A Phase 1/2a Clinical Trial to Evaluate the Safety and Immunogenicity of ALVAC-HIV (vCP2438) and of MF59®- or AS01B-adjuvanted Clade C Env Protein, in Healthy, HIV-uninfected Adult Participants
Phase: PHASE1
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

PROTOCOL 
HVTN 120 
A phase 1/2a clinical trial to evaluate the safety and 
immunogenicity of ALVAC-HIV (vCP2438) and of MF59®- 
or AS01B-adjuvanted clade C Env protein, in healthy, 
HIV-uninfected adult participants 
NCT03122223
DAIDS DOCUMENT ID 36128 
IND 017645 HELD BY DAIDS 
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 PRODUCTS PROVIDED BY 
GlaxoSmithKline Biologicals S.A. 
Rixensart, Belgium  
Sanofi Pasteur 
Swiftwater, Pennsylvania, USA 
September 12, 2018 
HVTN 120 
Version 3.0 

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Contents  
1 Ethical considerations ..............................................................................................5 
2 IRB/EC review considerations .................................................................................7 
2.1 
Minimized risks to participants ......................................................................7 
2.2 
Reasonable risk/benefit balance .....................................................................7 
2.3 
Equitable participant selection .......................................................................8 
2.4 
Appropriate informed consent ........................................................................8 
2.5 
Adequate safety monitoring ...........................................................................8 
2.6 
Protect privacy/confidentiality .......................................................................9 
3 Overview ................................................................................................................10 
3.1 
Protocol Team ..............................................................................................13 
4 Background ............................................................................................................14 
4.1 
Building on RV144 ......................................................................................14 
4.2 
The Global Burden of HIV ...........................................................................16 
4.3 
Rationale for HVTN 120 ..............................................................................17 
4.4 
Study product descriptions ...........................................................................23 
4.5 
Trial design rationale ....................................................................................28 
4.6 
Summary of preclinical safety studies .........................................................30 
4.7 
Clinical studies .............................................................................................42 
4.8 
Potential risks of study products and administration ...................................64 
5 Objectives and endpoints .......................................................................................65 
5.1 
Primary objectives and endpoints ................................................................65 
5.2 
Secondary objectives and endpoints ............................................................66 
5.3 
Exploratory objectives ..................................................................................66 
6 Statistical considerations ........................................................................................67 
6.1 
Accrual and sample size calculations ...........................................................67 
6.2 
Randomization .............................................................................................70 
6.3 
Blinding ........................................................................................................70 
6.4 
Statistical analysis ........................................................................................70 
7 Selection and withdrawal of participants ...............................................................76 
7.1 
Inclusion criteria ...........................................................................................76 
7.2 
Exclusion criteria ..........................................................................................80 
7.3 
Participant departure from vaccination schedule or withdrawal ..................83 
8 Study product preparation and administration .......................................................87 
8.1 
Vaccine regimen ...........................................................................................87 
8.2 
Study product formulation ...........................................................................89 
8.3 
Preparation of study products .......................................................................90 
8.4 
Administration ..............................................................................................95 
8.5 
Acquisition of study products ......................................................................95 
8.6 
Pharmacy records .........................................................................................95 
8.7 
Final disposition of study products ..............................................................96 
9 Clinical procedures ................................................................................................97 
9.1 
Informed consent ..........................................................................................97 

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9.2 
Pre-enrollment procedures ...........................................................................99 
9.3 
Enrollment and vaccination visits ..............................................................101 
9.4 
Follow-up visits ..........................................................................................102 
9.5 
Mucosal sampling ......................................................................................104 
9.6 
Stool sampling ............................................................................................106 
9.7 
HIV counseling and testing ........................................................................106 
9.8 
Contraception status ...................................................................................108 
9.9 
Urinalysis ...................................................................................................108 
9.10 Assessments of reactogenicity ...................................................................108 
9.11 Visit windows and missed visits ................................................................110 
9.12 Early termination visit ................................................................................110 
9.13 Pregnancy ...................................................................................................110 
9.14 HIV infection during the study ...................................................................111 
10 Laboratory ............................................................................................................112 
10.1 HVTN CRS laboratory procedures ............................................................112 
10.2 Total blood volume ....................................................................................112 
10.3 Primary immunogenicity timepoints ..........................................................112 
10.4 Endpoint assays: humoral ...........................................................................113 
10.5 Endpoint assays: cellular ............................................................................113 
10.6 Genotyping .................................................................................................114 
10.7 Lab assay algorithm ...................................................................................114 
10.8 Exploratory studies .....................................................................................114 
10.9 Specimen storage and other use of specimens ...........................................114 
10.10 Biohazard containment ...............................................................................115 
11 Safety monitoring and safety review ...................................................................116 
11.1 Safety monitoring and oversight ................................................................116 
11.2 Safety reporting ..........................................................................................117 
11.3 Safety pause and prompt PSRT AE review................................................121 
11.4 Review of cumulative safety data ..............................................................122 
11.5 Study termination .......................................................................................122 
12 Protocol conduct ..................................................................................................124 
12.1 Social impacts ............................................................................................124 
12.2 Compliance with NIH guidelines for research involving products containing 
recombinant DNA ......................................................................................125 
12.3 Regulatory considerations for African countries .......................................125 
12.4 Emergency communication with study participants ..................................125 
13 Version history .....................................................................................................126 
14 Document references (other than literature citations) ..........................................129 
15 Acronyms and abbreviations................................................................................131 
16 Literature cited .....................................................................................................134 
Appendix A Sample informed consent form ............................................................145 
Appendix B Approved birth control methods for persons assigned female sex at birth 
(for sample informed consent form) for African sites ..........................168 

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Appendix C Approved birth control methods for persons assigned female sex at birth 
(for sample informed consent form) for US sites .................................169 
Appendix D Table of procedures (for sample informed consent form) ....................170 
Appendix E Sample consent form for use of samples and information in other studies
 171 
Appendix F Laboratory procedures ..........................................................................175 
Appendix G Procedures at HVTN CRS ....................................................................177 
Appendix H Adverse events of special interest ........................................................179 
Appendix I Injection schedule for sample informed consent ..................................180 
Appendix J Low Risk Guidelines for the United States ..........................................181 
Appendix K Low Risk Guidelines for Africa ...........................................................183 
Appendix L Protocol Signature Page .......................................................................184 
 

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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: 
• 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 International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH) and/or Good Clinical Practice (GCP) guidelines. 
• 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. 
• 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.  
• 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. 
• Participants who become HIV-infected during the trial are referred to medical 
practitioners to manage their HIV infection and to identify potential clinical 
trials they may want to join. If a program for antiretroviral therapy (ART) 
provision 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. 
• 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. 

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• Prior to implementation, HVTN trials are rigorously reviewed by scientists 
who are not involved in the conduct of the trials under consideration.  
• HVTN trials are reviewed by local and national regulatory bodies and are 
conducted in compliance with all applicable national and local regulations. 
• 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.  
• 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. 
• The HVTN recognizes the importance of institutional review and values the 
role of in country Institutional Review Boards (IRBs), Ethics Committees 
(ECs), and other Regulatory Entities (REs) 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). The following section highlights how this 
protocol addresses each of these research requirements. Each HVTN Investigator 
welcomes IRB/EC questions or concerns regarding these research requirements. 
This trial is also being conducted in Africa, with funding from the US NIH among 
others. Due to this, the trial is subject to both US and local 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 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 international and local (as appropriate) ICH and/or GCP 
guidelines, each research location has a locally based Principal Investigator (PI) 
who is qualified to conduct (and supervise the conduct of) the research. The 
investigators take responsibility for the conduct of the study and the control of the 
study products, including obtaining all appropriate regulatory and ethical reviews 
of the research.  
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 persons assigned 
female sex at birth); and (f) providing safety monitoring. 
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 

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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 participant 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. 
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 11). Safety is 
monitored daily by HVTN Core and routinely by the HVTN 120 Protocol Safety 
Review Team (PSRT). In addition, the HVTN Safety Monitoring Board (SMB) 
periodically reviews study data. 

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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 (see 
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 the 
United States, research participants in HVTN protocols are protected by a 
Certificate of Confidentiality from the US NIH, which can prevent disclosure of 
study participation even when that information is requested by subpoena. 
Participants are told of the use and limits of the certificate in the study consent 
form. In addition, each staff member at each study site in this protocol signs a 
Confidentiality Agreement on Confidentiality and Use of Data and Specimens 
with the HVTN. In some cases, a comparable confidentiality agreement process 
may be acceptable. 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 phase 1/2a clinical trial to evaluate the safety and immunogenicity of ALVAC-
HIV (vCP2438) and of MF59®- or AS01B-adjuvanted clade C Env protein, in 
healthy, HIV-uninfected adult participants 
Primary objectives 
Primary objective 1 
• To evaluate the safety and tolerability of ALVAC-HIV and bivalent gp120 
protein/MF59 or bivalent gp120 protein/AS01B 
Primary objective 2 
• To compare HIV-specific CD4+ T-cell response rates at the month 6.5 
timepoint (2 weeks after the fourth vaccination) of ALVAC-HIV and bivalent 
gp120 protein/MF59 to each of the bivalent gp120 protein/AS01B vaccine 
regimens. 
Primary objective 3 
• To compare HIV-specific Env-gp120 binding antibody response magnitudes 
at the month 12 timepoint (6 months after the fourth vaccination) of ALVAC-
HIV and bivalent gp120 protein/MF59 to each of the bivalent gp120 
protein/AS01B vaccine regimens. 
Study products and routes of administration 
• ALVAC-HIV (vCP2438) expresses the gene products 96ZM651 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 viral titer ≥ 1 × 106 cell culture infectious dose (CCID)50 and < 1 
× 108 CCID50 (nominal dose of 107 CCID50) and is reconstituted with 1 mL of 
sterile sodium chloride solution (NaCl 0.4%), administered IM as a single 1 
mL dose. 
• Protein/MF59: Bivalent Subtype C gp120/MF59: clade C TV1.C gp120 Env 
and clade C 1086.C gp120 Env, each at a dose of 100 mcg, mixed with MF59 
adjuvant, administered IM as a single 0.5 mL dose. 
• Protein/AS01B: Bivalent Subtype C gp120/AS01B: clade C TV1.C gp120 Env 
and clade C 1086.C gp120 Env, each at a dose of 20 mcg or 100 mcg, mixed 
with AS01B adjuvant, administered IM as a single 0.75 mL dose.  

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• Placebo: Sodium Chloride for Injection, 0.9%, administered IM. 
Table 3-1 Schema 
Group 
N 
Dose of 
each protein 
Deltoid 
Month 0 
(Day 0) 
Month 1 
(Day 28) 
Month 3 
(Day 84) 
Month 6 
(Day 168) 
1 
50 
100 mcg 
Left 
ALVAC-HIV  
ALVAC-HIV  
ALVAC-HIV  
ALVAC-HIV  
Right 
- 
- 
Protein/MF59 
+ Placebo* 
Protein/MF59 
+ Placebo* 
2 
50 
100 mcg 
Left 
ALVAC-HIV  
ALVAC-HIV  
ALVAC-HIV  
ALVAC-HIV  
Right 
- 
- 
Protein/AS01B 
+ Placebo* 
Protein/AS01B 
+ Placebo* 
3 
50 
20 mcg 
Left 
ALVAC-HIV  
ALVAC-HIV  
ALVAC-HIV  
ALVAC-HIV  
Right 
- 
- 
Protein/AS01B 
+ Placebo* 
Protein/AS01B 
+ Placebo* 
4 
10 
N/A 
Left 
Placebo 
Placebo 
Placebo 
Placebo 
Right 
- 
- 
Placebo + 
Placebo* 
Placebo + 
Placebo* 
* Two distinct placebo preparations for protein/adjuvant will be needed to maintain the blind since 
Protein/AS01B and Protein/MF59 consist of different injection volumes. 
Participants 
160 healthy, HIV-uninfected volunteers aged 18 to 40 years; 150 vaccinees, 10 
placebo recipients 
Design 
Multicenter, randomized, controlled, double-blind trial 
Duration per participant 
12 months of scheduled clinic visits  
Estimated total study duration 
18 months (includes enrollment and follow-up) 
Investigational New Drug (IND) study sponsor 
DAIDS, NIAID, NIH, DHHS (Bethesda, Maryland, USA) 

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Study product providers 
• ALVAC-HIV (vCP2438) and diluent (NaCl 0.4%): Sanofi Pasteur 
(Swiftwater, PA, USA) 
• Bivalent Subtype C gp120: GlaxoSmithKline Biologicals S.A. (GSK 
Vaccines) (Rixensart, Belgium) 
• MF59: GSK Vaccines (Rixensart, Belgium) 
• AS01B: GSK Vaccines (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) 
HIV diagnostic laboratories 
HIV Sero-Molecular Laboratory–National Institute for Communicable Diseases 
(HSML-NICD) (Johannesburg, South Africa)  
University of Washington Virology Specialty Laboratory (UW-VSL) (Seattle, 
Washington, USA) 
Endpoint assay laboratories 
• Cape Town HVTN Immunology Laboratory (CHIL) (Cape Town, South 
Africa)  
• Duke University Medical Center (Durham, North Carolina, USA)  
• FHCRC/University of Washington (Seattle, Washington, USA) 
• South Africa Immunology Laboratory and National Institute for 
Communicable Diseases (SAIL-NICD) (Johannesburg, South Africa) 
Study sites 
HVTN Clinical Research Sites HVTN (CRSs) in Africa and US to be specified in 
the Site Announcement Memo 

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Safety monitoring 
HVTN 120 PSRT; HVTN SMB 
3.1 
Protocol Team 
Protocol leadership 
Chair 
Z Mike Chirenje 
UZ-UCSF Collaborative 
Research Program 
+263 4 704966 
chirenje@uz-ucsf.co.zw 
Statisticians 
Barbara Metch 
SCHARP, FHCRC 
206-667-4656 
bmetch@fredhutch.org 
Cochairs 
Monde Muyoyeta 
Center for Infectious Disease 
Research in Zambia (CIDRZ) 
+260 966 765615 
monde.muyoyeta@cidrz.org 
 
Allan deCamp 
SCHARP, FHCRC 
206-667-2569 
adecamp@fredhutch.org 
 
Fatima Laher 
Perinatal HIV Research Unit, 
Chris Hani Baragwanath 
Hospital, Soweto, South Africa 
+27-11-989-9720 
laherf@phru.co.za 
Medical officer 
Laura Polakowski 
DAIDS, NIAID 
240-627-3040 
laura.polakowski@nih.gov 
 
Protocol Team leaders 
and Core medical 
monitors 
Philipp Mann 
HVTN Core, FHCRC 
206-667-1651 
pmann@fredhutch.org 
Lab lead 
Nicole Frahm  
HVTN Lab, FHCRC 
206-667-6268 
nfrahm@fredhutch.org 
 
Carmen Paez 
HVTN Core, FHCRC 
206-667-2881 
cpaez@fredhutch.org 
 
 
Other contributors to the original protocol 
Vaccine developer 
representatives 
Sanjay Phogat 
Sanofi Pasteur 
Statistical research 
associate 
Kyle Marshall 
SCHARP, FHCRC 
 
Carlos DiazGranados 
Sanofi Pasteur 
Clinical safety specialists 
Megan Jones 
HVTN Core, FHCRC 
Jill Zeller 
HVTN Core, FHCRC 
 
Marguerite Koutsoukos 
GSK Vaccines 
Clinical trials manager 
India Tindale 
HVTN Core, FHCRC 
 
Olivier Van Der Meeren 
GSK Vaccines 
SDMC Senior Clinical data 
manager 
Gina Escamilla 
SCHARP, FHCRC 
Clinic coordinator 
Lynda Stranix-Chibanda 
University of Zimbabwe 
College of Health Sciences 
 
