.6). If the background HIV incidence rate is too low to support evaluation 
of vaccine efficacy, the DSMB will detect this and will make recommendations to 
the team accordingly. The study team will monitor PrEP availability and roll-out 
in-country and within the protocol will record use of PrEP drugs as concomitant 
medications and will evaluate individual and study population PrEP use through 
direct biomedical measures (see Section 11.7). In support of a comprehensive 
package of prevention, PrEP will be discussed in the informed consent process, in 
risk reduction counseling sessions, and referral systems into demonstration 
projects, health service delivery settings, and the private sector will be developed 
to support those who wish to access PrEP. 
4.7 
Nonclinical studies 
4.7.1 
ALVAC-HIV 
4.7.1.1 
IM local tolerability and systemic toxicity study in New Zealand White 
Rabbits (Study AB20670) 
The objective of the study was to determine the local tolerability and systemic 
toxicity of ALVAC-HIV (vCP2438)/ALVAC-HIV (vCP2438) with gp120+MF59 
vaccines and DNA-HIV-PT123 with gp120+MF59 vaccines administered by the 
IM route to New Zealand White Rabbits 7 or 6 times, respectively, at 2-week 
intervals, followed by a 2-week recovery period. 
There were no deaths during the study. No treatment-related clinical signs were 
reported during the study and treatment was locally well tolerated. Body 
temperature was slightly increased mostly after the 1st injection but returned to 
normal within 48 hours. There were no effects of treatment on body weight or 

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food consumption. No treatment-related ophthalmological findings were observed 
at the end of the treatment period. 
When compared to the control group, a transient increase in C-reactive protein, 
globulin, fibrinogen, or neutrophil count was observed after one or more of the 
immunizations. These effects correlated with the inflammatory findings observed 
histopathologically at the injection sites. There were no other treatment-related 
differences from the controls amongst the biochemistry or hematological 
parameters. 
At necropsy, at the end of treatment, the only histologic changes due to the test 
items were in the injection sites and iliolumbar and sacral lymph nodes. In the 
sites injected with ALVAC or gp120s+MF59, the changes comprised 
inflammatory cell infiltrates, necrosis, fibrosis, hemorrhage, acellular material and 
mineralization. These findings were often only minimal or slight. In the lymph 
nodes which drained the injected sites, there was minimal or slight increased 
lymphoid follicle development, increased paracortex and granulocyte infiltrate. 
There was evidence of partial resolution of the described changes at both injection 
site and lymph nodes, based on necropsy observations after the recovery period. 
In conclusion, under the defined study conditions, 7 intramuscular administrations 
of ALVAC-HIV (vCP2438) vaccine associated with gp120s/MF59 (last 4 
injections) to the New Zealand White Rabbit at two-week intervals were clinically 
and locally well tolerated. The study supports the use of this vaccine regimen in 
human clinical trials. 
4.7.1.2 
Other supportive nonclinical safety studies 
The nonclinical safety data from a variety of ALVAC constructs further inform 
the safety profile of ALVAC-HIV (vCP2438). These studies include the 
following: 
x Platform biodistribution study of ALVAC-HIV in rats 
x ALVAC viral replication in different cell lines 
x Virulence of the ALVAC vector versus Vaccinia strains 
x Single dose toxicity studies by intravenous route with various ALVAC 
recombinants in mice and rats 
x Repeated dose toxicity studies using several routes of administration 
(including IM) with various ALVAC recombinants in cynomolgus and rhesus 
macaques 
x Local tolerance and sensitization studies with various ALVAC recombinants 
in rabbits 
x Hypersensitivity study with ALVAC-HIV (vCP125) in guinea pigs 

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The results of these studies show a satisfactory nonclinical safety profile and 
support the administration of the ALVAC-HIV (vCP2438) construct to humans. 
For additional information, see the ALVAC-HIV (vCP2438) IB. 
4.7.2 
Toxicity studies of HIV Env vaccines 
The nonclinical safety of 4 doses of the gp120 proteins when co-administered 
with ALVAC-HIV (vCP2438) as a boost after 3 doses of ALVAC-HIV 
(vCP2438) given alone (prime), was evaluated in study AB20670 in New Zealand 
White Rabbits, as mentioned in Section 4.7.1.1. Overall, the immunizations were 
clinically and locally well tolerated. 
The nonclinical safety of 6 doses of the gp120 proteins, when co-administered 
with DNA-HIV-PT123, was also evaluated in study AB20670 in New Zealand 
White Rabbits. There were no deaths during the study. No treatment-related 
clinical signs were reported during the study and treatment was locally well 
tolerated. There was no obvious effect on body temperature. A lower body weight 
gain was noted in males only over the study period. However this was not related 
with lower food consumption. No treatment-related ophthalmological findings 
were observed at the end of the treatment period. When compared to the control 
group, a slight transient increase in C-reactive protein concentration was noted 
mainly after the first administration. These effects correlated with the 
inflammatory findings observed histopathologically at the injection sites. An 
increase in creatine kinase was noted after the first administration only. At 
necropsy, at the end of treatment, the only histologic changes due to the test items 
were in the injection sites and iliolumbar lymph nodes. In the sites injected with 
DNA-HIV-PT123 or gp120s+MF59, changes comprised fibrosis, hemorrhage, 
acellular material and inflammatory cell infiltrate usually minimal or slight, but 
occasionally more severe. In the lymph nodes which drained the injected sites, 
there was minimal to moderate increased paracortex and increased lymphoid 
follicle development and minimal granulocyte infiltration. There was evidence of 
partial resolution of the described changes at both injection site and lymph nodes, 
based on necropsy observations after the recovery period. In conclusion, under the 
defined study conditions, 6 intramuscular administrations of DNA-HIV-PT123 
vaccine associated with gp120 proteins adjuvanted with MF59 to New Zealand 
White Rabbits at two-week intervals were clinically and locally well tolerated. 
In addition, nonclinical in vivo Good Laboratory Practice (GLP) toxicology 
studies were conducted with early candidate subtype B and E gp120 Env protein 
vaccine candidates that were subsequently advanced to phase 1-2 clinical trials. 
More recently, similar subtype B gp140 and subtype C gp140 vaccine candidates 
with MF59 have been tested in nonclinical safety studies. The subtype C gp140 
previously tested was from the same strain (HIV-1 TV1) as one of the 
components (TV1.C gp120) in the proposed Bivalent Subtype C gp120/MF59 
vaccine, and hence is very similar in sequence. Overall, toxicology studies 
indicated that both the subtype B gp140 and subtype C gp140 vaccines with 
MF59 were well tolerated and testing revealed no adverse local or systemic 
effects. 

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Data from the following nonclinical studies are included in the IB: 
x Subchronic IM toxicity study of Biocine HIV Thai E gp120/SF2 gp120 
vaccine in rabbits 
x Repeat dose toxicity of IM HIV DNA/PLG prime followed by IM subtype B 
gp140/MF59 in rabbits 
x Repeat dose toxicity of intranasal (IN) subtype B gp140 with an LTK63 
adjuvant followed by IM subtype B gp140 with MF59 in rabbits 
x Repeat dose toxicity of IM South African AIDS Vaccine Initiative (SAAVI) 
DNA-C2 followed by IM SAAVI MVA-C with subtype C gp140/MF59 in 
rabbits 
4.7.2.1 
Toxicity studies of MF59 
The nonclinical safety of MF59 co-administered with the gp120 proteins included 
in HVTN 702 in the context of ALVAC-HIV (vCP2438) was evaluated in study 
AB20670 as described in Sections 4.7.1.1 and 4.7.2. Overall, the immunizations 
were clinically and locally well tolerated in New Zealand White Rabbits. 
MF59 is not associated with any potential for systemic toxicity and it has a low 
order of local reactogenicity. In repeat-dose rabbit studies, clinical pathology 
findings of increased fibrinogen and minor inflammatory and degenerative 
changes at the injection site are consistent with the effects of IM injections of an 
immunological adjuvant. These findings are readily reversible within days to 1 to 
2 weeks. In repeat-dose toxicology studies in dogs, there were no effects on 
cardiovascular or central nervous system (safety pharmacology) parameters. 
MF59 is not genotoxic (Ames test) or clastogenic (mouse micronucleus), is not a 
dermal sensitizer (Guinea pig), and was not teratogenic (rat and rabbit) or a 
developmental toxicant (rat). 
Pivotal toxicology studies performed with MF59 include: 
x single- and repeat-dose toxicity (including local tolerability), 
x genotoxicity, 
x sensitization, and 
x embryofetal and developmental toxicity. 
4.8 
Plans for future product development and testing 
HVTN 702 is designed to provide the efficacy data in support of a potential 
Marketing Authorisation Application in the Republic of South Africa. It is 

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anticipated that the efficacy data may be supplemented with data from additional 
safety and immunogenicity studies evaluating clinical lot-to-lot consistency, 
bridging to the adolescent age group, and, if required, addressing changes in 
vaccine manufacturing process and formulation. 
4.9 
Clinical studies 
4.9.1 
Clinical studies with related ALVAC-HIV vaccines 
The proposed ALVAC-HIV vaccine candidate specific for southern Africa is 
ALVAC-HIV (vCP2438). The vaccine is closest to ALVAC-HIV (vCP1521) (the 
ALVAC-HIV used in the RV144 trial) since it contains the same gag, pro and 
gp41env TM components. However, it has been adapted to include ZM96 gp120 
env insert (subtype C) (rather than the TH023 gp120 env insert [subtype E] used 
for the RV144 study regimen in Thailand). 
ALVAC-HIV (vCP2438) is currently being investigated in the ongoing trial 
HVTN 100 (Section 4.9.6). 
Extensive previous experience with other ALVAC-HIV vaccines informs the 
expected safety, tolerability, and immunogenicity profile of the new vaccine 
(Table 4-6). In all, more than 10,000 clinical trial participants have received 
ALVAC-HIV vaccines. The majority of these trials were performed with 
ALVAC-HIV (vCP205), (vCP1452), or (vCP1521). In these vaccines, different 
HIV gene inserts have been introduced into the ALVAC vector. 
ALVAC-HIV (vCP205) is an ALVAC vector vaccine with genetic inserts of the 
HIV-1 gag gene (expressing the Gag p55-polyprotein of the HIV-1 LAI strain 
[clade B]), a fragment of the pol gene (that expresses the p15 Protease of the HIV-
1 LAI strain), and a portion of the env gene (expressing the gp120 Env 
glycoprotein of the HIV-1 MN strain [clade B], and the anchoring TM region of 
gp41 of the HIV-1 LAI strain). The HIV genes are inserted in the C3 locus. 
ALVAC-HIV (vCP1452) vaccine is a preparation of a modified recombinant 
canarypox virus expressing the products of the HIV-1 env (Env gp160 protein of 
the HIV-1 MN Strain [clade B]) and gag (HIV-1 LAI strain [clade B]) genes, the 
protease portion of the pol gene on a synthetic polynucleotide encompassing the 
known human CTL epitopes from the nef (BRU Strain), and the pol (LAI strain) 
gene products. The C3 locus was used for the insertion of the HIV-1 env and gag 
gene sequences and the C5 locus was used for the insertion of the sequences 
encoding the HIV-1 Nef and Pol CTL epitopes. 
 

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Table 4-6 Recombinant ALVAC-HIV vaccine in human adult prevention trials 
Candidate vaccine 
# receiving 
ALVAC-HIV 
Protocol 
Status 
ALVAC-HIV (vCP125) 
20 
ANRS VAC01 
Completed 
ALVAC-HIV (vCP125) (low and high dose) 
92 
AVEG 012A/012B 
Completed 
ALVAC-HIV (vCP205) 
25 
ANRS VAC03 
Completed 
ALVAC-HIV (vCP205) (low and high dose) 
185 
AVEG 022/022A 
Completed 
ALVAC-HIV (vCP205) 
22 
AVEG 029 
Completed 
ALVAC-HIV (vCP205) 
56 
AVEG 027 
Completed 
ALVAC-HIV (vCP205) 
290 
HVTN 203 
Completed 
ALVAC-HIV (vCP205) 
56 
AVEG 032 
Completed 
ALVAC-HIV (vCP205) 
280 
AVEG 202/ HIVNET 014 
Completed 
ALVAC-HIV (vCP205) 
30 
AVEG 033 
Completed 
ALVAC-HIV (vCP205) 
20 
HIVNET 007 
Completed 
ALVAC-HIV (vCP300) 
20 
ANRS VAC07 
Completed 
ALVAC-HIV (vCP300) 
119 
AVEG 026 
Completed 
ALVAC-HIV vector (vCP205, 1433, 1452) 
20/35/35 
AVEG 034 
Completed 
ALVAC-HIV (vCP205/1452) 
15/40 
AVEG 034A 
Completed 
ALVAC-HIV (vCP1452) 
22 + 3 
ANRS 010 
Completed 
ALVAC-HIV (vCP1452) 
160 
HVTN 203 
Completed 
ALVAC-HIV (vCP1452) 
120 
HIVNET/HVTN 026 
Completed 
ALVAC-HIV (vCP1452) 
100 
HVTN 039 
Completed 
ALVAC-HIV (vCP1521) 
203 
RV132/135 
Completed 
ALVAC-HIV (vCP1521) 
8197 
RV144 
Completed 
ALVAC-HIV (vCP1521) 
135* 
RV 305 
Completed 
ALVAC-HIV (vCP1521) 
327** 
RV 306 
In progress 
ALVAC-HIV (vCP1521) 
80* 
HVTN 097 
Completed 
ALVAC-HIV (vCP2438) 
210 
HVTN 100 
In progress 
Total 
10.917 
 
 
* Primary study completed; extension in progress. 
** Planned study product sample size. Study remains blinded. 
ALVAC-HIV (vCP1521) vaccine was generated by co-insertion of genes 
encoding HIV-1 gene products into the ALVAC genome in the C6 locus. The 
inserted HIV-1 gene sequences are: the region of the env gene encoding the 
extracellular Env gp120 moiety of TH023 strain of HIV-1 (clade E) linked to the 
sequences encoding the HIV-1 TM anchor sequence of gp41 HIV-1 LAI strain 
(clade B); the gag gene encoding the entire Gag p55-polyprotein of the HIV-1 
LAI strain; and a portion of the pol sequences of the LAI strain of HIV-1 
sufficient to encode the protease function. 
ALVAC-HIV (vCP2438) is described in Section 4.3. 

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4.9.2 
Clinical safety experience with related ALVAC-HIV vaccines 
4.9.2.1 
Summary of safety, reactogenicity, and tolerability from related human 
experience 
The tolerability and safety of ALVAC-HIV (vCP1521) were evaluated initially in 
2 phase 1-2 studies in Thailand (87, 88). The most relevant data, however, come 
from the large RV144 efficacy study performed in Thailand (19, 89), during 
which more than 8000 participants received the vaccine and ALVAC-HIV 
(vCP1521) was found to be safe and well tolerated. Vaccine recipients 
experienced local and/or systemic reactions significantly more frequently than 
placebo recipients; the frequencies of local reactions such as pain and tenderness 
were higher than those of systemic reactions such as headache, fatigue, arthralgia 
and myalgia; fever was rarely reported; ALVAC-HIV (vCP1521) was associated 
with a higher frequency of local reactions compared to the protein subunit used in 
the study (AIDSVAX B/E); the frequency of both local and systemic reactions 
gradually declined with subsequent vaccine administrations; most local and 
systemic reactogenicity symptoms were mild to moderate, resolving rapidly and 
spontaneously in the vast majority of cases; and the frequencies of adverse events 
(AEs) and serious adverse events (SAEs) were not different between vaccine and 
placebo groups (89). Overall, results with ALVAC-HIV (vCP1521) are consistent 
with other ALVAC-HIV constructs, supporting the conclusion that the safety, 
reactogenicity, and tolerability profile of ALVAC-HIV is determined in greater 
measure by the vector than by the HIV genetic material inserted into it. 
De Bruyn et al (90) characterized the tolerability and safety profile of ALVAC-
HIV (vCP205) and ALVAC-HIV (vCP1452) (along with other ALVAC vectors) 
based on data from more than 1,000 clinical trial participants. The authors 
concluded that: 
1. ALVAC-HIV vaccines were safe and well tolerated, with a reactogenicity 
profile comparable to that of existing vaccines licensed for use in adults; and 
2. Reactogenicity was similar for different ALVAC-HIV constructs, suggesting 
that reactogenicity is determined in greater measure by the vector than by the 
additional genetic material inserted into the vector. 
Of interest as well was the observation that reactogenicity seemed to differ 
according to certain demographic variables: Black, non-Hispanic participants 
reported significantly less reactogenicity than did White, non-Hispanic 
participants; and males reported less pain than females. 
Additional information is available in the ALVAC-HIV (vCP2438) IB. 
4.9.2.2 
Summary of pregnancy occurrence and outcomes 
In study RV144 a total of 967 (30.6%) vaccine (vCP1521) and 955 (30.1%) 
placebo recipients reported a pregnancy during the study while 139 vaccine and 
116 placebo recipients reported more than one pregnancy. Birth was reported for 
1843 infants, 14 of them representing 7 twin pairs. Of these, 277 births (137 

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vaccine and 140 placebo recipients; 1 twin pair per treatment) occurred within 
450 days of study entry. For these infants, birth weight, gestational age, and 
Apgar scores were similar between the vaccine and placebo groups. Three 
congenital abnormalities (1 vaccine and 2 placebo recipients) were reported 
among these 277 births, the vaccine group abnormality being a respiratory distress 
syndrome with patent ductus arteriosus. Abnormal pregnancy outcomes were 
experienced in 165 out of 3165 (5.2%) vaccine female recipients and 139 out of 
3169 (4.4%) placebo female recipients (p = 0.13), and in 17.1% and 14.6% (p = 
0.13) of vaccine and placebo pregnancies, respectively (89). 
A total of 15 of the 245 female participants became pregnant during the phase 1-2 
AVEG studies. Twelve participants received ALVAC-HIV (vCP205) and 3 
received placebo. Of these 15 participants aged 19 to 37 years, 9 participants had 
live births, 3 participants had elective abortions, 1 subject had a spontaneous 
abortion, and the outcome of 2 pregnancies remains unknown. Of the 9 live births, 
3 were by cesarean section. Overall, no complications during pregnancy or 
congenital abnormalities at the time of birth were reported. 
In HVTN 203 (91) there were 2 participants with miscarriages among the total of 
80 female study participants who received ALVAC-HIV (vCP1452). These 
events were classified as unrelated to the study product by the investigators. 
4.9.2.3 
Summary of safety and tolerability data in African studies that have used 
ALVAC-HIV 
To date, 3 studies have been completed in Africa with ALVAC-HIV: HIVNET 
007, HPTN 027, and HVTN 097. 
HIVNET 007 (92) was a randomized, double-blind, placebo-controlled clinical 
trial conducted in Kampala, Uganda. In this study, 40 HIV-seronegative Ugandan 
volunteers were randomly assigned to receive ALVAC-HIV (vCP205) (n = 20), 
control ALVAC containing the rabies virus glycoprotein G gene (n = 10), or 
saline placebo (n = 10). Adverse reactions to immunizations were similar to those 
in previous trials with these vaccines in HIV-seronegative volunteers in the 
United States. No severe (grade 3 or 4) adverse reactions attributable to receipt of 
the vaccine were observed. 
HPTN 027 (93) was a phase 1 randomized, single center, double-blind, placebo-
controlled trial that evaluated the safety and immunogenicity of ALVAC-HIV 
(vCP1521) in infants born to HIV-1–infected women in Uganda. 60 infants were 
enrolled with 48 in the active group and 12 in the placebo group. Forty-seven 
infants received all 4 vaccinations and completed follow-up (38 in the vaccine 
group and 9 in the placebo group). There were 3 deaths in the HPTN 027 study (2 
in the vaccine group and 1 in the placebo group); all were reported as unrelated to 
the vaccine. The deaths included pneumonia-like illness, cor pulmonale secondary 
to congenital heart disease complicated by pneumonia, and gastroenteritis 
complicated with electrolyte imbalance. The rate of SAEs was similar between 
groups (56% in the vaccine group and 50% in the placebo group). In addition to 

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the 3 deaths, 4 were discontinued from vaccination due to HIV infection (of 
whom 3 were HIV-positive at birth and 1 HIV-positive at 2 weeks; no other infant 
was found to be HIV-positive in the study); 1 was lost to follow-up; 6 (5 vaccine, 
1 placebo) had AE requiring discontinuation (3 CD4 <25, anemia, gastroenteritis, 
increased liver enzymes). Thirteen infants in HPTN 027 experienced an AE that 
led to discontinuation of vaccinations: 10 participants in the vaccine group and 3 
in the placebo group. There were no severe or life-threatening reactogenicity 
events. Mild reactogenicity events were common in both study arms, with only 1 
moderate event (irritability) in the placebo group and 7 in the vaccine group 
(erythema, induration, pain, fever, and irritability). 
In addition, the primary protocol for HVTN 097, which administered the RV144 
vaccine regimen in a “low risk” South African population, is complete (Section 
4.9.5). 
4.9.2.4 
Previous human experience with ALVAC-HIV used in combination with 
subunit protein boost adjuvanted with MF59 
In addition to the ongoing HVTN 100 trial (Section 4.9.6), there has been 
meaningful previous human experience with the use of ALVAC-HIV vaccines in 
combination with recombinant gp120 proteins adjuvanted with MF59. In all, 440 
participants had received this combination across 7 clinical trials before initiation 
of HVTN 100 (Table 4-7). No safety signal of concern was identified in these 
studies. 
Table 4-7 Clinical studies performed with ALVAC-HIV and gp120+MF59 
Study 
(Country) 
ALVAC-
HIV 
Protein 
Participantsa 
RV132 (88) 
(Thailand) 
vCP1521 
gp120 + MF59 clades B/E 
made in CHO cells 
n = 45 
AVEG 022A (94) 
(USA) 
vCP205 
gp120 + MF59 clade B 
made in CHO cells 
n = 47 
AVEG 029 (95) 
(USA) 
vCP205 
gp120 + MF59 clade B 
made in CHO cells 
n = 22 
AVEG 202/HIVNET 014 
(96, 97) 
(USA) 
vCP205 
gp120 + MF59 clade B 
made in CHO cells 
n = 145 
AVEG 032 (98) 
(USA) 
vCP205 
gp120 +/- p24 + MF59 clade B 
gp120 made in CHO cells 
p24 made in S. cerevisiae 
n = 56 
AVEG 026 (99) 
(USA) 
vCP300b 
gp120 + MF59 clade B 
made in CHO cells 
n = 85 
AVEG 012A 012B (100) 
(USA) 
vCP125c 
gp120 + MF59 clade B 
made in CHO cells 
n = 40 
Total 
 
 
N = 440 
a Number of participants who received both the ALVAC-HIV prime and the gp120/MF59 boost. 
b ALVAC-HIV (vCP300) is similar to vCP205 and contains additional sequences encoding Pol and Nef 
epitopes. 
c ALVAC-HIV (vCP125) contains the gene for gp160 from clade B. 

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4.9.3 
Immunogenicity from related human clinical trial experience 
Immunogenicity measures in ALVAC-HIV studies have evolved over a period of 
more than 2 decades, informed by evolution in knowledge about relevant immune 
responses. Initial studies focused on the measurement of CTL activity, CD4+ T 
cell lymphoproliferation, and nAb activity. Subsequent studies have focused on 
Ab binding to the Env glycoproteins and on intracellular cytokine staining (ICS) 
as well. Most recently, a large collaborative consortium performed a case-control 
study to evaluate immune CoR based on the RV144 study that used the prime-
boost regimen of ALVAC-HIV (vCP1521) and the gp120 protein AIDSVAX B/E 
(Section 4.2.2) (21). 
As the development of assays for measuring immunogenicity has evolved during 
more than 20 years of testing in humans, immunogenicity data cannot be fully 
integrated. However, extensive data from previous studies with ALVAC-HIV can 
inform many relevant immunogenicity-related issues, as described below. 
4.9.3.1 
ALVAC-protein schedule and immunogenicity 
The selection of a vaccination schedule for the large efficacy trial in Thailand 
(RV144) was based on existing scientific knowledge at the time (101). In addition 
to safety, the key parameters taken into consideration were the CTL immune 
responses and the nAb responses. The HIV vaccine field has evolved significantly 
since then and the relevance of these immune measures is currently debated. 
However, the demonstration of vaccine protection in RV144 mandates the 
conservation of vaccination regimen features that are believed to have contributed 
to vaccine protection, even when the mechanism of protection has not been 
definitely established. The following paragraphs summarize the considerations 
that were taken into account in the selection of a vaccine regimen and schedule 
for the RV144 study. Section 4.5.3 explains the rationale for schedule 
modifications to address the goal of improving upon the RV144 results. 
Prior to RV144, several schedules of administration with ALVAC primes and 
protein boosts were examined in multiple clinical trials (80, 94, 97, 102, 103). 
While the studies were not designed or powered to discriminate statistically 
between the various vaccination schedules, an analysis of the data suggested that 
4 doses of ALVAC induced better CTL responses than 3 or 2 doses. Specifically, 
net point prevalence CTL response rates on Days 182 and 273 using 4-dose 
immunization regimens (Months 0, 1, 3, and 6 or Months 0, 1, 6, and 9) produced 
higher response rates than the 3-dose regimen (Months 0, 1, and 6) on Days 182 
and 273. Regarding neutralization data, both ALVAC schedules (ALVAC alone 
and ALVAC plus subunit protein boost), showed significantly higher 
neutralization response rates compared to the control schedule. 
The addition of a subunit protein boost to ALVAC did not appear to alter the CTL 
response rates (103). However, the protein boost did have a significant effect on 
Ab responses. The ALVAC plus subunit protein boost schedule had significantly 
higher nAb response rates when compared to the ALVAC alone schedule. 

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On the basis of these observations, a 4-dose regimen (Months 0, 1, 3, and 6) of 
ALVAC was proposed in order to maximize CTL responses. In addition, 2 doses 
of the protein boost were proposed at months 3 and 6 to maximize Ab responses. 
The RV144 study implemented this vaccination schedule. 
4.9.3.2 
Immunogenicity of ALVAC used in combination with protein boost plus 
MF59 
The vaccine regimen proposed for development in South Africa combines 
ALVAC-HIV (vCP2438) with a bivalent recombinant gp120 protein (total of 
200mcg, 100mcg of each protein) adjuvanted with MF59. This vaccine regimen is 
being evaluated in an ongoing study (HVTN 100), but no data are yet available to 
estimate its expected peak immunogenicity. However, previous studies with 
related vaccines provide useful preliminary information on whether peak 
immunogenicity is expected to be at least similar to that elicited by the RV144 
regimen and whether the use of MF59 could be dose-sparing for the protein. 
Study RV132 (88) used ALVAC-HIV (vCP1521) in the same dose and schedule 
as in study RV144 but 45 participants in one of the study arms received a bivalent 
recombinant gp120 protein manufactured in CHO cells by Novartis Vaccines and 
Diagnostics and adjuvanted with MF59 as a protein boost. The dose of the 
proteins was 150 mcg in total (100 mcg of the CM235 protein and 50 mcg of the 
SF2 protein). Study RV135 (87) used ALVAC-HIV (vCP1521) in the same dose 
and schedule as in study RV144, and 97 participants in two study arms received a 
bivalent recombinant gp120 protein manufactured in CHO cells by 
VaxGen/Global Solutions for Infectious Diseases (GSID) and adjuvanted with 
alum as a protein boost. The study explored two doses of the proteins: a total dose 
of 200 mcg (100 mcg for the A244 protein and 100 mcg for the MN protein) and 
a total dose of 600 mcg (300 mcg each of the same proteins in the lower dose 
formulation). The vaccine regimen with ALVAC-HIV and 600 mcg of gp120 
protein adjuvanted with alum was utilized in study RV144. Table 4-8 summarizes 
the nAb response rates for the pertinent study arms from these studies. 
Table 4-8 nAb response rates for selected regimens in RV132 and RV135 studies 
Study 
gp120 dose 
Adjuvant 
N 
NPO3 
strain 
SF2 
strain 
CM244 
strain 
MN 
strain 
Any clade 
E 
RV132 
[78] 
100mcg 
CM235* 
50 mcg SF2** 
MF59 
45 
89% 
61% 
95% 
19% 
100% 
RV135 
[87] 
100mcg 
A244* 
100mcg MN** 
alum 
50 
23% 
-- 
44% 
100% 
47% 
300mcg 
A244* 
300mcg MN** 
alum 
47 
31% 
-- 
64% 
98% 
71% 
* clade E Strain 
** clade B Strain 
The GM nAb titers were also reported in these studies for 2 of the clade E strains. 
Data are summarized in Table 4-9. 

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Table 4-9 nAb GM titers to clade E strains 
Study 
gp120 dose 
Adjuvant 
N 
NPO3 
Strain 
CM244 
Strain 
RV132 
[88] 
100mcg CM235* 
50 mcg SF2** 
MF59 
45 
45 
32.66 
RV135 
[87] 
100mcg A244* 
100mcg MN** 
alum 
50 
12.3 
7 
300mcg A244* 
300mcg MN** 
alum 
47 
14.8 
5.4 
* clade E Strain 
** clade B Strain 
Although the data should be interpreted with caution, they suggest that 100mcg of 
gp120 protein adjuvanted with MF59 can induce Ab responses after ALVAC 
prime at least comparable to and possibly greater than 300mcg of gp120 protein 
adjuvanted with alum after ALVAC prime. These data suggest that MF59 allows 
for protein dose sparing compared with the alum adjuvant. 
4.9.4 
Clinical studies with Novartis HIV-1 subunit protein vaccines 
Although clinical experience with Bivalent Subtype C gp120/MF59 vaccine is 
limited to the ongoing HVTN 100 trial (Section 4.9.6), other closely related 
recombinant monomeric (gp120) subunit vaccine formulations from Novartis 
Vaccines and Diagnostics (formerly Chiron, now GSK) have been tested in many 
clinical trials. In addition, recombinant oligomeric (o-gp140) Env proteins for 
subtypes B and C from Novartis have been or are currently in clinical trials. 
Overall, in these studies, recombinant HIV-Env proteins manufactured by 
Novartis were well tolerated and immunogenic. In most cases, recombinant HIV-
Env proteins (either gp120 or gp140) were CHO-based and administered with 
MF59 (50). MF59 safety has been established in clinical studies as well as in 
commercial products (47, 48). A seasonal influenza vaccine adjuvanted with 
MF59 (Fluad) is licensed in European Union (EU) countries and in other 
countries for use in the elderly (104). MF59 is also used in a prepandemic H5N1 
influenza vaccine (Aflunov) licensed in EU for use in adults, and in two pandemic 
H1N1 influenza vaccines (Focetria and Celtura), licensed in EU and other 
countries for use in adults and children (52). More than 100 million doses of 
MF59-adjuvanted influenza vaccines have been distributed in licensed products. 
Recombinant monomeric (gp120) vaccine candidates studied include Chiron’s 
early gp120-based candidate proteins from subtypes B and E, most of which were 
CHO-based and administered with MF59. More than 1200 clinical trials 
participants contributed in the evaluation of the Chiron HIV SF2 gp120/MF59 
vaccine and the Chiron HIV CM235 Thai E gp120/MF59 vaccine [55,88,99,105-
107]. Three clinical trials were conducted using Novartis CHO-based subtype B 
gp140 recombinant Env protein with MF59. There are 2 ongoing phase 1 studies 
with Novartis CHO-based subtype C gp140/MF59 being conducted by the NIH-
sponsored HVTN in the US and the RSA. Table 4-10 summarizes clinical trial 
experience with Novartis gp120 and gp140 recombinant vaccine candidates. 

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Table 4-10 Novartis recombinant gp120 and gp140 vaccines in human clinical trials* [106] 
Candidate vaccine 
# receiving 
Novartis protein 
Protocol 
Status 
Yeast derived recombinant subtype B SF2 
Env 2-3 protein with MF59 and MTP-PE 
60 
AVEG 005 
A/B/C 
Completed  
SF2 gp120 (CHO) with MF59 and MTP-PE 
50 
AVEG 007 
A/B/C 
Completed 
SF2 gp120 (CHO)/MF59 and ALVAC 
40 
AVEG 012A 
012B 
Completed 
SF2 gp120 (CHO) with MF59, SAF/2, SAF2 
+ MDP 
107 
AVEG 015 
Completed 
SF2 gp120 (CHO)/MF59 and ALVAC 
47 
AVEG 022A 
Completed 
SF2 gp120 (CHO) with MF59 
24 
AVEG 024 
Completed 
SF2 gp120 (CHO)/MF59 and ALVAC 
85 
AVEG 026 
Completed 
SF2 gp120 (CHO)/MF59 and ALVAC 
22 
AVEG 029 
Completed 
SF2 gp120 (CHO) +/- yeast derived 
p24/MF59 and ALVAC 
56 
AVEG 032 
Completed 
SF2 gp120 (CHO) with MF59 
126 
AVEG201 
Completed 
SF2 gp120 (CHO)/MF59 and ALVAC 
 
AVEG 202 
Completed 
SF2 gp120 & CM235 gp120 (CHO)/MF59 
and ALVAC 
45 
RV132 
Completed 
Subtype B (SF162) gp140 (CHO)/MF59 and 
Subtype B DNA/PLG  
90 
HVTN 049 
Completed 
Subtype B (SF162) gp140 (CHO)/MF59 IN 
with LTK63 
20 
C86P1 
Completed 
Subtype C (TV1) gp140 (CHO) & ISS TAT 
30 
ISS P-002 
Completed 
Subtype C (TV1) gp140 (CHO)/MF59 
20 
HVTN 088 
Completed 
Subtype C (TV1) gp140 (CHO)/MF59 and 
SAAVI DNA-C2 and SAAVI MVA-C 
24 
HVTN073E 
Completed 
Subtype C (TV1) gp140 (CHO)/MF59 and 
SAAVI DNA-C2 and SAAVI MVA-C 
114 
HVTN 086 
Ongoing 
Bivalent Subtype C gp120/MF59 (TV1.C and 
1086.C) and ALVAC 
210 
HVTN 100 
Ongoing 
Total 
1170 
 
 
In general, these recombinant protein vaccines were immunogenic and well 
tolerated with no unusual or serious vaccine-associated AEs reported. Most of the 
reactions were mild to moderate in nature, and of short duration (19, 55, 88, 99, 
105-109). 
4.9.4.1 
Summary of safety, reactogenicity, and tolerability from recent human 
experience 
Five clinical trials have been conducted recently using Novartis Chinese hamster 
ovary (CHO)-based subtype B gp140 with MF59. A sixth trial using Novartis 
CHO-based subtype C gp140, HVTN 086, is in extended follow-up (ie, annual 
health contacts). In addition, the HVTN 100 trial, which administers Bivalent 
Subtype C gp120/MF59, is currently ongoing (Section 4.9.6). 

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Among the clinical trials that have been completed, a phase 1 single-center trial 
(C86P1) was conducted using Novartis CHO-based subtype B gp140 recombinant 
Env protein in Great Britain by the Mucosal Vaccines for Poverty Related 
Diseases (MUVAPRED) Consortium to assess safety, tolerability, and 
immunogenicity of intranasal (IN) administration of subtype B gp140 with and 
without the mucosal adjuvant LTK63 (detoxified mutant heat labile protein) 
followed by IM boosting with subtype B gp140/MF59. This study enrolled 30 
healthy volunteers aged 18-45, with 20 to receive gp140. The protocol was 
amended to halt further IN administration of LTK63 following a report of an AE 
(facial nerve paralysis) with a possible association with the LTK63 adjuvant in 
another study (110). During the study, there was 1 SAE reported of Bell’s Palsy 
(facial nerve paralysis) considered possibly related to the study vaccine LTK63 in 
a subject who never received any subtype B gp140 protein or any protein with 
MF59 adjuvant. IN vaccination was reactogenic resulting in upper respiratory 
tract symptoms including nasal congestion, nasal discomfort, pharyngolaryngeal 
pain, and rhinorrhea. The subtype B gp140 MF59 was well tolerated following IM 
boost. 
Another completed study with Novartis subtype B gp140 MF59 was a 
multicenter, placebo-controlled trial (HVTN 049) conducted by the HVTN in the 
United States (111). Participants received one of three doses of a DNA/PLG 
vaccine (subtype B gag DNA/PLG and subtype B env DNA/PLG microparticles, 
at doses of 250/250, 500/500, or 1000/1000mcg) or placebo (5 to 1 ratio) as a 
single IM injection at 0, 1 and 2 months, followed by a boost of subtype B gp140 
with MF59 (or placebo) at 6 and 9 months. An additional group of participants 
received subtype B gp140 with MF59 without DNA prime, administered at 0, 3, 
and 9 months. Overall 96 healthy, HIV-1–uninfected adult participants were 
enrolled and 86 participants completed all planned vaccinations. There were no 
SAEs reported as related to study vaccine. There were four events reported as 
SAEs that were not considered related to the study vaccine. A death attributed to 
cocaine overdose occurred in one subject, 10 days after receipt of the second dose 
of the placebo. One subject had a Grade 3 increase in creatine phosphokinase 
(CPK) to 2311 U/L, 14 days after the first DNA prime vaccination, which 
resolved within a week. Another subject had a Grade 4 increase in CPK to 4806 
U/L 15 days after the first DNA prime vaccination, which resolved within two 
weeks. Both participants reported to have initiated new exercise programs. One 
subject experienced severe fatigue 20 days after the fourth immunization 
(including one dose of subtype B gp140/MF59), attributed to working two jobs 
and long hours. Overall, the regimens were generally well tolerated. 
A third trial, HVTN 088, was conducted in the United States in order to evaluate 
the safety and immunogenicity of a long-interval, cross-clade subtype C 
gp140/MF59 boost in participants administered subtype B gp120/MF59 or 
subtype B gp140/MF59 in previous trials. This included participants from the 
HVTN 049 DNA/PLG prime, gp140/MF59 boost study described above. The 
study enrolled 16 previously vaccinated participants and 20 naive controls. 
Individuals were identified who had received a clade B Env protein with MF59 4-
17 years earlier, most in combination with a DNA or ALVAC prime. These 

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individuals were enrolled in HVTN088 to receive a clade C protein boost in an 
open label phase 1 trial. The study was modified to add an additional late boost of 
the clade C gp140/MF59 vaccine. There were 3 SAEs reported in this trial, one 
involving traumatic injury, one instance of gastroenteritis, and one of 
appendicitis. All of these were assessed as unrelated to study agents. 
Another study, HVTN 073E, was conducted in the US and RSA as an extension 
to the previous HVTN 073/SAAVI03 study. This extension study examined the 
safety and immunogenicity of two boosting doses of Novartis subtype C 
gp140/MF59 or placebo in participants who previously received 3 vaccinations of 
SAAVI DNA-C2 and two vaccinations of SAAVI MVA-C. This study enrolled 
27 participants. There was one report of endometrial intra-epithelial neoplasia 
resulting in hospitalization for hysterectomy, which was assessed as unrelated to 
study agents. 
The Istituto Superiore di Sanità (ISS) study (ISS P-002) conducted in Italy 
examined the safety and immunogenicity of subtype C gp140 co-administered 
with ISS TAT compared to subtype C gp140 alone or TAT alone. The study 
includes intradermal and IM injections (100 mcg for subtype C gp140 and 7.5 
mcg for ISS TAT). This study did not include MF59. No SAEs were reported in 
this study. 
The study in extended follow-up, HVTN 086, is being conducted in the RSA. It is 
evaluating the safety and immunogenicity of various combinations of SAAVI 
DNA-C2, SAAVI MVA-C, and Novartis subtype C gp140/MF59. This study 
enrolled 184 participants. To date, 6 SAEs have been reported in this study, one 
case of acute tonsillitis that required hospitalization, one of schizophrenia 
requiring hospitalization (later determined to be a pre-existing condition), one of 
pelvic inflammatory disease, one soft-tissue injury, one instance of anemia, and 
one instance of alcohol-related cardiomyopathy. All were assessed as not related 
to the study products. During the annual health contact period, suspected 
unexpected serious adverse reactions (SUSARs) are collected; none have been 
reported thus far for HVTN 086. 
4.9.4.2 
Summary of immunogenicity from recent human experience 
The immunogenicity of Novartis recombinant proteins has been demonstrated 
consistently in all clinical trials and in both of the recently completed studies 
using Novartis CHO-based subtype B gp140 MF59. In the HVTN 049 DNA/PLG 
prime protein boost study, the primary cellular immunogenicity endpoints 
included interferon gamma (IFN-γ) enzyme-linked immunospot (ELISpot) and 
ICS responses. Immunogenicity was assessed 14 days after each vaccination. 
Env-specific IFN-γ ELISpot response rates did not increase substantially 
compared to baseline after the three DNA/PLG prime vaccinations, but did rise 
after the first protein/MF59 boost. nAb titers against the homologous SF162 
isolate were detectable in two vaccinees after the third DNA/PLG priming 
vaccination and in 13 vaccinees after the first protein boost. Neutralization was 
boosted to high titer in all but one vaccinee following the second protein boost. 

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Similarly in the group of participants who received subtype B gp140/MF59 
without a DNA/PLG prime, a nearly complete response to the SF162 isolate was 
observed at the second vaccination (all but one vaccinee) which lasted through the 
third vaccination. Binding Ab titers against Env, measured by enzyme-linked 
immunosorbent assay (ELISA), were detected following the first subtype B 
gp140/MF59 boost and were very high following the second boost administration. 
The C86P2 Mucosal Vaccines for Poverty Related Diseases (MUVAPRED) IN 
study demonstrated immunogenicity with considerable IgG and IgA Ab responses 
to subtype B gp140 in serum, cervical, and vaginal secretions of participants 
following IN administration of subtype B gp140 with the adjuvant LTK63 and an 
IM boost with subtype B gp140 and M59 adjuvant. nAb responses against the 
homologous SF162 were also detected in all groups following IM boost with 
subtype B gp140 and MF59 adjuvant. 
In the subtype C gp140/MF59 HVTN 088 long interval boost study, 
immunogenicity results are available for the vaccinations administered in Version 
1 of the protocol. Sixteen previously primed volunteers and 20 naïve volunteers 
each received 2 doses of the subtype C gp140/MF59 given 6 months apart. HIV-1 
specific CD4+ and CD8+ T-cell responses were measured by an ICS assay. Ab 
responses were measured with a Luminex binding Ab assay and a nAb assay in 
TZM-bl Cells. Despite the long interval (4-17 years from prior protein/MF59 
administration), 31% of primed participants demonstrated CD4+ T-cell responses 
to Env at baseline, which increased to 75% after a single protein boost. IgG and 
IgA responses to subtype C gp140/MF59 were present in 64% (IgG) and 7% 
(IgA) of primed participants at baseline, and rose to 93% and 85%, respectively, 
after one dose of protein. 71% of primed participants demonstrated nAb against 
Tier 1 clade B isolate MN at baseline. After a single booster dose of protein, 
100% of the primed participants neutralized MN and 93% showed neutralizing 
activity against a clade C isolate, MW965.26. Unprimed participants did not 
demonstrate CD4+ responses or Ab responses to Env until after the second dose, 
which elicited IgG and IgA responses to TV1 Env in 88% and 50%, respectively. 
nAb developed to MN in 38% and to MW965.26 in 88% of the unprimed 
participants. 
4.9.5 
HVTN 097 
As noted, development of the proposed vaccine regimen for South Africa was 
predicated on the results obtained in the RV144 trial in Thailand. The HVTN 097 
study was designed to confirm that the Thai prime boost would be comparably 
immunogenic in a South African study population. Hence, immune responses 
elicited in the South African population were evaluated and compared with those 
obtained in RV144 vaccinees. Note that, while the ALVAC-HIV (vCP1521) lots 
administered in the RV144 trial ranged from 107.06 CCID50 to 107.41 CCID50, the 
measured titer of the vaccine lot used in HVTN 097 was 107.72 CCID50. 
The HVTN 097 trial enrolled 100 healthy, HIV-1–uninfected participants aged 
18-40 years, 51 male and 49 female. Ninety-one participants completed 

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vaccinations and follow-up. The study opened in June 2013; it is now complete. 
The original HVTN 097 schema is shown in Table 4-11. Safety and 
immunogenicity results reported below are for the original study. 
Table 4-11 HVTN 097 schema 
Group 
N 
Month 0 
(Day 0) 
Month 1 
(Day 28) 
Month 2 
(Day 56) 
Month 4 
(Day 112) 
Month 7 
(Day 196) 
Month 7.5 
(Day 210) 
Month 8.5 
(Day 238) 
Month 13 
(Day 394) 
1 (T1) 
60 
Tetanus 
toxoid 
ALVAC 
ALVAC 
ALVAC + 
AIDSVAX 
B/E 
ALVAC + 
AIDSVAX 
B/E 
HBV 
vaccine 
HBV 
vaccine 
HBV 
vaccine 
2 (T2) 
20 
placebo 
ALVAC 
ALVAC 
ALVAC + 
AIDSVAX 
B/E 
ALVAC + 
AIDSVAX 
B/E 
placebo 
placebo 
placebo 
3 (T3)  
20 
Tetanus 
toxoid 
placebo 
placebo 
placebo 
placebo 
HBV 
vaccine 
HBV 
vaccine 
HBV 
vaccine 
4.9.5.1 
Safety data 
Four participants discontinued vaccinations (DOV), 2 due to pregnancy (both 
received active vaccine) and 2 due to “other” reason (1 received active vaccine); 
there were no DOVs due to AEs or reactogenicity. There were 7 early 
terminations due to participant refusal (3), nonadherence to schedule (3), and 
unable to contact (1). No participant was terminated early due to an AE. 
Local and systemic reactogenicity was assessed for the investigational ALVAC 
and AIDSVAX vaccinations. Local injection site reactions of pain and/or 
tenderness were more common in participants receiving active HIV vaccinations 
versus placebo injections. Most pain and/or tenderness reactions to the HIV 
vaccinations (T1 and T2 combined) were mild (48%), 28% were moderate, and 
~9% were severe. In placebo recipients the maximum pain and/or tenderness 
reactions were mild (52%). The majority of participants in both active (T1 and T2 
combined) and placebo groups experienced no erythema and/or induration 
reactions (84% and 95%, respectively); with all but 1 reaction (> 9 cm 
erythema/induration) being non-gradable by the DAIDS AE Grading table (0-25 
cm2), occurring in T1. 
Moderate or severe systemic reactions associated with vaccine administration 
included malaise and/or fatigue (15% vs 5.3% in placebo), myalgia (12.5% vs 0% 
in placebo), headache (7.5% vs 21% in placebo), nausea (1.25% vs 0% in 
placebo), chills (3.75% vs. 5.3% in placebo) and arthralgia (6.25% vs 0% in 
placebo). The maximum temperature elevations were grade 2, which occurred in 
2 vaccinees compared to 0 in placebo. 
Overall, 88.75% of vaccine recipients experienced at least 1 AE compared to 85% 
of placebo recipients. There were 2 SAEs and both were unrelated to treatment: 
thermal burn in a vaccinee and substance-induced psychotic disorder in a placebo 
recipient. There were no grade 4 (life threatening) or 5 (death) AEs. There were 5 
grade 3 AEs in vaccine recipients (6.25%) and 2 grade 3 events in one placebo 
recipient (5.3%), all deemed unrelated to study treatment. These included alanine 

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aminotransferase (ALT) increase, headache, hypertension, abnormal loss of 
weight, and thermal burn in vaccinees and substance induced psychotic disorder 
and abnormal loss of weight in one placebo recipient. Moderate AEs were 
experienced by 61.25% of vaccinees and 50% of placebo recipients. 
AEs considered related to the vaccine included itching at the injection site, lymph 
node swelling, faster heartbeat, abdominal pain, flu-like illness, diarrhea, injection 
site skin lump, and muscle spasms. Each of these reactions was mild or moderate, 
only occurred in one person (except for the skin lump which occurred in three 
participants), and was transient. The participants who had them recovered without 
any problems. A few participants had changes in their laboratory, blood, and urine 
test results that were considered related to the vaccinations and all returned to 
normal. 
4.9.5.2 
Immunogenicity 
Cellular/ICS 
HIV-specific T-cell responses were measured by intracellular cytokine staining 
(ICS) at day 210, corresponding to 2 weeks after the second ALVAC + 
AIDSVAX B/E vaccination (prior to the hepatitis B vaccination). CD4+ and 
CD8+ T-cell response rates and magnitudes (as measured by production of IL-2 
and/or IFN-γ) were evaluated for 92TH023-Env and LAI-Gag peptide pools. 
For CD4+ T cells, the vast majority of responses were generated to the antigen 
92TH023-Env in groups T1 (Group 1) (72%) and T2 (Group 2) (60%); responses 
were extremely low to the other two antigens (LAI-Gag and HBsAg) across all 
treatment groups (< 6%) (Figure 4-11). The response rate to 92TH023-Env was 
significantly higher in the combined treatment group “T1+T2” compared to group 
T3 (Group 3) (p < 0.0001) and there was no response difference between groups 1 
and 2 (p = 0.4). Differences in magnitudes of positive responders to antigen 
92TH023-Env were non-significant in all group comparisons. 

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Figure 4-11 HIV-specific CD4+ T cell responses 2 weeks post second ALVAC + AIDSVAX 
vaccination 
Comparisons of T-cell immune responses in vaccinees in HVTN 097 to responses 
from a random selection of samples from RV144 vaccine recipients adjusting for 
placebo responses, showed similar results (Table 4-12). 
 Table 4-12 Comparison of HVTN 097 and RV144 ICS results adjusting for placebo 
responses % responder (vaccine) - % responder (placebo) 
 
HVTN 097 
RV144 
P-value 
HVTN 097 vs RV144 
CD4+ Env 
58.1% (95% CI = 40.4%, 75.9%) 
50.3% (95% CI = 42.9%, 57.7%) 
0.425 
CD4+ Gag 
-1.7% (95% CI = -13.1%, 9.7%) 
2.5% (95% CI = -2.3%, 7.3%) 
0.506 
CD8+ Env 
5.1% (95% CI = 0.2%, 10.0%) 
0.6% (95% CI = -0.5%, 1.6%) 
0.074 
CD8+ Gag 
2.6% (95% CI = -0.9%, 6.1%) 
5.0% (95% CI = -1.8%, 11.8%) 
0.530 
For CD8+ T cells, only a few responses were observed to Env and Gag, which is 
also similar to results from RV144 vaccinees. 
Another goal of HVTN 097 was to evaluate the effect of body mass index (BMI) 
on immune responses. Neither BMI nor demographic factors of gender and age 
significantly affected T cell immune responses. 
Binding antibody 
The frequency and magnitude of IgA and IgG antibody binding were measured by 
the HIV-1 binding antibody multiplex assay (BAMA) on serum specimens 
obtained at baseline (day 0), on day 210, 2 weeks after the second ALVAC + 
AIDSVAX vaccination, and on day 394, 6 months after the second ALVAC + 
AIDSVAX vaccination. Antigens for primary analysis include ConS gp140 CFI, 
MN gp120, A244 gp120, clade A, B, and C consensus Env and V1/V2 antigens. 

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 IgG results: 
In general, response rates were significantly higher in group T1+T2 compared to 
group T3 and there are no significant differences between groups T1 and T2 
across all antigens at 2 weeks after the second ALVAC + AIDSVAX vaccination 
or 6 months after the second ALVAC + AIDSVAX vaccination). In groups T1 
and T2, the IgG response rates at peak in general are high for all tested antigens 
(82-100%) and IgG responses to V1V2 cross-clade antigens (clade A/AE, B, and 
C) were also high (66-99%), with the greatest magnitude of responses towards 
clade A/AE V1V2 antigens. At 6 months post the last HIV-specific vaccination, 
the response remained high to antigen A244 D11gp120_avi, but dropped 
significantly for all other antigens. The response magnitudes among positive 
responders at peak waned significantly 6 months post the second ALVAC + 
AIDSVAX vaccination in all groups. In general, no significant IgG antibody 
response was observed in group T3 across all antigens. Among IgG responders, 
and among group pairs where there were sufficient numbers of positive 
responders for statistical testing, there were no significant differences in 
magnitudes of responses to any antigen between groups T1 and T2. 
Comparisons of binding antibody responses in HVTN 097 vaccine recipients to 
immune responses from a random selection of RV144 vaccine recipients showed 
comparable response rates to gp120, V1V2, and gp140 antigens. Binding 
antibody responses were of higher magnitude in HVTN 097 compared to RV144 
vaccine recipients (Figure 4-12). 
 
 
Figure 4-12 Comparison of RV144 and HVTN 097 peak IgG response rates and magnitudes 
to V1V2, gp120, gp140, and other antigens overall. GM MFI (mean fluorescent intensity) 
differences were statistically significant between RV144 and HVTN 097 for each antigen 
group. 

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As with CD4+ T-cell responses, there were no significant differences in IgG 
responses to V1V2 antigens within BMI, gender, or age strata in HVTN 097 
(Table 4-13). 
Table 4-13 IgG responses to V1V2 by BMI, gender or age stratum in vaccine recipients in 
HVTN 097 
Stratum 
Responses 
Response rate % 
95% CI 
BMI ≤ 25 
40/42 
95.2% 
(84.2%, 98.7%) 
BMI 25-30 
16/17 
100.0% 
(73.0%, 99.0%) 
BMI > 30 
5/5 
100.0% 
(56.6%, 100.0%) 
Female 
28/28 
91.7% 
(78.2%, 97.1%) 
Male 
33/36 
100.0% 
(91.7%, 100.0%) 
Age ≤ 20 
19/19 
100.0% 
(83.2%, 100.0%) 
Age 21-25 
25/28 
89.3% 
(78.2%, 96.3%) 
Age ≥ 26 
17/17 
100.0% 
(81.6%, 100.0%) 
IgA results: 
At peak , 2 weeks post the last HIV-specific vaccination, IgA responses to most of 
the antigens are below 50% in group T1+T2, except for antigens A44 
D11gp120_avi (85%) and AE.01.con_env03 gp140CF_avi (78%). The 
differences in response rates and magnitudes across antigens are minimal between 
groups T1 and T2. At visit 17, 6 months post the last HIV-specific vaccination, 
response rates range from 0% to 11% and magnitudes dropped to very low levels 
in the vaccine groups. There is no response observed in group T3 across all IgA 
antigens at these timepoints. 
Neutralizing antibody assays 
Neutralization ID50 titers were measured by HIV neutralizing antibody assay from 
specimens obtained at visit days 28 and 210 (visits 3 and 14, respectively), 
corresponding to the first ALVAC vaccination and 2 weeks after the second 
ALVAC + AIDSVAX vaccination (Figure 4-13). Neutralizing antibodies against 
HIV-1 were measured as a function of reductions in Tat-regulated luciferase 
(Luc) reporter gene expression in TZM-bl cells. The assay measured 
neutralization titers against a panel of heterologous Env-pseudotyped viruses that 
exhibit a Tier 1 neutralization phenotype (clade B: BaL.26, MN.3, SF162.LS; 
clade C: MW965.26; CRF01_AE: NP03.13, TH023.6). Data from blood draw 
dates outside the allowable visit window and assay results deemed unreliable for 
analysis by the lab were excluded from the analysis. 

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Figure 4-13 Neutralizing antibody responses at visit 14 (2 weeks post second ALVAC + 
AIDSVAX vaccination) 
There were no neutralizing antibody responses to any of the 6 viruses at visit 3. At 
visit 14, response rates to viruses MN.3, TH023.6, MW965.26 and SF162.LS, 
were all significantly higher in the groups “T1+T2” and T1 compared to group 
T3, but no difference was observed between groups T1 and T2. Response rates 
against Bal.26 and NP03.13 viruses were extremely low (0-10%) and there was 
no difference between groups. Differences in magnitudes of positive responders 
were non-significant across all group comparisons. Groups “T1+T2” and T1 had 
significantly higher AUC- MB when compared to group T3 (p < 0.0001 for 
T1+T2 vs T3, T1 vs T3), and no difference in AUC-MB was detected between 
groups T1 and T2 (p = 0.9909). 
Neutralizing antibody responses also appeared to be relatively similar in HVTN 
097 compared to RV144 vaccine recipients; although a direct comparison cannot 
be made as there were differences in the assay techniques (Figure 4-14). 
 
Figure 4-14 Neutralizing antibody responses in HVTN 097 and RV144 vaccinees 

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4.9.6 
HVTN 100 
HVTN 100 is a phase 1-2 trial of the ALVAC-HIV (vCP2438) and Bivalent 
Subtype C gp120/MF59 vaccine regimen proposed for HVTN 702. HVTN 100 is 
currently being conducted at CRSs in the Republic of South Africa. Evaluation of 
the safety and immunogenicity of the primary vaccine regimen in HVTN 100 has 
informed a decision to initiate pivotal efficacy testing in HVTN 702. 
Immunogenicity criteria for initiating HVTN 702 were selected such that, if the 
V1V2 IgG binding antibody correlate of risk identified in the RV144 trial is 
actually a perfect correlate of vaccine protection against HIV-1 infection and if 
HVTN 100 vaccinees attain a threshold rate and magnitude of these binding 
antibodies, then similar immune responses in HVTN 702 would predict 
attainment of a target level of vaccine efficacy in HVTN 702. These criteria 
included binding antibody response rates and magnitudes to vaccine-matched Env 
proteins, CD4 response rates to the ALVAC-insert Env, and response rates to 
vaccine-matched Env V1V2 scaffold proteins (see Section 4.9.6.4). 
HVTN 100 enrolled 252 healthy HIV-1–uninfected volunteers aged 18 to 40 
years 142 male, 109 female, and one reported other. The first participant enrolled 
in February 2015 and enrollment was completed in May 2015. The HVTN 100 
schema is shown in Table 4-14. All Month 12 injections were completed by 2 
June 2016. The HVTN 100 protocol has been amended (Version 3.0, May 2017) 
to gather additional safety data and to explore the ability of late boost 
vaccinations administered at month 30 post-enrollment to boost immune 
responses in HVTN 100 vaccinees. These additional booster injections are 
expected to start in August 2017 (see Table 4-15). 
Table 4-14 HVTN 100 schema 
Group 
N 
Primary vaccine regimen 
Booster 
Month 0 
Month 1 
Month 3 
Month 6 
Month 12 
1 
210 
ALVAC-
HIV 
(vCP2438) 
ALVAC-
HIV 
(vCP2438) 
ALVAC-HIV 
(vCP2438) + Bivalent 
Subtype C gp120/MF59 
ALVAC-HIV 
(vCP2438) + Bivalent 
Subtype C gp120/MF59 
ALVAC-HIV 
(vCP2438) + Bivalent 
Subtype C gp120/MF59 
2 
42 
Placebo 
Placebo 
Placebo + Placebo 
Placebo + Placebo 
Placebo + Placebo 
Total  
252 
 
Table 4-15 Schema for HVTN 100 Part B 
 
Booster vaccination 
Part A Group 
Part B Group† 
N 
Month 30 
1 
1a 
~30 
ALVAC-HIV (vCP2438) + Bivalent 
Subtype C gp120/MF59 
1b 
~30 
Placebo +  
Bivalent Subtype C gp120/MF59  
2 
2 
~12 
Placebo + Placebo 
                                       Total     72 
 
† Vaccine recipients in Part A (Group 1) are randomized to Group 1a or 1b. Part A placebo 
recipients (Group 2) continue to receive placebo injections in Part B. 