SDMC Associate Director of 
Lab Science 
April Randhawa 
SCHARP, FHCRC 
Community Advisory Board 
(CAB) members 
Audry Tasaranarwo  
UZ-UCSF CTU CAB 
Protocol development 
manager 
Carter Bentley 
HVTN Core, FHCRC 
 
Mark Lungu  
CIDRZ CTU CAB 
Community engagement unit 
representatives 
Nandi Luthuli  
HVTN Core, FHCRC 
Regional medical liaison 
Simba Takuva 
HVTN Core, PHRU 
Community 
educator/recruiter 
Charles Chasakara  
UZ-UCSF Collaborative 
Research Programme 
Regulatory affairs 
Meg Brandon 
HVTN Core, FHCRC 
Technical editor 
Richa Chaturvedi 
HVTN Core, FHCRC 
DAIDS protocol pharmacist 
Irene Rwakazina 
DAIDS, NIAID 
 
Laboratory Program 
representative 
On Ho 
HVTN Lab, FHCRC 

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4 
Background 
4.1 
Building on RV144 
Following the RV144 study in Thailand that demonstrated modest (31%) 
protective efficacy for an HIV vaccine regimen comprising ALVAC-HIV 
(vCP1521) and clade B/E gp120 Env protein (AIDSVAX® B/E) formulated with 
Alum adjuvant [4], a large number of consultations with independent groups of 
scientists collected through the NIH, MHRP, and the Global Vaccine Enterprise 
were held providing input into the next steps for the field. Several consensus 
concepts emerged: (1) the need to evaluate the RV144 pox-protein prime-boost 
approach in a higher incidence population in a region of the world most affected 
by the HIV epidemic (ie, Southern Africa); (2) the consequent need to 
manufacture vaccines that more closely match those clades/subtypes that circulate 
in the proposed trial population (clade C); (3) at least one of the vaccine concepts 
to be tested should be analogous to the ALVAC/gp120 regimen used in RV144; 
and (4) the program to be developed should build upon the “correlates” analysis 
done after RV144 [5] to confirm the correlates identified in RV144 and to 
continue to define additional correlates of risk (CoR) for HIV vaccines. These 
recommendations led to the formation of the Pox Protein Public Private 
Partnership (P5), a group of vaccine developers, funders, and implementers, 
which was created to build on the RV144 results with the goal of improving the 
pox-protein regimen and enhancing the level and/or duration of protection seen in 
the RV144 study, with the hope of producing an effective prophylactic HIV 
vaccine with the potential to have a major public health impact.  
The P5 partnership is committed to evaluating multiple vaccine regimens and will 
address this goal by assessing regimens containing combinations of next-
generation vaccine products as well as different adjuvant systems to identify those 
exhibiting potent yet diverse immunological profiles, thus providing the greatest 
potential to confirm previous and identify new CoR in an efficacy trial.  
4.1.1 
The RV144 trial  
The RV144 trial was conducted by the US Military HIV Research Program and 
the Thailand Ministry of Health in a community-based sample of more than 
16,000 HIV-1–uninfected participants in Thailand, and results were published in 
2009 [4]. This community-based study enrolled individuals aged 18 to 30 years 
with varying degrees of HIV risk. The clinical trial evaluated the heterologous 
prime-boost combination of canarypox prime ALVAC-HIV (vCP1521), 
expressing clade E Env and clade B Gag and parts of Pol, followed by the 
AIDSVAX clades B/E gp120 protein boost. These products were based on viruses 
commonly circulating in Thailand at the time. This vaccine regimen demonstrated 
31.2% efficacy when compared with placebo (number of infections n = 51 vs. n = 
74, respectively; p = 0.04) at 3.5 years [4]. Although evaluation of vaccine 
efficacy at 12 months post vaccination was not included in the pre-specified 
analysis, substantially greater reduction in acquisition was observed 1 year post 

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vaccination (estimated 60.5%, 95% CI 22-80) with the vaccine effect waning over 
time to cumulative 31% through 3.5 years [6]  
4.1.2 
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 maximal information could be derived from samples 
obtained from participants who were vaccinated and became infected compared 
with those vaccinated but 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 [5]. 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 2 weeks after the 
final vaccination visit (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 V1V2 Ab→lower infection rate). The 
second was plasma Env-specific binding IgA, which correlated directly with 
infection rate (ie, higher immunoglobulin A [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 V1V2 Ab 
nor high levels of Env-specific IgA were associated with higher rates of infection 
than those found in the placebo group [5]. 
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, specifically that the vaccine induced better protection against viruses 
that matched the vaccine sequence at position 169 in the V2 loop of Env [7]. 
These data further substantiate the importance of antibodies directed against this 
region in protecting against infection [5]. Yates and colleagues noted that Env 
V1V2-specific IgG3 was the immunoglobulin subclass showing the strongest 
correlation with prevention of HIV acquisition in RV144 [8]. Chung and 
colleagues demonstrated that the IgG3 subclass was much better at engaging Fc-
mediated effector responses when compared to the other subclasses, thereby 
providing a possible mechanism explaining the association of Env V1V2 IgG3 
with a lower rate of HIV acquisition [9]. 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. They lay the 
groundwork for directing immune analyses planned for future HIV vaccine 
clinical trials. 

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4.2 
The Global Burden of HIV 
According to the UNAIDS 2016 Fact Sheet, there were an estimated 36.7 million 
people living with HIV in 2015 globally. There were 2.1 million new HIV 
infections globally and 1.1 million AIDS deaths in 2015 [10]. Therefore, despite 
the well-recognized benefits from scaling-up Antiretroviral Therapy (ART) and 
certain HIV prevention strategies, the global burden of HIV remains enormous. 
4.2.1 
HIV in sub-Saharan Africa 
While universal access to ART is a global ideal, in many regions of sub-Saharan 
Africa limited access undermines the prevention potential of widespread ART. 
Moreover, the costs and health care burden of delivering ever-increasing amounts 
of treatment in resource constrained settings pose significant challenges. In 
addition, while studies conducted over the past few years have confirmed the 
promise of antiretroviral chemoprophylaxis, it is well recognized that one way to 
eradicate a global viral epidemic is to design, mass produce, and then 
systematically immunize the target population with an effective prophylactic 
vaccine. Although the results of the RV144 trial are modest, these provide the 
first indications that a prophylactic vaccine can reduce HIV acquisition risk.  
Eastern and Southern Africa bears the preponderant burden of the HIV epidemic. 
With only 6.4% of the world’s population, this region harbors half of the world’s 
people living with HIV/AIDS and 46% of the world’s new infections occurred 
here in 2015. The vast majority of newly acquired infections in this region occur 
during unprotected heterosexual intercourse and subsequent transmission to 
newborns and breastfed babies. Approximately 910,000 new HIV infections 
occurred in Eastern and Southern Africa in 2015 [10]. These statistics give strong 
support to recent statements from top scientists and opinion leaders who have 
voiced the persistent unmet need for a preventive HIV vaccine [11]. 
4.2.2 
HIV in the United States 
Approximately 1.1 million people are living with HIV in the United States. 
Access to potent and safe ART has transformed a life-threatening disease into a 
manageable chronic condition for many of these individuals. Life expectancy has 
risen steadily, to the point where individuals, diagnosed early in infection and at a 
high CD4 count, may have a similar life-expectancy to the general population. 
Better tolerated treatment is now often provided as early as possible to reduce the 
contribution of HIV on non-AIDS related morbidity, and to prevent onward 
transmission.  
However, despite these advances in HIV care, HIV morbidity remains high and 
prevention efforts for the highest risk groups have had only partial success. There 
were an estimated 37,600 new infections in 2014, 45% of these in African 
Americans, and 24% in Hispanics/Latinos. 70% of new infections were estimated 
to be among men who have sex with men. It is unlikely that early treatment 

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strategies and the availability of pre-exposure prophylaxis alone will be able to 
stop this epidemic, and that therefore an effective vaccine will be essential. 
4.3 
Rationale for HVTN 120 
The P5 partnership is investigating new vaccine products and vaccination 
strategies in populations from the US and Sub-Saharan Africa. This will ensure 
the study of correlates of risk and protection is representative of the global HIV 
epidemic, resulting in the greatest impact on populations at risk in the US and 
globally. 
Based in large part on the success seen in the RV144 trial, the HVTN is 
conducting HIV vaccine studies in South Africa using a vaccine regimen that is 
similar to that tested in RV144. Two trials, designated HVTN 100 and HVTN 
702, are evaluating ALVAC-HIV (vCP2438) prime at months 0 and 1 followed 
with three boosts of ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59 
at months 3, 6, and 12. Based on HVTN 100 interim safety and immunogenicity 
from two weeks after the second boost a decision has been made to advance the 
same vaccine regimen into a pivotal efficacy trial. This pivotal trial, HVTN 702, 
opened to enrollment on 21-October-2016 in the Republic of South Africa. 
The ALVAC-HIV vector backbone in these trials is the same as was tested in 
RV144 but encodes a subtype C envelope, in lieu of the subtype E envelope, to 
better match the HIV subtype most prevalent in Southern Africa.  
HVTN 120 will compare the HVTN100/HVTN702 regimen (without a boost at 
Month 12) with two corresponding regimens containing the AS01B adjuvant, one 
at the same protein dose (100 mcg), and the other at a lower protein dose (20 
mcg). As such, HVTN 120 will generate supporting safety and immunological 
data regarding protein dose and adjuvant type in context of the HVTN 702 
regimen. Systematic evaluations of well-characterized adjuvant/immunogen 
formulations, such as proposed in HVTN 120, will aid in developing an HIV 
vaccine that can elicit and drive effective and durable functional immune 
responses against HIV. With that, results can help guide the way forward in the 
development of an efficacious preventative HIV vaccine regimen. Once the 
optimal dose and adjuvant have been determined, further trials, in a sequential 
manner, can be used to improve upon the current regimen. 
4.3.1 
Rationale for MF59 and AS01B adjuvantation  
A unique and scientifically compelling aspect of this trial design is the use of 
different adjuvants with the HIV envelope (Env) glycoproteins in the boosts. 
Adjuvants are known to enhance the potency, quality, and longevity of antigen-
specific immune responses [13], and the availability of novel commercial 
adjuvants that are potent and safe has been heralded as an important contribution 
that may advance HIV vaccines [14,15].  

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The MF59 adjuvant, an oil-in-water emulsion, is licensed for several flu vaccines 
in multiple countries, and in pre-clinical models [16] has demonstrated 
recruitment of antigen presenting cells and up-regulation of cytokines, 
chemokines, and receptors. The adjuvant has improved antibody affinity 
maturation [17], improving both epitope breadth and binding affinity, and elicits a 
balanced Th1 and Th2 response. It also increases T-cell proliferation by enhanced 
surface expression of MHC class II and co-stimulatory molecules [18]. 
Remarkably durable memory responses (T-cell and binding and neutralizing Ab 
responses) were induced by a DNA-prime/gp120 and MF59 boost regimen in 
HVTN 049 and HVTN 088. 
The Adjuvant System AS01 is a liposome-based class of adjuvants which 
contains 2 immunostimulants, 3-O-desacyl-4’-monophosphoryl lipid A (MPL) 
and QS-21 [19]. MPL is a non-toxic derivative of the lipopolysaccharide from 
Salmonella minnesota and is a TLR4 agonist [20]. It can stimulate NF-ĸB 
transcriptional activity and subsequent cytokine production [20]. MPL directly 
activates APCs such as dendritic cells (DCs) to produce cytokines and elevated 
levels of costimulatory molecules [21-23]. QS-21 is a natural saponin molecule 
extracted from the bark of the South American tree Quillaja saponaria Molina 
[24] (reviewed in [19,25]). The early evaluations of QS-21 as an adjuvant 
demonstrated that it could promote high Ag-specific Ab responses and CD8+ T-
cell responses in mice [26,27] and high Ag-specific Ab responses in humans [28]. 
However, specific receptors and signaling pathways induced by saponin-based 
adjuvants have yet to be clearly defined, most likely through the activation of the 
inflammasome as observed with QuilA [29]. AS01 has been selected in a number 
of human vaccine candidates because of its association with enhanced and durable 
immune responses, both humoral and cellular [19,30-38] and recently with 
protection against malaria in African children [30,31]. The ability of AS01 to 
improve adaptive immune responses was shown in mice to be linked to a transient 
stimulation of the innate immune system characterized by the induction of a 
specific pattern of cytokines and innate immune cell recruitment that occurred 
rapidly and transiently at the muscle injection site and draining lymph node 
postinjection, consistent with the rapid drainage of the vaccine components to the 
draining lymph node, and also linked to the generation of a high number and 
heterogeneous dendritic cell population in the draining lymph node that was 
efficient at priming T cells [39]. 
GSK PRO HIV-002 evaluated the gp120W6.1D 20 mcg / NefTat 20 mcg 
candidate HIV vaccine (clade B) formulated with 1 of 3 different Adjuvant 
Systems (AS02A, AS02V and AS01B) each in 60 healthy HIV-seronegative adults. 
The vaccine candidates were administered at month 0, month 1, month 3 and 
month 6. All vaccine formulations induced strong HIV-specific CD4+ T-cell 
responses characterized by high lymphoproliferative capacity and IL-2 production 
that were still detectable 18 months after the last immunization, with significantly 
stronger responses seen in the AS01B group (Figure 4-1 A and B). Broad coverage 
of CD4+ T-cell responses was demonstrated against gp120, and to a lesser extent 
Nef, derived from the most common circulating clades (B, C and circulating 
recombinant form [CRF]-01) (Figure 4-1 C showing AS01B responses).  

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Figure 4-1 CD4+ T cell responses following vaccination with the gp120/NefTat vaccine 
candidate formulated with 1 of 3 different Adjuvant Systems (AS02A, AS02V and AS01B) in 
study PRO HIV-002 
Strong antibody responses against gp120, Nef and Tat were observed in all 3 
groups. Responses were detected already after the second vaccine dose and 
peaked 2 weeks after the third or fourth vaccine dose.  
The demonstration of superior CD4+ T-cell induction by AS01B has guided 
selection of this Adjuvant System for further HIV vaccine evaluation [38]. CD4+ 
T-cell response rate and magnitude are widely applied, validated measures of HIV 
vaccine induced immunogenicity. CD4+ T-cell magnitude is also frequently 
correlated with the polyfunctionality score proposed by Lin et al, which has been 
identified as a correlate of risk in RV144 [40]. 
Retrospective testing of stored specimens from the GSK PRO HIV-002 clinical 
study that evaluated gp120W6.1D/NefTat in different Adjuvant Systems was 
performed in Dr. Georgia Tomaras’ lab, which had contributed to the correlate 
analysis of the RV144 trial. Samples collected at various timepoints from 30 
subjects vaccinated with gp120W6.1D (20 mcg) /NefTat/AS01B were tested. The 
analysis of the isotype-specific responses showed, after the vaccination all 
subjects had detectable IgG1 responses, and had detectable IgA against gp120 
vaccine protein [41].  
In all cases, IgG1 was found to have the highest serum concentration among the 
IgG subclasses (mean concentration of serum antibody to gp120 was 5 µg/ml). 
IgG2 vaccine-induced antibodies were detected in a minority (8/30, 27%) of 

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participants. When IgG3 and IgG4 vaccine-induced antibodies were detected, 
they were found in concentrations less than IgG2 vaccine-induced antibodies.  
The V1V2 specificity was also assessed and the results showed that after vaccine 
dose 3, 100% of the subjects had total anti-V1V2 concentrations comparable to 
the high levels seen in RV144 and that this response was persistent, with total IgG 
anti-V1V2 detected in 87% of the subjects 18 months after the administration of 
the last vaccine dose (4-dose schedule) (see Figure 4-2) [42].  
 
Figure 4-2 Total IgG Ab to gp70 V1V2 (Case A2, Clade B) elicited in GSK Pro HIV-002 and 
RV144 trials 
Vaccination with gp120W6.1D (AS01B) induces increased total IgG but not high 
IgG3 response magnitude and half-life. IgG3 V1V2 response rates and magnitude 
significantly declined 12-18 months post last boost (see Figure 4-3) [42]. 
 