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4.9.6.1 
Interim summary of blinded safety and tolerability data 
Blinded safety data reported as of November 2016 are summarized here. A total 
of 1198 ALVAC or placebo injections were given to participants in the left 
deltoid and 703 Bivalent Subtype C gp120/MF59 or placebo injections were 
given to participants in the right deltoid.  
The vaccine regimen is very well tolerated thus far with the vast majority 
experiencing no or mild local reactogenicity symptoms. Mild pain and/or 
tenderness was reported by 58% of participants for injections in the left deltoid 
and by 48% for injections in the right deltoid. Moderate pain and/or tenderness 
was reported by 18% of participants for injections in the left deltoid and by 11% 
for injections in the right deltoid. Severe pain and/or tenderness was reported 
from a left deltoid injection by 1 participant (following the 1st injection) and for a 
right deltoid injection by 2 participants (following the 3rd or 5th injection).  
For the left deltoid, grade 1 (mild) erythema and/or induration injection site 
reactions were reported by 6% of participants and grade 2 (moderate) reactions by 
5% of participants. For the right deltoid, grade 1 erythema and/or induration 
injection site reactions were reported by 4% of participants and grade 2 reactions 
by 2% of participants. Three participants have reported erythema and/or 
induration reactions meeting grade 3 criteria (severe) based on size (≥ 10cm 
diameter or ≥ 100cm2 surface area) with no complications (such as ulceration, 
secondary infection, phlebitis, sterile abscess, or drainage). One person reported a 
grade 3 right deltoid erythema reaction (> 100 cm2) occurring on Day 2 of the 4th 
injection timepoint, which resolved within 4 days. This participant also self-
reported severe induration on Day 3, which resolved within 1 day. The participant 
returned to clinic on Day 4 for examination, and clinic staff observed severe 
erythema alone without induration or swelling. Antibiotics, analgesics, and 
antihistamines were prescribed and the participant was discontinued from further 
vaccinations but continued in follow-up. Another person reported grade 3 
induration and erythema in the right deltoid on Day 3 after the 5th vaccination 
timepoint, resolving by Day 5. Antibiotics, anti-inflammatory and analgesic 
medications were prescribed and were taken for 3 days. Another person reported 
severe erythema and induration reactions in the left deltoid occurring on Day 0 
after the 5th vaccination timepoint and resolving by Day 3. Antihistamine, oral 
steroid and analgesic/anti-inflammatory medications were taken. In all 3 
participants, the needle used for injection was < 1.5” long, consistent with weight-
based guidance for needle length choice provided to sites in the SSPs (112, 113).  
Systemic reactions have been reported in 69% of participants thus far, with the 
vast majority of those reactions being mild in intensity. Malaise and/or fatigue, 
headache, myalgia and arthralgia appear to be the most common reactions, 
occurring in 42%, 41%, 37% and 30% of participants, respectively thus far. Other 
systemic reactogenicity symptoms have included nausea (15%), chills (10%), 
fever (8%), and vomiting (4%). Maximum severity of systemic symptoms of 
moderate intensity has been reported in a total of 19% of participants; 7% 
reported systemic symptoms of moderate intensity after the 1st injection, 3% after 

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the 2nd, 5% after the 3rd, 2% after the 4th and 5% after the 5th. Severe systemic 
symptoms have occurred in 2% of participants (4 participants): 2 participants with 
severe arthralgia occurring after the 1st injection, 1 person with severe malaise 
and/or fatigue and 1 with severe headache, each after the 5th injection. 
4.9.6.2 
Interim summary of Adverse Events (AEs) and Serious Adverse Events 
(SAEs) 
As of November 2016, 467 adverse events (AEs) have occurred in 181 
participants (72% of participants), of which 282 AEs (60%) were mild, 165 were 
moderate, (35%), 13 (3%) were classified as severe, 3 (0.6%) were classified as 
potentially life-threatening, and 2 (0.4%) were fatal. AEs were reported by 
participants most frequently in the Systems Organ Class (SOC) Infections and 
infestations (132 participants [52% of enrolled participants]), followed by the 
SOC Investigations (71 participants [28%]). Fourteen AEs occurring in 11 
participants have been assessed by the site investigator as being related to study 
product; 11 were mild, 3 were moderate and none were severe. These include 
injection site pruritus in 3 individuals (mild in 2, moderate in 1), 
lymphadenopathy in 2 individuals (both mild), abdominal pain (moderate), 
generalized pruritus (moderate), and mild events of diarrhea, injection site nodule, 
gastritis, dizziness, headache, neutrophil count decreased, and oral paresthesia in 
1 individual each.  
Eight SAEs, including 2 deaths, have occurred in 6 participants during the trial, 
all unrelated to study product. One participant experienced 3 separate SAE events 
resulting from 3 separate assault attacks: severe soft tissue injuries due to assault, 
potentially life-threatening subdural hematoma, and then multiple injuries to the 
head and chest that were fatal. SAEs in other participants were: gastrointestinal 
infection, bi-polar mood disorder, acute rheumatic fever, transient ischemic 
attack, and completed suicide. 
4.9.6.3 
Discontinued vaccinations and early terminations 
As of 21 November 2016, 232 participants have terminated the study: 207 at 
scheduled study exit (on-time) and 25 participants have terminated the study 
prematurely. Twenty-two participants have discontinued vaccinations. Clinical 
events leading to early terminations and discontinuation of vaccinations (DOV) 
occurred in 6 participants: death from multiple injuries (unrelated to study 
product); death from completed suicide (unrelated to study product); severe local 
reactogenicity (DOV); hypertension (DOV for AE unrelated to study product); 
mild vomiting occurring on the day of 1st vaccination only (participant declined 
further study participation); psychiatric diagnosis (DOV and early termination for 
investigator discretion). Reasons for DOV or early termination in other 
participants included HIV infection, participant refusal, unable to contact, unable 
to schedule within visit windows, unable to adhere to study schedule, relocation, 
desiring to fall pregnant, desiring to donate eggs, unwilling to use contraception, 
and pregnancy. Two pregnancies have been reported to date, with one participant 

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reporting a full term live birth and the other pregnant participant is continuing in 
follow-up.  
4.9.6.4 
Summary of interim immunogenicity data from HVTN 100 
Section 6.1.2 of version 1.0 of HVTN 100 (Part A) describes the immunological 
criteria guiding the decision whether to advance development of the ALVAC-HIV 
(vCP2438), Bivalent Subtype C gp120/MF59® regimen. Except for the increased 
stringency of the V1V2 response rate criteria (LL of the 95% CI increased from 
≥ 45% to ≥ 56%), these same criteria ultimately formed the basis of the decision 
to proceed with HVTN 702, A pivotal phase 2b/3 multi-site, randomized, double-
blind, placebo-controlled clinical trial to evaluate the safety and efficacy of 
ALVAC-HIV (vCP2438) and Bivalent Subtype C gp120/MF59 in preventing HIV-
1 infection in adults in South Africa (Table 4-16). Immunogenicity data from 
samples collected from HVTN 100 participants at the month 6.5 timepoint (2 
weeks post 6 month vaccination) were compared to data from a new, randomly 
selected subset of stored samples from RV144 vaccine recipients who were HIV-
1 uninfected upon completion of follow-up (the RV144 “comparator arm”). 
Samples from the RV144 comparator arm and HVTN 100 participants were 
analyzed contemporaneously using qualified assays in the same laboratories 
(along with placebo samples for blinding).  
All four immunogenicity Go criteria were met. 
Table 4-16 Go/No-Go criteria for advancement of the HVTN 100 vaccine regimen to efficacy 
testing 
Variable Measured at Month 6.5 
Rationale 
Go Criteria Threshold 
(LL of 95% CI) 
1. Env Ab Response Rate (≥ 2 of 3 
antigens) 
Adequate Ab take to vaccine Env 
≥75% 
2. Env Ab Magnitude(≥ 2 of 3 
antigens) 
Non-inferior Ab magnitude vs. RV144 
GM ratio 
(new/RV144) ≥50%* 
3. Env CD4 Response Rate (1 of 1 
antigen) 
Non-inferior CD4 T-cell take vs. RV144 
Difference within 
30%*  
4. Env V1V2 Response Rate (≥ 1 of 
3 antigens) 
Adequate to predict achieving estimated 
VE=50% for 2 years if V1V2 Ab is a 
predictive immune correlate  
≥ 56% 
*Non-inferior to RV144 response based on contemporaneous assessment of clade C vaccine samples vs. 
RV144 vaccinee samples by the same lab. 
Binding antibody responses to Env (criteria 1 and 2): 
At the month 6.5 timepoint, 100% of vaccinees in HVTN 100 part A developed 
binding antibodies to the gp120 Clade C strain Env antigens in the ALVAC 

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vector, as well as the two Clade C strains in the bivalent gp120 protein boost 
(Figure 4-15). Antibody magnitude values measured by geometric mean titers 
were 3.6-8.8 fold greater than IgG binding antibody to vaccine-matched responses 
to Env antigens included in RV144 (Table 4-17). Hence criteria 1 and 2 were met. 
 
Figure 4-15 Box plots of the binding antibody titers to the vaccine antigens used in RV144 
and HVTN 100. The midline of the box plot indicates the median, the ends of the box indicate 
the 25th and 75th percentiles. Closed dots represent positive responses, open triangles 
represent negative responses. 
Table 4-17 HVTN 100 vs. RV144 Peak bAb magnitudes to gp120 among vaccinees 
Protocol 
Antigen 
n 
Geometric Mean Titer 
GMR 
(100/RV144) 
GMR  
95% CI 
100 
1086 
185 
26,257.5 
8.8 
(7.64, 10.2) 
RV144 
A244 
201 
2,968.9 
100 
TV1 
185 
10,726.7 
3.6 
(3.01, 4.34) 
RV144 
A244 
201 
2,968.9 
100 
ZM96 
185 
2,685.4 
3.6 
(2.95, 4.39) 
RV144 
92TH023 
201 
746.1 

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CD4 responses (criterion 3) 
The CD4+ T cell response rate to vaccine-matched Env sequences in ALVAC 
(vCP2438), (Env peptide pool ZM96) in HVTN 100 participants was 58%. This 
was compared to the CD4+ T cell response rate to vaccine-matched Env 
sequences in ALVAC (vCP1521), (Env peptide pool 92TH023) in RV144 
participants of 41%. The response rate difference (100-RV144) was 16% (95% 
CI: 6, 26%; p = 0.0019). This exceeded the LL response rate difference of -30% 
and meeting criterion #3. 
V1V2 antibody response rates (criterion 4) 
The binding antibody response rate to the vaccine-matched 1086.C V1V2 antigen 
was 71% (95% CI 64% - 77%), thereby meeting criterion #4 that the prevalence 
of IgG antibodies to the Clade C V1V2 loop in at least one vaccine antigen must 
be at a lower limit threshold of > 56% (which equates to a response rate of 63%) 
(Table 4-16). The cumulative V1V2 response is 80%; well above the 63% 
threshold that was established for modeling a 50% efficacy if V1V2 was the sole 
Correlate of Protection. 
Table 4-18 HVTN 100 Binding Antibody Env V1V2 Response Rates, Per-Protocol Cohort 
(Go/No-Go Criterion 4) 
Antigen 
Treatment 
Response 
Rate 
95% CI 
LL of CI 
≥56% 
Criterion 4 
Passed? 
1086.C.V1V2 tags 
T1 (n=183) 
P2 (n=35) 
71% 
0% 
(64%, 77%) 
(0%, 10%) 
Yes 
Yes 
gp70-V1V2CladeB CaseA2 
T1 (n=183) 
P2 (n=35) 
50% 
0 % 
(43%, 57%) 
(0.0%, 9.9%) 
No 
 
gp70-V1V2.TV1 
T1 (n=183) 
P2 (n=35) 
62% 
0% 
(55%, 69%) 
(0%, 10%) 
No 
 
 
1086.C.V1V2 tags or gp70-V1V2.TV1 
T1 (n=183) 
80% 
(74%, 85%) 
N/A 
 
1086.C.V1V2 tags or 
 gp70-V1V2CladeB CaseA2 or gp70-
V1V2.TV1 
T1 (n=183) 
80% 
(74%, 85%) 
N/A 
 
Based on the immunogenicity results of the month 6.5 timepoint in HVTN 100, 
the decision was made to proceed with HVTN 702. 

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4.10 
Potential risks of study products and administration 
Table 4-19 includes general risks of vaccine administration along with risks 
known from prior clinical studies of ALVAC-HIV products and of envelope 
protein vaccines adjuvanted with MF59. 
Table 4-19 Summary of potential risks of study products and administration 
Common (> 10%) 
Mild to moderate injection site pain, tenderness, erythema, or 
swelling/induration/edema 
Malaise/fatigue, myalgia, arthralgia, nausea/vomiting, lymphadenopathy, asthenia, 
fever, or headache in the first few days following injection 
Arm movement limitation 
A vaccine-induced positive HIV antibody test result 
Less common (1% to 10%) 
Severe injection site pain or tenderness 
Chills, flu-like syndrome, diarrhea, rash, or dizziness in the first few days 
following injection 
Vasovagal reaction/lightheadedness/dizziness related to the injection procedure 
Transient changes in clinical laboratory values 
Injection site hematoma, bruising/ecchymosis, other transient lesions, or bleeding 
related to the injection procedure 
Uncommon (< 1%) or rare  
(< 0.1%) 
Severe localized injection site reaction, such as > 10 cm diameter erythema or 
induration, sterile abscess or secondary bacterial infection 
Allergic reaction, including rash, urticaria, angioedema, eyelid swelling, 
bronchospasm, or anaphylaxis 
Injection site pruritus, warmth or other non-specific injection site reaction 
Generalized pruritus 
Oral paresthesia 
Syncope, insomnia 
Abdominal pain, anorexia, gastritis, dysgeusia 
Skin disorder, acne 
Muscle damage at the injection site 
Theoretical risks 
Autoimmune disease 
Effects on a participant’s response to an approved HIV vaccine administered in the 
future 
Effects on susceptibility to HIV, if the participant is exposed to HIV 
Effects on the course of HIV infection/disease, if the participant is infected with 
HIV 
Effects on the fetus and on pregnancy 
 

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5 
Objectives and endpoints 
5.1 
Primary objectives and endpoints 
Primary objective 1: 
To evaluate the vaccine efficacy (VE) of ALVAC-HIV (vCP2438) + Bivalent 
Subtype C gp120/MF59 for the prevention of HIV infection in HIV-seronegative 
South African adults over 24 months from enrollment 
Per the 23 January 2020 DSMB finding that monitoring boundaries for non-
efficacy have been met, Primary objective 1 has been superseded by Primary 
objective 3 below. 
Primary endpoint 1: 
HIV-1 infection diagnosed after enrollment (concurrent with first vaccination) 
through 24 months after enrollment 
The main vaccine efficacy endpoint is diagnosis of HIV-1 infection during the 
follow-up of the trial. The occurrence of HIV-1 infection will be detected through 
HIV-1 tests administered at specified timepoints. Participants found to be HIV-1–
infected will have additional testing to confirm the diagnosis of HIV-1 infection 
(Section 10.3). The vaccine-induced immune responses may lead to reactive HIV-
1 tests and difficulty in interpretation. Therefore, the study will utilize blinded 
Endpoint Adjudicator(s) to review all data that support diagnoses of HIV-1 
infection. 
Primary objective 2: 
To evaluate the safety and tolerability of ALVAC-HIV (vCP2438) + Bivalent 
Subtype C gp120/MF59 in adults in South Africa 
Primary endpoints 2: 
Number and frequency of local and systemic reactogenicity signs and symptoms 
(pain, tenderness, maximum severity of pain and/or tenderness, erythema, 
induration, fever, malaise/fatigue, myalgia, headache, nausea, vomiting, chills, 
arthralgia) occurring within 3 days after each vaccine/placebo dose  
AEs by body system, Medical Dictionary for Regulatory Activities (MedDRA) 
Preferred Term, severity, and assessed relationship to study products within 30 
days after each vaccine/placebo dose 
SAEs, AEs of special interest (AESIs), and new chronic medical conditions 
(defined as a new onset or exacerbation of medical condition requiring 2 or more 

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visits to a medical provider during a period of at least 30 days) occurring at any 
time throughout the study 
AEs leading to early participant withdrawal or early discontinuation of study 
product(s) administration throughout the study 
Primary objective 3:  
To evaluate the effect of ALVAC-HIV (vCP2438) +Bivalent Subtype C 
gp120/MF59 vaccination on HIV acquisition in HIV-seronegative African adults 
Primary endpoint 3: 
HIV infections diagnosed following enrollment and throughout all participant 
follow-up 
5.2 
Secondary objectives and endpoints 
Secondary objective 1: 
To evaluate durability of vaccine efficacy from enrollment through 36 months if 
Stage 2 occurs 
Secondary endpoint 1: 
HIV-1 infection diagnosed after enrollment through 36 months post enrollment 
Secondary objective 2: 
To evaluate vaccine efficacy from Month 6.5 (Week 26) through 24 months post 
enrollment 
Secondary endpoint 2: 
HIV-1 infection diagnosed after Month 6.5 through 24 months post enrollment 
Secondary objective 3: 
To evaluate the immunogenicity of the vaccine regimen 
Secondary endpoint 3: 
Immune responses at Month 6.5 (week 26 visit) from assays based on the HVTN 
Laboratory Center assay portfolio (available at 
http://www.hvtn.org/en/science.html/) such as vaccine-specific binding antibodies 
and T cell responses. 
Secondary objective 4: 

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To evaluate immunogenicity and immune response biomarkers among vaccine 
recipients at Month 6.5 (week 26 visit) and Month 12.5 (week 54 visit) as 
correlates of risk of subsequent HIV acquisition between Month 6.5 and Month 
24 and between Month 12.5 and Month 24.  
Secondary endpoint 4: 
Immune responses from assays based on the HVTN Laboratory Center assay 
portfolio (available at http://www.hvtn.org/en/science.html/) and/or more assays 
down-selected from a larger pool of pilot studies, in HIV-1–infected vaccine cases 
and HIV-1–uninfected vaccine controls 
Secondary objective 5: 
To evaluate VE by various demographic characteristics 
Secondary endpoint 5: 
HIV-1 infection diagnosed after enrollment through 24 months, and through 36 
months if Stage 2 occurs, by demographic characteristics 
Secondary objective 6: 
If significant positive evidence of vaccine efficacy from enrollment through 24 
months is seen, to assess if and how vaccine efficacy depends on genotypic 
characteristics of HIV such as signature mutations 
Secondary endpoint 6: 
HIV-1 infection diagnosed after enrollment through Month 24 and genotypic 
characteristics of viral sequences from HIV-1–infected participants at HIV-1 
diagnosis, such as signature site mutations 
Secondary objective 7: 
To evaluate and compare genomic sequences of viral isolates from HIV-1–
infected vaccine and placebo recipients, and use sieve analysis methods to assess 
whether there is evidence of vaccine-induced immune pressure on the viral 
sequences 
Secondary endpoint 7: 
Viral sequences from HIV-1–infected participants at HIV-1 diagnosis 
5.3 
Exploratory objectives 
Exploratory objective 1: 

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To evaluate vaccine effects (“vaccine activity”) on virologic and immunologic 
outcomes (eg, HIV-1 viral load (VL) and postdiagnosis CD4+ T-cell count) 
among HIV-1–infected participants for 6 months post diagnosis, irrespective of 
ARV use 
Exploratory objective 2: 
To further evaluate the immunogenicity of the vaccine regimen, additional 
immunogenicity assays may be performed, and assays may be performed on 
samples from other timepoints, based on the HVTN Laboratory Center assay 
portfolio. 
Exploratory objective 3: 
To evaluate the role of host genetic factors in the immune response to the vaccine 
regimen and in vaccine effects on study endpoints 
Exploratory objective 4: 
To understand changes in risk behavior and the potential for risk compensation 
for all study participants 
Exploratory objective 5: 
To assess use of biomedical interventions and biological and behavioral factors in 
the study cohort and how they affect HIV acquisition rates 
Exploratory objective 6: 
To assess whether the diversity of gut microbiome correlates with vaccine 
responses and/or HIV infection risk using optionally provided stool specimens. 
Exploratory objective 7: 
To perform comparative analyses of correlates of risk identified in HVTN 702 
and those identified in other HIV vaccine efficacy studies 
Exploratory objective 8: 
To conduct analyses related to furthering the understanding of HIV, immunology, 
vaccines, and clinical trial conduct 

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6 
Statistical considerations 
6.1 
Definitions of study cohorts for analysis 
We define 6 study cohorts that are analyzed for addressing various study 
objectives. This terminology is used throughout the protocol and statistical 
analysis plan (SAP). 
 
1. Safety Cohort: Randomized participants who receive at least one study 
injection of vaccine or placebo 
2. Modified Intent-to-Treat (MITT) Cohort: Participants in the Safety Cohort 
who are HIV-1 negative on the date of first injection (Day 0) 
3. Week 26 At-Risk Cohort: Participants in the MITT Cohort who have an HIV-
1 negative test result at or after the 2 weeks post fourth immunization visit 
(Week 26 visit) 
4. Per-Protocol (PP) Cohort: Participants in the Week 26 At-Risk Cohort who 
receive all planned immunizations at the first four immunization visits within 
specified visit windows 
5. Immunogenicity Cohort (IC): Participants in the Week 26 At-Risk Cohort 
who are selected for measurement of immune response endpoints at the 
primary immunogenicity timepoint (Week 26) 
6. Full Immunization Cohort (FIC): Participants in the MITT Cohort who have 
an HIV-1 negative test result at the 2 weeks after the fifth immunization visit 
and who receive all planned immunizations within specified visit windows 
The MITT Cohort and the Safety Cohort are very similar but not identical to a full 
Intention-to-Treat Cohort (ie, all randomized participants); the Safety Cohort 
differs by excluding randomized volunteers who do not enroll; and the MITT 
Cohort is the subset of the Safety Cohort that also excludes randomized 
participants discovered later to be HIV-positive by Day 0. Because of blinding 
and the brief length of time between randomization and enrollment—typically no 
more than 4 working days—we expect almost all randomized volunteers to be in 
the Safety Cohort. Given that eligibility for the study requires recent evidence of 
being HIV-1 uninfected (within 30 days prior to enrollment), we expect almost all 
enrolled participants to also be in the MITT Cohort. 
The primary analyses of safety objectives will be based on the Safety Cohort, 
whereas the primary analyses of the vaccine efficacy objectives, and the 
secondary analyses of viral sequence data, will be based on the MITT Cohort. 
Secondary analyses of the vaccine efficacy objectives will be based on the Week 
26 At-Risk Cohort and the Per-Protocol Cohort, in addition to the MITT cohort. 
Secondary analyses of vaccine immunogenicity and of immune correlates of risk 

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and protection will be based on participants in both the Immunogenicity and 
Week 26 At-Risk Cohorts, with additional supportive secondary analyses 
conducted based on the intersections of the Immunogenicity and, respectively, 
Per-Protocol or FIC Cohorts. Immunogenicity and immune correlates assessments 
focus on the Week 26 At-Risk Cohort so as to ensure that immune responses at 
the primary immunogenicity timepoint (Week 26 visit) are measured in 
participants who are HIV-1 uninfected at the time of sampling. 
The safety analysis will be done according to the treatment received (“as 
treated”), where participants with AEs or SAEs will be counted as “vaccinated” if 
they received at least one injection. The efficacy and immunogenicity analysis 
will be done according to the treatment randomly assigned (“as randomized”), 
except for analyses of the per-protocol and FIC cohorts which will be as-treated. 
In addition, 7 cohorts of participants who are diagnosed with HIV-1 infection 
during the trial are analyzed for addressing various study objectives. Terminology 
for these cohorts is defined in Table 6-1, which will be used throughout the 
protocol and SAP. 
Table 6-1 Cohorts of HIV-1–infected study participants 
Cohort Name 
Definition of Cohort 
MITT Infected by 24 Months Cohort 
Participants in the MITT Cohort who are diagnosed with HIV-1 
infection during the follow-up period after enrollment through 
the Month 24 visit 
MITT Infected by 36 Months Cohort  
Participants in the MITT Cohort who are diagnosed with HIV-1 
infection during the follow-up period after enrollment through 
the Month 36 visit 
Week 26 At-Risk Infected by 24 Months 
Cohort  
Participants in the MITT Cohort who are diagnosed with HIV-1 
infection on or after Week 26 through the Month 24 visit 
Week 26 At-Risk Infected by 36 Months 
Cohort  
Participants in the MITT Cohort who are diagnosed with HIV-1 
infection on or after Week 26 through the Month 36 visit 
Per-protocol Infected by 24 Months Cohort  
Participants in the PP Cohort who are also in the Week 26 At-
Risk Infected by 24 Months Cohort 
Per-protocol Infected by 36 Months Cohort  
Participants in the PP Cohort who are also in the Week 26 At-
Risk Infected by 36 Months Cohort 
6.2 
Objectives 
The primary, secondary, and exploratory objectives are defined in Section 5. 
6.3 
Study cohorts utilized for evaluations of study endpoints 
Analyses of the HIV-1 infection endpoint and of vaccine activity endpoints will 
be based on the full MITT Cohort (Section 6.1). Secondary analyses of the 
vaccine efficacy objectives will be based on the MITT cohort, the Week 26 At-
Risk Cohorts, and the Per-Protocol Cohorts. 

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6.3.1 
Primary and secondary endpoints 
Primary and secondary endpoints are described in Sections 5.1 and 5.2. 
6.4 
Accrual and sample size 
6.4.1 
Sample size calculation for primary endpoint 1 (vaccine efficacy for 
HIV-1 acquisition) 
Recruitment will target a total of 5,400 HIV-uninfected adult participants. 
Participants will be enrolled over 20 months and randomized with equal 
probability to the placebo or vaccine regimen with n = 2700 in each group. 
Participants will receive immunizations at Months 0, 1, 3, 6, 12, and 18 and be 
followed for HIV infection for a maximum of 18 additional months to the final 
study visit at Month 36. HIV diagnostic tests will be administered at Month 0 and 
every 3 months thereafter.  
For the comparisons of HIV infection rate between the vaccine and placebo 
groups in Stage 1, we assume a 4% annual HIV incidence in the placebo group, a 
20-month enrollment period with a uniform enrollment rate that is halved in the 
first 3 months, halved VE in the first 6 months, and a 5% annual dropout 
incidence. Under these assumptions and the sequential monitoring as described in 
Section 6.5, n = 2700 per group is selected to ensure approximately 90% power to 
detect vaccine efficacy from enrollment through 24 months [VE(0-24)] of at least 
50% using a 1-sided alpha = 0.025-level log-rank test (versus the null hypothesis 
of H0: VE(0-24) ≤ 25%). Table 6-2 provides estimates of power to detect varying 
levels of VE(0-24), under these same assumptions. 
Table 6-2 Estimated power to detect different levels of VE(0-24) based on a sample size of 
n = 2700/group.  
True Average VE(0-24)  Power to reject null: VE(0-24) ≤ 25% 
30% 
7 
40% 
45 
50% 
90 
60% 
100 
70% 
100 
80% 
100 
To assess the impact of potential emerging prevention modalities on the study 
power, reports the estimated power to detect VE(0-24) of 50% (versus the null 
hypothesis of H0: VE(0-24) ≤ 25%) for annual HIV incidence rates in the placebo 
group ranging from 2.0% to 4.5%, holding the other assumptions and sequential 
monitoring the same as above. The range of annual HIV incidence rates might 
reflect various levels of PrEP use. For example, assuming a placebo-group annual 
incidence of 4% without PrEP, a placebo-group annual incidence of 3% could 

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arise from one extreme where 25% of the person-years of follow-up in the trial 
are under PrEP use and PrEP has 100% efficacy, the other extreme where 100% 
of the person-years of follow-up are under PrEP use and PrEP has 25% efficacy, 
or something in between such as 31% of the person-years of follow-up are under 
PrEP use and PrEP has 80% efficacy. Table 6-3 indicates that the study has power 
above 80% to detect VE(0-24) of 50% or higher (against the null of VE(0-24) ≤ 
25%) for incidence as low as 3% annually. 
Table 6-3 Estimated power to detect different levels of VE (0-24) based on a sample size of 
n = 2700/group, for various levels of annual HIV incidence rates in the placebo group. 
Simulation-based power calculations assume a 20-month enrollment period with a uniform 
enrollment rate that is halved in the first 3 months, halved VE in the first 6 months, and a 5% 
annual dropout incidence. 
Incidence Rate 
Power to reject null: VE(0-24) ≤ 25% 
when true average VE(0-24) = 50% 
2.0% 
65% 
2.5% 
75% 
3.0% 
81% 
3.5% 
86% 
4.0% 
91% 
4.5% 
93% 
To enhance the likelihood that the background incidence assumption is valid and 
thereby to preserve study power to assess vaccine efficacy, while still maintaining 
representation of both sexes, no more than 35% and no fewer than 30% males (ie, 
persons assigned male sex at birth) will be enrolled. 
6.4.2 
Sample size calculations for primary endpoint 2 (safety for local and 
systemic reactions) 
N = 5400 participants in total provides ample power for assessing safety of the 
vaccine regimen. If no SAE that is considered related to the study vaccine is 
observed in the vaccine group (N = 2700), the upper limit of the 95% CI for the 
true incidence will be 0.14%. Hence, observing no SAE among the vaccinated 
participants in the vaccine group would provide us with 95% confidence that the 
true incidence is no more than 0.14%. In addition, as shown in Figure 6-1, 
sufficient power can be achieved to detect relatively small event rate differences 
between the vaccine and placebo groups using a 2-sided alpha = 0.05-level 
Fisher’s exact test. For example, if the true safety event rate in the placebo group 
is 2% (4%), there is 90% power to detect an event rate of 4% (6%) or higher in 
the vaccine group. 

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Figure 6-1 Power to detect safety event rate differences between the vaccine (N = 2700) and 
placebo (N = 2700) arms for assumed true event rates of 2% (red) and 4% (blue) in the 
placebo arm 
6.5 
Monitoring of trial 
The last DSMB meeting occurred on 23 January 2020 and the interim monitoring 
is now complete. The following describes the original monitoring plan for the 
trial. 
HVTN 702 will be formally monitored for four types of events that may lead to a 
modification or termination of the trial. The first three components of the plan 
monitor vaccine efficacy for potential-harm, non-efficacy/efficacy futility, and 
high-efficacy (Table 6-4). The potential harm monitoring uses exact binomial 
tests to compare the rates of vaccine and placebo infections. The non-efficacy and 
high-efficacy monitoring are based on VE measured by the ratio of cumulative 
incidences (vaccine vs placebo), with point estimates calculated by the 
transformation of the Nelson-Aalen estimator and Wald-based confidence 
intervals. 
This section provides an overview of the principles underlying the monitoring 
approach. The details of the approach and its operating characteristics will be 
described in the SAP. Of note, all 4 types of monitoring apply to pooled data 
across both sexes. Sex-specific infection numbers, incidence estimates, and VE 
estimates will be provided to the DSMB, but no formal sex-specific monitoring 
guideline will be used due to the smaller number of infections, and hence lower 
precision of estimation, within each sex. 
 
 

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Table 6-4 Sequential monitoring of vaccine efficacy. CI = confidence interval, LL = lower 
limit, UL= upper limit. VE(0-24) is vaccine efficacy from enrollment through Month 24; 
VE(6.5-36) is vaccine efficacy from Month 6.5 (Week 26) through Month 24; VE(0-36) is 
vaccine efficacy from enrollment through Month 36. 
Monitoring 
Type 
Hypotheses 
Statistical Method 
Timing of 
Interim Analyses 
Potential 
Harm 
H0: VE(0-24) ≥ 0% 
vs. 
H1: VE(0-24) < 0% 
Exact binomial test 
5% overall Type I error rate 
After every infection starting at 
the 12th until the first non-efficacy 
analysis 
Non-
Efficacy 
H0: VE(0-24) ≥ 40% 
vs. 
H1: VE(0-24) < 40% 
and 
H0: VE(6.5-24) ≥ 40% 
vs. 
H1: VE(6.5-24) < 40% 
 
For both VE(0-24) and VE(6.5-
24), LLs of 95% CIs < 0% and 
ULs of 95% CIs < 40%.. 
 
 Starting at 59 infections and 
occurring every 50 infections 
thereafter, until the end of Stage 
1 (up to 7 analyses) 
High 
Efficacy 
H0: VE(0-36) ≤ 70% 
vs. 
H1: VE(0-36) > 70% 
95% CI for VE(0-36) lies above 
70% 
Synchronized with non-efficacy 
monitoring in Stage 1 contingent 
on at least 100 participants having 
reached the Month 36 visit to 
evaluate VE(0-36), and one 
analysis halfway through Stage 2 
6.5.1 
Monitoring for harm 
The unblinded statisticians (Section 6.5.8) will “continuously monitor” the trial 
(ie, examine the data after each confirmed MITT infection endpoint) for early 
evidence of a potential elevated rate of HIV-1 infection in the vaccine group 
compared to the placebo group [ie, VE(0-24) < 0%]. The potential harm 
monitoring follows a classic sequential monitoring framework and utilizes a 
(nearly) constant boundary on the p-value scale that is determined via controlling 
the overall type I error rate across tests at 0.05. Such analyses start at the 12th 
infection (pooled over the vaccine regimen and placebo) and will occur 
subsequently at each additional infection until the first interim analysis for non-
efficacy, after which the non-efficacy analyses serve the function of stopping for 
potential harm. If the prespecified stopping boundary is reached, then the 
unblinded statisticians will immediately inform the DSMB. In addition, the 
DSMB chair will be updated on the accruing unblinded HIV-1 infection data after 
each confirmed MITT infection. This monitoring guideline is chosen to allow 
stopping for prudence as early as possible, maximizing participant safety. 
Note that the potential-harm monitoring is not intended to reliably establish harm 
[ie, VE(0-24) < 0%], as a vaccine regimen could meet the boundary and the 
reported 95% confidence interval for VE(0-24) would include 0%. Rather, the 
objective is to apply extra caution and prudence for a prevention trial that enrolls 
healthy volunteers. 
6.5.2 
Monitoring for non-efficacy/efficacy futility 
The DSMB will monitor the vaccine for non-efficacy/efficacy futility, defined as 
evidence that it is highly unlikely that the vaccine has a beneficial effect on 
acquisition of VE(0-24) of 40% or more. Such analyses will start at 59 infections, 
which is chosen as the first infection total when a 95% confidence interval about 

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an estimated VE(0-24) = 0% (based on a Cox proportional hazards model) would 
lie below 40%. Analyses will take place in increments of 50 infections until the 
end of Stage 1.The criterion for non-efficacy is that, for both VE(0-24) and 
VE(6.5-24), the lower limit of the 95% confidence interval lies below 0% and the 
upper limit lies below 40%. By checking both VE(0-24) and VE(6.5-24) 
confidence intervals, the monitoring plan is designed to protect against stopping 
prematurely based on ramping vaccine efficacy over the intercurrent period of 0-6 
months. For each parameter, VE is estimated 2 ways. First, defining VE as 1 
minus the ratio of cumulative HIV incidence estimates, vaccine vs. placebo, VE is 
estimated by the transformation of the Nelson-Aalen estimator for the cumulative 
hazard function. Second, VE measured by 1 minus the hazard ratio (HR) for HIV 
infection is estimated using Cox proportional hazards regression. Confidence 
intervals for both VE estimates must satisfy the non-efficacy criterion for both 
VE(0-24) and VE(6.5-24). The rationale for using both cumulative-incidence-
based and proportional-hazards-based VE estimates is that: 1) the former better 
protects against concluding non-efficacy due to ramping vaccine efficacy but the 
latter is more stable at early interim analyses; and 2) proportional-hazards-based 
VE estimates are used to determine when to start the interim monitoring and are 
universally used in vaccine efficacy studies. When there are sufficient numbers of 
infections in each sex at birth to ensure stable confidence interval estimates, sex-
stratified VE estimates based on both approaches will be provided as described in 
Section 6.9.5.1. 
6.5.3 
Monitoring for high efficacy 
Monitoring of high efficacy allows early detection of a highly protective vaccine 
if there is evidence that vaccine efficacy from enrollment through 36 months 
[VE(0-36)] is above 70%. Analyses will be harmonized with those for non-
efficacy monitoring, with the exception that the high efficacy analyses will only 
start once at least 100 participants have reached the terminal Month 36 visit. This 
condition ensures that sufficient follow-up has accumulated to estimate VE(0-36). 
If Stage 2 occurs, there will be one final high efficacy interim analysis that occurs 
6 months into Stage 2. The criterion for high efficacy is that the 95% confidence 
interval for VE(0-36) lies above 70%. Here again, VE is estimated using a ratio of 
cumulative incidences and using Cox proportional hazards regression, and the 
high efficacy criterion must be satisfied by both estimators. Note that, whereas the 
monitoring for potential-harm and non-efficacy restricts to infections diagnosed 
between Months 0 and 24, the monitoring for high-efficacy counts all infections 
during Months 0-36, given that early-stopping for high-efficacy would only be 
warranted under some evidence for durability of vaccine efficacy. 
6.5.4 
Definition of the end of Stage 1 and criterion for continuing to Stage 
2 
Whereas the timing of interim analyses is event-driven, the total number of Stage 
1 infections is not fixed. The end of Stage 1 is when the last enrolled participant 
reaches the Month 24 visit. Ensuring all participants are followed to Month 24 
maximizes power and precision for assessing VE(0-24). 

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Early stopping of the vaccine regimen will be recommended if one of the 
potential harm or non-efficacy boundaries is met at a prespecified analysis time, 
in which case a decision will be made regarding whether to follow participants to 
Month 24 (Stage 2 will not occur). If the high-efficacy boundary is met at a 
planned interim analysis, the vaccine regimen will be declared highly efficacious 
and placebo recipients may be offered the vaccine even while follow-up continues 
through Stage 1 (or Stage 2, if applicable). If none of the stopping boundaries are 
reached by the end of Stage 1, vaccine efficacy from enrollment through Month 
24 [VE(0-24)] is evaluated at the end of Stage 1. VE is defined as 1-cumulative 
incidence ratio (vaccine vs. placebo) and is estimated by the transformation of the 
Nelson-Aalen estimator for the cumulative hazard function. If the lower bound of 
the 95% confidence interval for VE(0-24) is > 0% at the end of Stage 1 
(equivalently, the 1-sided p-value for testing H0: VE(0-24) ≤ 0% is above 0.025), 
trial participants will continue blinded follow-up through Stage 2. On the other 
hand, if at the Stage 1 efficacy analysis the lower bound of the 95% confidence 
interval for VE(0-24) ≤ 0%, Stage 2 will not occur even if none of the stopping 
boundaries were reached by the end of Stage 1. This corresponds to continuing to 
Stage 2 if, at the end of Stage 1, the estimated VE(0-24) is approximately 19-21% 
or greater; the range of VE values is due to uncertainty in the total number of 
Stage 1 infections. 
6.5.5 
Monitoring for operational futility 
The DSMB monitors the trial for operational futility, defined as overly slow 
progress toward full enrollment or sufficient numbers of MITT infections to 
support the primary analysis, and by other measures of underperformance. 
Approximately semi-annual DSMB meetings will be held for monitoring 
operational futility during the closed session, synchronized with interim analyses 
of vaccine efficacy. At the time of each semi-annual DSMB meeting, the HVTN 
702 Oversight Group (OG) will receive the components of the operational futility 
analysis that are based on blinded data (pooled across treatment arms), as 
described below. 
The first component of the operational futility monitoring plan includes 
projections of the time until enrollment completes. Under design assumptions, 
enrollment is expected to take 20 months. The projection of this time, including 
an assessment of its probability distribution, will be presented to the DSMB, and 
compared with the pre-trial assumptions.  
The second component of the operational futility monitoring plan includes 
projections of the probability distribution of the treatment-arm-pooled infection 
total, and the arm-specific infection totals, over 0-24 months. These distributions 
will be calculated under 3 scenarios: 1) using the observed treatment-arm-pooled 
infection rate to-date and assuming that VE(0-24) = 25% [the null hypothesis]; 2) 
using the observed treatment-arm-pooled infection rate to-date and assuming 
VE(0-24) = 50% [the alternative hypothesis]; and 3) using the observed by-arm 
infection rates observed to date. Methods for performing these calculations will be 
specified in the SAP.  

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A report based on blinded data will be shared with the study OG. It will only 
contain projections of the treatment-arm-pooled infection total (not the arm-
specific totals), and only projections under scenarios 1 and 2, since scenario 3 
contains information about the observed VE to date. 
The probability distribution of the Stage 1 (0-24 month) treatment-arm-pooled 
infection total, under design assumptions on enrollment, dropout, and infections, 
is shown in Table 6-5. 
Table 6-5 Distribution of Stage 1 infections (pooled over treatment arms) ignoring interim 
monitoring  
True VE 
(0-24) 
Percentiles of the distribution of the number of Stage 1 infections 
2.5% 
5% 
10% 
20% 
25% 
30% 
40% 
50% 
60% 
70% 
75% 
80% 
90% 
95% 
97.5% 
0% 
357 
362 
369 
377 
380 
383 
388 
393 
397 
403 
405 
409 
417 
424 
431 
50% 
265 
271 
277 
284 
286 
289 
293 
297 
301 
306 
308 
311 
319 
325 
330 
The estimated reverse cumulative distribution function (rcdf) of the pooled 
number of HIV infection endpoints will be shown, for each of the 3 scenarios 
above, for a range of endpoint counts on the x-axis. The rcdf plot will include an 
additional axis on the top, showing the approximate power under the proportional 
hazards assumption of a one-sided test with significance level 0.025 to reject H0: 
VE(0-24) ≤ 25% assuming VE(0-24) = 50% throughout the trial, for the range of 
endpoint counts on the bottom x-axis. While the rcdf of the pooled number of 
endpoints conditions on the observed data to date, the power approximation 
follows an analytical formula (calculated by solving equation (1) in (114)) and 
disregards observed data to date to maintain trial integrity. Rcdfs will also be used 
to summarize the distribution of the number of HIV infection endpoints by arm. 
In addition, information on use of antiretroviral drugs that could affect accrual of 
endpoint infections will be provided to the DSMB as available. If the HIV 
incidence estimates are below projected despite good retention and adherence, the 
DSMB may elect to engage with the protocol team and OG as to what corrective 
actions can be undertaken, including expanding enrollment, and using specific 
demographic or behavioral risk factors to enroll higher risk participants or those 
coming from high epidemic communities. 
If the DSMB does recommend termination and the trial is stopped, then the final 
analysis will be performed and the results made public. 
If at any time operational futility guidelines are met and yet it appears that value 
exists in continuing the trial, the statisticians will provide the DSMB with 
additional information, as appropriate, for use in their consideration of whether to 
recommend trial termination. 

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6.5.6 
Operational analysis near the end of enrollment to decide whether to 
consider expanding enrollment 
As mentioned above, the HVTN 702 OGC will receive the results of the 
components of the operational futility analysis that are based on blinded data. The 
committee will also be provided additional information at the time of a special 
DSMB meeting scheduled to take place approximately 3 months before the 
completion of enrollment—based on ongoing projections of time until full 
enrollment by study statisticians. For this meeting, study statisticians will prepare 
a report that includes the calculations typically in an operational futility analysis, 
along with additional guidance as to whether the HIV incidence – pooled over 
treatment arms—is “too low” or “acceptable” to sufficiently power the study. 
(The details of this guidance will be described in the study SAP.) The report will 
be shared both with the DSMB and with the study OG. The OG will then have the 
opportunity to decide whether, if incidence is lower than anticipated but not so 
low that operational futility is declared, to expand enrollment beyond the 
originally planned 5400, in order to maintain the ability of the study to meet the 
study’s primary objectives. The meeting will be timed before but near to the end 
of enrollment, to allow a potential decision to expand enrollment to occur before 
the enrollment apparatus is scaled down, while also allowing the decision to be 
made on the maximal amount of primary endpoint infections. The OG may also 
be presented information on the degrees of enrollment expansion that would be 
required in order to achieve treatment arm-pooled infection totals corresponding 
to various levels of power to reject the primary null hypothesis if VE(0-24) = 
50%, approximated under the proportional hazards assumption. 
6.5.7 
Performance standards for quality of trial conduct 
The protocol team and study investigators will have performance standards 
regarding the quality of trial conduct in addition to the study event rate. Some of 
these standards will relate to achievement of targeted levels of: (i) participant 
enrollment into the trial; (ii) adherence to study interventions; and (iii) retention 
of participants. In addition to using the above guidelines for operational futility, 
the DSMB and the HVTN 702 leadership will monitor whether the trial is 
achieving at least minimally acceptable levels regarding key performance 
standards. 
6.5.8 
Roles of study statisticians 
HVTN SDMC statisticians will be “blinded” or “unblinded”. During protocol 
development and after primary follow-up is completed, there will be no 
distinction between the roles; both types of statisticians will be responsible for 
designing and analyzing the study. During the primary follow-up period, 
however, only the unblinded statisticians will see interim data broken down by 
treatment arm. Their role will be to conduct the interim monitoring and to produce 
and present reports on accruing data to the study DSMB. During the primary 
follow-up period, blinded statisticians will see only the interim data pooled across 
treatment arms. This way, blinded statisticians can assist protocol leadership in 

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making decisions about modifications to the protocol without being influenced by 
interim efficacy results. 
6.5.9 
Power for secondary VE analysis 
Secondary Objective 2 evaluates vaccine efficacy against infections diagnosed 
between the Month 6.5 and Month 24 visits in the per-protocol cohort. 
Unconditional power to address this objective is summarized in Table 6-6. For 
example, there is 77% power to detect VE(6.5-24) ≥ 50% (versus the null of H0: 
VE(6.5-24) ≤ 25%) assuming a 10% probability that a participant misses a 
vaccination and is therefore not included in the per-protocol cohort. 
Table 6-6 Power to detect different levels of VE(6.5-24) based on a sample size of n = 2700 
per group.  
True Average VE(6.5-24) 
Power to reject null: VE(6.5-24) ≤ 25% 
30% 
6% 
40% 
31% 
50% 
75% 
60% 
97% 
70% 
100% 
80% 
100% 
Under Secondary Objective 5, vaccine efficacy will be assessed by various 
demographic characteristics, including gender. Given that the trial will enroll 
more women than men, and that HIV incidence is expected to be lower in men 
than in women, calculations were performed to assess the precision with which 
vaccine efficacy can be assessed among men. Table 6-7 describes the precision 
with which VE(0-24) can be estimated among men, assuming VE(0-24) = 50% 
and under different assumed HIV incidence rates among men. Importantly, these 
confidence intervals rule out VE(0-24) ≤ 0%, as long as HIV incidence among 
men is 2.0% or more annually and 30% men are enrolled, and as long as HIV 
incidence among men is 1.5% or more annually, if 35% men are enrolled.  
Table 6-7 Expected confidence interval around VE(0-24) = 50% among men, assuming 30% 
or 35% men, under different assumed HIV incidence rates among men, for a trial with n = 
2700 per group 
Fraction of Men 
in study (%) 
Assumed Infection Rate for 
Men (% per year) 
Expected Number 
of Infections (Men) 
95% CI for VE 
(men) 
30 
1.0 
22 
(-0.213, 0.794) 
30 
1.5 
34 
(-0.02 , 0.755) 
30 
2.0 
45 
(0.071, 0.731) 
35 
1.0 
26 
(-0.13 , 0.779) 
35 
1.5 
39 
(0.027, 0.743) 
35 
2.0 
53 
(0.115, 0.718) 

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6.5.10 
Trial duration 
In addition to enrollment rates, the duration of the trial will depend on the 
duration of the vaccine regimen’s evaluation and hence the probabilities of 
reaching each possible trial outcome (potential harm, non-efficacy, positive 
efficacy but not high efficacy, and high efficacy).  
Figure 6-2 shows the distribution of the duration of the vaccine regimen’s 
evaluation over both Stages 1 and 2. The figure shows that, if VE(0-24) = 50% 
with VE halved in the first 6 months, there is probability of nearly 1 (or 100% 
chance) that the evaluation of the vaccine regimen will carry all the way through 
Stage 2 (56 months), which includes 20 months of enrollment plus 36 months of 
follow-up for all enrolled participants. In addition the median trial duration is 56 
months. If VE(0-24) = 0%, then there is a 100% chance that the vaccine 
regimen’s evaluation will be completed in Stage 1, with a median trial duration of 
24 months. 
The duration of the trial is now determined by when the last enrolled participant 
reaches the end of follow-up (12 months after the last received vaccination), 
which is expected to be a maximum of 44 months from study opening. 
 
Figure 6-2 Total trial duration for the evaluation of the vaccine regimen over Stages 1 and 2 
6.6 
Assessment of PrEP use 
The use of oral FTC/TDF as PrEP (either off-study or provided in the study) may 
impact study outcomes (eg, by lowering HIV incidence with a loss of study 
power). Dried blood spot samples will be collected and stored for assessment of 

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quantitative concentrations of intracellular TFV (see Section 11.7), using a 
calendar based selection of visits that will ensure representative sampling of 
participants across the entire visit schedule at all sites throughout the study. A 
detailed testing plan, specified in the study monitoring plan, has been developed 
to prospectively monitor FTC/TDF use during the trial to inform the DSMB, and 
assess the potential impact of FTC/TDF use on endpoint accrual during the study. 
Prevalence of PrEP will be reported both as the estimated proportion of 
participant visits with highly adherent PrEP use (above the concentration of TFV 
designated as consistent with daily dosing) and the proportion of participant visits 
with any detectable PrEP use (concentration of TFV above the lower limit of 
detection for the dried blood spot assay). Additionally, we will use knowledge of 
pharmacokinetic quantitative levels to estimate the proportion of study person 
years protected by highly adherent use of FTC/TDF. PrEP use measures will be 
reported by arm to the DSMB in the closed session; in addition both the OG and 
the protocol team leadership will see pooled estimates of FTC/TDF use. 
6.7 
Randomization of treatment assignments 
The randomization sequence will be obtained by computer-generated random 
numbers and provided to each HVTN CRS through the SDMC’s Web-based 
randomization system. The randomization will be stratified by sex at birth and site 
and done in such a way as to ensure balance across arms within levels jointly 
determined by these factors. At each institution, the pharmacist with primary 
responsibility for dispensing study products is charged with maintaining security 
of the treatment assignments. Participants and site staff will be blinded as to the 
treatment group assignment throughout both Stage 1 and Stage 2, if it occurs.  
6.8 
Blinding 
Participants, site staff (except for site pharmacists), and the OG will be blinded as 
to participant treatment group assignments (eg, vaccine or control) throughout 
both Stage 1 and Stage 2, if it occurs. Study product assignments are accessible to 
those HVTN CRS pharmacists, DAIDS protocol pharmacists and contract 
monitors, and SDMC staff who are required to know this information in order to 
ensure proper trial conduct. Any discussion of study product assignment between 
pharmacy staff and any other HVTN CRS staff is prohibited. The DSMB 
members also are unblinded to treatment assignment in order to conduct review of 
trial safety and efficacy. 
When a participant leaves the trial prior to study completion, the participant will 
be told he or she must wait until all participants have completed follow-up to 
learn his or her treatment assignment. 
Emergency unblinding decisions will be made by the site investigator. If time 
permits, the HVTN 702 PSRT should be consulted before emergency unblinding 
occurs. 

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6.9 
Statistical analysis 
This section describes the final study analysis, unblinded as to treatment group 
assignment. With the exceptions noted for safety analyses, all data from enrolled 
participants will be analyzed according to the initial randomization assignment 
regardless of how many vaccinations they received. The analysis is a modified 
intent-to-treat analysis in that individuals who are randomized but not enrolled do 
not contribute data and hence are excluded. Because of blinding and the brief 
length of time between randomization and enrollment—typically no more than 4 
working days—very few such individuals are expected. 
Analyses for primary endpoints will be performed using SAS and R. All other 
descriptive and inferential statistical analyses will be performed using SAS, 
StatXact, or R statistical software. 
No formal multiple comparison adjustments will be employed for multiple safety 
endpoints, multiple efficacy endpoints, multiple immunogenicity endpoints, or 
secondary endpoints. However, multiplicity adjustments will be made for certain 
immunogenicity assays, as discussed below, when the assay endpoint is viewed as 
a collection of hypotheses (eg, testing multiple peptide pools to determine a 
positive response). 
6.9.1 
Analysis variables and cohorts for analysis 
The analysis variables consist of baseline participant characteristics, safety, 
efficacy, activity, immunogenicity, and for primary- and secondary-objective 
analyses. Analyses of safety are done in the Safety Cohort, analyses of efficacy 
against HIV-1 infection are done in the MITT Cohort, analyses of vaccine activity 
against postinfection endpoints are done in the Infected MITT Cohort, 
immunogenicity analyses are done in the Week 26 At-Risk Cohort, analyses are 
done in the MITT Cohort, and HIV genetics analyses are done in the Infected 
MITT Cohort. The primary efficacy analysis for VE(0-24) will be done in the 
MITT Cohort. Other estimates of efficacy will be supportive. 
6.9.2 
Baseline comparability 
Treatment arms will be compared for baseline participant characteristics using 
descriptive statistics. 
6.9.3 
Safety/tolerability analysis 
Since enrollment is concurrent with receiving the first injection, all participants 
will have received at least 1 vaccination and therefore will provide some safety 
data. During the course of the trial, unblinded analyses of safety data will be 
prepared approximately every 6 months for review by the DSMB. Ad hoc safety 
reports may also be prepared for DSMB review at the request of the HVTN 702 
PSRT. The HVTN leadership must approve any other requests for unblinded 
safety data prior to the end of the scheduled follow-up visits. 

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6.9.3.1 
Reactogenicity 
The number and percentage of participants experiencing each type of 
reactogenicity sign or symptom will be tabulated by severity and treatment group 
and the percentages displayed graphically by arm. For a given sign or symptom, 
each participant’s reactogenicity will be counted once under the maximum 
severity for all injection visits. In addition, to the individual types of events, the 
maximum severity of local pain or tenderness, induration or erythema, and of 
systemic symptoms will be calculated. Kruskal-Wallis tests will be used to test for 
differences in severity between arms. 
6.9.3.2 
AEs and SAEs 
AEs will be summarized using MedDRA System Organ Class and preferred 
terms. Tables will show by treatment group the number and percentage of 
participants experiencing an AE within a System Organ Class or within preferred 
term category by severity and by relationship to study product. For the 
calculations in these tables, a participant with multiple AEs within a category will 
be counted once under the maximum severity and by causal relationship to study 
product. Formal statistical testing comparing arms is not planned for all AEs since 
interpretation of differences must rely heavily upon clinical judgment. Fisher’s 
exact tests will be used to compare rates of AEs deemed related to study products 
between vaccine and placebo. In addition, several aggregate safety endpoints will 
be compared across vaccine and placebo arms, as detailed in the study SAP. The 
false-discovery rate procedure of Mehrotra and Heyse (115) will be applied to 
compare grouped systemic AEs divided by body systems between treatment arms. 
Parallel analyses will include all AEs and AEs leading to participant withdrawal 
or early discontinuation of study product(s). 
A listing of SAEs reported to the DAIDS Regulatory Support Center (RSC) 
Safety Office will provide details of the events including severity, relationship to 
study product, time between onset and last vaccination, and number of 
vaccinations received. A separate listing will do the same for AESIs, AEs leading 
to early participant withdrawal or early discontinuation of study product(s), and 
AEs of new chronic medical conditions, AESIs for this protocol include but are 
not limited to potential immune-mediated disorders; a sample list of AESIs is 
provided in Appendix J. 
6.9.3.3 
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 reason and treatment arm. 
6.9.4 
Immunogenicity analysis 
Data from quantitative assays will be summarized for the treatment group using 
crude and net percentages with positive responses, and crude geometric means, 
for each timepoint for which an assessment is performed. Data from qualitative 

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(ie, positive or negative) assays will be summarized by tabulating the frequency 
of positive responses for each assay by group at each timepoint that an assessment 
is performed. 
6.9.5 
Vaccine efficacy and activity analyses 
6.9.5.1 
Primary vaccine efficacy analysis: HIV-1 acquisition 
We define the date of diagnosis of HIV-1 infection to be the draw date of the first 
sample that leads to a positive result by the diagnostic algorithm described in 
Section 10.3. To evaluate the primary vaccine efficacy endpoint (HIV-1 
acquisition), the incidence of acquired HIV-1 infections (“events”) in the vaccine 
group will be compared to the incidence in the placebo group within the first 24 
months since first vaccination. The vaccine effect will be assessed using a ratio of 
cumulative incidences of HIV infection over the first 24 months (vaccine vs. 
placebo), estimated using the transformed Nelson-Aalen cumulative hazard 
function estimator, and tested using a Wald test. Cox proportional hazards 
regression will also be used for estimating VE(0-24), measured by 1 minus the 
HR (vaccine vs. placebo) and for testing whether the VE(0-24) differs from 25%. 
Both VE estimators will allow for different HIV incidence by gender. The Cox 
regression analysis will do this by stratifying on sex at birth, allowing for a 
different baseline risk of HIV-infection by sex. The cumulative incidence 
estimation method will estimate VE separately by sex and then combine the sex-
specific BE estimates into 1 estimate using the stratified Aalen-Johansen 
estimator with a single failure type (116). The influence curve-based variance 
estimator will be used (117). 
In addition, to assess potential time-effects of vaccine efficacy, the Kaplan-Meier 
method will be used to plot the estimated cumulative incidence rates over time for 
the vaccine and placebo groups. This method will be used to estimate cumulative 
vaccine efficacy over time, defined as [(1 - ratio (vaccine/placebo) of cumulative 
incidence by time t) u 100%], with the method of Parzen, Wei, and Ying (118) 
applied to estimate pointwise and simultaneous 95% CIs. 
For evaluating the vaccine effect on HIV-1 acquisition using pre- and post-
unblinding data, analyses will adjust for potential confounding. The cumulative-
incidence-based VE method will do this by stratification on potential confounders 
as described above for adjusting for gender. The Cox regression analysis will 
adjust for potential confounders as covariates. The analyses will include all 
baseline variables predictive of HIV infection pooled over the vaccine and 
placebo arms and will include the baseline risk score. If there is evidence of 
differences in risk behavior over time between treatment arms, a time-dependent 
version of the behavioral risk score will be included in the Cox model. Depending 
on data completeness and covariate patterns, the Cox model may also include 
time-dependent indicators of STIs (gonorrhea, chlamydia, syphilis, and HSV if 
available). Goodness-of-fit tests will be performed [including the Grambsch and 
Therneau (119) test based on Schoenfeld residuals] to assess the proportional 
hazards assumption of the Cox model.  