Figure 4-3 IgG3 Ab to gp70 V1V2 (Case A2, Clade B) elicited in GSK Pro HIV-002 and RV144 
trials 
A subset of GSK PRO HIV-005 (Section 4.3.2) volunteers primed 3 years before 
with 2 doses of 10 mcg F4, which is a recombinant fusion protein containing 4 

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HIV-1 clade B antigens (Gag p24, Pol-RT, Nef, and Gag p17) adjuvanted with 
AS01B, received a booster dose of F4 10 mcg / AS01B (GSK ECR-004). Before 
the administration of the booster dose, all participants were still seropositive for 
anti-F4 antibodies and high levels of CD4+ T-cell responses were still detected. 
The F4/ AS01B booster induced strong F4-specific CD4+ T-cell responses, with 
similar frequencies and polyfunctional phenotypes as following primary 
vaccination, and high anti-F4 antibody concentrations, reaching higher levels than 
those following primary vaccination (see Figure 4-4) [33]. 
 
Figure 4-4 CD4+ T cell and antibody responses following primary and booster doses of the 
F4 / AS01B vaccine candidate in studies PRO HIV-005 and ECR-004. 
4.3.2 
Rationale for 2 protein doses with AS01B (20 mcg vs. 100 mcg) 
There are only limited data available evaluating differences in immune responses 
with varying doses of Env proteins in the context of a common adjuvant and co-
administration with a common ALVAC-HIV. Study RV135 evaluated the 
immune responses to a regimen identical to the one used in RV144 but utilizing 
two different doses of Env proteins (either 200 mcg or 600 mcg total [100 or 300 
each of MN and A244 proteins]), both adjuvanted with Alum and given in 
combination with ALVAC-HIV (vCP1521) as a boost. 
In RV135, humoral immune response assessments included Env binding and 
neutralizing antibody titers. Study participants receiving 200 mcg of AIDSVAX 
B/E had lower anti-MN and anti-A244 antibody response rates (95% and 86%, 
respectively) at peak immunogenicity (2 weeks after the fourth immunization) 
compared to participants receiving 600 mcg of AIDSVAX B/E (100% and 96%, 
respectively). Geometric mean titers (GMT) of antibodies to MN and A244 were 
also lower overall for participants in the lower dose group (3744 and 596, 
respectively) compared to the higher dose group (7730 and 1691, respectively). 
Similarly, neutralization titers indicated a dose-dependent humoral response to 
AIDSVAX B/E, with 47% of lower dose recipients and 71% of higher dose 
recipients showing neutralizing antibodies to either of two CRF01_AE targets 
(NP03/H9 or CM244/A3R5).  

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There are no studies evaluating differences in immune responses with varying 
doses of Env proteins in the context of ALVAC prime-boost and protein 
adjuvantation with MF59, AS01 or AS02 (oil-in-water emulsion of a combination 
of MPL and QS-21). However, there are trials evaluating different doses of AS01 
adjuvanted proteins without viral vectors. 
Clinical trials assessing gp120 with a GSK Adjuvant System provide evidence 
that an Env protein with AS01B can elicit strong humoral and cellular responses. 
Currently, it is unclear whether too high a protein dose in the presence of the 
AS01B adjuvant leads to suboptimal vaccine responses. 
HVTN 041 evaluated a combination vaccine (NefTat and gp120W6.1D) 
formulated with AS02A administered at 0, 1 and 3 months with varying doses (5, 
20 and 100 mcg in 20 subjects each) of the gp120 vaccine component (the NefTat 
antigen dose was constant at 20mcg). The vaccine was safe and well tolerated at 
all dose amounts and Nef-, Tat-, and gp120-specific binding antibodies were 
induced in all individuals that received the respective antigen, lasting up to 9 
months after the final immunization (Figure 4-5).  
 
Figure 4-5 Kinetic of binding IgG antibodies induced by the NefTat/gp120/AS02A vaccine 
candidate in study HVTN 041 
Antibodies able to neutralize the T-cell laboratory-adapted strain of HIV-
1gp120W6.1D were detected in the majority of vaccinees, but did not neutralize 
primary isolates. Envelope specific ADCC was detected in most of the individuals 
receiving gp120. Robust and persistent HIV-specific lymphoproliferative 
responses were detected against all subunits proteins in the majority of 
immunized participants. Most immune responses were similar across all doses, 
except for a significant dampening effect on the CD4+ T-cell responses occurring 
at the highest gp120 dose (100 mcg) measured by lymphoproliferative and ICS 
assays [36] (see Figure 4-6).  

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Figure 4-6 gp120-specific CD4+ T cell responses (IFN- and/or IL-2) induced by the 
NefTat/gp120/AS02A vaccine candidate in study HVTN 041 
GSK PRO HIV-005 evaluated an HIV vaccine candidate consisting of a 
recombinant fusion protein (F4) containing 4 HIV-1 clade B antigens (Gag p24, 
Pol-RT, Nef, and Gag p17) adjuvanted with AS01B in 3 different doses: 10, 30, 
and 90 mcg. Each dose of the AS01B-adjuvanted vaccine candidate was 
administered twice in a group of 50 subjects, following a month 0 and month 1 
schedule. Three control groups of 10 subjects received a dose of 10, 30 or 90 mcg 
without AS01B. The 10 mcg AS01B-dose elicited a statistically significantly 
higher CD4+ T-cell response as compared to the other doses (p < 0.0001 at 2 
weeks post second vaccination), while anti-F4 IgG responses were elicited in 
100% of vaccinees with no significant difference in GMC titers amongst the 
groups [43].  
Combined together, data from HVTN 041 and GSK PRO HIV-005 have been 
used to generate the hypothesis that a higher dose of gp120 may dampen resulting 
CD4+ T-cell responses. However, as stated above, there are no data evaluating 
differences in immune responses with varying doses of Env proteins in the 
context of ALVAC prime and a boost of ALVAC co-administered with protein 
adjuvanted with MF59 or AS01. HVTN 120 will provide the direct comparison of 
different doses of gp120 adjuvanted with AS01B in the context of ALVAC prime-
boost and another study (HVTN 108) will provide this direct comparison in the 
context of DNA prime-boost, DNA co-administration, and gp120 alone. 
4.4 
Study product descriptions 
4.4.1 
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 

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C), env gp41 TM (clade B), gag (clade B), and protease (clade B) coding 
sequences and cultured in primary chicken embryo fibroblasts (CEFs). 
4.4.1.1 
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 ALVAC-HIV 
(vCP2438) Investigator’s Brochure (IB). 
The inserted HIV-1 gene sequences are:  
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. 
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 
4.4.1.2 
Formulation characteristics 
ALVAC-HIV (vCP2438) is formulated as a lyophilized vaccine for injection and 
is reconstituted with 1 mL of sterile sodium chloride solution (NaCl 0.4%) for 
injection of 1 mL as a single dose. The composition of 1 dose of ALVAC-HIV 
(vCP2438) is provided in Table 4-2. 

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Table 4-2 Composition of ALVAC-HIV (vCP2438) 
Ingredient 
Amount in 1 dose 
Function 
ALVAC-HIV (vCP2438) 
≥ 1 x 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 
HCl 
1.75 mg 
Component of freeze-drying stabilizer 
4.4.1.3 
Manufacturing 
ALVAC-HIV (vCP2438) Bulk Drug Substance is manufactured by IDT 
Biologika GmbH, Am Pharmapark, Dessau-Rosslau, Germany, under contract to 
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 virus seed into cultured 
primary CEFs derived from eggs produced by specific pathogen free (SPF) flocks. 
The manufacturing process for ALVAC-HIV (vCP2438) is similar to the 
manufacturing process for ALVAC-HIV (vCP1521) used in RV144. 
4.4.2 
Bivalent Subtype C gp120 
4.4.2.1 
Constructs 
Bivalent Subtype C gp120, manufactured by GSK Vaccines at Rentschler 
Biotechnologie (Laupheim, Germany), consists of 2 separate subtype C 
recombinant monomeric proteins, TV1.C gp120 and 1086.C gp120. These 
recombinant gp120s represent the HIV Env surface glycoprotein containing the 
receptor-binding domain. 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.  

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4.4.2.2 
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 as described in the following paragraph. 
Following clone selection, a fed batch cell culture at 500 L or 1000 L scale is 
employed for cell propagation. Once the cells reach optimum cell density, the 
culture is harvested and purified using standard methods. Harvest clarification 
was performed using a series of depth filters followed by bioburden reduction 
using a sterilizing-grade filter. The harvest was collected in single use disposable 
bags and purified including further enrichment for monomer. Additional 
processing utilizes multiple filtration steps and a series of chromatography steps 
that remove process related impurities. 
Both TV1.C and 1086.C bulk drug substances are stored frozen at -61°C or 
colder. The formulations are similar for both drug substances, containing Env 
antigen, sodium citrate, and sodium chloride, pH 6.5-7.0. Each of the HIV gp120 
proteins as final products are tested for pH, appearance, identity, strength 
(concentration), purity, potency, as well as safety and content uniformity 
following US Pharmacopoeia methods where applicable. 
The qualitative 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 
Bivalent Subtype C gp120/MF59 for injection 
The combination of the 2 subtype C gp120 proteins and the MF59 adjuvant is 
referred to as Bivalent Subtype C gp120/MF59. A final dose of 100 mcg of each 
recombinant Env protein will be mixed with MF59 adjuvant. The composition of 
1 dose of the resulting vaccine is shown in Table 4-4. 

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Table 4-4 Composition of 0.5 mL dose of Bivalent Subtype C gp120/MF59 for injection 
Ingredient  
Amount in1 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  
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  
4.4.4 
Bivalent Subtype C gp120/AS01B for injection 
The combination of the 2 subtype C gp120 proteins and the AS01B adjuvant is 
referred to as Bivalent Subtype C gp120/AS01B. A final dose of 20mcg of each 
recombinant Env protein will be mixed with AS01B adjuvant and a final dose of 
100mcg of each recombinant Env protein will be mixed with AS01B adjuvant. 
The compositions of 1 dose of each of the resulting vaccines are shown in Table 
4-5 and Table 4-6. 
Table 4-5 Composition of 0.75 mL dose of Bivalent Subtype C gp120/AS01B for injection with 20 
mcg of each gp120 protein 
Ingredient  
Amount in 
one dose  
Function  
Drug Substances  
TV1.C gp120 protein  
20 mcg  
active  
1086.C gp120 protein 
20 mcg 
active 
Adjuvant (AS01B)  
Liposome 
 
Vesicles for MPL and QS-21 
MPL 
50 mcg 
 
Immunoenhancer  
QS21 
50 mcg 
Immunoenhancer 
Excipients  
Sodium citrate, dihydrate 
0.07 mg 
buffer 
Citric acid, monohydrate 
<0.01 mg 
buffer 
Sodium chloride 
7.06 mg 
tonicity modifying agent 
Sodium phosphate dibasic (Na2HPO4) 
0.15 mg 
buffer 
Potassium phosphate monobasic (KH2PO4) 
0.54 mg 
buffer 
Water for injection 
q.s. ad 0.75 mL 
solvent 

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Table 4-6 Composition of 0.75 mL dose of Bivalent Subtype C gp120/AS01B for injection with 100 
mcg of each gp120 protein 
Ingredient  
Amount in 
one dose  
Function  
Drug Substances  
TV1.C gp120 protein  
100 mcg  
active  
1086.C gp120 protein 
100 mcg 
active 
Adjuvant (AS01B)  
Liposome 
 
Vesicles for MPL and QS-21 
MPL 
50 mcg 
 
Immunoenhancer  
QS21 
50 mcg 
Immunoenhancer 
Excipients  
Sodium citrate, dihydrate 
0.34 mg 
buffer 
Citric acid, monohydrate 
0.02 mg 
buffer 
Sodium chloride 
8.77 mg 
tonicity modifying agent 
Sodium phosphate dibasic (Na2HPO4) 
0.15 mg 
buffer 
Potassium phosphate monobasic (KH2PO4) 
0.54 mg 
buffer 
Water for injection 
q.s. ad 0.75 mL 
solvent 
4.5 
Trial design rationale 
HVTN 120 has 3 active groups and 1 placebo group. The study will compare 
ALVAC priming at months 0 and 1 followed by ALVAC + Protein boosting at 
months 3 and 6. Group 1 will evaluate a protein dose of 100 mcg, adjuvanted with 
MF59, which represents the regimen applied in HVTN 100 and HVTN 702. 
Group 2 will evaluate the same protein dose, with the AS01B adjuvant. Group 3 
will evaluate the proteins at a lower dose of 20 mcg, adjuvanted with AS01B. This 
approach can help to determine the protein dose and the adjuvant that can elicit 
the most promising immune responses in the context of the ALVAC + protein 
regimen, and as such can pave the way to potentially improve upon this already 
promising vaccine regimen. The placebo group is primarily included to provide 
controls for immunological endpoints. 
4.5.1 
Dose rationale 
4.5.1.1 
ALVAC-HIV (vCP2438) dose 
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 the same ALVAC-HIV dose that was used for the RV144 
study. 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. 

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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 [44]. The high-dose ALVAC-HIV 
(vCP1452) resulted in unacceptable levels of reactogenicity, without evidence of 
improved 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.  
4.5.1.2 
Bivalent Subtype C gp120/MF59 dose 
For the Bivalent Subtype C gp120/MF59 vaccine component, 100 mcg each of 
the 2 gp120 subtype C proteins (TV1 gp120 and 1086 gp120) will be mixed 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 was selected based on previous clinical experience with 
similar proteins. 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, totaling 150 mcg, doses with MF59 adjuvant were 
immunogenic and well tolerated [45]. Bivalent Subtype C gp120/MF59 vaccine 
has been administered to humans in HVTN 100 and interim data are summarized 
in 4.7.2. For a detailed overview on previous human experience with MF59 and 
similar protein vaccines, see Section 4.7.6. 
4.5.1.3 
Bivalent Subtype C gp120/AS01B dose 
For the Bivalent Subtype C gp120/AS01B vaccine component, 100 mcg or 20 mcg 
each of the 2 gp120 subtype C proteins (TV1 gp120 and 1086 gp120) will be 
mixed with the adjuvant by the Pharmacist at each CRS prior to IM 
administration. This dose comparison is supported by previous data obtained by 
GSK showing that protein doses that are too high may lead to suboptimal vaccine 
responses. This specific combination of Bivalent Subtype C gp120/AS01B at both 
doses will also be evaluated in combination with an HIV clade C DNA vaccine in 
another trial, HVTN 108. As of 09 December 2017, HVTN 108 has enrolled 246 
participants. The study is still blinded, but approximately 78% of participants will 
receive Bivalent Subtype C gp120/AS01B. So far, there have been no related 
serious adverse events. 13 adverse events have been deemed related to study 
product, 11 mild and 2 moderate. There have been 2 cases of grade 3 fever, and 3 

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cases of grade 4 fever, and 12 cases of other grade 3 systemic reactions, all self-
limiting, as well as 5 cases of grade 3 erythema/induration, all self-limiting. 
4.5.2 
Schedule 
The vaccination schedule of the regimens in this study is based upon the 
schedules used in RV144, HVTN 100, and HVTN 702.  
4.5.3 
Rationale for the adaptive and mucosal sampling timepoints 
Examining the effects that the two adjuvants have on a variety of immune 
responses relative to each other is an important goal of this study. Adjuvants may 
influence antigen delivery, presentation, and immune responses and the 
constitution of the microbiome may influence immune responses in the context of 
either adjuvant. 
Systemic adaptive immune responses will be measured in samples collected at 
day 0 prior to vaccination, month 3.5 (2 weeks following the third vaccination), 
month 6.25 (1 week following the fourth vaccination), and month 6.5 (2 weeks 
following the fourth vaccination). These samples will provide both baseline and 
postvaccine information.  
Mucosal samples collected at day 0 provide the baseline values prior to 
vaccination while those collected at month 6.5 (2 weeks following the final 
vaccination), provide data on peak vaccine-induced systemic and mucosal 
adaptive immune responses.  
Finally, collection at month 12 will provide the opportunity to assess the 
durability of systemic and mucosal immune responses 6 months after the last 
vaccination. 
4.5.4 
Choice of placebo 
Sodium Chloride for Injection, 0.9% will be administered as a placebo for 
ALVAC-HIV.  
Sodium Chloride for Injection, 0.9% will also serve as a placebo for the Bivalent 
Subtype C gp120/MF59 and Bivalent Subtype C gp120/AS01B vaccines. These 
placebos are necessary to maintain blinding as Protein/AS01B and Protein/MF59 
consist of different injection volumes. 
4.6 
Summary of preclinical safety studies 
4.6.1 
ALVAC-HIV (vCP2438) 
The toxicity studies described in Sections 4.6.1.1 and 4.6.1.2 were originally 
designed to match a different clinical trial protocol that included additional 

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vaccine regimens with the DNA-HIV-PT123 study product. However, the vaccine 
regimens relevant to HVTN 120 were also evaluated, therefore, the resulting data 
summaries from these studies have been included. 
4.6.1.1 
Intramuscular 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 
intramuscular route to New Zealand White Rabbits 7 or six times, respectively, at 
two-week intervals, followed by a two-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 first injection but returned to 
normal with 48 hours. There were no effects of treatment on body weight or 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 haematological 
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 that 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, seven 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. 