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Additive differences in cumulative infection probabilities for the vaccine versus 
placebo group will also be estimated, and plots used to show estimated additive 
differences and associated 95% confidence intervals over time The collaborative 
targeted maximum likelihood estimation method (120) may be also used for 
inference, which in addition to allowing confounding adjustment can correct for 
potential bias due to covariate-dependent censoring. 
6.9.5.2 
Secondary vaccine efficacy analyses: HIV-1 acquisition 
Vaccine efficacy absent PrEP 
The primary analysis will be repeated, where only MITT infections in participants 
who were not using prophylactic ARVs at the time of HIV-1 diagnosis or first 
evidence of infection will be included in the analysis. Plasma drug levels will be 
used to determine eligibility for this analysis. A participant is eligible if the 
plasma drug levels are undetectable at the diagnosis visit and at the visit with 
earliest evidence of HIV-1 infection (if different from the diagnosis visit). Since 
the ARVs are only detectable in plasma through roughly 14 days (121) and some 
participants may have become infected before the 14-day window, with this 
approach we are not assured that all those invluded in the analysis were not using 
prophylactic ARVs at the time of infection. Therefore, an additional analysis will 
address this issue by also excluding participants from the HIV-1 acquisition 
analysis if they self-reported drug use in the last 30 days at either the diagnosis 
visit or the last visit prior to diagnosis. This additional analysis will evaluate 
uninfected participants without accounting for data on their plasma drug levels. 
Per-protocol vaccine efficacy 
The primary analysis will be repeated in the Per-Protocol Cohort, with the time 
origin the date of the Week 26 immunization visit; participants becoming HIV 
infected or dropping out before Week 26 will be excluded from the analysis. In 
addition, the causal inference method of Gilbert, Shepherd, and Hudgens (122) 
will be used to assess vaccine efficacy in the subgroup who would be per-protocol 
under either treatment assignment. 
Durability of vaccine efficacy 
Vaccine efficacy over all available follow-up times will be assessed using the 
method of Parzen, Wei, and Ying (118) described above, as well as with 
nonparametric HR estimation (123) and with Cox proportional hazards modeling 
with time-dependent covariates. If the analysis suggests time-invariant vaccine 
efficacy, then the Cox model and the method of Lu and Tsiatis (124) will be used 
to estimate proportional-hazards VE and to test for VE different from zero 
accounting for all available follow-up time. The SAP will provide details of these 
analyses. 
Vaccine efficacy by sex at birth 

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Generalized Wald tests for interaction will be used to test for evidence of 
differential VE by sex, using cumulative-incidence-based VE estimates. In the 
context of Cox proportional hazards models, Wald tests for interaction will be 
used to test for evidence of differential vaccine efficacy by sex at birth. 
Vaccine efficacy in a population with equal gender distribution 
Due to the small number of infections in men at birth, this analysis will not be 
performed.  
The primary analysis of vaccine efficacy will evaluate efficacy in a population 
with a gender distribution equal to that in the 702 trial. As a secondary analysis, 
vaccine efficacy in a population with equal gender distribution will be estimated. 
The cumulative-incidence-based VE estimator will be used; VE will be estimated 
separately by sex and then combined using equal weights into one vaccine 
efficacy estimate. 
Vaccine efficacy, taking into account number of founding viruses 
A secondary analysis will assess the vaccine effect on HIV-1 acquisition over 0-
24 months using the method of Follmann and Huang (125) that incorporates 
information on the number of HIV-1 founder viruses in HIV-1–infected 
participants. By incorporating this additional information, the method increases 
efficiency if the vaccine reduces the number of founders. 
6.9.5.3 
Secondary vaccine efficacy analysis: HIV-1 acquisition over 36 months 
If the vaccine regimen is not stopped at an interim analysis and meets the criteria 
to proceed to Stage 2, then it will be evaluated for 36 months of follow-up for all 
participants. Vaccine efficacy as a continuous function of time since entry [VE(t)] 
will be estimated using a variety of methods including the Cox model with 
flexible parametric regression coefficients and nonparametric smoothing (123). In 
addition, the causal inference method of Shepherd et al. (122, 126), as described 
in the commentary by Hughes and Dai (in (127)), may be used to assess the causal 
vaccine efficacy over various time-periods in the subgroup that would be 
uninfected under either treatment assignment up to that time-point. 
6.9.5.4 
Secondary vaccine efficacy and activity analyses of viral sequences 
Vaccine efficacy and genotypic characteristics 
A variety of methods including cause-specific Cox model and case-only method 
(128) may be used to assess genotypic characteristics of HIV as potential effect 
modifiers of VE(0-24). 
Sieve analysis 

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Acquisition sieve analysis methods including genome scanning tests described in 
Gilbert et al. (129) and their extensions will be used to evaluate the relationship 
between VE(0-24), and the genotypic differences between the incoming 
exposing/founder sequences and the HIV insert sequence(s) represented in the 
vaccine construct. 
6.9.5.5 
Secondary vaccine activity analyses of pre-HAART viral load and CD4+ 
cell counts 
Due to the limited pre-HAART viral load and CD4+ cell count data collected, 
these analyses will primarily be descriptive.  
Early pre-HAART VL endpoint 
The vaccine effect on the mean early pre-HAART VL endpoint will be assessed, 
in terms of point and 95% confidence interval estimates of the mean difference 
(vaccine minus placebo) and a 2-sided p-value for whether the mean difference 
equals zero. The robust likelihood-based method of Little and An [128] will be 
used, which provides unbiased inferences if the missing endpoint data due to 
highly active antiretroviral therapy (HAART) initiation or dropout are missing at 
random (MAR), and is selected to minimize potential bias in the analysis that 
could occur due to missing VL endpoint data. The MAR assumption can be stated 
as follows: Whether an infected participant is missing an early VL endpoint 
depends only on his or her observed data. The MAR assumption is expected to 
hold, at least for most infected participants. The reasons for this will be described 
in the SAP, as will be reasons why Little and An’s method (130) is expected to 
work well. If an analysis suggests a vaccine effect, then sensitivity analysis 
methods (such as doubly robust methods (131)) will be applied to evaluate the 
robustness of the vaccine effect, as elaborated in the SAP. The Little and An 
method may be substituted for a complete-case analysis that compares mean 
VL/CD4+ endpoints using t-statistics, if the rate of missing endpoint data is low 
(eg, less than 10% of participants with at least one missing endpoint value, for 
longitudinal endpoints, or less than 10% of participants missing the endpoint of 
interest, for univariate endpoints). The Little and An method is also designed to 
maximize efficiency by leveraging information in auxiliary covariates that predict 
missing values of pre-HAART VL. 
Preseroconversion VL endpoint 
The Little and An method will be used for assessing the vaccine effect on the 
preseroconversion VL endpoint. As will be detailed in the SAP, similar to the 
analysis of pre-HAART VL endpoint, sensitivity analysis and complete-case 
analysis may be performed when appropriate. 
Longitudinal pre-HAART VL and CD4+ T-cell count endpoints 
Early VL and pre-HAART VL and CD4+ T-cell trajectories will be assessed. The 
method of Little and An will be applied to assess the vaccine effect on the pre-

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HAART VL or the pre-HAART CD4+ cell count at early fixed visit timepoints. 
The SAP will detail additional longitudinal data methods that may be applied to 
the longitudinal VL and CD4+ T-cell count data.  

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7 
Selection and withdrawal of participants 
Participants will be healthy, HIV-uninfected (seronegative) adults who 
comprehend the purpose of the study and have provided written informed consent. 
Volunteers will be recruited and screened; those determined to be eligible, based 
on the inclusion and exclusion criteria, will be enrolled in the study. Final 
eligibility determination will depend on information available at the time of 
enrollment, including results of screening laboratory tests, medical history, 
physical examinations, and answers to self-administered and/or interview 
questions. 
Investigators should always use good clinical judgment in considering a 
volunteer’s overall fitness for trial participation. Some volunteers may not be 
appropriate for enrollment even if they meet all inclusion/exclusion criteria. 
Medical, psychiatric, occupational, or other conditions may make evaluation of 
safety and/or immunogenicity difficult, and some volunteers may be poor 
candidates for retention. 
Determination of eligibility, taking into account all inclusion and exclusion 
criteria, must be made within 56 days prior to enrollment unless otherwise noted 
in Sections 7.1 and 7.2. 
Consult the HVTN 702 PSRT for questions related to selection and withdrawal of 
participants that are not specifically addressed below. 
7.1 
Inclusion criteria 
General and Demographic Criteria 
1. Age of 18 to 35 years 
2. Sexually active, defined as having had sexual intercourse at least twice in the past 
30 days prior to screening, and is considered by the site staff to be at risk for HIV 
infection. 
3. Access to a participating HVTN CRS and willingness to be followed for the 
planned duration of the study 
4. Ability and willingness to provide informed consent 
5. Assessment of understanding: volunteer demonstrates understanding of this 
study prior to first vaccination with verbal demonstration of understanding of all 
questions. 
6. Agrees not to enroll in another study of an investigational research agent until 
the participant is unblinded or their study participation ends, whichever occurs 
last 

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7. Good general health as shown by medical history, physical exam, and screening 
laboratory tests 
HIV-Related Criteria: 
8. Willingness to receive HIV test results 
9. Willingness to discuss HIV infection risks and willing to receive HIV risk 
reduction counseling 
Laboratory Inclusion Values 
Chemistry 
10. Alanine aminotransferase (ALT) < 2.5 times the institutional upper limit of 
normal 
Virology 
11. Negative HIV-1 and -2 blood test within 30 days prior to enrollment: Sites 
may use locally available assays that have been approved by HVTN Laboratory 
Operations. 
Reproductive Status 
12. Volunteers who were born female: negative serum or urine beta human 
chorionic gonadotropin (β-HCG) pregnancy test performed prior to vaccination 
on the day of initial vaccination. Persons who are NOT of reproductive potential 
due to having undergone total hysterectomy or bilateral oophorectomy (verified 
by medical records), are not required to undergo pregnancy testing. 
13. Reproductive status: A volunteer who was born female must: 
x Agree to consistently use effective contraception (Appendix B and Appendix 
C) for sexual activity that could lead to pregnancy from at least 21 days prior 
to enrollment through 3 months after the last vaccination. Effective 
contraception is defined as using 1 of the following methods. 
 Intrauterine device (IUD), or 
 Hormonal contraception, or 
 Any other contraceptive method approved by the HVTN 702 PSRT; 
x Or not be of reproductive potential, such as having been diagnosed with 
premature menopause (with no menses for 1 year) or having undergone 
hysterectomy, bilateral oophorectomy, or tubal ligation. 

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14. Volunteers who were born female must also agree not to seek pregnancy 
through alternative methods, such as artificial insemination or in vitro 
fertilization until 3 months after the last vaccination 
7.2 
Exclusion criteria 
General 
1. Blood products received within 90 days before first vaccination 
2. Investigational research agents received within 30 days before first vaccination 
3. Intent to participate in another study of an investigational research agent or 
any other study that requires non-HVTN HIV antibody testing during the planned 
duration of the HVTN 702 study 
4. Pregnant or breastfeeding 
Vaccines and other Injections 
5. HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have 
received control/placebo in an HIV vaccine trial, the HVTN 702 PSRT will 
determine eligibility on a case-by-case basis. 
6. Non-HIV experimental vaccine(s) received within the last 5 years in a prior 
vaccine trial. Exceptions may be made for vaccines that have subsequently 
undergone licensure. For volunteers who have received control/placebo in an 
experimental vaccine trial, the HVTN 702 PSRT will determine eligibility on a 
case-by-case basis. For volunteers who have received an experimental vaccine(s) 
greater than 5 years ago, eligibility for enrollment will be determined by the 
HVTN 702 PSRT on a case-by-case basis. 
7. Live attenuated vaccines other than influenza vaccine received within 30 days 
before first vaccination or scheduled within 14 days after injection (eg, measles, 
mumps, and rubella [MMR]; oral polio vaccine [OPV]; varicella; yellow fever) 
8. Influenza vaccine or any vaccines that are not live attenuated vaccines and 
were received within 14 days prior to first vaccination (eg, tetanus, 
pneumococcal, Hepatitis A or B) 
Immune System 
9. Immunosuppressive medications received within 168 days before first 
vaccination. (Not exclusionary: [1] corticosteroid nasal spray; [2] inhaled 
corticosteroids; [3] topical corticosteroids for mild, uncomplicated dermatitis; or 
[4] a single course of oral/parenteral corticosteroids at doses < 2 mg/kg/day and 
length of therapy < 11 days with completion at least 30 days prior to enrollment.) 

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10. Serious adverse reactions to vaccines or to vaccine components such as eggs, 
egg products, or neomycin including history of anaphylaxis and related 
symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal 
pain. (Not excluded from participation: a volunteer who had a non-anaphylactic 
adverse reaction to pertussis vaccine as a child.) 
11. Immunoglobulin received within 60 days before first vaccination 
12. Immunodeficiency 
Clinically significant medical conditions 
13. Clinically significant medical condition, physical examination findings, 
clinically significant abnormal laboratory results, or past medical history with 
clinically significant implications for current health. A clinically significant 
condition or process includes but is not limited to: 
x A process that would affect the immune response, 
x A process that would require medication that affects the immune response, 
x Any contraindication to repeated injections or blood draws, 
x A condition that requires active medical intervention or monitoring to avert 
grave danger to the volunteer’s health or well-being during the study period, 
x A condition or process for which signs or symptoms could be confused with 
reactions to vaccine, or 
x Any condition specifically listed among the exclusion criteria below. 
14. Any medical, psychiatric, occupational, or other condition that, in the 
judgment of the investigator, would interfere with, or serve as a contraindication 
to, protocol adherence, assessment of safety or reactogenicity, or a volunteer’s 
ability to give informed consent 
15. Psychiatric condition that precludes compliance with the protocol. 
Specifically excluded are persons with psychoses within the past 3 years, ongoing 
risk for suicide, or history of suicide attempt or gesture within the past 3 years. 
16. Active tuberculosis (TB) disease 
17. Uncontrolled hypertension: systolic blood pressure (SBP) ≥ 160 mm Hg or 
diastolic blood pressure (DBP) ≥ 100 mm Hg 
18. Bleeding disorder (diagnosed by a doctor) contraindicating IM injection and/or 
blood draws, based on investigator’s judgment 

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19. Malignancy (Not excluded from participation: Volunteer who has had 
malignancy excised surgically and who, in the investigator’s estimation, has a 
reasonable assurance of sustained cure or who is unlikely to experience 
recurrence of malignancy during the period of the study) 
20. History of hereditary angioedema, acquired angioedema, or idiopathic 
angioedema 
7.3 
Participant departure from vaccination schedule or withdrawal 
This section concerns an individual participant’s departure from the vaccination 
schedule. Pause rules for the trial as a whole are described in Section 12.3. 
7.3.1 
Delaying vaccinations for a participant 
Under certain circumstances, a participant’s scheduled vaccination will be 
delayed. The factors to be considered in such a decision include but are not 
limited to the following: 
x Within 45 days prior to any study injection 
 Receipt of blood products or immunoglobulin 
x Within 30 days prior to any study injection 
 Receipt of live attenuated vaccines other than influenza vaccine 
 Receipt of allergy treatment with antigen injections 
x Within 14 days prior to any study injection 
 Receipt of influenza vaccine or any vaccines that are not live attenuated 
vaccines (eg, pneumococcal) 
x Pre-vaccination abnormal vital signs or clinical symptoms that may mask 
assessment of vaccine reaction. 
x Pregnancy: For participants, who become pregnant, no study vaccinations will 
be given; except for participants who may have been pregnant during the 
study but are no longer pregnant as shown by two negative urine pregnancy 
tests taken from two different urine samples; in this circumstance, the HVTN 
702 PSRT should be consulted to determine if the participant may resume 
vaccinations. 
Vaccinations should not be administered outside the visit window period specified 
in the HVTN 702 Study Specific Procedures (SSP). 
In order to avoid vaccination delays and missed vaccinations, participants who 
plan to receive licensed vaccines should be counseled to schedule receipt of these 

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substances, when possible, outside the intervals indicated above. The effects of 
these substances on safety and immunogenicity assessments and their interactions 
with study vaccines are unknown. Therefore, if circumstances allow, these 
substances should also be avoided in the 2-week interval between a study 
vaccination and the next visit. 
7.3.2 
Participant departure from vaccination schedule 
Every effort should be made to follow the vaccination schedule per the protocol. 
If a participant misses a vaccination and the visit window period for the 
vaccination has passed, that vaccination cannot be given. The participant should 
be asked to continue study visits. The participant should resume the vaccination 
schedule with the next vaccination unless there are circumstances that require 
further delay or permanent discontinuation of vaccination (Sections 7.3.1 and 
7.3.3). 
7.3.3 
Discontinuing vaccination for a participant 
Under certain circumstances, an individual participant’s vaccinations will be 
permanently discontinued. Specific events that will result in stopping a 
participant’s vaccination schedule include: 
x Co-enrollment in a study with an investigational research agent (rare 
exceptions allowing for the continuation of vaccinations may be granted with 
the unanimous consent of the HVTN 702 PSRT). 
x Clinically significant condition (ie, a condition that affects the immune system 
or for which continued vaccinations and/or blood draws may pose additional 
risk), including but not limited to the following: 
 Pregnancy: Vaccinations will be stopped while a participant is pregnant. If 
the participant is no longer pregnant and can be vaccinated within an 
appropriate visit window, vaccinations may resume (Section 7.3.1); 
 Any grade 4 local or systemic reactogenicity symptom, lab abnormality, or 
AE that is subsequently considered to be related to vaccination; 
 Any grade 3 lab abnormality or other clinical AE (exception: fever or 
vomiting and subjective local and systemic symptoms) that is 
subsequently considered to be related to vaccination; upon review, the 
PSRT may allow continuation of vaccination if the participant has grade 3 
erythema and/or induration; or 
 Clinically significant type 1 hypersensitivity reaction associated with 
study vaccination. Consultation with the HVTN 702 PSRT is required 
prior to subsequent vaccinations following any type 1 hypersensitivity 
reaction associated with study vaccination; or 
x Investigator determination in consultation with Protocol Team leadership (eg, 
for repeated nonadherence to study staff instructions). 

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Such participants should be counseled on the importance of continuing with the 
study and strongly encouraged to participate in follow-up visits and protocol-
related procedures per the protocol for the remainder of the trial, unless medically 
contraindicated. 
In addition, vaccinations will be stopped for participants diagnosed with HIV 
infection. 
7.3.4 
Participant termination from the study 
Under certain circumstances, an individual participant may be terminated from 
participation in this study. Specific events that will result in early termination 
include: 
x Participant refuses further participation, 
x Participant relocates and remote follow-up or transfer to another HVTN CRS 
is not possible, 
x HVTN CRS determines that the participant is lost to follow-up, 
x Investigator decides, in consultation with Protocol Team leadership, to 
terminate participation (eg, if participant exhibits inappropriate behavior 
toward clinic staff). 
x Any condition where termination from the study is required by applicable 
regulations. 

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8 
Study product preparation and administration 
CRS pharmacists should consult the Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks for standard pharmacy operations. The protocol 
schema is shown in Table 3-1. See the IBs for further information about study 
products. 
8.1 
Vaccine regimen 
The schedule of vaccination is shown in Section 3 and additional information is 
given below. 
Group 1 
Treatment 1 (T1): ALVAC-HIV (vCP2438) to be administered as 1 mL IM in 
LEFT deltoid (unless medically contraindicated) at months 0, 1, 3, 6, 12, and 18 
AND 
Bivalent Subtype C gp120/MF59 (an admixture of 100 mcg of TV1.C gp120, 100 
mcg of 1086.C gp120, and MF59C.1) to be administered as 0.5 mL IM in RIGHT 
deltoid (unless medically contraindicated) at Months 3, 6, 12, and 18 
Group 2 
Placebo 2 (P2): Placebo for ALVAC-HIV (Sodium Chloride for Injection, 0.9%) 
to be administered as 1 mL IM in LEFT deltoid (unless medically 
contraindicated) at months 0, 1, 3, 6, 12, and 18 
AND 
Placebo for Bivalent Subtype C gp120/MF59 (Sodium Chloride for Injection, 
0.9%)  administered as 0.5 mL IM in RIGHT deltoid (unless medically 
contraindicated) at Months 3, 6, 12, and 18 
8.2 
Study product formulation 
ALVAC-HIV (vCP2438) [Labeled as ALVAC-HIV (vCP2438)] 
ALVAC-HIV (vCP2438) is provided as a lyophilized, white to beige product. It 
must be stored refrigerated (2-8°C). Once reconstituted with 1 mL of Diluent 
0.4% NaCl, it appears as a clear to slightly opalescent solution, colorless with 
possible presence of particles or filaments. 
The study product is described in further detail in the IB. 

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Diluent for ALVAC-HIV (vCP2438) 
The diluent is provided in a vial filled with a volume to deliver 0.5 mL of sterile 
sodium chloride solution (NaCl 0.4%). Two vials of diluent are required to 
prepare one dose. It must be stored refrigerated (2-8°C). DO NOT FREEZE. 
Placebo for ALVAC-HIV (Sodium Chloride for Injection, 0.9%) 
Sodium Chloride for Injection, 0.9% will be used as the placebo for ALVAC-
HIV. Product must be stored as directed by the manufacturer. 
Bivalent gp120 composed of two different proteins: 
TV1.C gp120 protein [labeled as TV1.C gp120]: The TV1.C gp120 protein will 
be provided in a glass vial containing approximately 0.58 mL (462 mcg) of 
protein in buffer. The protein is a clear colorless to slightly yellow liquid when 
thawed. The product must be stored frozen at -61°C or colder. 
The study product is described in further detail in the IB. 
1086.C gp120 protein [labeled as 1086.C gp120]: The 1086.C gp120 protein 
will be provided in a glass vial containing approximately 0.58 mL (462 mcg) of 
protein in buffer. The protein is a clear colorless to slightly yellow liquid when 
thawed. The product must be stored frozen at -61°C or colder. 
The study product is described in further detail in the IB. 
MF59 [labeled as MF59C.1] is supplied as an oil-in-water emulsion. The MF59 
adjuvant has a milky white opaque appearance and is provided in a glass vial 
containing a total volume of 0.7 mL. The product must be stored refrigerated at 2-
8°C. Do not freeze. 
The study product is described in further detail in the IB. 
Placebo for Bivalent Subtype C gp120/MF59 (Sodium Chloride for Injection, 
0.9%) 
Sodium Chloride for Injection, 0.9% will be used as the placebo for the Bivalent 
Subtype C gp120/MF59. Product must be stored as directed by the manufacturer. 
8.3 
Preparation of study products 
Pharmacists should refer to USP 38 General Chapter Physical Tests / <797> 
Pharmaceutical Compounding - Sterile, and should follow the requirements of 
their country, their institution, and their pharmacy regulatory authority regarding 
these procedures. At a minimum, study products must be prepared in a biological 

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safety cabinet/isolator by appropriately trained/qualified pharmacy personnel 
using aseptic technique. 
8.3.1 
ALVAC-HIV (vCP2438) 
One vial of ALVAC-HIV (vCP2438) and 2 vials of diluent (NaCl 0.4%) are 
needed to prepare this dose. 
Before reconstitution, the pharmacist will allow the vials to equilibrate to room 
temperature. The pharmacist, using aseptic technique, will withdraw a total of 
1 mL from the 2 vials containing diluent (NaCl 0.4%) and slowly inject the 1 mL 
of diluent into the vial containing the lyophilized ALVAC-HIV. The pharmacist 
will then set the vial aside and allow the vial to sit for up to 3 minutes to allow for 
dissolution of the vaccine. The pharmacist will gently swirl the vial to assure the 
contents are well dissolved. DO NOT SHAKE. (Note: Presence of particles or 
filaments in the dissolved solution is possible). The study product is stable in the 
vial for 6 hours after reconstitution. Using aseptic technique, the pharmacist will 
then withdraw the total contents of the ALVAC-HIV vial into a 2 to 5 mL 
syringe. The pharmacist will apply an overlay to the syringe. 
The syringe should be labeled as “ALVAC-HIV or placebo 1 mL” as well as 
“Administer in Left Deltoid”. Once the dose is drawn up in a syringe, the study 
product should be administered as soon as possible within 30 minutes (per 
Immunization Action Coalition [IAC] and US Centers for Disease Control and 
Prevention [CDC] recommendations). 
Any unused portion of reconstituted vials or expired prefilled syringes is disposed 
of in accordance with institutional or pharmacy policy for a biological safety level 
1 product. 
8.3.2 
Placebo for ALVAC-HIV 
Using aseptic technique, the pharmacist will withdraw 1 mL of Sodium Chloride 
for Injection, 0.9% into a 2 to 5 mL syringe. The pharmacist will apply an overlay 
to the syringe. 
The syringe should be labeled as “ALVAC-HIV or placebo 1 mL” as well as 
“Administer in Left Deltoid”. Once the dose is drawn up in a syringe, the study 
product should be administered as soon as possible within 30 minutes (per IAC 
and US CDC recommendations) 
Any unused portion of entered vials or expired prefilled syringes should be 
disposed of in accordance with institutional or pharmacy policy. 
8.3.3 
Bivalent Subtype C gp120/MF59 vaccine 
One vial of TV1.C gp120 protein, one vial of 1086.C gp120 protein, and one vial 
of MF59C.1 will be needed to prepare the dose. Prior to dispensing, the 

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pharmacist will remove the TV1.C gp120 and 1086.C gp120 vials from the 
freezer and allow to thaw at room temperature. The pharmacist will also remove 
the MF59C.1 vial from the refrigerator and mix by repeated gentle swirling and 
inversion (do not shake vigorously). (Note: Once thawed the 1086.C gp120 and/or 
TV1.C gp120 vials should be used immediately for preparation or stored in a 
refrigerator at 2-8°C for no longer than 24 hours. Unused 1086.C gp120 and/or 
TV1.C gp120 protein vials should be quarantined for destruction after this time.) 
Using aseptic technique, the pharmacist will gently swirl the contents of the vial 
containing TV1.C gp120 and then withdraw 0.35 mL of TV1.C gp120 from the 
correct vial and inject it into the vial containing MF59C.1. The pharmacist will 
then gently swirl the vial containing 1086.C gp120 after which, using aseptic 
technique, the pharmacist will withdraw 0.35 mL of 1086.C gp120 from the 
correct vial and inject it into the MF59C.1 vial (which contains TV1.C gp120 and 
MF59C.1). After gentle swirling and inversion (do not shake vigorously) the 
pharmacist, using aseptic technique, will withdraw 0.5 mL of the mixed 
preparation for dosing into a 1 to 2 mL syringe. The pharmacist will apply an 
overlay to the syringe. 
The syringe should be labeled as “Bivalent Subtype C gp120/MF59 or Placebo 
0.5 mL”, as well as “Administer in RIGHT deltoid”. The syringe containing study 
product should be bagged for transport to the clinic where it will be administered. 
This study product should be administered immediately, defined as within 30 
minutes as per IAC recommendations. If this is not possible, the vaccine should 
be stored at 2°C-8°C until administration and if not used within 2 hours, it should 
be discarded.” 
Any unused portion of entered vials or expired prefilled syringes should be 
disposed of in accordance with institutional or pharmacy policy. 
8.3.4 
Placebo for Bivalent Subtype C gp120/MF59 vaccine 
Using aseptic technique, the pharmacist will withdraw 0.5 mL of Sodium 
Chloride for Injection, 0.9% into a 1 to 2 mL syringe. The pharmacist will apply 
an overlay to the syringe. 
The syringe should be labeled as “Bivalent Subtype C gp120/MF59 or Placebo 
0.5 mL”, as well as “Administer in RIGHT deltoid”. The syringe containing study 
product should be bagged for transport to the clinic where it will be administered. 
This study product should be administered immediately, defined as within 30 
minutes as per IAC recommendations. If this is not possible, the vaccine should 
be stored at 2°C-8°C until administration and if not used within 2 hours, it should 
be discarded.” 
Any unused portion of entered vials or expired prefilled syringes should be 
disposed of in accordance with institutional or pharmacy policy. 

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8.4 
Administration 
All injections are to be given IM in the deltoid indicated. Any administrator of 
study product must be blinded to the individual participant’s treatment 
assignment. 
When preparing a dose in a syringe and administering the dose, consideration 
should be given to the volume of solution in the needle before and after the dose 
is administered. Particularly, if the needle used to withdraw the product is 
replaced prior to vaccine administration, consideration should be given to 
conserving the full dose of product. The pharmacy and clinic staff members are 
encouraged to work together to administer the dose specified in the protocol. 
All injections are to be given using standard IM injection technique. 
For all syringes containing Bivalent gp120/MF59 or placebo, the person 
administering the injection should gently roll the syringe prior to administration 
of the study product. 
If an injection is administered in the contralateral deltoid due to a medical 
contraindication, the appropriate study staff should document this clearly. Under 
this circumstance, this is NOT a protocol violation. Two injections administered 
into the same deltoid should be at least 2.4 cm apart and should be documented in 
the participant’s study record. 
8.5 
Acquisition of study products 
The ALVAC-HIV (vCP2438) will be supplied (along with the Diluent) by Sanofi 
Pasteur and will be available through the NIAID Clinical Research Products 
Management Center (CRPMC). 
Bivalent Subtype C gp120 and MF59 will be supplied by GlaxoSmithKline 
Biologicals, S.A. and will be available through the CRPMC. 
Placebo for ALVAC-HIV and Placebo for Bivalent Subtype C gp120/MF59 
(Sodium Chloride for Injection, 0.9%) will not be provided through the protocol 
and must be obtained by the site. 
Once an HVTN CRS is protocol registered, the pharmacist can obtain study 
products from the CRPMC by following the ordering procedures outlined in the 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks. 
8.6 
Pharmacy records 
The HVTN CRS pharmacist is required to maintain complete records of all study 
products. The pharmacist of record is responsible for maintaining randomization 

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codes and randomization confirmation notices for each participant in a secure 
manner. 
8.7 
Final disposition of study products 
All unused study products must be returned to the CRPMC after the study is 
completed or terminated unless otherwise instructed by the CRPMC. The 
procedures and relevant form are included in the Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks. 