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4.6.1.2 
DNA-HIV-PT123 + ALVAC/Bivalent Subtype C gp120 with MF59C.1 or 
AS01B and ALVAC/Bivalent Subtype C gp120 with AS01B – Intramuscular 
local tolerability and systemic toxicity (repeated dose, total of 7 doses) 
study in the New Zealand White rabbit (Study No. AB20850) 
A GLP local tolerance and toxicity study in rabbits was conducted to evaluate the 
potential toxicity of vaccine regimens consisting of the combination of DNA-
HIV-PT123, ALVAC-HIV (vCP2438), and Bivalent Subtype C gp120 with MF59 
or AS01B. 
The test formulations were administered every other week (i.e., days 1, 15, 29, 43, 
57, 71 and 85) during the study via intramuscular injection into the quadriceps 
muscle for all groups.  
Animals were subjected to a full macroscopic examination at necropsy 
(5/group/sex) on day 87 and on day 99 following a two week no-treatment 
recovery period.  
Parameters evaluated during the study period included mortality, clinical and 
cage-side observations, dermal injection site observations, body weights, body 
temperatures, food consumption, ophthalmology, clinical pathology, 
immunogenicity, macroscopic pathology, absolute and relative organ weights, and 
histopathology.  
All animals survived to their scheduled necropsies. Treatment with DNA-HIV-
PT123 + ALVAC/Bivalent Subtype C gp120 administered with MF59C.1 or 
AS01B adjuvant, as well as ALVAC/Bivalent Subtype C gp120 administered with 
AS01B adjuvant was well tolerated and there were no effects on systemic clinical 
observations or local reactions, body weight, food consumption, and 
ophthalmological evaluations. 
Limited and transient increases in body temperature were noted in some animals 
mainly following ALVAC administration. Reversible treatment-related clinical 
pathology changes indicative of inflammatory reaction consisted of increased 
neutrophil counts, slightly elevated fibrinogen concentration, increased CRP and 
globulin concentrations. Consistent with these changes, and the immune response 
to vaccination, findings were observed histopathologically at the injection sites 
and in the spleen and draining iliolumbar lymph nodes.  
At the injection sites, histopathological changes consisted of hemorrhage, 
inflammatory changes (mixed inflammatory cell infiltration) and myofiber 
degeneration in the muscular tissue in almost all treated rabbits, which accounted 
for the dark appearance of the injection sites noted in some treated rabbits. 
Additional test item-related histopathological changes, such as granulomatous 
changes and presence of foreign material in the injected muscle, were at a low 
incidence. In the draining iliolumbar lymph nodes, there was a test item-related 
increase in development of the lymphoid follicles and paracortical/medullary 
region. In the spleen, there was a test item-related increase in development of 

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lymphoid follicles, which accounted for the increased spleen weight. These 
findings were partially reversible on day 99, two weeks after the last 
administration. There were no relevant differences in the incidence and severity of 
the test item-related changes between the left and right quadriceps muscles and 
between the corresponding draining lymph nodes and between the treatment 
regimens.  
Results of immunogenicity testing confirmed that all sera analyzed from animals 
receiving the DNA vaccines with gp120/MF59C.1 or gp120/AS01B and the 
ALVAC vaccine with gp120/AS01B contained specific antibodies to each 1086.C 
and TV1.C gp120 protein.  
In conclusion, three intramuscular administrations of DNA-HIV PT123 vaccine 
with gp120s/MF59C.1 (group 2) or with gp120s/AS01B (group 4) or of ALVAC 
vaccine alone (group 3) at two-week intervals followed by four intramuscular 
administrations of ALVAC associated with gp120s/MF59C.1 (group 2) or with 
gp120s/AS01B (groups 3 and 4), at two-week intervals, to the NZW Rabbit were 
clinically and locally well tolerated with only slight and partially reversible 
microscopic inflammatory findings at the injection sites. Changes in draining 
lymph node and spleen that correlated with inflammation and/or the immune 
response to vaccination. There were no treatment related effects on body weight 
or food consumption. Limited and transient increases in body temperature were 
noted in some animals mainly following ALVAC administration. Clinical 
pathology findings were limited to signs of inflammation, such as increased 
neutrophil counts, CRP, globulin levels, and fibrinogen.  
The sera of all treated animals contained specific antibodies to each protein 
(1086.C and TV1.C gp120) with no obvious differences between groups. 
4.6.1.3 
Other supportive nonclinical safety studies 
In addition to the nonclinical safety study summarized above, the nonclinical 
safety data from a variety of ALVAC constructs further inform the safety profile 
of ALVAC-HIV (vCP2438). These studies include the following: 
▪ Platform biodistribution study of ALVAC-HIV in rats; 
▪ ALVAC viral replication in different cell lines; 
▪ Virulence of the ALVAC vector versus Vaccinia strains; 
▪ Single dose toxicity studies by intravenous route with various ALVAC 
recombinants in mice and rats; 
▪ Repeated dose toxicity studies using several routes of administration 
(including IM) with various ALVAC recombinants in cynomolgus and 
rhesus monkeys; 
▪ Local tolerance and sensitization studies with various ALVAC 
recombinants in rabbits; and  
▪ 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. 
4.6.2 
Toxicity studies of HIV Env vaccines  
The nonclinical safety of 4 doses of the gp120 proteins included in HVTN 120 
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 4.6.1.1. Overall, the 
immunizations were clinically and locally well tolerated. 
The nonclinical safety of 6 doses of the gp120 proteins included in HVTN 120 
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 CRP 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 that 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. 
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 1 of the components 
(TV1 gp120) in the proposed Bivalent Subtype C gp120/MF59 vaccine, and 
hence is very similar in sequence. Overall, toxicology studies revealed 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:  
• Subchronic IM toxicity study of Biocine® HIV Thai E gp120/SF 2 gp120 
vaccine in rabbits 
• Repeat dose toxicity of IM HIV DNA/PLG prime followed by IM subtype B 
gp140/MF59 in rabbits 
• Repeat dose toxicity of intranasal (IN) subtype B gp140 with an LTK63 
adjuvant followed by IM subtype B gp140 with MF59 in rabbits 
• Repeat dose toxicity of IM SAAVI DNA-C2 followed by IM SAAVI MVA-C 
with subtype C gp140/ MF59 in rabbits 
4.6.3 
Toxicity studies of MF59  
The nonclinical safety of MF59 co-administered with the gp120 proteins included 
in HVTN 120 in the context of ALVAC-HIV (vCP2438) or DNA-HIV-PT123 
was evaluated in study AB20670 as described in sections 4.6.1.1 and 4.6.1.2 and 
4.6.2. 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 - 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) [46].  
4.6.4 
Toxicity studies of AS01B 
Toxicology studies performed with AS01B included: 
• Repeated dose studies (Rabbit, Rat) 
• Local tolerance studies (Rabbit) 
• Safety/pharmacology studies (Rat, Dog) 
• Genotoxicity (micronucleus) studies (Rat) 
The pre-clinical toxicity studies indicated that no treatment-related systemic 
toxicity was associated with single or repeated IM injection of AS01B, alone or in 
combination with antigens. In addition, no adverse treatment-related effects on 

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male mating performance, fertility, early embryonic development, pre- and 
postnatal survival, growth or development of the offspring up to day 25 of age 
were associated with repeated IM injection of AS01B, alone or in combination 
with antigens. AS01B was considered safe with regard to cardio-respiratory side 
effects in two different animal species. Moreover, single or repeated IM injection 
of AS01B did not adversely affect RBC production in the bone marrow. The only 
treatment-related effects of vaccine administration were mild local injection site 
reactions. Hematology parameters such as increased WBC and neutrophil counts, 
both related to the local inflammation reaction, were transiently affected. 
Details of these studies and more information are included in the Bivalent 
Subtype C gp120/AS01B IB. 
4.6.5 
Dose-range Immunogenicity study of Bivalent Clade C gp120 (TV1.C 
and 1086) / AS01B in mice 
The objective of this experiment was to assess the dose response relationship of 
bivalent Clade C gp120 (TV1.C and 1086) antigens in CB6F1 mice when 
formulated in combination with AS01B, in terms of antigen-specific cellular and 
humoral responses. Animals were immunized intramuscularly on day 0, 14, and 
28 with 10 mcg, 2 mcg, 0.4 mcg, or 0.08 mcg of bivalent (TV1.C and 1086) 
gp120 antigens formulated with 50 mcL of AS01B. The induced T cell and 
antibody responses were characterized at 7 and 14 days post third dose, 
respectively. 
The Bivalent Subtype C gp120/AS01B vaccine formulation elicited 1086C and 
TV1.C-specific CD4+ T cell responses for all tested doses. No statistically 
significant differences were observed between doses, however, a trend for higher 
1086C-specific CD4+ T cell responses was observed with lower doses of 1086-
TV1.C / AS01B (Figure 4-7-Panel A). This was not observed when measuring the 
TV1.C-specific CD4+ T cell responses (Figure 4-7-Panel B). The vaccine-
induced CD8+ T cell responses at 7 days after third immunization were low to 
undetectable for both, TV1 and 1086 responses. The Bivalent Subtype C gp120 
antigens adjuvanted in AS01B induced dose-dependent high levels of 1086C and 
TV1.C-specific antibody responses at 14 days post second and third immunization 
(Figure 4-7-Panel C). Moreover, for all antigen doses tested, similar levels of 
1086C and TV1.C specific total immunoglobulin (Ig) responses were observed, 
suggesting that there is no negative impact on the humoral responses when 
combining 1086C and TV1.C antigens in AS01B. Anti-V1V2 total Ig responses 
were also detected in all the groups (Figure 4-7-Panel D). 

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Figure 4-7: Immunogenicity of Bivalent Subtype C gp120 (TV1.C and 1086.C)/AS01B in 
CB6F1 mice.  
Animals were intramuscularly immunized with 10 μg, 2 μg, 0.4 μg or 0.08 μg of bivalent (TV1 and 
1086) antigen formulated in 50 μL of AS01B at days 0, 14 and 28. Percentage of CD4+ T cells 
secreting IFN-g and/or IL-2 and/or TNFα was measured at 7 days post-third immunization (Panels 
A and B). Intracellular staining performed on peripheral blood lymphocytes after a 6-hour re-

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stimulation with TV1 and 1086 clade C gp120 antigens. 4 pools of 6 mice with median are 
represented. Anti-TV1 and anti-1086 (Panel C) and anti-gp70-V1V2 (Clade B/Case A2) (Panel D) 
binding antibody titers measured by ELISA 14 days post-third immunization (Blue dots=14 days 
post-dose 2; Red dots=14 days post-dose 3). 
4.6.6 
Evaluation of the need for using an adjuvant system to induce potent 
bivalent Subtype C gp120 (1086.C & TV1.C)-specific binding 
antibodies and cellular responses in CB6F1 mice (20150024) 
To assess the need for an adjuvant system to elicit potent binding antibody and 
CD4+ T cell responses, the immunogenicity of the bivalent 1086.C & TV1.C 
gp120 antigens was characterized following immunization of CB6F1 mice 
(hybrid of C57Bl/6 and BALB/C mice) with 2 μg of each gp120 antigens, without 
adjuvant or formulated with 50 μg Al(OH)3 or 50 μL AS01B (containing 5 μg 
MPL and 5 μg QS-21 Stimulon® in a liposome-based formulation). Animals 
received IM injections at days 0, 14 and 28, and the T cell and antibody responses 
were characterized at 14 days post-second and third dose. The non-adjuvanted 
bivalent 1086.C & TV1.C gp120 antigens elicited detectable but low levels of 
binding antibodies with geometric mean titers (GMT) of 1973 and 1145, 
respectively, at 14 days post-third dose (Figure 4-8, A and B). Al(OH)3 
formulation significantly increased the binding antibody titers up to 8807 (anti-
1086.C GMT) and 4698 (anti-TV1.C GMT) and the AS01B-based formulation 
elicited the highest binding antibody responses reaching anti-1086.C and anti-
TV1.C binding antibody titers of 32936 and 31860 respectively (GMTs) (Figure 
4-8, A and B). Post-third immunization, cross-reactive anti-V1V2 binding 
antibody responses (gp70- V1V2 scaffold Subtype B/Case A2) were detected with 
the strongest titers measured when the bivalent Subtype C gp120 antigens were 
formulated with AS01B, although some animals remained negative (Figure 4-8, 
C). 
Very low to undetectable 1086.C- and TV1.C-specific CD4+ T cell responses 
were measured at 14 days post-third immunization with the bivalent Subtype C 
gp120 antigens alone or formulated with Al(OH)3. In contrast, the bivalent 
Subtype C gp120/AS01B formulation elicited robust 1086.C- and TV1.C-specific 
CD4+ T cell responses (medians of 1% and 0.75% respectively) 14 days post-
third dose (Figure 4-9). All together these data show that the bivalent Subtype C 
gp120 antigens (1086.C & TV1.C, 2 μg each) formulated with AS01B elicit potent 
1086.C & TV1.C gp120-specific antibody and CD4+ T cell responses in CB6F1 
mice, with higher intensities as compared to Al(OH)3 or non-adjuvanted 
formulations, supporting the use of AS01B for further clinical development. 

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Figure 4-8 Antibody responses induced by Bivalent Subtype C gp120 (1086.C and TV1.C) 
with or without Aluminum hydroxide or AS01B in CB6F1 mice.  
Animals were immunized intramuscularly on day 0, 14 and 28 with 2 μg of each gp120 (1086.C & 
TV1.C) alone or formulated with 50 μg of Al(OH)3 or 50 μL AS01B. (A) anti-1086.C and (B) anti-
TV1.C IgG binding antibody titers measured by ELISA 14 days post-second (blue) and third (red) 
immunization. (C) Anti-gp70-V1V2 (Subtype B/Case A2) binding antibodies measured by ELISA at 
14 days post-third dose. Each dot corresponds to individual animals. Statistical analysis: Analysis 
of variance (ANOVA), with multiplicity adjustment. 

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Figure 4-9 CD4+ T cell responses induced by Bivalent Subtype C gp120 (1086.C and TV1.C) 
with or without Aluminum hydroxide or AS01B in CB6F1 mice.  
Animals were immunized intramuscularly on day 0, 14 and 28 with 2 μg of each gp120 (1086.C & 
TV1.C) alone or formulated with 50 μg of Al(OH)3 or 50 μL AS01B. Percentage of (A) 1086.C- and 
(B) TV1.C-specific CD4+ T cells secreting IFN- γ and/or IL-2 and/or TNF-α were measured at 14 
days post-third immunization. Intracellular staining was performed on splenocytes after a 6-hour re-
stimulation with 1086 and TV1 Subtype C gp120 antigens. 5 individual animals with medians are 
represented. 
4.6.7 
Head to head immunogenicity comparison of the MF59 and AS01B 
adjuvant systems to formulate the bivalent Subtype C gp120 
antigens in CB6 F1 mice: Acute and persistent responses (20150168) 
The immunogenicity of the bivalent 1086.C & TV1.C gp120 Tox lots was 
characterized following immunization of CB6F1 mice (hybrid of C57Bl/6 and 
BALB/C mice) with a dose range of gp120 antigens (0.4 μg, 2 μg or 10 μg each), 
formulated with either 50 μL MF59 or 50 μL AS01B. As a benchmark, mice were 
immunized with 2 μg of the consolidation lots of the bivalent Subtype C gp120 
formulated with 50 μL AS01B. Animals received IM injections at days 0, 14 and 
28, and the T cell and antibody responses were monitored at 7 days or 14 days 
post-third dose respectively. The bivalent Subtype C gp120 formulated in AS01B 
elicited potent 1086.C- and TV1.C-specific CD4+ T cell responses according to 
an inverse dose-range, suggesting that a high amount of antigen may trigger 
regulatory mechanisms leading to a decreased intensity of the induced-CD4+ T 
cell responses (Figure 4-10, A and B). In contrast, very low to undetectable 
gp120-specific CD4+ T cell responses were measured following immunizations 
with the bivalent Subtype C gp120 formulated in MF59. At 2.5 months post 
immunization, bivalent Subtype C gp120s-specific CD4+ T cells were still 
detectable (frequencies of ~0.5%) in animals immunized with the AS01B-based 
formulations (Figure 11, A and B). 
The bivalent Subtype C gp120 antigens formulated in AS01B or MF59 induced 
dose dependent high levels of anti-1086.C and TV1.C antibody responses at 14 
days post third immunization (Figure 4-10, C and D). The intensities of both anti-
1086.C and TV1.C antibody responses were statistically significantly higher after 
immunization with the AS01B-based formulations as compared to MF59-based 

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formulations at all gp120 doses tested. Interestingly, very good persistence was 
observed for the anti-1086.C and TV1.C binding antibody responses at 2 months 
post-last immunization, with both adjuvant systems tested (MF59 and AS01B) and 
these responses were still statistically significantly higher for the AS01B 
formulations as compared to the MF59 formulations (Figure 4-11). All together, 
these data show that the bivalent Subtype C gp120 antigens (1086.C & TV1.C) 
formulated with AS01B elicit potent 1086.C & TV1.C gp120-specific antibody 
and CD4+ T cell responses with higher intensities than MF59-based formulations 
in CB6F1mice. 
 
Figure 4-10 Immunogenicity of Bivalent Subtype C gp120 (TV1.C and 1086.C) formulated in 
AS01B or MF59 in CB6F1 mice.  
Animals were intramuscularly immunized with 10 μg, 2 μg, or 0.4 μg of bivalent (1086.C & TV1.C) 
gp120 antigens (Tox lots 1023719 and 1023444) formulated in 50 μL of AS01B or 50 μL MF59 at 
days 0, 14 and 28. An additional group of mice was immunized with 2 μg of the gp120 
consolidation lots (1086.C CR02 and TV1.C CR04) formulated in 50 μL AS01B as a control. 
Percentage of 1086.C- (A) and TV1.C- (B) specific CD4+ T cells secreting IFN-g and/or IL-2 and/or 
TNF-α was measured at 7 days post-third immunization. Intracellular staining performed on 
peripheral blood lymphocytes after a 6-hour re-stimulation with 1086.C and TV1.C gp120 antigens. 
5 pools of 7 mice with medians are represented. Anti-1086.C (C) and TV1.C (D) binding antibody 
titers measured by ELISA 14 days post-third immunization. Each dot corresponds to individual 
animals for antibodies. Statistical analysis: Analysis of variance (ANOVA), with multiplicity 
adjustment. 

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Figure 4-11 Persistence of the CD4+ T cell and binding antibody responses induced by the 
Bivalent Subtype C gp120s (TV1.C and 1086.C) formulated in AS01B or MF59 in CB6F1 mice, 
2 months post-last dose.  
Percentage of 1086.C- (A) and TV1.C- (B) specific CD4+ T cells secreting IFN-γ and/or IL-2 and/or 
TNFα was measured at 77 days post-third immunization. Intracellular staining performed on PBLs 
after a 6-hour re-stimulation with 1086.C and TV1.C gp120 antigens. 5 pools of 7 mice with 
medians are represented. Anti-1086.C (C) and TV1.C (D) binding antibody titers measured by 
ELISA 77 days post-third immunization. Each dot corresponds to individual animals (N=20/group) 
and geometric means with 95% CI are represented. Statistical analysis: Analysis of variance 
(ANOVA), with multiplicity adjustment. 
4.7 
Clinical studies 
4.7.1 
Clinical studies with ALVAC-HIV 
The proposed ALVAC-HIV vaccine candidate specific for Southern Africa is 
ALVAC-HIV (vCP2438). The vaccine is very similar to ALVAC-HIV (vCP1521) 
(the ALVAC-HIV used in the RV144 trial) since it contains the same gag, pro 
and gp41 env TM components. However, it has been adapted to include 96ZM651 
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.  
4.7.2 
HVTN 100 
HVTN 100 enrolled 252 participants (210 received vaccine and 42 placebo) 
between February and May 2015. All month 12 injections were completed by 2 
June 2016.  

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4.7.2.1 
Interim summary of blinded safety and tolerability data 
Blinded safety data reported as of July 7, 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 were 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 
were 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 (at injection timepoint #1) and for a 
right deltoid injection by 2 participants (1 at injection timepoint #3 and 1 at 
injection timepoint #5).  
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 
fourth 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 fifth 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 fifth 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 inches long, consistent with 
weight-based guidance for needle length choice provided to sites in the SSPs 
[47,48].  
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 

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moderate intensity has been reported in a total of 19% of participants; 7% 
reported systemic symptoms of moderate intensity after the first injection, 3% 
after the second, 5% after the third, 2% after the fourth and 5% after the fifth. 
Severe systemic reactions, have occurred in 2% of participants (4 participants): 2 
participants with severe arthralgia occurring after the first injection, 1 person with 
severe malaise and/or fatigue and 1 with severe headache, each after the fifth 
injection. 
4.7.2.2 
Interim summary of Adverse Events (AEs) and Serious Adverse Events 
(SAEs) 
As of July 7, 2016, 468 adverse events (AEs) have occurred in 180 participants 
(71.4% of participants), of which 288 AEs (61.5%) were mild, 163 were 
moderate, (34.8%), 13 (2.8%) were classified as severe, 3 (0.6%) were classified 
as potentially life-threatening, and 1 (0.2%) was fatal (see details in the next 
paragraph). AEs were reported by participants most frequently in the Systems 
Organ Class (SOC) Infections and infestations (107 participants [42.4% of 
enrolled participants]), followed by the SOC Investigations (55 participants 
[21.8%]). Fifteen AEs occurring in 11 participants have been assessed by the site 
investigator as being related to study product; 12 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.  
Seven SAEs have occurred in 5 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, and transient ischemic attack. 
4.7.2.3 
Discontinued vaccinations and early terminations 
As of July 14, 2016, 17 participants have terminated the study prematurely and 16 
participants have discontinued vaccinations. Clinical events leading to early 
terminations and discontinuation of vaccinations (DOV) occurred in 5 
participants: death from multiple injuries (unrelated to study product); severe 
local reactogenicity (DOV); hypertension (DOV for AE unrelated to study 
product); mild vomiting occurring on the day of first vaccination only (participant 
declined further study participation); psychiatric diagnosis (DOV and early 
termination for investigator discretion). Six other participants have terminated the 
study due to HIV infection. Reasons for DOV or early termination in other 
participants included 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 

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pregnancy. One pregnancy has been reported to date and this participant is 
continuing in follow-up.  
4.7.2.4 
Summary of Interim Immunogenicity data from HVTN 100 
The immunological criteria guiding the decision whether to advance development 
of the ALVAC-HIV (vCP2438), Bivalent Subtype C gp120/MF59 regimen into 
efficacy testing in adults in South Africa (HVTN 702) are described in Table 4-7. 
Immunogenicity data from samples collected from HVTN 100 participants at the 
month 6.5 timepoint (2 weeks post month 6 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 4-7 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 developed binding 
antibodies to the gp120 Clade C strain Env antigens in the ALVAC vector, as 
well as the two Clade C strains in the bivalent gp120 protein boost (Figure 4-12). 
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 4-8). Hence, criteria 1 and 2 were met. 

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Figure 4-12 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 4-8 HVTN 100 vs. RV144 Peak bAb magnitudes to gp120 among vaccinees 
Protocol 
Antigen 
n 
Geometric Mean Titer 
GMR 
(100/RV144) 
GMR  
95% CI 
HVTN 100 
1086 
185 
26,257.5 
8.8 
(7.64, 10.2) 
RV144 
A244 
201 
2,968.9 
HVTN 100 
TV1 
185 
10,726.7 
3.6 
(3.01, 4.34) 
RV144 
A244 
201 
2,968.9 
HVTN 100 
96ZM651 
185 
2,685.4 
3.6 
(2.95, 4.39) 
RV144 
92TH023 
201 
746.1 
CD4 responses (criterion 3) 
The CD4+ T cell response rate to vaccine-matched Env sequences in ALVAC 
(vCP2438), (Env peptide pool 96ZM651) 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 (HVTN 100-RV144) was 16% 
(95% CI: 6, 16%; p-value 0.0019). This exceeded the LL response rate difference 
of -30% and therefore met criterion #3. 
V1V2 antibody response rates (criterion 4) 

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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 4-7). The cumulative V1V2 response rate is 80%; well above the 63% 
threshold that was established for modeling a 50% efficacy if V1V2 was the sole 
correlate of protection. 
Table 4-9 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. 
4.7.3 
Other clinical studies with related ALVAC-HIV® vaccines 
Extensive previous experience with other ALVAC-HIV vaccines informs the 
expected safety, tolerability, and immunogenicity profile of the new vaccine (see 
Table 4-10). In all, more than 10,000 people have received ALVAC-HIV vaccines 
in clinical trials. The majority of these trials have been performed with ALVAC-
HIV (vCP205), (vCP1452), or (vCP1521). These vaccines differ in the HIV gene 
inserts that have been introduced into the ALVAC vector.  

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Table 4-10 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 
RV 132/135 
Completed 
ALVAC-HIV (vCP1521) 
8197 
RV 144 
Completed 
ALVAC-HIV (vCP1521) 
135 
RV 305 
Completed 
ALVAC-HIV (vCP1521) 
327 
RV 306 
Ongoing 
ALVAC-HIV (vCP1521) 
80 
HVTN 097 
Completed 
ALVAC-HIV (vCP2438) 
210 
HVTN 100  
Ongoing 
Total 
10,917 
 
 
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 an ALVAC vector vaccine 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.  
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 

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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. 
4.7.4 
Clinical safety experience with related ALVAC-HIV vaccines 
4.7.4.1 
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 [49,50]. The most relevant data, however, come 
from the RV144 efficacy study performed in Thailand [4,51], during which more 
than 8000 human subjects 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. 
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.  
Prior to the RV144 study, De Bruyn et al [52] characterized the tolerability and 
safety profile of ALVAC-HIV (vCP205) and ALVAC-HIV (vCP1452) (along 
with other ALVAC-vector vaccines) based on data from more than 1,000 clinical 
trial subjects. The authors concluded that:  
▪  ALVAC-HIV vaccines were safe and well tolerated, with a reactogenicity 
profile comparable to that of existing vaccines licensed for use in adults; and  
▪ 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. 

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Additional information is available in the ALVAC-HIV (vCP2438) IB. 
4.7.4.2 
Summary of pregnancy occurrence and outcomes 
In study RV144, over a period of 3.5 years of follow-up, among women a total of 
967 (30.6%) vaccine (vCP1521) and 955 (30.1%) placebo recipients reported a 
pregnancy during the study, with 139 vaccine and 116 placebo recipients 
reporting more than 1 pregnancy. Birth was reported for 1843 infants, 14 of them 
representing 7 twin pairs. Of these, 277 births (137 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 3,165 (5.2%) 
female vaccine recipients and 139 out of 3,169 (4.4%) female placebo recipients 
(p = 0.13), and in 17.1% and 14.6% (p = 0.13) of vaccine and placebo 
pregnancies, respectively [51]. 
A total of 15 of the 245 female subjects became pregnant during the AVEG 
studies. Twelve subjects received ALVAC-HIV (vCP205) and 3 received 
placebo. Of these 15 subjects aged 19 to 37 years, 9 subjects had live births, 3 
subjects 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 
caesarean section. Overall, no complications during pregnancy or congenital 
abnormalities at the time of birth were reported. 
In study HVTN 203 [53] 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. 
4.7.4.3 
Summary of safety and tolerability data in African studies that have used 
ALVAC-HIV 
To date, 3 studies have been conducted and completed in Africa with ALVAC-
HIV: HIVNET 007, HIV Prevention Trials Network (HPTN) 027, and HVTN 
097.  
HIVNET 007 [54] 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. 

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HPTN 027 [55] 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. Sixty infants 
were enrolled; 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 
arm and 9 in the placebo arm). 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). Thirteen infants 
in HPTN 027 experienced an AE that led to discontinuation of vaccinations: 10 
subjects 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 arm 
and 7 in the vaccine group (erythema, induration, pain, fever, and irritability). 
HVTN 097 was designed to evaluate whether the same vaccine regimen (with a 
higher dose of ALVAC-HIV) that was used in Thailand in Study RV144 would 
be comparably safe and immunogenic in a South African population. The study 
enrolled 100 healthy, HIV-1–uninfected participants aged 18 to 40 years, 51 male 
and 49 female. One hundred percent were black, non-Hispanic. Ninety-one 
participants completed vaccinations and follow-up. The study was completed in 
December 2013. There were 4 participants who discontinued vaccinations, 2 due 
to pregnancy and 2 due to “other” reason; there were no discontinuations due to 
AEs or reactogenicity. 
Local and systemic reactogenicity was assessed for the investigational ALVAC-
HIV (vCP1521) 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 were mild (48%), 28% were moderate (similar rates for 
ALVAC compared to the AIDSVAX vaccinations) and approximately 9% were 
severe (all but 1 severe pain/tenderness reactions were from ALVAC 
vaccination). In placebo recipients, the maximum pain and/or tenderness reactions 
were mild (52%). The majority of participants in both active (Group [G]1 and G2 
combined) and placebo groups experienced no erythema and/or induration 
reactions (84% and 95%, respectively); with all but 1 reaction (> 9 cm 
erythema/induration from an ALVAC vaccination) being non-gradable by the 
Division of AIDS (DAIDS) AE Grading Table (0-25 cm2), occurring in G1. 
Moderate or severe systemic reactions associated with vaccine administration 
included malaise and/or fatigue (15% versus 5.3% in placebo), myalgia (12.5% 
versus 0% in placebo), headache (7.5% versus 21% in placebo), nausea (1.25% 
versus 0% in placebo), chills (3.75% versus. 5.3% in placebo), and arthralgia 
(6.25% versus 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 

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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 1 placebo recipient 
(5.3%), all deemed unrelated to study treatment. These included alanine 
transaminase (ALT) increase, headache, hypertension, abnormal loss of weight, 
and thermal burn in vaccinees and substance-induced psychotic disorder and 
abnormal loss of weight in 1 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 were mild or moderate, only occurred in 1 
person (except for the skin lump which occurred in 3 participants), and did not 
last long. All participants recovered without sequelae. 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. Overall, the study indicated 
that the vaccine regimen used in RV144 appears safe and well-tolerated in South 
Africans. 
4.7.4.4 
Previous human experience with ALVAC-HIV used in combination with 
subunit protein boost adjuvanted with MF59 
There has been meaningful previous human experience with the use of ALVAC-
HIV vaccines in combination with recombinant gp120 proteins adjuvanted with 
MF59. In addition to the exposures that occurred in the context of study HVTN 
100, 440 human subjects have received this combination across 7 clinical trials 
(Table 4-11). No safety signal of concern was identified in these studies.  