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9 
Clinical procedures 
The schedules of clinical procedures are shown in Appendix H, Appendix I, and 
Appendix N. 
All study data will be recorded on paper source documents prior to being entered 
into the study database (see the HVTN 702 SSP). 
9.1 
Informed consent 
Informed consent is the process of working with participants so that they fully 
understand what will and may happen to them while participating in a research 
study. The HVTN informed consent form documents that a participant (1) has 
been informed about the potential risks, benefits, and alternatives to participation, 
and (2) is willing to participate in an HVTN study. Informed consent 
encompasses all written or verbal study information HVTN CRS staff provide to 
the participant, before and during the trial. HVTN CRS staff will obtain informed 
consent of participants according to HVTN policies and procedures. 
The informed consent process continues throughout the study. Key study concepts 
should be reviewed periodically with the participant and the review should be 
documented. At each study visit, HVTN CRS staff should consider reviewing the 
procedures and requirements for that visit and for the remaining visits. 
Additionally, if any new information is learned that might affect the participants’ 
decisions to stay in the trial, this information will be shared with trial participants. 
If necessary, participants will be asked to sign revised informed consent forms. 
An HVTN CRS may employ recruitment efforts prior to the participant 
consenting. For example, some HVTN CRSs use a telephone script to prescreen 
people before they come to the clinic for a full screening visit. Participants must 
sign a screening or protocol-specific consent before any procedures are performed 
to determine eligibility. HVTN CRSs must submit recruitment and prescreening 
materials to their IRB/EC and any applicable Regulatory Entity (RE) for human 
subjects protection review and approval. 
Note: As defined in the DAIDS Protocol Registration Manual, an RE is “Any 
group other than the local IRB/EC responsible for reviewing and/or approving a 
clinical research protocol and site-specific ICFs [informed consent forms] prior to 
implementation at a site.” CRSs are responsible for knowing the requirements of 
their applicable REs. 
9.1.1 
Screening consent form 
Without a general screening consent, screening for a specific study cannot take 
place until the site receives protocol registration from the DAIDS RSC Protocol 
Registration Office. 

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Some HVTN CRSs have approval from their IRB/EC and any applicable RE to 
use a general screening consent form that allows screening for an unspecified HIV 
vaccine trial. In this way, HVTN CRS staff can continually screen potential 
participants and, when needed, proceed quickly to obtain protocol-specific 
enrollment consent. Sites conducting general screening or prescreening approved 
by their IRB/EC and any applicable RE may use the results from this screening to 
determine eligibility for this protocol, provided the tests are conducted within the 
time periods specified in the eligibility criteria. 
9.1.2 
Protocol-specific consent forms 
The protocol-specific consent forms describe the study products to be used and all 
aspects of protocol participation, including screening and enrollment procedures. 
A sample protocol-specific consent form for the main study is located in 
Appendix A. A separate sample consent form for other uses of specimens is 
located in Appendix D. A post-unblinding addendum to the sample informed 
consent form is located in Appendix K. 
Each HVTN CRS is responsible for developing a protocol-specific consent 
form(s) for local use, based on the sample protocol-specific consent forms in 
Appendix A, Appendix D, and Appendix K. The consent form(s) must be 
developed in accordance with requirements of the following: 
x CRS’s IRB/EC, and any applicable REs; 
x CRS’s institution; and 
x Elements of informed consent as described in Title 45, CFR Part 46 and Title 
21 CFR, Part 50, and in the International Conference on Harmonisation (ICH) 
E6, Good Clinical Practice: Consolidated Guidance 4.8. 
Study sites are strongly encouraged to have their local CABs review their sites-
specific consent forms. This review should include, but should not be limited to, 
issues of cultural competence, local language considerations, and the level of 
understandability. 
The sample informed consent form includes instructions throughout the document 
for developing specific content. 
Sites should follow the instructions in the Protocol-specific Official Memo 
distributed along with this protocol regarding when they may begin using their 
site-specific protocol consent forms. 
Regarding protocol registration, sites should follow procedures outlined in the 
current version of the DAIDS Protocol Registration Manual. 

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9.1.3 
Assessment of understanding 
Study staff are responsible for ensuring that participants fully understand the 
study before enrolling them. This process involves reviewing the informed 
consent form with the participant, allowing time for the participant to reflect on 
the procedures and issues presented, and answering all questions completely. 
An assessment of understanding is used to document the participant’s 
understanding of key concepts in this HIV vaccine trial. This process and the 
participant’s understanding of the key concepts should be recorded in source 
documentation at the site. 
IRB/EC and any applicable RE may require that a participant has signed either a 
screening or protocol-specific consent document prior to administering the 
Assessment of Understanding. The consent process (including the use of the 
Assessment of Understanding) should be explained thoroughly to the IRB/EC and 
any applicable RE, whose recommendations should be followed. 
9.2 
Pre-enrollment procedures 
Screening may occur over the course of several contacts/visits, up to and 
including before vaccination on Day 0. All inclusion and exclusion criteria must 
be assessed within 56 days before enrollment with the exception of HIV testing, 
which must be performed within 30 days before enrollment. 
After the appropriate informed consent has been obtained and before enrollment, 
the following procedures are performed: 
x Medical history, documented in the case history record; 
x Complete physical examination, including height, weight, vital signs, and 
male circumcision status; clinical assessments of head, ears, eyes, nose, and 
throat; neck; lymph nodes; heart; chest; abdomen; extremities; neurological 
function; and skin. Note: A man who wants to enroll in the study, but who is 
not circumcised and wishes to be, will be referred to a practitioner for 
circumcision, but the study sponsors will not pay for the procedure. 
x Assessment of concomitant medications and contraceptives the volunteer is 
taking, including prescription drugs (eg, ARVs) and nonprescription drugs, 
vitamins, topical products, alternative/complementary medicines (eg, herbal 
and health food supplements), recreational drugs, vaccinations, and allergy 
shots; 
x Laboratory tests as defined in the inclusion and exclusion criteria, including: 
 Screening HIV testing at local lab; 
 ALT 

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 Urine or serum pregnancy test (volunteers who were born female), 
x Administration of behavioral risk assessment questionnaire; 
x Obtaining of volunteer demographics in compliance with the NIH Policy on 
Reporting Race and Ethnicity Data: Subjects in Clinical Research, Aug. 8, 
2001 (available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-
053.html); 
x Counseling on HIV testing and risk reduction, as described in Section 9.7; and 
x Discussion of pregnancy prevention. A pregnant or breastfeeding person may 
not be enrolled in this trial. Specific criteria and assessment of contraception 
and pregnancy status are described in study inclusion criteria. 
9.2.1 
Use of screening results from another HVTN study 
If a participant screens for an HVTN study at the same HVTN CRS but then does 
not join that study, screening results from that effort may be applied to the 
screening for this protocol, as long as the screening was done under participant 
consent, the participant has signed a consent form to begin screening for this 
study, and the tests were conducted within the time periods specified in the 
eligibility criteria (Sections 7.1 and 7.2). 
9.3 
Enrollment and vaccination visits (pre-unblinding) 
Enrollment is simultaneous with first vaccination. The time interval between 
randomization and enrollment should not exceed 4 working days. The HVTN 
CRS registers the participant by scheduling the day 0 visit (enrollment) via the 
Web-based randomization system, and requests the randomization assignment. 
Circumstances may require a participant’s enrollment visit to be changed. This 
may exceed the 4-day randomization time limit. 
At all vaccination visits, the following procedures are performed before 
vaccination: 
Abbreviated physical examination, including weight, vital signs, and a symptom-
directed evaluation by history and/or appropriate physical exam based on 
participant self-reported symptoms or complaints; Assessment of baseline 
reactogenicity parameters; 
x Assessment of concomitant medications (as described in Section 9.2); 
x Assessment of any new or unresolved AEs/intercurrent illnesses; and 
x Urine or serum pregnancy test (for participants who were born female). 
Persons who are NOT of reproductive potential due to having undergone total 

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hysterectomy or bilateral oophorectomy (verified by medical records), are not 
required to undergo pregnancy testing. 
Following completion of all procedures in the preceding list, and if results 
indicate that vaccination may proceed, vaccination is prepared and administered 
(Sections 8.3 and 8.4). 
Administration of all injections during a vaccination visit must be accomplished 
within 1 calendar day. 
Immediately following vaccination, the participant remains in the clinic for 
observation. An initial reactogenicity assessment is made at a target of 30 minutes 
after injection, with an acceptable range of 25-60 minutes. Before leaving the 
clinic, the participant will be given the postvaccination memory tool and 
instructed on how to use it. The site will make arrangements to obtain a report of 
reactogenicity events from the participant after the 3-day reactogenicity period (as 
described in Section 9.9).  
The following procedures will be performed at all vaccination visits. These 
procedures may be performed prior to or following vaccination: 
x Risk reduction counseling (as described in Section 9.7); 
x Pregnancy prevention assessment (as described in Section 9.2 and 9.8); and 
x Assessment of new or unresolved social impacts (CRS staff will ask 
participant about the status of any unresolved social impacts and if s/he has 
experienced any new social impacts as a result of the trial participation). 
Additional procedures will be performed at scheduled visits as specified in 
Appendix H: 
x HIV infection assessment including pre-test counseling. A subsequent follow-
up contact is conducted to provide post-test counseling and to report results to 
the participant; 
x Behavioral risk assessment questionnaire; 
x Outside testing and belief questionnaire; 
x CBC/differential; 
x Hgb; 
x Confirm that participants received HIV test results from previous visit. If not, 
provide test results and post-test counseling as appropriate; and 
x Syphilis serology testing, 

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x Gonorrhea (GC)/chlamydia (CT) testing by urine or cervical/vaginal swab for 
persons born female; by urine for persons born male; and additionally by 
rectal swab for transgender persons (TG) and MSM, 
x Trichomonas by cervical/vaginal swab, and 
x With the exception of samples collected for STI testing and for ARV detection 
by dried blood spots (see Appendix H, footnote “b”), specimen collection 
(blood and/or stool) should be completed prior to vaccination. 
9.4 
Follow-up visits (pre-unblinding) 
The following procedures are performed at all scheduled follow-up visits: 
x Risk reduction counseling (as described in Section 9.7); 
x Pregnancy prevention assessment (as described in Section 9.2 and 9.8);  
x Assessment of new or unresolved social impacts (site staff will ask participant 
about the status of any unresolved social impacts and if s/he has experienced 
any new social impacts as a result of the trial participation); 
x Assessment of new or continuing concomitant medications (as described in 
Section 9.2); and 
x Assessment of new or unresolved AEs/intercurrent illnesses. 
Additional procedures will be performed at scheduled follow-up visits as 
specified in Appendix H: 
x Abbreviated physical examination including weight, vital signs, and a 
symptom-directed evaluation by history and/or appropriate physical exam 
based on participant self-reported symptoms or complaints; 
x Complete physical examination, including weight, vital signs, and clinical 
assessments of head, ears, eyes, nose, and throat; neck; lymph nodes; heart; 
chest; abdomen; extremities; neurological function; skin; and, if applicable, 
male circumcision status 
x Outside testing and belief questionnaire 
x Administration of behavioral risk assessment questionnaire; 
x HIV infection assessment including pre-test counseling. A subsequent follow-
up contact is conducted to provide post-test counseling and to report results to 
participant; 

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x Confirm that participants received HIV test results from previous visit. If not, 
provide test results and post-test counseling as appropriate; 
x Specimen collection (blood and/or stool);  
x Syphilis serology testing, 
x Gonorrhea (GC)/chlamydia (CT) testing by urine or cervical/vaginal swab for 
persons born female; by urine for persons born male; and additionally by 
rectal swab for TG and MSM, 
x Trichomonas by cervical/vaginal swab, and 
x Urine or serum pregnancy test (for participants who were born female). 
Persons who are NOT of reproductive potential due to having undergone total 
hysterectomy or bilateral oophorectomy (verified by medical records), are not 
required to undergo pregnancy testing. 
9.4.1 
Follow-up visits (post-unblinding) 
Following participant unblinding, the following procedures are performed at all 
scheduled follow-up visits to 12 months following the participant’s last 
vaccination: 
x Risk reduction counseling (as described in Section 9.7); 
x Assessment of new or unresolved social impacts (site staff will ask participant 
about the status of any unresolved social impacts and if s/he has experienced 
any new social impacts as a result of the trial participation); 
x Assessment of new or continuing concomitant medications (as described in 
Section 9.2); 
x Assessment of new or unresolved AEs/intercurrent illnesses. 
Additional procedures will be performed at scheduled follow-up visits as 
specified in Appendix M and Appendix N: 
x Abbreviated physical examination including weight, vital signs, and a 
symptom-directed evaluation by history and/or appropriate physical exam 
based on participant self-reported symptoms or complaints; 
x Complete physical examination, including weight, vital signs, and clinical 
assessments of head, ears, eyes, nose, and throat; neck; lymph nodes; heart; 
chest; abdomen; extremities; neurological function; skin; and, if applicable, 
male circumcision status 
x Administration of behavioral risk assessment questionnaire; 

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x HIV infection assessment including pre-test counseling. A subsequent follow-
up contact is conducted to provide post-test counseling and to report results to 
participant; 
x Confirm that participants received HIV test results from previous visit. If not, 
provide test results and post-test counseling as appropriate; 
x Specimen collection (blood);  
x Syphilis serology testing, 
x Gonorrhea (GC)/chlamydia (CT) testing by urine or cervical/vaginal swab for 
persons born female; by urine for persons born male; and additionally, by 
rectal swab for TG and MSM, and 
x Trichomonas by cervical/vaginal swab. 
At a participant’s final scheduled clinic visit  (ie, termination visit), the laboratory 
and CRS procedures specified for Visit 16 in Appendix M and Appendix N 
should be performed. 
In order to ensure participant and staff safety during the COVID-19 pandemic, 
“clinic visits” for purposes of data collection and procedures may be conducted by 
phone, text message, email, or other electronic means. An in-person clinic visit is 
required only for physical exam, point-of-care testing, and collecting biological 
samples, where these can be done safely. 
9.5 
Stool sampling 
Two stool samples will be collected from the study participants who agree to this 
procedure: 1 prior to enrollment (before the injection of the vaccine) and 1 at the 
Month 6.5 timepoint. These samples will be collected using swabs, either via 
rectal swabs or by taking swabs from stool. 
9.6 
Procedures for HIV-infected participants 
The following procedures are performed at follow-up visits for HIV-infected 
participants, as specified in Appendix I: 
x Counseling on HIV-1 testing/diagnosis; 
x Abbreviated physical examination including weight, vital signs, and a 
symptom-directed evaluation by history and/or appropriate physical exam 
based on participant self-reported symptoms or complaints; 

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x Complete physical examination, including clinical assessments of head, ears, 
eyes, nose, and throat; neck; lymph nodes; heart; chest; abdomen; extremities; 
neurological function; and skin; 
x Assessment of HIV/AIDS-related conditions and non-HIV disease 
progression-related events; 
x Assessment of new or continuing concomitant medications (as described in 
Section 9.2); 
x Assessment of new or continuing antiretroviral therapies and reason for 
initiation; 
x Assessment of new or unresolved AEs/intercurrent illnesses; 
x Counseling to reduce the risk of HIV transmission; 
x Administration of behavioral risk assessment questionnaire; 
x Assessment of new or unresolved social impacts (site staff will ask participant 
about the status of any unresolved social impacts and about any new social 
impacts experienced as a result of the trial participation); 
x Specimen collection (Appendix G). 
9.7 
HIV counseling and testing 
HIV counseling will be performed in compliance with the US Centers for Disease 
Control and Prevention (CDC) guidelines or other local guidelines for HIV 
counseling and referral. HIV testing will be performed in accordance with the 
current HVTN HIV testing algorithm following enrollment. 
Participants will be counseled routinely during the trial on the avoidance of HIV 
infection and on the potential negative social impacts of testing antibody positive 
due to the vaccine. They will also be counseled on the risks of HIV antibody 
testing outside of the HVTN CRSs and will be discouraged from doing so during 
study participation and/or during any period of vaccine-induced positive serology. 
Following study unblinding, participants who did not receive HIV vaccine study 
product or who have been determined to not have vaccine-induced positive 
serology (VISP) may have HIV testing performed within the community. 
Study staff will take particular care to inform study participants of the likelihood 
of routine HIV testing being offered or performed outside the study CRS at 
emergency rooms, clinics, and medical offices. Such testing has become more 
likely due to the CDC’s revised guidelines for HIV counseling and testing, as well 
as policy changes in many countries to make HIV testing more frequent and 

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routine. CRS staff should inform participants of their right to opt out of HIV 
testing outside the study site. CRS staff should inform study participants if local 
and/or state policies and regulations permit medical providers to perform HIV 
testing without first informing patients. If this is the case, then CRS staff should 
advise study participants that they may decline testing preemptively. CRS staff 
should also inform participants if positive results must be reported to local public 
health authorities. CRS staff should also inform participants of the need to 
maintain study blinding by getting HIV testing only at the study CRS. CRS staff 
should provide participants with CRS contact information and should encourage 
participants to ask medical providers to contact the CRS. The CRS can verify that 
the participant is in an HIV vaccine clinical trial and should only be tested at the 
study CRS. 
9.7.1 
Distinguishing intercurrent HIV infection from vaccine-induced 
positive serology 
The study product may elicit an antibody response to HIV proteins. Therefore, 
vaccine-induced positive serology may occur in this study. Several precautionary 
measures will be taken to distinguish intercurrent HIV infection from vaccine-
induced positive serology. These precautionary measures include: 
x Participants will have physical examinations at visits specified in Appendix H. 
Signs or symptoms of an acute HIV infection syndrome, an intercurrent illness 
consistent with HIV-1 infection, or probable HIV exposure would prompt a 
diagnostic workup per the HVTN algorithm for Recent Exposure/Acute 
Infection Testing to determine HIV infection. 
x HIV testing will be performed at multiple timepoints throughout the study 
(Appendix F). The Laboratory Program (or approved diagnostic laboratory) 
will follow the HVTN HIV testing algorithm (see Study Specific Procedures 
[SSP]), which is able to distinguish vaccine-induced antibody responses from 
actual HIV infections. 
x All participants can receive HIV-1 diagnostic testing from the site until they 
are told that they did not receive an HIV vaccine or that they do not have 
vaccine-induced seropositivity (VISP). 
x All participants who received vaccine product and who have vaccine-induced 
positive or indeterminate HIV-1 serology (as measured by the standard anti-
HIV antibody screening tests) at or after the study is unblinded will be offered 
poststudy HIV-1 diagnostic testing (per the HVTN poststudy HIV-1 testing 
algorithm) periodically and free of charge as medically/socially indicated 
(approximately every 6 months) unless or until HIV Ab testing is no longer 
the standard test in clinical settings. 

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9.7.2 
VISP registry 
Experimental HIV vaccines may induce antibody production to HIV antigens, 
producing reactive results on commercially available HIV test kits. In order to 
provide poststudy HIV testing to distinguish between VISP and HIV infection, 
and to mitigate potential social harms resulting from VISP in HIV vaccine 
recipients who are not infected with HIV, the HVTN has created a VISP registry. 
Following study unblinding, the registry will allow trained staff to verify that an 
individual has received an HIV vaccine, and therefore has the potential for VISP. 
Information in the VISP registry will not be used for research. Rather, the registry 
exists to support provision of poststudy testing and counseling services to HIV 
vaccine recipients. The registry contains the names of all study participants, 
unless they request that their names be removed. 
9.8 
Pregnancy prevention assessment 
Per Section 7.1, use of effective contraception is required from 21 days prior to 
enrollment (ie, first vaccination) until 3 months after the last vaccination for 
participants who were born female and who are of reproductive potential (capable 
of becoming pregnant). Prior to enrollment and throughout the period for which 
contraceptive use is required, staff will ask these participants to verbally confirm 
their use of adequate contraceptive methods. During this period, participants for 
whom contraceptive use is required should be reminded at all scheduled clinic 
visits of the importance of using contraception and should be referred to specific 
counseling, information, and advice as needed. This reminder should be 
documented in the participant’s study record. 
Self-reported infertility—including having been diagnosed with premature 
menopause (with no menses for 1 year) or having undergone hysterectomy, 
bilateral oophorectomy, or tubal ligation—must be documented in the 
participant’s study record. 
9.9 
Assessments of reactogenicity 
For all participants, baseline assessments are performed before and reactogenicity 
assessments are performed after each vaccination. All reactogenicity symptoms 
are followed until resolution and graded according to the Division of AIDS Table 
for Grading the Severity of Adult and Pediatric Adverse Events, Corrected 
Version 2.1, dated July 2017, except as noted in Section 12.2.2. 
The reactogenicity assessment period is 3 full days following each vaccination. 
The maximum severity reached for each symptom during the assessment period is 
reported on CRFs. Participants will be given a postvaccination memory tool to 
assist with recall of symptoms. The site staff and the participant will be in contact 
after the 3-day reactogenicity period, or sooner if indicated. At that time, site staff 
will discuss reactogenicity events with the participant and will record the relevant 

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information on either the appropriate CRF(s) or participant chart note. Clinic staff 
will follow new or unresolved reactogenicity symptoms present at day 3 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. 
Reactogenicity assessments include assessments of systemic and local symptoms 
and vaccine-related lesions. Events not listed on a CRF, or with an onset after the 
reactogenicity assessment period (day of vaccination and 3 full days after), or 
those meeting SAE/AEs requiring expedited reporting criteria, are recorded on an 
AE log form. 
9.9.1 
Assessment of systemic and local symptoms 
Systemic symptoms include increased body temperature, malaise and/or fatigue, 
myalgia, headache, chills, arthralgia, nausea, and vomiting. Local symptoms 
include pain and/or tenderness proximal to the injection site. Body temperature is 
measured by oral or infrared thermometry and reported in degrees Celsius. If 
temperature is measured in Fahrenheit, the conversion to Celsius should be 
documented in the participant’s chart note. A measurement is taken once daily 
during the assessment period and should be repeated if participant is feeling 
feverish. Body temperature measurement is not required during the in-clinic 
reactogenicity assessment immediately following vaccination. 
9.9.2 
Assessment of injection site 
Typical injection site reactions are erythema/redness and induration/swelling. The 
maximum horizontal and maximum vertical measurements for all injection site 
reactions are recorded. 
All injection site reactions are monitored until resolution. Areas greater than 25 
cm2 are followed daily; otherwise, the frequency of follow-up is based on 
clinician judgment. 
9.10 
Visit windows and missed visits 
Visit windows are defined in HVTN 702 Study Specific Procedures. The 
procedures for documenting missed visits and out-of-window visits are described 
in HVTN 702 Study Specific Procedures. If the missed visit is one that required 
safety assessments, HVTN CRS staff should attempt to bring the participant in for 
an interim visit as soon as possible. 
Procedures performed at an interim visit are usually toxicity/safety assessments 
(including local safety labs) and HIV testing. With the exception of HIV testing, 
these procedures are performed only if they were required at the missed visit or if 

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clinically indicated. HIV testing may be performed as deemed appropriate by the 
study staff. Blood samples for immunogenicity assays are not typically collected 
at interim visits. 
If a missed visit required vaccination, please refer to Section 7.3.2 and Section 
7.3.3 for resolution. 
9.11 
Early termination visit 
In the event of early participant termination, site staff should consider whether, in 
addition to procedures performed at all scheduled clinic visits, the following 
assessments are appropriate: a final physical examination, behavioral risk 
assessment questionnaire, STI test, and HIV test. 
9.12 
Pregnancy 
If a participant becomes pregnant during the course of the study, no more 
injections of study product will be given during the pregnancy, but remaining 
visits and study procedures should be completed unless medically contraindicated 
or applicable regulations require termination from the study. For participants who 
are no longer pregnant, see Section 7.3.1. If the participant terminates from the 
study prior to the pregnancy outcome, the site should make every effort to keep in 
touch with the participant in order to ascertain the pregnancy outcome. All 
pregnancies and pregnancy outcomes should be recorded and reported (see the 
HVTN 702 SSP). 

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10 
HIV-1 infection assessment and clinical response 
10.1 
HIV-1 symptom assessment 
At scheduled visits indicated in Appendix F and Appendix H and at unscheduled 
visits due to illness or suspected exposure, if necessary, information will be 
collected about any signs or symptoms suggestive of acute HIV-1 infection. 
Participants will be counseled about signs and symptoms of acute HIV infection 
and at visits following recent high-risk exposure, participants will be queried 
about any signs/symptoms suggestive of acute HIV-1 infection. Presence of 
signs/symptoms suggestive of acute HIV-1 infection, an intercurrent illness 
consistent with acute retroviral syndrome, or history of high-risk exposure would 
prompt a diagnostic work-up per the protocol-specific algorithm to determine 
HIV infection, except that in this instance the algorithm is modified to conduct 
serology and nucleic acid testing simultaneously. 
10.2 
HIV-1 screening test (prior to randomization) 
Prior to randomization, participants will be screened for HIV-1/2 infection by 
blood tests approved by the US FDA or locally available assays that have been 
approved by HVTN Laboratory Operations. Potential participants identified as 
being HIV infected during screening will be referred for medical treatment and 
management of the HIV infection. These individuals may also be referred to 
appropriate ongoing clinical trials or observational studies. 
10.3 
HIV-1 testing postvaccination 
Surveillance for HIV-1 takes place at vaccination visits and follow-up visits 
specified in Appendix F. 
In-study HIV testing will be performed using the HVTN HIV diagnostic testing 
algorithm. Routinely, specimens are initially assayed with an HVTN Lab 
Program–approved fourth-generation HIV 1/2 enzyme immunoassay (EIA) or 
chemiluminescent microparticle immunoassay (CMIA). If the EIA/CMIA is 
reactive, nucleic acid polymerase chain reaction (PCR) test will be performed as 
indicated in the algorithm. The algorithm is repeated on a second specimen to 
confirm a diagnosis of HIV-1 infection. The second specimen for confirmatory 
testing may be collected at an interim visit (designated as visit #.X, where # is the 
visit at which the first reactive test was obtained and X designates the interim 
visit; specified in Appendix G and Appendix I). Samples to be stored for future 
immunogenicity or virology studies will also be collected at this time (Appendix 
G). 
A ‘case’ will be defined as a participant with confirmed detectable HIV-1 nucleic 
acid PCR on 2 different specimen collection dates. The nucleic acid test will most 

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commonly be the HIV-1 RNA VL PCR test. Confirmation of HIV-1 infection will 
be determined through use of the HIV testing algorithm (available on the HVTN 
702 protocol-specific website). Before issuing an HIV-1 infection report for a 
participant diagnosed with HIV-1 infection prior to study unblinding, all testing 
results will be reviewed by a blinded, independent Endpoint Adjudicator(s) and/or 
designee(s) (Section 10.4). 
If a participant is confirmed to have become HIV-1 infected prior to study 
unblinding, plasma HIV-1 viral RNA will be measured on archived samples 
collected according to Appendix G. In addition to plasma HIV-1 viral RNA 
testing, participants will also have measurements of immunogenicity assessments 
and a clinical assessment performed at all of these visits. 
The HVTN Laboratory Program is responsible for all in-study diagnostic HIV 
testing. 
10.4 
Endpoint adjudication 
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 a 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, the HVTN will have an endpoint adjudication 
process to assess all serological and virological testing, in a blinded manner, on 
each participant in the trial who, prior to study unblinding, tests positive per the 
HVTN 702 HIV-1 diagnostic testing algorithm. The assessment of the Endpoint 
Adjudicator(s) or designee(s) will be reported to the SDMC and to the HIV 
diagnostics laboratory. 
The Endpoint Adjudicator(s) and/or designee(s) must notify the SDMC within 1 
working day of any confirmed HIV-1 infection. The HIV diagnostics lab will 
inform the clinic of the outcome of the HIV testing algorithm (ie, HIV-infected, 
HIV-uninfected, or redraw required). 
The Endpoint Adjudicator(s) and/or designee(s) will be an expert in the fields of 
infectious diseases or laboratory medicine independent of the clinical 
investigators participating in this trial. A separate Standard Operating Procedure 
will govern the activities of the Endpoint Adjudicator(s) and/or designee(s). 
10.5 
HIV-1 infection during the study 
It is critical to the success of the study that HIV-1–infected participants be 
properly identified and all data postdiagnosis be carefully recorded. Information 

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obtained from these cases of HIV-1 infection will form the basis of the primary 
endpoint assessment. 
Participants who develop HIV-1 infection following receipt of study product may 
remain in the study for follow-up but will receive no further injections. All 
participants who become HIV-1 infected following enrollment will be monitored 
as indicated in Appendix G and Appendix I Longer-term follow-up for these 
participants may be accomplished through enrollment in another protocol. 
Archived samples from earlier visits may also be tested to determine the earliest 
date of HIV-1 infection. 
10.6 
Medical care for participants who become HIV-1–infected 
It is anticipated that some study participants, whether they are randomized to 
receive vaccine or placebo, will become HIV-1 infected during the course of the 
trial. It is critical that these HIV-1–infected participants receive appropriate 
medical care. 
The investigators associated with this trial will refer participants who develop 
HIV infection while participating in this trial to medical professionals for care. 