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Table 4-11 Clinical studies performed with ALVAC-HIV and gp120+MF59 before HVTN 100 
Study 
(Country) 
ALVAC-HIV 
Protein 
Subjectsa 
RV132 [50] 
(Thailand) 
vCP1521 
gp120 + MF59  
clades B/E  
made in CHO cells 
n = 45 
AVEG 022A [56] 
(USA) 
vCP205 
gp120 + MF59  
clade B 
made in CHO cells 
n = 47 
AVEG 029 [57] 
(USA) 
vCP205 
gp120 + MF59  
clade B 
made in CHO cells 
n = 22 
AVEG 
202/HIVNET 014 
[58] 
(USA) 
vCP205 
gp120 + MF59  
clade B 
made in CHO cells 
n = 145 
AVEG 032 [59] 
(USA) 
vCP205 
gp120 +/- p24 + MF59  
clade B  
gp120 made in CHO cells  
p24 made in S. cerevisiae 
n = 56 
AVEG 026 [60] 
(USA) 
vCP300b 
gp120 + MF59 
clade B  
made in CHO cells 
n = 85 
AVEG 012A 012B 
[61] 
(USA) 
vCP125c 
gp120 + MF59 
clade B  
made in CHO cells 
n = 40 
Total 
 
 
N = 440 
aNumber of subjects that received both the ALVAC-HIV prime and the gp120/MF59 boost. 
bALVAC-HIV (vCP300) is similar to vCP205 and contains additional sequences encoding Pol and Nef epitopes. 
cALVAC-HIV (vCP125) contains the gene for gp160 from clade B 
4.7.4.5 
Previous human experience with ALVAC-HIV used in combination with 
subunit protein boost adjuvanted with AS01B 
There is no previous human experience with this specific product combination. 
4.7.5 
Immunogenicity experience with related ALVAC-HIV vaccines 
4.7.5.1 
Summary of immunogenicity from related human 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 
[5]. 

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The development of assays for measuring immunogenicity has evolved during 
more than 20 years of testing in humans. Therefore, 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. 
4.7.5.2 
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 [62]. 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. 
Prior to RV144, several schedules of administration with ALVAC and protein 
boost were examined in multiple clinical trials [56,58,63-65]. 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 [64]. In contrast, the protein boost had 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.  
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.  
4.7.5.3 
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 200 
mcg, 100 mcg of each protein) adjuvanted with MF59. Both vaccine components 
have been adapted to target the predominant HIV clade circulating in South 

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Africa (clade C). Interim immunogenicity data from HVTN 100 are summarized 
in Section 4.7.2.4. Studies prior to HVTN 100 with related vaccines provided 
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 [50] used ALVAC-HIV (vCP1521) in the same dose and schedule 
as in study RV144 but 45 subjects in 1 of the study arms received a bivalent 
recombinant gp120 protein manufactured in CHO cells by Novartis Vaccines 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 [49] used ALVAC-HIV (vCP1521) in the same dose and schedule as in 
study RV144, and 97 subjects in 2 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 2 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 4-12 summarizes the nAb response rates for 
the pertinent study arms from these studies.  
Table 4-12 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 
[50] 
100mcg 
CM235* 
50 mcg SF2** 
MF59 
45 
89% 
61% 
95% 
19% 
100% 
RV135 
[49] 
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 geometric mean (GM) nAb titers were also reported in these studies for 2 of 
the clade E strains. Data are summarized in Table 4-13. 
Table 4-13 nAb GM titers to clade E strains 
Study 
gp120 dose 
Adjuvant 
N 
NPO3 
Strain 
CM244 
Strain 
RV132 
[50] 
100mcg CM235* 
50 mcg SF2** 
MF59 
45 
45 
32.66 
RV135 
[49] 
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 100 mcg 
of gp120 protein adjuvanted with MF59 can induce Ab responses after ALVAC 

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prime at least comparable to and possibly greater than 300 mcg of gp120 protein 
adjuvanted with alum after ALVAC prime. These data suggest that MF59 allows 
for protein dose sparing compared with the less potent alum adjuvant. 
4.7.6 
Clinical studies with HIV-1 subunit protein vaccines  
For description of interim safety/tolerability and immunogenicity results from 
HVTN 100, see Section 4.7.2.4. 
In addition, other closely related recombinant monomeric (gp120) subunit vaccine 
formulations from GSK Vaccines (formerly Novartis) have been tested in 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, Novartis’ 
proprietary oil-in-water emulsion adjuvant [66]. MF59 safety has been established 
in clinical studies as well as in commercial products. A seasonal influenza vaccine 
adjuvanted with MF59 (Fluad®) is licensed in the EU and other countries for use 
in the elderly. MF59 is also used in a prepandemic H5N1 influenza vaccine 
(Aflunov®) licensed in the EU for use in adults, and in 2 pandemic H1N1 
influenza vaccines (Focetria® and Celtura®), licensed in the EU and other 
countries for use in adults and children. 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 candidates from subtypes B and E, most of which were CHO-
based and administered with MF59. More than 1200 subjects participated in the 
evaluation of the Chiron HIV SF2 gp120/MF59 vaccine and the Chiron HIV 
CM235 Thai E gp120/MF59 vaccine [45,50,60,67-69]. Two clinical trials were 
conducted using Novartis CHO-based subtype B gp140 recombinant Env protein 
with MF59. There are 3 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 4-14 summarizes clinical trial experience with Novartis 
gp120 and gp140 recombinant vaccine candidates. 
Table 4-14 Novartis recombinant gp120 and gp140 vaccines in human clinical trials [68] 
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  
SF-2 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, 
aluminum hydroxide, MPL-A, liposome-encapsulate 
MPL-A, MTP-PE/MF59® 
107 
AVEG 015 
Completed 
SF2 gp120 (CHO)/MF59® and ALVAC 
47 
AVEG 022A 
Completed 

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Candidate vaccine 
# receiving 
Novartis protein 
Protocol 
Status 
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 
145 
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 
Completed 
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 [4,45,50,60,67-
71]. 
4.7.6.1 
Summary of safety, reactogenicity, and tolerability from recent human 
experience 
For description of interim safety/tolerability results from HVTN 100, see Section 
4.7.2.4 
In addition, two other clinical trials have been conducted recently using Novartis 
CHO-based subtype B gp140 with MF59 and there have been 4 recent clinical 
trials using Novartis CHO-based subtype C gp140.  
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 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 years, with 20 to receive gp140. The 
protocol was amended to halt further IN administration of LTK63 following a 
report of an AE (ie, facial nerve paralysis) with a possible association with the 
LTK63 adjuvant in another study [72]. 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 

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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 
US[73]. Subjects received 1 of 3 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 1000/1000 mcg) 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 subjects received subtype B gp140 with 
MF59 without DNA prime, administered at 0, 3, and 9 months. Overall 96 
healthy, HIV-1–uninfected adult subjects were enrolled and 86 subjects 
completed all planned vaccinations. There were no SAEs reported as related to 
study vaccine. There were 4 events reported as SAEs that were not considered 
related to the study vaccine. A death attributed to cocaine overdose occurred in 1 
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 2 weeks. Both subjects reported to have 
initiated new exercise programs. One subject experienced severe fatigue 20 days 
after the fourth immunization (including 1 dose of subtype B gp140/MF59), 
attributed to working 2 jobs and long hours. Overall, the regimens were generally 
well tolerated.  
A third study, HVTN 073E, was conducted in the US and the Republic of South 
Africa (RSA) as an extension to the previous HVTN 073/SAAVI03 study. This 
extension study examined the safety and immunogenicity of 2 boosting doses of 
Novartis subtype C gp140/MF59 or placebo in subjects who previously received 3 
vaccinations of SAAVI DNA-C2 and 2 vaccinations of SAAVI MVA-C. This 
study enrolled 27 subjects. There was 1 report of endometrial intra-epithelial 
neoplasia resulting in hospitalization for hysterectomy, which was assessed as 
unrelated to study agents. 
Two other recent phase 1 studies with Novartis subtype C gp140/MF59 have been 
conducted by the HVTN in the US and RSA. In addition, 1 phase 1 trial was 
conducted by the Istituto Superiore di Sanità (ISS) in Italy. One of these trials, 
HVTN 088, was conducted in the US in order to evaluate the safety and 
immunogenicity of a long-interval, cross-clade subtype C gp140/MF59 boost in 
subjects previously administered subtype B gp120/MF59 or subtype B 
gp140/MF59 in previous trials. This includes subjects from the HVTN049 
DNA/PLG prime, gp140/MF59 boost study already described. The study enrolled 
16 previously vaccinated subjects 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 individuals were 
enrolled in HVTN 088 to receive a clade C protein boost in an open label phase 1 

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trial. There have been 3 SAEs reported in this trial, 1 involving traumatic injury, 1 
instance of gastroenteritis, and 1 of appendicitis. All of these were assessed as 
unrelated to study agents.  
The second HVTN study, HVTN 086, was conducted in the RSA. It evaluated the 
safety and immunogenicity of various combinations of SAAVI DNA-C2, SAAVI 
MVA-C, and Novartis subtype C gp140/MF59. All scheduled clinic visits have 
been completed, though study participants remain subject to annual contacts to 
assess their health status. This study enrolled 184 subjects. To date, 6 SAEs have 
been reported in this study, 1 case of acute tonsillitis that required hospitalization, 
1 of schizophrenia requiring hospitalization (later determined to be a pre-existing 
condition), 1 of pelvic inflammatory disease, 1 soft-tissue injury, 1 instance of 
anemia, and 1 instance of alcohol-related cardiomyopathy. All were assessed as 
not related to the study products. 
The 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. This study was stopped early due to slow enrollment and 
subsequent expiration for the study product stability program. No SAEs were 
reported in this study. 
4.7.6.2 
Summary of immunogenicity from recent human experience 
The immunogenicity of Novartis recombinant proteins has been demonstrated 
consistently in all clinical trials and in all 3 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 3 DNA/PLG prime vaccinations, but did rise after 
the first protein/MF59 boost. nAb titers against the homologous SF162 isolate 
were detectable in 2 subjects after the third DNA/PLG priming vaccination and in 
13 subjects after the first protein boost. Neutralization was boosted to high titers 
in all but 1 subject following the second protein boost. Similarly, in the group of 
subjects 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 1 subject) 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 MUVAPRED IN study, demonstrated immunogenicity with 
considerable IgG and IgA Ab responses to subtype B gp140 in serum, cervical, 
and vaginal secretions of subjects following IN administration of subtype B 
gp140 with the adjuvant LTK63 and an IM boost with subtype B gp140 and M59 

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adjuvant. nAb responses against the homologous SF162 were also detected in all 
groups following IM boost with subtype B gp140 and MF59 adjuvant. 
HVTN 073E data are available from specimens collected 2 weeks after each 
protein administration. Boosting with protein enhanced levels of binding and 
neutralizing antibodies as well as CD4+ T-cell responses to HIV-1 envelope. The 
protein boost increased CD4+ T-cell response rates from 74% to 87% of the 
subjects. No neutralizing antibodies were detected with the DNA/MVA regimen 
before the protein boosts. After the first protein boost, neutralizing antibodies to 
tier 1 viruses were detected in up to 56% of participants. After the second protein 
boost, neutralizing antibody responses were seen in up to 100% of participants 
and persisted in 75% of those participants for at least 6 months [74]. 
In addition, in the subtype C gp140/MF59 HVTN 088 long-interval boost study, 
16 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), 5 
of 16 (31%) of primed participants demonstrated CD4+ T-cell responses to Env at 
baseline, which increased to 12 of 16 (75%) after a single protein boost. IgG and 
IgA responses to Con S gp140 were present in 64% (IgG) and 7% (IgA) of 
primed participants at baseline, and rose to 93% and 85%, respectively, after 1 
dose of protein. Primed participants demonstrated (71%) 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 vaccine-matched oligomeric TV1 Env in 88% and 50%, 
respectively. nAb developed to MN in 38% and to MW965.26 in 88% of the 
unprimed participants.  
Three of the 4 vaccine regimens in HVTN 086 contained Novartis subtype C 
gp140/MF59, either as a boost following pox-vector (MVA) primes, administered 
concurrently with a pox-vector (MVA) vaccine, or in a concurrent pox-
vector/protein boost and second protein boost following DNA plasmid primes. Ab 
responses were measured with a Luminex binding Ab assay and a nAb assay in 
TZM-bl cells. All three vaccine regimens containing subtype C gp140/MF59 
elicited high rates (82–100%) and magnitudes of IgG binding Ab against a range 
of gp120 and gp140 antigens. All vaccine regimens had evidence of nAb to (Tier 
1) HIV strains MN.3, MW965.26, and SF162.LS, with the MVA- and DNA-
primed regimens showing the highest titers to MW965.26, a clade C strain. HIV-1 
specific CD4+ and CD8+ T-cell responses to global potential T-cell epitopes 
(PTEg) were measured by an ICS assay. The MVA- and DNA-primed vaccine 
regimens elicited the highest rates of CD4+ T cells producing IFN-γ and/or IL-2 
(77% and 45%, respectively), while the regimen with concurrent MVA/protein 
administration elicited the lowest rate (13%). 

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4.7.7 
Clinical studies with HIV-1 subunit protein vaccines and AS01B 
Immunogenicity data for studies HVTN 041, PRO HIV-005, ECR-004 and PRO 
HIV-002 are presented in Section 4.3.1 and 4.3.2.  
The safety, reactogenicity and tolerability profiles of the vaccine regimens 
investigated in these studies were considered acceptable and are presented below. 
HVTN 041 evaluated a combination vaccine (NefTat and gp120W6.1D) 
formulated with AS02A (oil-in-water emulsion of a combination of MPL and QS-
21) administered at 0, 1 and 3 months with varying doses (5, 20 and 100 mcg) of 
the gp120 vaccine component (the NefTat antigen dose was constant at 20mcg).  
The vaccinations were well tolerated and none were discontinued because of 
vaccine-associated reactogenicity. The most common local symptoms were pain 
and tenderness. Systemic symptoms were generally mild with the exception of 
moderate myalgia and headache occurring in 20 and 25%, respectively. Both 
symptoms were evenly distributed in the 3 NefTat and gp120W6.1D groups (20% 
in each group for myalgia and from 10 [2/20 subjects] to 40% [8/20 subjects] per 
group for headache). Severe pain was observed in 2/20 subjects of 2 NefTat and 
gp120W6.1D groups (5 mcg and 100 mcg of gp120). Severe tenderness was 
observed in 2/20 subjects of 1 NefTat and gp120W6.1D group (5 mcg of gp120). 
Severe malaise was observed in 2/20 subjects of 1 NefTat and gp120W6.1D 
group (20 mcg of gp120). All vaccine-related reactogenicities were transient and 
had either improved or resolved within 48 hours of onset. Grade 4 laboratory 
abnormalities were observed in 1 single participant who was administered the 
AS02A-adjuvanted NefTat 20 mcg / gp120W6.1D 5 mcg vaccine. This 
participant had an elevated CPK value, which may have been due to creatine 
supplements taken prior to exercise and likely not vaccine related. There were 6 
serious adverse events during the trial that occurred within 24 hours 
postvaccination and were felt to be probably or definitely due to the 
immunizations. These included 2 severe local site reactions in group NefTat 20 
mcg and gp120W6.1D 5 mcg (associated to limitation of limb movement in 1 
case), 2 occurrences of severe malaise in 2 subjects of group NefTat 20 mcg / 
gp120W6.1D 20 mcg, a febrile illness (103.2 ◦F) in 1 subject of group NefTat 20 
mcg / gp120W6.1D 20 mcg, and an episode of generalized urticaria in 1 subject 
from group NefTat 20 mcg / gp120W6.1D 100 mcg. All of these SAEs 
significantly improved within 24 hours of onset. It is important to note that none 
of these SAEs would be regarded as serious in accordance with the current ICH 
E2A definitions. Grade 3 and Grade 4 related Adverse Events were considered 
SAEs per the “SAE reporting manual” active at the time of the study. 
PRO HIV-002 evaluated the gp120W6.1D 20 mcg / NefTat 20 mcg candidate 
HIV vaccine formulated with 1 of 3 different Adjuvant Systems (AS02A, AS02V 
and AS01B), each in 60 healthy HIV-seronegative adults. The vaccine candidates 
were administered at month 0, month 1, month 3 and month 6.  

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During the 7-day follow-up period after vaccination, almost all doses (90.4% to 
98.8%) were followed by at least 1 solicited or unsolicited symptom considered to 
be related to vaccination with no difference between groups. The reactogenicity 
profiles obtained in the present study were expected and confirmed the previous 
results obtained with these adjuvants. During the course of the study, a total of 14 
SAEs were reported in 12 subjects, none of them was causally related to 
vaccination.  
Local and general solicited symptoms could be divided into 4 groups given their 
frequency per dose given into brackets (by decreasing order): 
• Pain (between 86.3% and 96.3%) with few grade 3 symptoms (≤ 3.4%). 
• Fatigue (between 33.8% and 46.6%), feverishness (between 22.9% and 
53.4%), headache (between 35.0% and 48.3%) and myalgia (between 25.8% 
and 43.3%). Few cases of grade 3 myalgia and fatigue were reported (≤ 
4.2%). For feverishness, the frequency of grade 3 symptoms was 10.1% and 
for headache was 5.9% in the gp120/ NefTat/ AS01B group. 
• Redness, swelling, nausea and fever: the frequency of those symptoms did not 
exceed 30.3%. Few grade 3 nausea and fever were reported (≤ 2.1%). The 
frequency of grade 3 redness and swelling was 20.2% and 13.9% respectively 
in the gp120/ NefTat/ AS01B group.  
• Diarrhea and vomiting: the frequency of these symptoms was less than or 
equal to 7.5%. No grade 3 diarrhea was observed, and only 0.4% of the doses 
were followed by grade 3 vomiting. 
Almost all general symptoms (fatigue, feverishness, headache, myalgia, nausea 
and fever, vomiting) were considered as related to the vaccination, except for 
diarrhea.  
The duration of general symptoms was less than or equal to 2 days in most cases 
whereas the duration of local symptoms was often more than 2 days. In the 
gp120/ NefTat/AS01B group the overall frequency of the general symptoms 
tended to be higher after the second, third, or fourth dose of vaccine compared to 
the first dose (but not for all symptoms and all groups). 
The incidence of unsolicited AEs ranged from 78.3% to 83.3%. The most 
frequently reported symptoms were upper respiratory tract infections and 
headache, followed by injection site induration, injection site pruritus and 
pharyngeal pain. Less than half unsolicited symptoms were causally related to 
vaccination (incidence between 31.7% and 36.7%). The most frequent symptoms 
causally related to vaccination were administration site reactions (injection site 
induration, pruritus or warmth) and asthenia. Few grade 3 or grade 3 related 
symptoms occurred: 18 subjects (incidence between 6.7% and 13.3%. according 
to group) experienced grade 3 unsolicited symptoms, among which a majority 
were non-related infectious conditions (cystitis, gastroenteritis, otitis, 

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pyelonephritis, tonsillitis, tooth abscess, upper respiratory tract infection and 
vaginal candidiasis). Six of them had symptoms considered to be causally related 
to vaccination (lymphadenopathy, palpitations, application site hyperesthesia, 
asthenia, muscle rigidity, headache, and tremor).  
No significant changes in laboratory parameters (hematology, biochemistry, 
urinalysis) and vital signs were observed throughout the study. This study had no 
negative social impact (only 2.8% of the subjects reported any disturbance) and 
19.4% of the subjects notified even a beneficial impact.  
PRO HIV-005 evaluated an HIV vaccine candidate consisting of a recombinant 
fusion protein (F4) containing 4 HIV-1 clade B antigens (Gag p24, Pol-RT, Nef, 
and Gag p17) adjuvanted with AS01B in 3 different doses: 10, 30, and 90 mcg. 
Each dose of the AS01B-adjuvanted vaccine candidate was administered twice in 
a group of 50 subjects, following a month 0 and month 1 schedule. Three control 
groups of 10 subjects received a dose of 10, 30 or 90 mcg F4 in water for 
injection (WFI).  
Reactogenicity was higher during the 7-day period after each vaccine dose in the 
F4/AS01 groups than in the F4 in WFI groups. The incidence of local and general 
symptoms tended to be higher in the F4/AS01 groups after the second vaccine 
dose. Pain was the most common solicited local symptom, reported after 96.0%–
98.0% of doses in the F4/AS01 groups and after 10.0%–30.0% of doses in the F4 
in WFI groups (grade 3 severity after 5.0%-10.1% of doses in the F4/AS01 
groups). Fatigue was the most common solicited general symptom, reported after 
66.0%-77.8% and 30.0%-45.0% of doses in the F4/AS01 and F4 in WFI groups, 
respectively (grade 3 severity after 7.0%-12.1% of doses in the F4/AS01 groups). 
Fever of more than 39°C was reported in 3.0%, 2.0% and 1.0% of the doses in the 
respective 10, 30 and 100 mcg F4/AS01 groups). No solicited local or general 
grade 3 symptoms were reported in the F4 in WFI groups. No differences in 
reactogenicity were observed between the antigen dose levels in the F4/AS01 
groups. During the 30-day postvaccination period, 60.0%–84.0% of subjects in 
the F4/AS01 groups reported unsolicited symptoms, compared with 50.0%–
70.0% in the F4 in WFI groups. In the F4/AS01 groups, unsolicited symptoms 
(mainly chills and injection site reactions) were considered causally related to 
vaccination in 30.0%–44.0% of subjects and were of grade 3 severity in <10.0%. 
All related symptoms were transient and resolved without sequelae, generally 
within 2–3 days. Six serious adverse events were reported in the F4/AS01 groups, 
all considered unrelated to vaccination. No subjects died during the study period, 
and no subject withdrew because of adverse events. 
ECR 004, a subset of volunteers primed 3 years before with 2 doses F4 10 mcg / 
AS01B (PRO HIV-005) received a (third) single booster dose of F4 10 mcg / 
AS01B.  
93.3% (ie, 14 out of 15 subjects) of the subjects reported at least 1 AE and 40% 
(ie, 6 out of 15 subjects) of the subjects in the group F4 reported at least 1 grade 3 
symptom considered by the investigator to be related to vaccination. Pain was the 

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most frequent solicited local AE. Grade 3 pain (13.3% or in 2 out of 15 subjects), 
redness (in 6.7% or in 1 out of 15 subjects) or swelling (in 13.3% or in 2 out of 13 
subjects) were reported for a maximum duration of 2 days. Fatigue and headache 
were the 2 most frequently reported solicited general AEs. Fever was recorded in 
6 out of 15 subjects (40%) within the 2 days after vaccination. Grade 3 fatigue (in 
20% or in 3 out of 15 subjects) or fever (in 1 out of 15 subjects) was reported with 
a maximum duration of 1 day. Grade 3 unsolicited AEs were reported by 13.3% 
(ie, 2 out of 15 subjects). Out of these cases, 2 cases were considered by the 
investigator to be causally related to vaccination: 1 case of chills and 1 case of 
insomnia. All of the grade 3 unsolicited AEs were resolved without sequelae. No 
subjects died, experienced an SAE, or withdrew due to an AE. 
4.8 
Potential risks of study products and administration 
Table 4-15 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 and with AS01B.  
Table 4-15 Summary of potential risks of study products and administration 
Common 
• Mild to moderate injection site pain, tenderness, erythema, or 
swelling/induration/edema 
• Malaise/fatigue/weakness, myalgia, arthralgia, nausea/vomiting, 
lymphadenopathy, asthenia, fever, chills, or headache in the first few days 
following injection 
• Arm movement limitation 
• A vaccine-induced positive HIV Ab test result 
Less common 
• Severe injection site pain or tenderness 
• 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 or rare 
• 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, nodule or other non-specific injection site 
reaction 
• Generalized pruritis 
• Oral parasthesia 
• 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 safety and tolerability of ALVAC-HIV and bivalent gp120 
protein/MF59 or bivalent gp120 protein/AS01B. 
Primary endpoints 1 
• Severe local and systemic reactogenicity signs and symptoms (pain, 
tenderness, erythema, induration, fever, malaise/fatigue, myalgia, headache, 
nausea, vomiting, chills, arthralgia) up to 7 days after each vaccine dose 
• AEs by body system, Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term, severity, and assessed relationship to study 
products up to 30 days after each vaccine dose 
• SAEs, AESIs, and new chronic conditions (requiring medical intervention for 
≥ 30 days) throughout the study 
• Laboratory measures: white blood cells (WBC), neutrophils, lymphocytes, 
hemoglobin, platelets, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphate (ALP), and creatinine at baseline 
and following vaccinations 
• AEs leading to early participant withdrawal or early discontinuation of study 
products administration throughout the study. 
Primary objective 2 
• To compare HIV-specific CD4+ T-cell response rates at the month 6.5 
timepoint (2 weeks after the fourth vaccination) of ALVAC-HIV and bivalent 
gp120 protein/MF59 to each of the bivalent gp120 protein/AS01B vaccine 
regimens. 
Primary endpoint 2 
• HIV-specific CD4+ T-cell response rates as assessed by flow cytometry. 
Primary objective 3 
• To compare HIV-specific Env-gp120 binding antibody response magnitudes 
at the month 12 timepoint (6 months after the fourth vaccination) of ALVAC-
HIV and bivalent gp120 protein/MF59 to each of the bivalent gp120 
protein/AS01B vaccine regimens. 

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Primary endpoint 3 
• HIV-specific Env-gp120 binding antibody response magnitude as assessed by 
multiplex assay. 
5.2 
Secondary objectives and endpoints 
Secondary objective 1 
• To further evaluate the systemic immune responses and the durability of 
immunogenicity of each vaccine regimen at the month 6.5 and month 12 
timepoints. 
Secondary endpoint 1 
• HIV-specific total IgG binding antibody response breadth and magnitude as 
assessed by multiplex assay. 
• Anti –V1/V2 scaffold IgG binding antibody responses as assessed by 
multiplex assay. 
• HIV-specific CD4+ and CD8+ T-cell responses as assessed by flow 
cytometry. 
• Additional immunogenicity assays may be performed on blood samples based 
on the HVTN Laboratory Assay Algorithm 
5.3 
Exploratory objectives 
Exploratory objective 1 
• To further evaluate immunogenicity of each vaccine regimen, additional 
immunogenicity assays may be performed on blood and optionally provided 
mucosal samples, including samples from other timepoints, based on the 
HVTN Laboratory Assay Algorithm.  
Exploratory objective 2 
• To assess whether the diversity of gut microbiome correlates with vaccine 
responses using optionally provided stool specimens. 
Exploratory objective 3 
• 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 
Accrual and sample size calculations 
Recruitment will target enrolling 160 healthy, HIV-uninfected adult participants 
ages 18-40 years in Africa and the United States. Participants will be randomized 
to 4 treatment groups (3 vaccine groups of size 50 each and a placebo group of 
size 10). The three vaccine groups (groups 1-3) will evaluate ALVAC priming 
followed by boosting with ALVAC and gp120 protein. Three different 
formulations of the protein will be evaluated: 1) a dose of 100 mcg of each 
protein formulated with MF59; 2) a dose of 100 mcg of each protein formulated 
with AS01B; and 3) a dose of 20 mcg of each protein formulated with AS01B. To 
ensure that both participants assigned male and female at birth will be adequately 
represented in the trial, the trial will enroll at least approximately 40% of each 
sex. Hence, when approximately 96 participants of one sex are enrolled, 
recruitment of persons born of that sex will stop. 
Since enrollment is concurrent with receiving the first study vaccination, all 
participants will provide some safety data. However, for immunogenicity 
analyses, it is possible that data may be missing for various reasons, such as 
participants terminating from the study early, problems in shipping specimens, 
low cell viability of processed peripheral blood mononuclear cells (PBMCs), or 
high assay background. Immunogenicity data from 17 phase 1 and 2 phase 2a 
HVTN vaccine trials, which began enrolling after June 2005 (data as of 
September 2014), indicate that 15% is a reasonable estimate for the rate of 
missing data at month 6.5. For this reason, the sample size calculations in Section 
6.1.2 account for 8 enrolled participants on each of the vaccine groups having 
missing data for the primary immunogenicity endpoints.  
6.1.1 
Sample size calculations for safety 
The goal of the safety evaluation for this study is to identify safety concerns 
associated with product administration. The ability of the study to detect SAEs 
can be expressed by the true event rate above which at least 1 SAE would likely 
be observed and the true event rate below which no events would likely be 
observed. Specifically, for each vaccine group of the study (n =50), there is a 90% 
chance of observing at least 1 event if the true rate of such an event is 4.5% or 
more; and there is a 90% chance of observing no events if the true rate is 0.1% or 
less. As a reference, in HVTN vaccine trials from December 2000 through April 
2014, about 4% of participants who received placebos experienced an SAE.  
Probabilities of observing 0, 1 or more, and 2 or more events among groups of 
size 50 are presented in Table 6-1 for a range of possible true adverse event rates. 
These calculations provide a more complete picture of the sensitivity of this study 
design to identify potential safety problems with a vaccine regimen. 