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11 
Laboratory 
11.1 
HVTN CRS laboratory procedures 
The HVTN Site Lab Instructions and SSP provides further guidelines for 
operational issues concerning the clinical and processing laboratories. The manual 
includes guidelines for general specimen collection, special considerations for 
phlebotomy, specimen labeling, whole blood processing, HIV 
screening/diagnostic testing, and general screening and safety testing. 
Tube types for blood collection are specified in Appendix F, Appendix G, and 
Appendix M. For tests performed locally, the local lab may assign appropriate 
tube types. 
In specific situations, the blood collection tubes may be redirected to another 
laboratory or may require study-specific processing techniques. In these cases, 
laboratory special instructions will be posted on the protocol-specific section of 
the HVTN website. 
11.2 
Total blood volume 
Required blood volumes per visit are shown in Appendix F, Appendix G, and 
Appendix M. Not shown is any additional blood volume that would be required if 
a safety lab needs to be repeated, or if a serum pregnancy test needs to be 
performed. The additional blood volume would likely be minimal. The total blood 
volume drawn for each participant will not exceed 500 mL in any 56-day (8-
week) period. 
11.3 
Assay timepoints 
The primary immunogenicity timepoint in this study is at visit 6 (day 182) (ie, 2 
weeks after the fourth vaccination visit). Endpoint assays for humoral and cellular 
responses may be performed on participant samples at the primary 
immunogenicity timepoint and may be performed at baseline. Assays for humoral 
and cellular responses may be performed on participant samples at other 
timepoints; the schedules are shown in Appendix F, Appendix G, and Appendix 
M. 
11.4 
Endpoint assays: humoral 
11.4.1 
Binding antibody multiplex assay (BAMA) 
HIV-1-specific total binding IgG antibodies may be assessed on serum samples 
from study participants taken at the primary immunogenicity timepoint and 

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baseline. In addition, HIV-1-specific total binding IgA antibodies and binding to 
IgG subclasses (IgG1, IgG2, IgG3, IgG4) may also be assessed. Specimens from 
other timepoints as well as other HIV antigens may also be assayed based on the 
results of the initial assay. 
11.4.2 
Neutralizing antibody assay 
HIV-1–specific nAb assays may be performed on serum samples from study 
participants taken at the primary immunogenicity timepoint. Specimens from the 
baseline and other timepoints may also be analyzed at the discretion of the HVTN 
Laboratory Program, which may be contingent on the results of the primary 
immunogenicity timepoint. The TZM-bl assay may be used to test neutralization 
of the vaccine strains ZM96, 1086.C, and TV1.C and a single highly 
neutralization-sensitive Tier 1 virus as a positive control. The global panel and/or 
clade-specific panels may be used to assess Tier 2 neutralization (132, 133). 
11.5 
Endpoint assays: cellular 
11.5.1 
Flow cytometry 
Flow cytometry may be used to examine vaccine-specific CD4+ and CD8+ T-cell 
responses following stimulation of PBMCs with synthetic HIV peptides that span 
the proteins encoded by the vaccine. ICS parameters for this protocol include 
cytokines such as IFN-γ, interleukin (IL)-2, and tumor necrosis factor (TNF)-α, 
and may include other cytokines (such as cytokines relevant to Th2 and Th17 
responses) to identify T cells of specific functionality. Markers of cytotoxic 
potential (Granzyme B, perforin, and CD57) may also be included. Data will be 
reported as percentages of CD4+ or CD8+ T cells responding to a specific peptide 
pool. Additional cell surface markers, cytokines, or functional markers may also 
be analyzed. 
11.6 
Viral sequencing 
Viral sequencing may be conducted on the earliest available plasma specimens 
with positive HIV-1 RNA PCR tests from study participants who are diagnosed 
with HIV-1 infection. Viral sequencing may be conducted on subsequently 
collected samples to assess viral evolution. 
11.7 
ARV detection 
A direct, biomedical measure is used to assess ARV use in this study. This 
approach is used because self-report of ARV use for PrEP or PEP and other 
purposes has been shown to be unreliable in a variety of settings (134-136). For 
this study, ARV testing may be performed using a test that measures the amount 
of tenofovir-diphosphate (a metabolite of tenofovir) in red blood cells. This test 

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utilizes a dried blood spot as the sample source and analyzes for tenofovir 
diphosphate by liquid chromatography and tandem mass-spectroscopy, as 
previously described (137, 138). Because of a long half-life, high amounts of the 
metabolite in the dried blood spot correspond with consistent dosing of Truvada 
and low amounts correspond with inconsistent dosing (139). Samples are 
collected and stored on regularly scheduled calendar days throughout the study 
and testing will be performed periodically on batched samples. In addition, both 
serum and plasma samples are collected from all HIV-uninfected participants at 
multiple timepoints (see Appendix F). This will allow additional assessment of 
PrEP use by selected participants if warranted by the results of the dried blood 
spot assay. Individual test results will not be returned to study sites or study 
participants. 
11.8 
Genotyping 
Molecular human leukocyte antigen (HLA) typing may be performed on enrolled 
participants using cryopreserved PBMC collected at baseline, initially on 
specimens from participants who demonstrate vaccine-induced T-cell responses at 
postvaccination timepoints. Other participants (including control recipients) may 
be HLA-typed to support future studies of immunological interest at the discretion 
of the HVTN Laboratory Program. Other markers, such as genes associated with 
immune responses or HIV-1 disease progression may also be assessed. 
11.9 
Laboratory Center assay portfolio 
Additional assays may be performed per the HVTN Laboratory Center assay 
portfolio, which includes immune assessments such as those for cellular, humoral, 
and innate immune responses, and host genetics. The assay portfolio will be 
updated periodically to include new assays and adjust qualification levels of 
existing assays. 
11.10 
Exploratory studies 
Samples may be used for other testing and research related to furthering the 
understanding of HIV immunology or vaccines. In addition, cryopreserved 
samples may be used to perform additional assays to support standardization and 
validation of existing or newly developed methods. 
11.10.1 
Microbiome analysis 
Stool swab specimens are processed to enable nucleic acid sequencing. 16s rRNA 
sequences may then be determined using pyro-sequencing approaches or other 
methods. 

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11.11 
Other use of stored specimens 
The HVTN stores specimens from all study participants indefinitely, unless a 
participant requests that specimens be destroyed or if required by IRB/EC, or RE. 
Other use of specimens is defined as studies not described in the protocol. 
This research may relate to HIV, vaccines, the immune system, and other 
diseases. This could include limited genetic testing and, potentially, genome-wide 
studies. This research is done only to the extent authorized in each study site’s 
informed consent form, or as otherwise authorized under applicable law. Other 
testing on specimens will occur only after review and approval by the HVTN, the 
IRB/EC of the researcher requesting the specimens, and the CRS’s IRBs/ECs if 
required. 
The protocol sample informed consent form is written so that the participant 
either explicitly allows or does not allow their samples to be used in other 
research when they sign the form. Participants who initially agree to other use of 
their samples may rescind their approval once they enter the study; such 
participants will remain in this study and their samples will only be used for the 
studies described in this protocol. If a participant decides against allowing other 
research using his or her samples, or at any time rescinds prior approval for such 
other use, the study site investigator or designee must notify HVTN Regulatory 
Affairs in writing. In either case, HVTN Regulatory Affairs directs the HVTN 
Lab Program not to use samples from these participants for such other uses. 
CRSs must notify HVTN Regulatory Affairs if institutional or local governmental 
requirements pose a conflict with or impose restrictions on other use of 
specimens. 
11.12 
Biohazard containment 
As the transmission of HIV and other blood-borne pathogens can occur through 
contact with contaminated needles, blood, and blood products, appropriate 
precautions will be employed by all personnel in the drawing of blood and 
shipping and handling of all specimens for this study, as currently recommended 
by the CDC and the NIH or other applicable agencies. 
All dangerous goods materials, including Biological Substances, Category A or 
Category B, must be transported according to instructions detailed in the 
International Air Transport Association Dangerous Goods Regulations. 

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12 
Safety monitoring and safety review 
12.1 
Safety monitoring and oversight 
12.1.1 
HVTN 702 PSRT 
The HVTN 702 PSRT is composed of the following members: 
x DAIDS medical officer representative, 
x Protocol chair and cochairs, 
x Protocol Team leader, 
x Core medical monitor, 
x Clinical safety specialist, and 
x Regional medical liaison (RML). 
The clinician members of HVTN 702 PSRT are responsible for decisions related 
to participant safety. 
A medical officer from an in-country organization designated by the study 
sponsor will also participate in the PSRT. 
The Protocol Team clinic coordinator, project manager, vaccine developer 
representative, clinical trial manager, and others may also be included in HVTN 
702 PSRT meetings. 
12.1.2 
NIAID DSMB  
The NIAID DSMB assesses the effects of the study vaccine during the trial, 
provides other monitoring as described in Sections 6.5, 6.9.3, and 13.1.4, and may 
give advice to the HVTN 702 OG.  
As of the 23 January 2020 DSMB meeting, the DSMB oversight of the study is 
complete. 
12.1.3 
SDMC roles and responsibilities in safety monitoring 
The roles and responsibilities of the SDMC in relation to safety monitoring 
include: 
x Maintaining a central database management system for HVTN clinical data; 

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x Providing reports of clinical data to appropriate groups such as the HVTN 702 
PSRT and NIAID DSMB; 
12.1.4 
HVTN Core roles and responsibilities in safety monitoring 
x Daily monitoring of clinical data for events that meet immediate HVTN 702 
PSRT notification criteria (Section 12.3); 
x Notifying HVTN CRSs and other groups when safety pauses are instituted 
and lifted (Section 12.3); 
x Querying HVTN CRSs for additional information regarding reported clinical 
data; and 
x Providing support to the HVTN 702 PSRT. 
12.2 
Safety reporting 
12.2.1 
Submission of safety forms to SDMC 
Sites must submit all safety forms (eg, reactogenicity, AE, concomitant 
medications) before the end of the next business day after receiving the 
information. The forms should not be held in anticipation of additional 
information at a later date. If additional information is received at a later date, the 
forms should be updated and resubmitted before the end of the next business day 
after receiving the new information. 
12.2.2 
AE reporting 
An AE is any untoward medical occurrence in a clinical investigation participant 
administered a study product/procedure(s) and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an investigational study 
product/procedure(s), whether or not related to the investigational study 
product/procedure(s). All AEs are graded according to the Division of AIDS Table 
for Grading the Severity of Adult and Pediatric Adverse Events, Corrected 
Version 2.1 dated July 2017, available at https://rsc.niaid.nih.gov/clinical-
research-sites/daids-adverse-event-grading-tables, except that: 
x Unintentional weight loss is required to be reported as an AE only if it is 
considered to be potentially deleterious to the participant’s health (HVTN 702 
SSP); 
x Injection Site Erythema or Redness and Injection Site Induration or Swelling 
will not consider interference with usual social and functional activities such 
that: 

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 Grade 1 is: 2.5 to < 5 cm in diameter OR 6.25 to < 25 cm2 surface area; 
 Grade 2 is: ≥ 5 to < 10 cm in diameter OR ≥ 25 to < 100 cm2 surface area; 
 Grade 3 is: ≥ 10 cm in diameter OR ≥ 100 cm2 surface area OR 
Ulceration OR Secondary infection OR Phlebitis OR Sterile abscess OR 
Drainage; 
 Grade 4 is: Potentially life-threatening consequences (eg, abscess, 
exfoliative dermatitis, necrosis involving dermis or deeper tissue); 
In addition, clarifying footnote 16 (page 21) in Version 2.1 of the AE Grading 
Table, for transgender participants ≥ 13 years of age who have been on feminizing 
hormone therapy for more than 6 consecutive months, grade hemoglobin based on 
the female sex at birth hemoglobin lab values. For transgender participants ≥13 
years of age who have been on masculinizing hormone therapy for more than 6 
consecutive months, grade hemoglobin based on the male sex at birth hemoglobin 
lab values. 
Unsolicited AEs will be collected over 30 days post each vaccination visit. All 
collected AEs are reported to the SDMC on the appropriate CRF. Clinic staff 
should evaluate every AE to determine if (1) the AE meets the requirements for 
expedited reporting to the study sponsor (Section 12.2.3), (2) if the AE meets the 
criteria for immediate notification to HVTN Core (Section 12.3), and (3) if the 
AE is a potential immune-mediated disease that may be listed as an AESI. A 
sample list of AESI is provided in Appendix J. Attribution with regard to 
relationship to study product will be reported for all AEs. 
Certain AEs will be collected and reported throughout the entire study: 
x SAEs/AEs requiring expedited reporting to DAIDS (EAEs),  
x AESIs 
x AEs of STIs  
x New chronic medical conditions (defined as a new onset or exacerbation of 
medical condition requiring 2 or more visits to a medical provider during a 
period of at least 30 days). and  
x AEs leading to early participant withdrawal or early discontinuation of study 
product(s) administration.  
In addition, site investigators are required to submit AE information in accordance 
with IRB/EC and any applicable RE requirements. 

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12.2.3 
Expedited reporting of adverse events 
Requirements, definitions and methods for expedited reporting of AEs to the 
study sponsor are outlined in Version 2.0 (January 2010) of the Manual for 
Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), which 
is available on the RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/manual-expedited-reporting-adverse-events-daids. The SAE Reporting 
Category will be used for this study. 
The DAIDS Adverse Event Reporting System (DAERS) must be used for 
expedited AE reporting to DAIDS. In the event of system outages or technical 
difficulties, expedited AE reports may be submitted via the DAIDS EAE Form. 
This form is available at https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-
reporting.  
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSsupport@niaid.nih.gov. Please note that site queries may also be sent from 
within the DAERS application itself. 
For questions about expedited AE reporting, please contact the RSC 
(DAIDSRSCSafetyOffice@tech-res.com). 
An AE is considered to be an SAE according to MCC (now SAHPRA) guidelines 
(Safety Reporting During Clinical Trials in South Africa, 
https://www.sahpra.org.za/wp-content/uploads/2020/02/2_Safety-Reporting-
during-Clinical-Trial_Nov19_v3-1.pdf), if it: 
x results in death, 
x is life-threatening, 
x requires patient hospitalisation or prolongation of existing hospitalisation, 
x results in persistent or significant disability/incapacity, 
x is a congenital anomaly/birth defect, or 
x is a medically important event or reaction. 
The term “life-threatening” in the definition of “serious” refers to an event in 
which the patient was at risk of death at the time of the reaction/event. It does not 
refer to an event, which, hypothetically, might have caused death, if it were more 
severe. 
Medical and scientific judgment should be exercised when deciding whether other 
situations are serious or not. Such instances could include medical events that 
may not be immediately life-threatening or result in death or hospitalization, but 
which may jeopardize the patient or may require intervention to prevent one of 

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the other outcomes listed in the definition above. Examples include blood 
dyscrasias or convulsions not resulting in hospitalization, or development of drug 
dependency or drug abuse. 
The sponsor or designee(s) prepares and files expedited reports to appropriate 
regulatory authorities and ECs within the timelines required by the South African 
MCC (now SAHPRA) guidelines, which are detailed in Safety Reporting During 
Clinical Trials in South Africa, Version 3, November 2019. 
Any SAE that is considered unexpected and for which the contribution of the 
study products cannot be ruled out will qualify for expedited reporting to the 
SAHPRA. The expedited reporting period for this study comprises the entire 
study period for each individual participant (from study enrolment until study 
completion or discontinuation from the study). 
The study products for which expedited reporting are required are: 
x ALVAC-HIV (vCP2438) 
x Placebo for ALVAC-HIV (vCP2438) 
x Bivalent Subtype C gp120/MF59 
x Placebo for Bivalent Subtype C gp120/MF59 
After a participant’s final scheduled study visit, only SUSARs as defined in 
Version 2.0 of the DAIDS EAE Manual must be reported to DAIDS, if the study 
staff become aware of the events. All AESIs will be considered “unexpected”, 
and, if deemed related to the study products, will be reported as SUSARs, if 
applicable. 
12.3 
AEs requiring immediate PSRT notification and prompt PSRT AE 
review 
Prior to study participants being unblinded to their treatment assignments, certain 
events require immediate telephone notification by the site to the HVTN Core 
safety staff. Telephone numbers and email addresses for contacting HVTN Core 
safety staff are found on the Protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/hvtn702/SitePages/Home.aspx). For the 
events described in this section, the site will also email and fax forms 
immediately. 
The events which require immediate telephone notification by the site to the 
HVTN Core 24 hour safety phone, include: 
x Any SAE described by the study site as related to the study vaccination 

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HVTN Core then immediately notifies the PSRT via email or phone. The Protocol 
Chair or Co-chair then decides how to review the event (via email or conference 
call). The PSRT will convene within 24 hours and decide whether the event 
necessitates a pause in further injections. If the team cannot convene to review the 
event within 24 hours, the medical officer or protocol chair will make the final 
decision. 
The events which require immediate telephone notification by the site to the RML 
or CSS include: 
x any Grade 4 objective local or systemic reactogenicity signs/symptom, or 
x Grade 4 AE related to study product, or 
x any Grade 5 event 
The RML or CSS notifies the HVTN 702 PSRT as soon as possible during 
working hours (South Africa Standard time or US Pacific Time, respectively)—
or, if the information was received during off hours, by the morning of the next 
work day. If a prompt HVTN 702 PSRT AE review cannot be completed within 
72 hours of notification (excluding weekends and US federal holidays), the 
medical officer or protocol chair will make the final determination as to whether 
the event necessitates a pause in further injections. 
Subjective reactogenicity symptoms (injection site pain, tenderness, 
fatigue/malaise, myalgia, arthralgia, chills, headache, and nausea) do not require 
immediate telephone notification by the site to HVTN Core. Objective 
reactogenicity signs include injection site erythema/redness, induration/swelling, 
vomiting, and fever.  
If the trial is placed on safety pause, all enrollment and vaccination with the 
product related to the event that triggered the pause will be held until further 
notice. 
If the study is stopped early and CRSs are unblinded, immediate telephone 
notification is not required and the PSRT will routinely review AE reports. 
For all safety pauses, HVTN Core notifies the HVTN 702 PSRT, HVTN 
Regulatory Affairs, DAIDS Pharmaceutical Affairs Branch (PAB), DAIDS 
Regulatory Affairs Branch (RAB), DAIDS Safety and Pharmacovigilance Team 
(SPT), and participating HVTN CRSs. 
Once a trial is paused, the HVTN 702 PSRT reviews safety data and decides 
whether the pause can be lifted or permanent discontinuation of vaccination is 
appropriate, consulting the DSMB if necessary. HVTN Core notifies the 
participating HVTN CRSs, HVTN Regulatory Affairs, DAIDS PAB, DAIDS 
RAB, and DAIDS SPT of the decision regarding resumption or discontinuation of 

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study vaccinations. Based on the HVTN 702 PSRT assessment, the trial sponsor 
or designee(s) notifies the SAHPRA as needed. 
The HVTN requires that each CRS submit to its IRB/EC protocol-related safety 
information (such as IND safety reports, notification of unplanned safety pauses). 
CRSs must also follow all applicable RE reporting requirements. 
In addition, all other AEs are reviewed routinely by the HVTN 702 PSRT 
(Section 12.4.2). 
12.4 
Review of cumulative safety data 
Routine safety review occurs at the start of enrollment and then throughout the 
study. 
Reviews proceed from a standardized set of protocol-specific safety data reports. 
These reports are produced by the SDMC and include queries to the HVTN CRSs. 
Events are tracked by internal reports until resolution. 
12.4.1 
Daily review 
Blinded daily safety reviews are routinely conducted by HVTN Core for events 
that meet immediate HVTN 702 PSRT notification criteria, as described in 
Section 12.3. 
12.4.2 
Weekly review 
During the injection phase of the trial, the HVTN 702 PSRT reviews clinical 
safety reports on a weekly basis and conducts calls to review the data as 
appropriate. After the 2-week-post-final-vaccination visits are completed, less 
frequent reporting and safety reviews may be conducted at the discretion of the 
HVTN 702 PSRT. HVTN Core reviews reports of all reported AEs. Events 
identified during the review that are considered questionable, inconsistent, or 
unexplained are referred to the HVTN CRS clinic coordinator for verification. 
12.4.3 
DSMB review of cumulative safety data 
The DSMB will periodically review accumulating unblinded safety data by group. 
Prior to each meeting, the SDMC will provide the DSMB with data as described 
in Section 6.5. Reports will be cumulative, generated from an up-to-date data file. 
Based upon the reports, the DSMB will determine whether to recommend that the 
study should be continued, modified, or stopped for safety reasons. 
As of the 23 January 2020 DSMB meeting, DSMB oversight of the study is 
complete. 

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12.5 
Study termination 
This study may be terminated early by NIAID upon recommendation by the 
DSMB, the SAHPRA, NIH, Office for Human Research Protections (OHRP), or 
vaccine developer(s). In addition, the conduct of this study at an individual HVTN 
CRS may be terminated by the determination of the IRB/EC and any applicable 
RE. 

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13 
Protocol conduct 
This protocol and all actions and activities connected with it will be conducted in 
compliance with the principles of GCP (ICHe6), and according to DAIDS and 
HVTN policies and procedures as specified in the HVTN Manual of Operations 
and DAIDS Clinical Research Policies and Standard Procedures Documents, 
including procedures for the following: 
x Protocol registration, activation, and implementation; 
x Informed consent, screening, and enrollment; 
x Study participant reimbursement; 
x Clinical and safety assessments; 
x Safety monitoring and reporting; 
x Data collection, documentation, transfer, and storage; 
x Participant confidentiality; 
x Study follow-up and close-out; 
x Unblinding of staff and participants; 
x Quality control; 
x Protocol monitoring and compliance; 
x Advocacy and assistance to participants regarding negative social impacts 
associated with the vaccine trial; 
x Risk reduction counseling; 
x Specimen collection, processing, and analysis; 
x Ancillary studies, and 
x Destruction of specimens. 
Any policies or procedures that vary from DAIDS and HVTN standards or require 
additional instructions (eg, instructions for randomization specific to this study) 
will be described in the HVTN 702 SSP. 

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13.1 
Protocol governance 
13.1.1 
Protocol Team 
The Protocol Team will be responsible for administrative oversight of the study, 
provides the overall operational direction for the trial, and is responsible for the 
conduct of the trial according to the highest scientific and ethical standards, as 
well as approving revisions and amendments to the protocol. The Protocol Team 
will remain blinded to the treatment group assignment of individual participants 
during the course of the study. 
13.1.2 
PSRT 
The PSRT will review all clinical and laboratory safety data during the course of 
the study as described in Section 12.4. 
13.1.3 
Oversight Group (OG) 
The OG provides the overall scientific direction for the trial, and will receive and 
decide on any recommendations made by the DSMB, including stopping the 
study. The OG must approve all scientific reports concerning the main findings of 
the trial. 
13.1.4 
NIAID DSMB 
The NIAID DSMB assesses the effects of the study vaccine during the trial and 
may give advice to the OG. The DSMB membership for this trial will include 
representatives from South Africa and is the same DSMB constituted for safety 
oversight for HVTN 100. With the exception of an unblinded statistician, the 
members of the committee are independent of the sponsor DAIDS, the HVTN and 
clinical investigators participating in this trial, will not have any other 
involvement in the study, and will not have any relation to study participants. The 
DSMB will monitor the trial for evidence of beneficial or adverse effects of the 
study vaccine using the guidelines proposed by the protocol. The DSMB may 
recommend any steps to ensure the safety of study participants and the integrity of 
the trial. Furthermore, it may recommend that the trial be terminated or that 
specific groups be withdrawn from the study, if any subgroup manifests serious or 
widespread side effects. To guarantee the unrestricted performance of its task, the 
DSMB may receive the individual study morbidity and mortality data from the 
unblinded statistician. 
The DSMB will be informed immediately by an independent statistician if the 
pre-specified stopping boundary is met, indicating that the vaccine causes harm 
by increasing the rate of HIV acquisition (Section 6.5.1). In addition, the DSMB 
will monitor the study for futility to detect vaccine activity (Section 6.5.2), for 
high vaccine efficacy (Section 6.5.3), and for operational futility, defined as an 
unacceptably low rate of HIV-1 infections and by other measures of under-

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performance (Section 6.5.5). Semiannual DSMB meetings will be held for 
monitoring operational futility. 
Should ongoing clinical trials of HIV prevention modalities produce results 
having implications for recruitment or endpoint enrollment in HVTN 702, those 
results will be reported to the DSMB, whose recommendations will inform 
consultations with applicable experts and stakeholders regarding possible changes 
in trial design and conduct. 
As of the 23 January 2020 DSMB meeting, DSMB oversight of the study is 
complete. 
13.2 
Social impacts 
Participants in this study risk experiencing discrimination or other personal 
problems, resulting from the study participation itself or from the development of 
VISP. The HVTN CRS is obliged to provide advocacy for and assistance to 
participants regarding these negative social impacts associated with the vaccine 
trial. If HVTN CRS staff have questions regarding ways to assist a participant 
dealing with a social impact, a designated NIAID or HVTN Core representative 
can be contacted. 
Social harms are tabulated by the SDMC and are subjected to descriptive analysis. 
The goal is to reduce their incidence and enhance the ability of study staff to 
mitigate them when possible. 
Summary tables of social impact events will be generated weekly, and made 
available for review by the protocol chairs, protocol team leader, and the 
designated NIAID representative. 
13.3 
Compliance with NIH guidelines for research involving products 
containing recombinant DNA 
Because this study is evaluating products containing recombinant DNA, it must 
comply with regulations set forth in the NIH’s Guidelines for Research Involving 
Recombinant or Synthetic Nucleic Acid Molecules. Information about the study 
must be submitted to site Institutional Biosafety Committees (IBC) and must be 
approved before participants are enrolled at the site. Investigators at each site are 
responsible for obtaining IBC approval per NIH guideline section IV-B07-a-(1). 
IBC review and approval must be documented by the investigator and submitted 
as part of initial protocol registration for this trial. If this protocol is amended, 
investigators should follow the requirements of their IBC. 

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13.4 
Specific regulatory considerations for Republic of South Africa 
The Republic of South Africa has laws regarding the use, manufacture, 
importation, and experimentation of products which are genetically modified. 
These are contained in the Genetically Modified Organism (GMO) Act 15 of 
1997, administered by the South African National Department of Agriculture, 
Pretoria. The Registrar of GMO shall be consulted on all formal developments 
relating to this protocol and clinical trial, and as required, a formal application 
will be made to the Registrar of GMO to review the HVTN 702 clinical trial, to 
obtain approval for the proposed clinical trial and for the importation of the study 
products. 
13.5 
Emergency communication with study participants 
As in all clinical research, this study may generate a need to reach participants 
quickly to avoid imminent harm, or to report study findings that may otherwise 
concern their health or welfare. 
When such communication is needed, the CRS will request that its IRB/EC and 
any applicable RE expedite review of the message. If this review cannot be 
completed in a timeframe consistent with the urgency of the required 
communication, the site should contact the participant first, and then notify the 
IRB/EC and any applicable RE of the matter as soon as possible. 

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14 
Version history 
The Protocol Team may modify the original version of the protocol. 
Modifications are made to HVTN protocols via clarification memos, letters of 
amendment, or full protocol amendments. 
The version history of, and modifications to, Protocol HVTN 702 are described 
below. 
Protocol history and modifications 
Date: May 20, 2020 
Protocol version: Version 4.0 
Protocol modification: Full Protocol Amendment 3 
Item 1 
Boxed text added following title page: Vaccinations stopped, visit 
schedule and study procedures revised, consent addendum added 
Item 2 
Updated in Section 3, Overview: Participants, duration per participant, 
and estimated total study duration 
Item 3 
Updated in Section 3.1, Protocol team: Membership 
Item 4 
Revised in Section 5.1: Primary objectives and endpoints 
Item 5 
Revised in Section 5.2: Secondary objective 4 
Item 6 
Updated in Sections 5.2, 5.3, 11.9, and 15: Lab Center assay portfolio 
Item 7 
Clarified in Section 6.5, 12, and 13: End of DSMB trial oversight 
Item 8 
Updated in Section 6.5.10: Trial duration 
Item 9 
Added in Section 6.9.5.1: Analysis strategy for primary objective 3 
Item 10 
Added in Sections 6.9.5.2 and 6.9.5.5: Qualifications to planned 
analyses 
Item 11 
Added in Section 9.1.2, Protocol-specific consent forms: Post-
unblinding addendum to sample informed consent form 
Item 12 
Added to titles of Section 9.3 and 9.4: “pre-unblinding” 
Item 13 
Added: Section 9.4.1, Follow-up visits (post-unblinding) 
Item 14 
Added in Section 9.7, HIV counseling and testing: Instructions for post-
unblinding HIV testing 
Item 15 
Revised in Section 9.8, Pregnancy prevention assessment: Time period 
for documentation of participant contraceptive use 
Item 16 
Updated in Section 9.11, Early termination visit: Procedures 
Item 17 
Updated in Section 11, Laboratory: Assays and sample shipping 
Item 18 
Updated in Sections 12 and 15: Safety reporting guidance URLs 

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Item 19 
Added: Appendix K, Sample addendum to informed consent form (post-
unblinding) 
Item 20 
Added: Appendix L, Tables of procedures (for addendum to sample 
informed consent form) 
Item 21 
Added: Appendix M, Schedule 3: Follow-up laboratory procedures for 
HIV-uninfected participants (post-unblinding) 
Item 22 
Added: Appendix N, Schedule 3: Follow-up procedures at HVTN CRS 
for HIV-uninfected participants (post-unblinding) 
Item 23 
Revised per Clarification Memo 1 to Version 3.0: Procedure timing and 
regulator access to participant records 
Item 24 
Revised per Clarification Memo 2 to Version 3.0: DBS timing, Visit 12 
timepoint, and SAHPRA update 
Item 25 
Clarified per Clarification Memo 3 to Version 3.0: Questionnaires at 
early termination visit 
Item 26 
Clarified per Clarification Memo 4 to Version 3.0: Missed visit 
documentation 
Item 27 
Clarified per Clarification Memo 5 to Version 3.0: Clinic visits 
Item 28 
Version history updated in Section 14 
Item 29 
Cross-references and literature citations updated and minor errors 
corrected 
Date: April 6, 2020 
Protocol version: Version 3.0 
Protocol modification: Clarification Memo 5 
Item 1 
Clarified throughout protocol: “Clinic visits” 
Date: March 19, 2019 
Protocol version: Version 3.0 
Protocol modification: Clarification Memo 4 
Item 1 
Clarified in Section 9.10, Visit windows and missed visits: Procedures for 
documenting out-of-window and missed visits 
Date: July 23, 2018 
Protocol version: Version 3.0 
Protocol modification: Clarification Memo 3 
Item 1 
Clarified in Section 9.11: Questionnaires recommended at early termination 
visit 

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Date: March 21, 2018 
Protocol version: Version 3.0 
Protocol modification: Clarification Memo 2 
Item 1 
Clarified in Section 9.3 and Appendix H: DBS blood drawing timing 
Item 2 
Corrected in Appendix H: Visit 12 timepoint 
Item 3 
Updated in Sections 12 and 16, Appendices A and D: MCC now SAHPRA 
Date: January 19, 2018 
Protocol version: Version 3.0 
Protocol modification: Clarification Memo 1 
Item 1 
Corrected: “Transmission risk reduction counseling” at Visit 31 in 
Appendix E and Appendix I 
Item 2 
Added in Appendices A and D: Broad regulatory agency access to 
participant study records 
Date: December 7, 2017 
Protocol version: Version 2.0 
Protocol modification: Clarification Memo 3 
Item 1 
Corrected: Appendix F, Schedule 1: Laboratory procedures for HIV-
uninfected participants 
Date: October 5, 2017 
Protocol version: Version 3.0 
Protocol modification: Full Protocol Amendment 2 
Item 1 
Added: Month 18 booster vaccination 
Item 2 
Revised in Sections 3, 6.4.1, 6.9.5.2, and Appendix A: Study population 
sex-at-birth balance 
Item 3 
Updated in Section 3.1, Protocol team: Team membership, roles, and 
institutional affiliations 
Item 4 
Updated and corrected in Section 4.1, Burden of HIV and rationale for HIV 
vaccine development and Section 17, Literature cited: Literature citations 
Item 5 
Clarified in Section 4.4.2, Manufacturing and formulation: Protein storage 
temperature and formulation characteristics 
Item 6 
Updated in Section 4.9.6, HVTN 100: Amendment description 
Item 7 
Revised in Sections 6.5.5 and 6.5.6: Statistical analysis for operational 
feasibility assessment 
Item 8 
Revised in Section 6.5.9, Power for secondary VE analysis: Study power 
under different HIV incidence and gender balance assumptions 

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Item 9 
Added in Section 6.9.5.2. Secondary vaccine efficacy analyses: HIV-1 
acquisition: Vaccine efficacy in a population with equal gender distribution 
Item 10 
Clarified in Section 7, Selection and withdrawal of participants: Eligibility 
determination 
Item 11 
Clarified in Section 8, Study product preparation and administration: 
Regimen, syringe labeling, and blinding 
Item 12 
Added in Section 9.3 and Appendices F and H: Hemoglobin testing 
Item 13 
Clarified in Section 9.8 and Appendix H: Pregnancy prevention assessment 
Item 14 
Updated and corrected in Sections 9.7.1, 11.1, and 15: Laboratory reference 
documents 
Item 15 
Clarified in Section 9.8 and footnote to Appendix H: Duration of 
contraception use requirement 
Item 16 
Updated in Sections 9.9, 12.2.2, and 15: DAIDS AE grading table version 
Item 17 
Clarified in Section 9.11 and Appendix H: Procedures at early termination 
visits 
Item 18 
Updated in Section 11.4: Humoral endpoint assays 
Item 19 
Updated in Sections 9.9, 12.2.2, and 15: DAIDS AE grading table and 
exceptions 
Item 20 
Updated in Section 12, Appendix A, and Section 15: Document references 
and URLs 
Item 21 
Updated in Section 16: Acronyms and abbreviations 
Item 22 
Updated in Appendix A, Sample informed consent form: 
Item 23 
Updated in Appendix A, Sample informed consent form: Sample testing, 
and stool sampling 
Item 24 
Updated in Appendix A and Appendix D: Use of extra samples, contact 
information, permissions 
Item 25 
Corrected in Appendix E, Tables of procedures (for sample informed 
consent form): 
Item 26 
Updated in footnote to Appendix F: HVTN laboratories 
Item 27 
Revised in footnotes to Appendices G and I: Subsequent HIV-testing 
redraw visits 
Item 28 
Corrected in Appendix H: Consent procedure 
Item 29 
Restored in Appendix H: Behavioral risk assessment questionnaire 
timepoints 
Item 30 
Added in Appendices H and I: Footnote clarifying stool sampling data 
collection 
Item 31 
Clarified in Appendix H footnotes: Blood draw windows at vaccination 
visits, HIV test results provision, and STI testing timepoints 

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Item 32 
Clarified in Appendix I, Schedule 2: Procedures at HVTN CRS for HIV-
infected participants: Procedures at visit #.X 
Item 33 
Added as Appendix K: Protocol signature page 
Item 34 
Corrected: Oversight Group (OG) terminology 
Item 35 
Corrected, Updated, and Clarified in Clarification Memo 1 to protocol 
Version 2.0: Appendix G procedures table, assay location and lab listings, 
and HIV-testing redraw visit blood draws 
Item 36 
Added via Clarification Memo 2 to protocol Version 2.0: Backup HIV 
diagnostic testing laboratory 
Item 37 
Corrected: Typographical errors and stylistic inconsistencies 
Date: August 16, 2017 
Protocol version: Version 2.0 
Protocol modification: Clarification Memo 2 
Item 1 
Added in Section 3, Overview, and Appendices F and G: Backup laboratory 
for HIV diagnostics 
Date: February 27, 2017 
Protocol version: Version 2.0 
Protocol modification: Clarification Memo 1 
Item 1 
Corrected: Appendix G, Schedule 2: Laboratory procedures for HIV-
infected participants 
Item 2 
Updated in Appendices F and G: Assay locations and HVTN laboratory 
listings 
Item 3 
Clarified in footnotes to Appendices G and I: Blood draws required at extra 
HIV-testing redraw visits 
Date: December 8, 2016 
Protocol version: Version 2.0 
Protocol modification: Full Protocol Amendment 1 
Item 1 
Clarified in Section 3, Overview: Duration per participant 
Item 2 
Updated in Section 3.1: Protocol Team 
Item 3 
Corrected in Section 4.4.4, Bivalent Subtype C gp120/MF59 for injection: 
Buffer quantities 
Item 4 
Corrected in Section 4.5.2: Assumptions regarding HIV-1 incidence 
Item 5 
Added: Section 4.6, Combination prevention of HIV acquisition 
Item 6 
Updated in Sections 4.9 and 4.10: HVTN 100 clinical experience 
Item 7 
Added: Adverse events of special interest (AESIs) 
Item 8 
Added: Optional stool sampling and gut microbiome analysis 

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Item 9 
Added: PrEP use monitoring using dried blood spots 
Item 10 Added: STI testing 
Item 11 Removed from clinical and laboratory procedures: Urine testing 
Item 12 Clarified in Section 5, Objectives and endpoints: Primary endpoint 
adjudication and effect modifications 
Item 13 Added in Section 5.3, Exploratory objectives: Comparative correlates of risk 
analysis 
Item 14 Updated and clarified in Section 6.5: Trial monitoring 
Item 15 Clarified in Section 6.9: Statistical analyses 
Item 16 Clarified in Section 6.7, Randomization of treatment assignments: 
Item 17 Removed in Section 7.1, Inclusion criteria and Appendices B and C: Barrier 
contraception requirement and partner vasectomy as contraception 
Item 18 Clarified in Section 7.3.3, Discontinuing vaccination for a participant: 
Exception for specified injection-site reactions with PSRT approval 
Item 19 Clarified in Section 9, Clinical procedures: Source documents 
Item 20 Clarified in Section 9, Clinical procedures: Reactogenicity assessments 
Item 21 Removed in Section 9, Clinical procedures and Appendix H, Schedule 1: 
Procedures at HVTN CRS for HIV-uninfected participants: Contraceptive 
assessment 
Item 22 Removed in Section 9.2, Pre-enrollment procedures: Required recording of 
generic names for concomitant medications 
Item 23 Clarified in Section 12.2, Safety reporting: AE/SAE and SUSAR reporting 
Item 24 Updated in Section 12.3: HVTN 702 protocol home page URL 
Item 25 Updated: Section 14, Version history 
Item 26 Updated in Section 15, Document references (other than literature 
citations): Document URLs 
Item 27 Updated in Appendix A, Sample informed consent form: Risks of study 
vaccines and description of sample testing 
Item 28 Added to Appendix A, Sample informed consent form: Information on oral 
PrEP 
Item 29 Updated in Appendix A, Sample informed consent form: Sample testing 
language 
Item 30 Clarified in Appendix A, Sample informed consent form: Funder access to 
study information 
Item 31 Added to Appendix A, Sample informed consent form: MCC contact 
information 
Item 32 Clarified in Appendix E, Tables of procedures (for sample informed consent 
form): Questions/questionnaire 

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Item 33 Revised in Appendix F, Schedule 1: Laboratory procedures for HIV-
uninfected participants: Blood draw volumes 
Item 34 Revised in Appendices G and I: Laboratory and CRS procedures for HIV-
infected participants 
Item 35 Clarified in Appendix H, Schedule 1: Procedures at HVTN CRS for HIV-
uninfected participants: Timing of final visit procedures 
Item 36 Revised in Appendix H, Schedule 1: Procedures at HVTN CRS for HIV-
uninfected participants: Frequency of behavioral risk assessment 
questionnaire 
Item 37 Revised in Appendix H, Schedule 1: Procedures at HVTN CRS for HIV-
uninfected participants: Window for blood draws prior to vaccination 
Item 38 Revised in Appendix F and G: Laboratory designations 
Item 39 Clarified in footnotes to Appendices F and H: Pregnancy testing 
Item 40 Updated via Clarification Memo 1: Study product information and 
reactogenicity symptoms 
Item 41 Minor typographical, grammatical, stylistic, and formatting errors have been 
corrected and cross-references have been updated throughout the protocol 
document 
Date: September 16, 2016 
Protocol version: Version 1.0 
Protocol modification: Clarification Memo 1 
Item 1 Clarified in Section 4.3.3, Manufacturing, Section 8.2, Study product 
formulation, and Section 8.5, Acquisition of study products: ALVAC-HIV 
(vCP2438) manufacturers, labeling, and study product acquisition 
Item 2 Clarified in Section 8.3, Preparation of study products: Diluent vials, study 
product stability, and preparation 
Item 3 Clarified in Section 12.3, AEs requiring immediate PSRT notification and 
prompt PSRT AE review: Subjective and objective reactogenicity symptoms 
Date: December 23, 2015 
Protocol version: 1.0 
Protocol modification: Original protocol 
 

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15 
Document references (other than literature 
citations) 
Other documents referred to in this protocol, and containing information relevant 
to the conduct of this study, include: 
x Assessment of Understanding. Accessible through the HVTN protocol-
specific website. 
x ABPI. Guidelines for Phase 1 Clinical Trials 2012 Edition Available at 
http://www.abpi.org.uk/our-work/library/guidelines/Pages/phase-1-trials-
2012.aspx  
x Current CDC Guidelines. Revised Recommendations for HIV Testing of 
Adults, Adolescents, and Pregnant Women in Health-Care Settings. Available 
at http://www.cdc.gov/mmwr/PDF/rr/rr5514.pdf  
x Division of AIDS (DAIDS) Clinical Research Policies and Standard 
Procedures Documents. Available at 
https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-
procedures  
x Division of AIDS Protocol Registration Manual. Available at 
https://www.niaid.nih.gov/sites/default/files/prmanual.pdf  
x Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events. Corrected Version 2.1 dated July 2017. Available at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-
tables  
x The Manual for Expedited Reporting of Adverse Events to DAIDS. Version 
2.0, January 2010. Available at http://rsc.tech-res.com/clinical-research-
sites/safety-reporting/manual  
x Safety Reporting During Clinical Trials in South Africa. Available at 
https://www.sahpra.org.za/wp-content/uploads/2020/02/1_SA-GCP-
Guidelines_2nd-edition_2006-1.pdf 
x Guidelines for Good Practice in the Conduct of Clinical Trials with Human 
Participants in South Africa. Available at 
http://www.mccza.com/documents/7c21ba77SA_GCP_guidelines_second_edi
tion_2006.pdf  
x Republic of South Africa: National Contraception Clinical Guidelines. 
December 2012. Available at  
http://www.mm3admin.co.za/documents/docmanager/3c53e82b-24f2-49e1-
b997-5a35803be10a/00037761.pdf  

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x Ethics in Health Research: Principles, Processes and Structures (Second 
edition, 2015), Department of Health, Republic of South Africa. Available at 
http://www.nhrec.org.za/docs/Documents/EthicsHealthResearchFinalAused.p
df  
x Declaration of Helsinki (last updated October 2013), World Medical 
Association. Available at 
http://www.wma.net/en/30publications/10policies/b3/ 
x Republic of South Africa, Medical Research Council: Guidelines on Ethics for 
Medical Research: HIV Preventive Vaccine Research. Available at 
http://www.mrc.ac.za//ethics/ethicsbook5.pdf  
x South Africa Genetically Modified Organism (GMO) Act 15 of 1997 
Available at http://www.saflii.org/za/legis/num_act/gmoa1997286/  
x HVTN 702 Special Instructions. Accessible through the HVTN protocol-
specific website. 
x HVTN 702 Study Specific Procedures. Accessible through the HVTN 
protocol-specific website. 
x HVTN 702 Site Lab Instructions. Accessible through the HVTN protocol-
specific website. 
x HVTN Manual of Operations. Accessible through the HVTN website. 
x Dangerous Goods Regulations (updated annually), International Air Transport 
Association. Available for purchase at 
http://www.iata.org/publications/dgr/Pages/index.aspx  
x Laboratory Center assay portfolio Available at 
http://www.hvtn.org/en/science.html 
x International Conference on Harmonisation (ICH) E6 (R1), Guideline for 
Good Clinical Practice: Section 4.8, Informed consent of trial subjects. 
Available at http://www.ich.org/products/guidelines/efficacy/article/efficacy-
guidelines.html  
x Participants’ Bill of Rights and Responsibilities. Accessible through the 
HVTN website. 
x NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic 
Acid Molecules, April 2016. Available at 
http://osp.od.nih.gov/sites/default/files/resources/NIH_Guidelines.pdf  

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x NIH Policy on Reporting Race and Ethnicity Data: Subjects in Clinical 
Research. Available at http://grants1.nih.gov/grants/guide/notice-files/NOT-
OD-01-053.html  
x Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks, 
July 2008. 
x Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials. Available at 
https://www.niaid.nih.gov/sites/default/files/documents/daids-
sourcedocpolicy.pdf  
x Title 21, Code of Federal Regulations, Part 50. Available at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFR
Part=50 
x Title 45, Code of Federal Regulations, Part 46. Available at 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html 
x Immunization Action Coalition, Vaccines with Diluents: How to Use Them. 
Available at http://www.immunize.org/catg.d/p3040.pdf 
x US Centers for Disease Control and Prevention. Vaccine Storage & Handling 
Toolkit, June 2016. Available at 
http://www.cdc.gov/vaccines/hcp/admin/storage/toolkit/storage-handling-
toolkit.pdf  
See Section 17 for literature cited in the background and statistics sections of this 
protocol. 

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16 
Acronyms and abbreviations 
Ab 
antibody 
ADCC 
antibody dependent cellular cytotoxicity 
ADCVI 
antibody dependent cellular viral inhibition 
AE 
adverse event 
AESI 
adverse event of special interest 
AIDS 
acquired immune deficiency syndrome 
ALT 
alanine aminotransferase 
ART 
antiretroviral therapy 
ARV 
antiretroviral 
AVEG 
AIDS Vaccine Evaluation Group 
β-HCG 
beta human chorionic gonadotropin 
BAMA 
binding antibody multiplex assay 
BMI 
body mass index 
CAB 
Community Advisory Board 
CCID50 
cell culture infectious dose (50%) 
CDC 
US Centers for Disease Control and Prevention 
CEB 
chick embryo fibroblasts 
CFR 
Code of Federal Regulations 
CHIL 
Cape Town HVTN Immunology Laboratory 
CHO 
Chinese hamster ovary 
CI 
confidence intervals 
CMIA 
chemiluminescent microparticle immunoassay 
CoR 
correlate of risk 
CPK 
creatine phosphokinase 
CRF 
case report form 
CRPMC 
NIAID Clinical Research Products Management Center 
CRS* 
clinical research site 
CTL 
cytotoxic T lymphocyte 
DAERS 
DAIDS Adverse Event Reporting System 
DAIDS 
Division of AIDS (US NIH) 
DBP 
diastolic blood pressure 
DHHS 
US Department of Health and Human Services 
DNA 
deoxyribonucleic acid 
DSMB 
NIAID Data and Safety Monitoring Board 
EAE 
adverse events requiring expedited reporting to DAIDS 
EC 
Ethics Committee 
EIA 
enzyme immunoassay 
ELISA 
enzyme-linked immunosorbent assay 

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ELISpot 
enzyme-linked immunospot 
EU 
European Union 
FDA 
US Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 
FIC 
full immunization cohort 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GM 
geometric mean 
GMO 
genetically modified organism 
GPP 
Good Participatory Practice 
GSK 
GlaxoSmithKline 
HAART 
highly active antiretroviral therapy 
HBV 
hepatitis B virus 
HCl 
hydrogen chloride 
HCRISA 
HVTN Centre for Research Institute of South Africa 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HMSL-NICD HIV Sero-Molecular Laboratory, National Institute for 
Communicable Diseases 
HVTN 
HIV Vaccine Trials Network 
IAC 
Immunization Action Coalition 
IB 
Investigator’s Brochure 
IBC 
Institutional Biosafety Committee 
IC 
immunogenicity cohort 
ICH 
International Conference on Harmonisation 
ICS 
intracellular cytokine staining 
IFN-γ 
interferon gamma 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IM 
intramuscular 
IN 
intranasal 
IRB 
Institutional Review Board 
ISS 
Istituto Superiore di Sanità (Rome) 
IUD 
intrauterine device 
LC 
Laboratory Center 
MAR 
missing at random 
MCC 
Medicines Control Council 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFI 
mean fluorescent intensity 

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MIGEE 
multiple imputation generalized estimating equation 
MITT 
modified intent-to-treat 
MMR 
measles, mumps, and rubella 
MSM 
men who have sex with men 
MUVAPRED Mucosal Vaccines for Poverty Related Diseases 
nAb 
neutralizing antibody 
NaCl 
sodium chloride 
NHP 
nonhuman primate 
NIAID 
National Institute of Allergy and Infectious Diseases (US NIH) 
NICD 
National Institute for Communicable Diseases 
NIH 
US National Institutes of Health 
OG 
Oversight Group 
OHRP 
US Office for Human Research Protections 
OPV 
oral polio vaccine 
P5 
Pox Protein Public Private Partnership 
PAB 
DAIDS Pharmaceutical Affairs Branch 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PEP 
postexposure prophylaxis 
PHRU 
Perinatal HIV Research Unit 
PLG 
polylactide-co-glycolide (microparticle) 
PP 
per-protocol [cohort] 
PrEP 
pre-exposure prophylaxis 
PI 
Principal Investigator 
PSRT 
Protocol Safety Review Team 
RAB 
DAIDS Regulatory Affairs Branch 
rcdf 
reverse cumulative distribution function 
RE 
regulatory entity 
REML 
restricted maximum likelihood 
RML 
Regional Medical Liaison 
RSA 
Republic of South Africa 
RSC 
DAIDS Regulatory Support Center 
SAAVI 
South African AIDS Vaccine Initiative 
SAE 
serious adverse event 
SAHPRA 
South African Health Products Regulatory Authority 
SAIL-NICD South African Immunology Laboratory 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SCHARP 
Statistical Center for HIV/AIDS Research and Prevention 

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SDMC 
statistical and data management center 
SOC  
Systems Organ Class 
SPF 
specific pathogen free 
SPT 
DAIDS Safety and Pharmacovigilance Team 
SSP 
study specific procedures 
STI 
sexually transmitted infection 
SUSAR 
suspected, unexpected serious adverse reaction 
TB 
tuberculosis 
TG 
transgender persons 
TM 
transmembrane 
TNF-α 
tumor necrosis factor alpha 
UL 
upper limit 
USMHRP 
US Military HIV Research Program 
VE 
vaccine efficacy 
VISP 
Vaccine induced seropositivity 
VL 
viral load 
* CRSs were formerly referred to as HIV Vaccine Trial Units (HVTUs). 
Conversion to use of the term CRS is in process, and some HVTN documents 
may still refer to HVTUs. 

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17 
Literature cited 
1. 
UNAIDS. Ethical considerations in HIV preventive vaccine research. 2002 2002. 
2. 
The National Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Subjects of Research. 1979 4/18/1979. 
3. 
Council for International Organizations of Medical Sciences (CIOMS). International 
ethical guidelines for biomedical research involving human subjects. Bull Med Ethics. 
2002(182):17-23. 
4. 
World Health Organization. Use of antiretroviral drugs for treating pregnant women 
and preventing HIV infection in infants: Programmatic update. 2012 2012. Report No.: 
WHO/HIV/2012.6. 
5. 
Abdool Karim SS. An AIDS-free generation? Science. 2012;337(6091):133. 
6. 
Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. 
Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J 
Med. 2012;367(5):399-410. 
7. 
Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. 
Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J 
Med. 2010;363(27):2587-99. 
8. 
Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, et al. 
Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N 
Engl J Med. 2012;367(5):423-34. 
9. 
Choopanya K, Martin M, Suntharasamai P, Sangkum U, Mock PA, Leethochawalit 
M, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, 
Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled 
phase 3 trial. Lancet. 2013;381(9883):2083-90. 
10. 
UNAIDS. The GAP Report. 2014.  
11. 
UNAIDS. Global AIDS Update. 2016. 
http://www.unaids.org/sites/default/files/media_asset/global-AIDS-update-2016_en.pdf. 
12. 
UNAIDS. Prevention Gap Report. 2016. 
http://www.unaids.org/sies/default/files/media_asset/2016-prevention-gap-report_en.pdf. 
13. 
Ramjee G, Daniels B. Women and HIV in Sub-Saharan Africa. AIDS Res Ther. 
2013;10(1):30. 
14. 
Shisana O, Rehle T, Simbayi L, Zuma K, Jooste S, Zungu N, et al. South African 
National HIV Prevalence, Incidence and Behaviour Survey, 2012. 2014. 

HVTN 702 Version 4.0 / May 20, 2020 
HVTN702_v4.0_FINAL.docx / Page 152 of 212 
15. 
UNAIDS. South Africa, HIV and AIDS estimates (2014) 2015 [updated 2015. 
Available from: http://www.unaids.org/en/regionscountries/countries/southafrica/] 
16. 
AVERT. Treatment as Prevention (TASP) for HIV. 2017 [Available from: 
https://www.avert.org/professionals/hiv-programming/prevention/treatment-as-prevention] 
17. 
WHO/UNAIDS. Voluntary medical male circumcision for HIV prevention 2012 
[Available from: http://www.who.int/hiv/topics/malecircumcision/fact_sheet/en/] 
18. 
Fauci AS, Marston HD. Ending AIDS--is an HIV vaccine necessary? N Engl J Med. 
2014;370(6):495-8. 
19. 
Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, et al. 
Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J 
Med. 2009;361(23):2209-20. 
20. 
Robb ML, Rerks-Ngarm S, Nitayaphan S, Pitisuttithum P, Kaewkungwal J, Kunasol 
P, et al. Risk behaviour and time as covariates for efficacy of the HIV vaccine regimen 
ALVAC-HIV (vCP1521) and AIDSVAX B/E: a post-hoc analysis of the Thai phase 3 
efficacy trial RV 144. Lancet Infect Dis. 2012;12(7):531-7. 
21. 
Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras GD, Alam SM, et al. 
Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med. 
2012;366(14):1275-86. 
22. 
Bredell H, Williamson C, Sonnenberg P, Martin DJ, Morris L. Genetic 
characterization of HIV type 1 from migrant workers in three South African gold mines. 
AIDS Res Hum Retroviruses. 1998;14(8):677-84. 
23. 
Van Harmelen JH, Van der RE, Loubser AS, York D, Madurai S, Lyons S, et al. A 
predominantly HIV type 1 subtype C-restricted epidemic in South African urban populations. 
AIDS Res Hum Retroviruses. 1999;15(4):395-8. 
24. 
Novitsky V, Smith UR, Gilbert P, McLane MF, Chigwedere P, Williamson C, et al. 
Human immunodeficiency virus type 1 subtype C molecular phylogeny: consensus sequence 
for an AIDS vaccine design? J Virol. 2002;76(11):5435-51. 
25. 
Guevara H, Johnston E, Zijenah L, Tobaiwa O, Mason P, Contag C, et al. Prenatal 
transmission of subtype C HIV-1 in Zimbabwe: HIV-1 RNA and DNA in maternal and cord 
blood. J Acquir Immune Defic Syndr. 2000;25(5):390-7. 
26. 
Sher R. HIV infection in South Africa, 1982-1988—a review. S Afr Med J. 
1989;76(7):314-8. 
27. 
Van Harmelen JH, Wood R, Lambrick M, Rybicki EP, Williamson AL, Williamson 
C. An association between HIV-1 subtypes and mode of transmission in Cape Town, South 
Africa. AIDS. 1997;11(1):81-7. 

HVTN 702 Version 4.0 / May 20, 2020 
HVTN702_v4.0_FINAL.docx / Page 153 of 212 
28. 
Peeters M, Toure-Kane C, Nkengasong JN. Genetic diversity of HIV in Africa: 
impact on diagnosis, treatment, vaccine development and trials. AIDS. 2003;17(18):2547-60. 
29. 
McCormack GP, Glynn JR, Crampin AC, Sibande F, Mulawa D, Bliss L, et al. Early 
evolution of the human immunodeficiency virus type 1 subtype C epidemic in rural Malawi. 
J Virol. 2002;76(24):12890-9. 
30. 
Jacobs GB, Loxton AG, Laten A, Robson B, van Rensburg EJ, Engelbrecht S. 
Emergence and diversity of different HIV-1 subtypes in South Africa, 2000-2001. J Med 
Virol. 2009;81(11):1852-9. 
31. 
Romani B, Glashoff R, Engelbrecht S. Molecular and phylogenetic analysis of HIV 
type 1 vpr sequences of South African strains. AIDS Res Hum Retroviruses. 2009;25(3):357-
62. 
32. 
Jacobs GB, Laten A, van Rensburg EJ, Bodem J, Weissbrich B, Rethwilm A, et al. 
Phylogenetic diversity and low level antiretroviral resistance mutations in HIV type 1 
treatment-naive patients from Cape Town, South Africa. AIDS Res Hum Retroviruses. 
2008;24(7):1009-12. 
33. 
Hemelaar J, Gouws E, Ghys PD, Osmanov S. Global and regional distribution of 
HIV-1 genetic subtypes and recombinants in 2004. AIDS. 2006;20(16):W13-W23. 
34. 
UNAIDS. Report on the Global AIDS Epidemic. 2012. UNAIDS / JC2417E. 
35. 
UNAIDS. Report on the Global AIDS Epidemic. 2010 2010. UNAIDS/10.11E | 
JC1958E. 
36. 
WHO. Country Health Profile of South Africa-2006. 2010. 
37. 
UNAIDS WHO. Epidemiological Fact Sheet on HIV and AIDS: Core data on 
epidemiology and response: South Africa. 2008. 
38. 
AVERT. Children orphaned by HIV and AIDS. 2012 [Available from: 
http://www.avert.org/aids-orphans.htm#contentTable1] 
39. 
Zolla-Pazner S, DeCamp A, Gilbert PB, Williams C, Yates NL, Williams WT, et al. 
Vaccine-Induced IgG Antibodies to V1V2 Regions of Multiple HIV-1 Subtypes Correlate 
with Decreased Risk of HIV-1 Infection. PLoS ONE. 2014;9(2):e87572. 
40. 
Rolland M, Edlefsen PT, Larsen BB, Tovanabutra S, Sanders-Buell E, Hertz T, et al. 
Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2. Nature. 
2012;490(7420):417-20. 
41. 
Yates NL, Liao HX, Fong Y, DeCamp A, Vandergrift NA, Williams WT, et al. 
Vaccine-induced Env V1-V2 IgG3 correlates with lower HIV-1 infection risk and declines 
soon after vaccination. Sci Transl Med. 2014;6(228):228ra39.