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Table 6-1 Probability of observing no events, 1 or more events, and 2 or more events, 
among groups of size 50, for different true event rates 
True event rate (%) 
Pr(0/100) 
Pr(1+/100) 
Pr(2+/100) 
1 
0.61 
0.39 
0.09 
4 
0.13 
0.87 
0.60 
10 
0.005 
>0.99 
0.97 
20 
<0.001 
>0.99 
>0.99 
30 
<0.001 
>0.99 
>0.99 
An alternative way of describing the statistical properties of the study design is in 
terms of the 95% confidence interval (CI) for the true rate of an adverse event 
based on the observed data. Table 6-2 shows the 2-sided 95% CIs for the 
probability of an event based on a particular observed rate. Calculations are done 
using the score test method [75]. If none of the 50 participants receiving a vaccine 
regimen experience a safety event, the 95% 2-sided upper confidence bound for 
the true rate for such an event is 7.1%. 
Table 6-2 Two-sided 95% confidence intervals based on observing a particular rate of safety 
endpoints for vaccine groups of size 50 
Observed event rate 
Confidence interval (%) 
0/50 = 0.0% 
(0.0, 7.1) 
1/50 = 2.0% 
(0.4, 10.5) 
2/50 = 4.0% 
(1.1, 13.5) 
  5/50 = 10.0% 
(4.3, 21.4) 
10/50 = 20.0% 
(11.2, 33.0) 
20/50 = 40.0% 
(27.6, 53.8) 
6.1.2 
Sample size calculations for immunogenicity 
The primary immunogenicity evaluation is to compare Groups 2 and 3 (AS01B 
groups) separately to Group 1 (MF59 group) based on the following two criteria: 
1. Establish superiority of the AS01B regimen in CD4+ T-cell response rate at 
month 6.5 for either TV1 or 1086; AND 
2. Establish superiority of the AS01 B regimen in magnitude of anti-gp120 
antibody response at month 12 for 1086. 
Power is calculated for each group comparison separately and assumes that:  
1. The CD4+ T-cell response rate for the AS01 B regimen is at least 31% higher 
for both antigens; AND, 
2. The true geometric mean anti-gp120 binding antibody response is 1.5-fold 
higher for the AS01 B regimen. 
Power is based on data simulations using HVTN 100 CD4+ T-cell data from the 
month 6.5 visit (2 weeks after the fourth vaccination) and predicted anti-gp120 

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1086 antibody binding magnitude at the month 12 visit. Simulated HVTN 120 
data sets were generated by sampling with replacement from the HVTN 100 data 
and power is reported as the percentage of the 10,000 simulated HVTN 120 trials 
that reject the composite null hypothesis defined by the primary immunogenicity 
evaluation (“Overall power”) and separately for the null hypotheses defined by 
the CD4+ T-cell and the anti-gp120 antibody criteria. CD4+ T-cell response calls 
were simulated for the MF59 group (Group 1) by dichotomizing the ICS 
IL2/IFNγ CD4+ T-cell response magnitude using a threshold defined by the 
observed response rates of 49% to the TV1 antigen and 40% to the 1086 antigen. 
For the AS01 B comparator group (Group 2 or 3), CD4+ T-cell response calls 
were simulated based on threshold corresponding to response rates of 80% for 
TV1 and 71% for 1086 antigens. The rationale for this approach is to maintain the 
between antigen correlation and allow simulation of a higher response rate in the 
AS01 B group. Predicted HVTN 100 Env-gp120 binding data at month 12 were 
used for the second primary immunogenicity criterion. Env-gp120 binding 
magnitudes in the MF59 group (Group 1) at month 12 were predicted using 
HVTN 100 month 6.5 data and assuming the same antibody decline between 6.5 
and 12 months that was obtained from modeling the decline of the antibody 
response to the A244 gp120 antigen in RV144 [76]. AS01B (Group 2 or 3) IgG 
response magnitudes were simulated on a logit scale using a fold-change 
equivalent to a 1.5-fold change between group geometric means on the MFI scale. 
Specifically, the logit transformation of MFI is defined by logit(MFI) = log((M-
L)/L) – log(MFI/(M-MFI)) where M=215 and L=100, the upper and lower limits 
of detection of the binding antibody multiplex assay (BAMA). The rationale for 
using the logit scale is to simulate MFI values within the range of the assay. 
Overall power, accounting for both primary immunogenicity criteria defined 
above, depends on inter-correlations between the CD4+ T-cell and anti-gp120 
readouts. The correlation coefficient between month 6.5 TV1 and 1086 CD4+ T-
cell magnitudes in HVTN 100 is high (0.86, Spearman rank correlation). 
Correlation coefficients between month 6.5 CD4+ T-cell magnitude (TV1 or 
1086) and month 12 anti-gp120 1086 antibody magnitude are low (0.35 and 0.33, 
Spearman rank correlation). Although these correlations are difficult to interpret 
since they are based on predicted month 12 antibody responses, they are 
consistent with correlations between week 26 cellular and week 52 antibody 
responses from HVTN 096 and HVTN 205 [76]. Therefore, the results for overall 
power shown in Table 6-3, are based on the correlation between month 6.5 CD4+ 
T-cell magnitude and predicted anti-gp120 1086 antibody magnitude. An 
alternative is to assume independence between the month 6.5 CD4+ T-cell 
responses and the month 12 anti-gp120 responses. Under this scenario the overall 
power is virtually the same (results not shown). 
Power calculations are based on 1-sided Fisher’s exact tests for the TV1 and 1086 
CD4+ T-cell response rate comparisons and a 1-sided t-test comparing log(MFI) 
for the anti-gp120 responses comparison. Comparisons are based on an alpha 
level of 0.025. 

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Table 6-3 Power for each primary immunogenicity endpoint separately and overall 
Sample Size 
Power 
ASO1B 
MF59 
CD4+ T-
cell 
response 
gp120 
magnitude 
Overall 
43 
43 
0.892 
0.913 
0.819 
6.2 
Randomization  
A participant’s randomization assignment will be computer generated and 
provided to the HVTN CRS pharmacist through a Web-based randomization 
system. At each institution, the pharmacist with primary responsibility for 
dispensing study products is charged with maintaining security of the treatment 
assignments (except in emergency situations as specified in the HVTN MOP). 
6.3 
Blinding 
Participants and site staff (except for site pharmacists) will be blinded as to 
participants’ treatment group assignments. 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 HVTN 
SMB members also are unblinded to treatment assignment in order to conduct 
review of trial safety.  
When a participant leaves the trial prior to study completion, the participant will 
be told he or she must wait until all participants are unblinded to learn his or her 
treatment assignment.  
In some cases, the CRS, PSRT, or study sponsor may believe unblinding of the 
site PI and participant would be appropriate to facilitate the clinical management 
of an AE or SAE. The HVTN Unblinding MOP specifies procedures for 
emergency unblinding, and for early unblinding for medical reasons. 
6.4 
Statistical analysis 
This section describes the final study analysis, unblinded as to treatment group 
assignment. All data from enrolled participants will be analyzed according to the 
initial randomization assignment regardless of how many vaccinations they 
received. In the rare instance that a participant receives the wrong treatment at a 
specific vaccination time, the Statistical Analysis Plan will address how to 
analyze the participant’s safety data. Analyses are modified intent-to-treat 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 

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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 primary immunogenicity endpoints, or secondary endpoints. 
However, multiplicity adjustments will be made for certain immunogenicity 
assays, as specified in the SAP, when the assay endpoint is viewed as a collection 
of hypotheses (eg, testing multiple peptide pools to determine a positive 
response). 
Immunogenicity data from this study may be combined with other phase 1/2a 
studies within the P5 partnership HIV vaccine program. Comparable eligibility 
criteria and validated assays for primary immunogenicity endpoints will be used 
to mitigate the potential bias introduced by combining data across studies 
conducted over an extended period of time.  
6.4.1 
Analysis variables 
The analysis variables consist of baseline participant characteristics, safety, and 
immunogenicity for primary- and secondary-objective analyses. 
6.4.2 
Baseline comparability 
Treatment groups will be compared for baseline participant characteristics using 
descriptive statistics. 
6.4.3 
Safety/tolerability analysis 
Since enrollment is concurrent with receiving the first vaccination, all participants 
will have received at least 1 vaccination and therefore will provide some safety 
data. 
6.4.3.1 
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 group. 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 groups. 

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6.4.3.2 
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 or 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 or the strongest recorded causal relationship to 
study product. Formal statistical testing comparing groups is not planned since 
interpretation of differences must rely heavily upon clinical judgment. 
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 AEs of special 
interest (AESI). AESI for this protocol include but are not limited to potential 
immune-mediated disorders; a sample list of AESI is provided in Appendix H. 
These listings will be submitted to the FDA in all annual reports and clinical trial 
reports. 
6.4.3.3 
Local laboratory values  
Boxplots of local laboratory values will be generated for baseline values and for 
values measured during the course of the study by treatment group and visit. Each 
boxplot will show the first quartile, the median, and the third quartile. Outliers 
(values outside the boxplot) will also be plotted. If appropriate, horizontal lines 
representing boundaries for abnormal values will be plotted. 
For each local laboratory measure, summary statistics will be presented by 
treatment group and timepoint, as well as changes from baseline for 
postenrollment values. In addition, the number (percentage) of participants with 
local laboratory values recorded as meeting Grade 1 AE criteria or above as 
specified in the DAIDS AE Grading Table (see Section 11.2.2) will be tabulated 
by treatment group for each postvaccination timepoint. Reportable clinical 
laboratory abnormalities without an associated clinical diagnosis will also be 
included in the tabulation of AEs described above. 
6.4.3.4 
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 group. 
6.4.4 
Immunogenicity analysis 
6.4.4.1 
General approach 
For the statistical analysis of immunogenicity endpoints, data from enrolled 
participants will be used according to the initial randomization assignment 
regardless of how many injections they received. Additional analyses may be 

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performed, limited to participants who received all scheduled injections per 
protocol. Assay results that are unreliable, from specimens collected outside of 
the visit window, or from HIV-infected participants after infection are excluded. 
Since the exact date of HIV infection is unknown, any assay data from blood 
draws 4 weeks prior to an infected participant’s last seronegative sample and 
thereafter may be excluded. If an HIV-infected participant does not have a 
seronegative sample after enrollment, then all data from that participant may be 
excluded from the analysis.  
Response rates will be analyzed by tabulating the frequency of positive response 
for each endpoint and treatment group at each timepoint for which an assessment 
is performed. For CD4+ and CD8+ T-cell response, response rates to the 
individual peptide pools will also be calculated. Crude response rates will be 
presented with their corresponding 95% confidence interval estimate calculated 
using the score test method [75]. For the primary endpoints of CD4+ T-cell 
response rates for TV1 and 1086, differences between groups will be tested with a 
2-sided Barnard’s or Fisher’s exact test (as specified in the SAP) at an alpha level 
of 0.05. For secondary and exploratory assay endpoints, response rates and 95% 
confidence intervals will be calculated if appropriate for the endpoint. No 
adjustment will be made to the vaccine group estimates for the false positive rates 
in the placebo group. 
The primary endpoint of anti-gp120 binding antibody response magnitude, and 
likely some of the secondary assays, will have quantitative assay data. Other 
quantitative measures include binding antibody magnitude from the multiplex 
assay, neutralizing antibody titers, area under the magnitude-breadth curve [AUC-
MB] for the neutralizing antibody assay, and percentage of positive cells from the 
ICS assay. Quantitative data will be displayed as graphical and tabular summaries 
of the distributions by antigen, treatment group, and timepoint. For the primary 
and secondary immunogenicity endpoints, box plots and plots of estimated 
reverse cumulative distribution curves will be presented by group. For the primary 
endpoint, differences between groups will be tested with a nonparametric 
Wilcoxon rank sum test if the data are not normally distributed or with a 2-sample 
t-test if the data appear to be normally distributed, at an alpha level of 0.05. 
Formal statistical comparisons between groups for secondary and exploratory 
immunogenicity endpoints are not objectives of the trial, although these are likely 
to be made to better understand the effect of each vaccine regimen. For 
comparisons in which the response rate for 1 of the groups is low (eg, ≤ 20% for 
the class), statistical testing will use Barnard’s or Fisher’s exact tests (as specified 
in the SAP) comparing the 2 response rates as most of the continuous data 
readouts would be left censored at the lower limit of detection. For comparisons 
in which the response rates for both groups are high (eg, ≥ 75%), the difference 
between groups will be tested using the continuous readouts with a nonparametric 
Wilcoxon rank sum test if the data are not normally distributed and with a 2-
sample t-test if the data appear to be normally distributed. 

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Some immunologic assays have underlying continuous or count-type readout that 
are dichotomized into responder/nonresponder categories. If treatment group 
differences for these assays are best summarized by a mixture model, then either 
Lachenbruch’s test statistic [77] or an alternative two-part test [78] (as defined in 
the SAP) will be used to evaluate the composite null hypothesis of equal response 
rates in the 2 groups and equal response distributions among responders in the 2 
such groups. For estimation, differences in response rates between groups will be 
estimated using the methods described above, and in the subgroup of positive 
responders, differences in location parameters between groups will be estimated 
using the methods described above.  
6.4.4.2 
Missing data considerations 
Based upon previous HVTN trials, missing 15% of immunogenicity results for a 
specific assay is common due to study participants terminating from the study 
early, problems in shipping specimens, or low cell viability of processed PBMCs. 
To achieve unbiased statistical estimation and inferences with standard methods 
applied in a complete-case manner (only including participants with observed data 
in the analysis), missing data need to be missing completely at random (MCAR). 
MCAR assumes that the probability of an observation being missing does not 
depend on any participant characteristics (observed or unobserved). When 
missing data are minimal (specifically, if no more than 20% of participants are 
missing values), then standard complete-case methods will be used, because 
violations of the MCAR assumption will have little impact on the estimates.  
If a substantial amount of immunogenicity data are missing (at least 1 value 
missing from more than 20% of participants), then using the methods that require 
the MCAR assumption may give misleading results. In this situation, analyses of 
the immunogenicity endpoints at a specific timepoint will be performed using 
parametric generalized linear models fit by maximum likelihood. These methods 
provide unbiased estimation and inferences under the parametric modeling 
assumptions and the assumption that the missing data are missing at random 
(MAR). MAR assumes that the probability of an observation being missing may 
depend upon the observed responses and upon observed covariates, but not upon 
any unobserved factors. Generalized linear models for response rates will use a 
binomial error distribution and for quantitative endpoints, a normal error 
distribution. For assessing repeated immunogenicity measurement, linear mixed 
effects models will be used. If the immunological outcomes are left- and/or right- 
censored, then the linear mixed effects models of Hughes [79] will be used, 
because they accommodate the censoring. In addition, secondary analyses of 
repeated immunogenicity measurements may be done using weighted GEE [80] 
methods, which are valid under MAR. All of the models described above will 
include as covariates all available baseline predictors of the missing outcomes.  
6.4.5 
Analyses and data sharing prior to end of scheduled follow-up visits 
Any analyses conducted prior to the end of the scheduled follow-up visits should 
not compromise the integrity of the trial in terms of participant retention or safety 

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or immunogenicity endpoint assessments. In particular, early unblinded analyses 
by treatment assignment require careful consideration and should be made 
available on a need to know basis in accordance with Sections 6.4.5.1 and 6.4.5.2. 
Interim blinded safety and immunogenicity data should not be shared outside of 
the SMB, HVTN 120 PSRT, the protocol team leadership, the HVTN Executive 
Management Team, the study product developer, and the study sponsor and/or its 
designee(s) for their regulatory reporting unless approved by the protocol 
leadership and the HVTN leadership. 
6.4.5.1 
Safety 
During the course of the trial, unblinded analyses of safety data will be prepared 
approximately every 4 months during the study, as defined in Section 11.1.2, for 
review by the HVTN SMB. Ad hoc safety reports may also be prepared for SMB 
review at the request of the HVTN 120 PSRT. Refer to the process described in 
the HVTN unblinding MOP any requests for unblinded safety data prior to the 
end of the scheduled follow-up visits. 
6.4.5.2 
Immunogenicity analyses 
The unblinded analysis of the primary endpoint of CD4+ T-cell response rates 
measured at month 6.5 will be conducted when all participants have completed 
the visit and all samples have been analyzed. Unblinded results will not be made 
publicly available until participants have completed their month 12 visit. 
Unblinded data analyses of secondary and exploratory endpoints (ie, additional 
immunogenicity assays) measured at month 6.5 will occur after the unblinded 
CD4+ T-cell immunogenicity analysis since selection of secondary assays is 
dependent upon the primary analysis. Analysis of secondary and exploratory 
objectives for month 6.5 will take place after the primary analysis and may be 
performed when assay data are available for analysis from at least 80% of 
participants.  
Analysis of anti-gp120 binding antibody response magnitudes measured at month 
12 will be conducted when all participants have completed the visit and all 
samples have been analyzed. Unblinded analysis of secondary and exploratory 
endpoints from the month 12 timepoint will take place after the primary analysis 
of anti-gp120 binding antibody and may be performed when assay data are 
available for analysis from at least 80% of participants.  
The Laboratory Program will review analysis reports prior to distribution to the 
protocol chairs, DAIDS, vaccine developer, and other key HVTN members and 
investigators. Distribution of reports will be limited to those with a need to know 
for the purpose of informing decisions related to future trials. The HVTN 
leadership must approve any other requests for HVTN immunogenicity analyses 
prior to the end of the scheduled follow-up visits. 

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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. 
7.1 
Inclusion criteria 
General and Demographic Criteria 
1. Age of 18 to 40 years 
2. Access to a participating HVTN CRS and willingness to be followed for the 
planned duration of the study 
3. Ability and willingness to provide informed consent 
4. Assessment of understanding: volunteer demonstrates understanding of this 
study; provides answers to a questionnaire prior to first vaccination with verbal 
demonstration of understanding of all questionnaire items answered incorrectly 
5. Agrees not to enroll in another study of an investigational research agent before 
the last required clinic visit 
6. Good general health as shown by medical history, physical exam, and screening 
laboratory tests 
HIV-Related Criteria: 
7. Willingness to receive HIV test results 

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8. Willingness to discuss HIV infection risks and amenable to HIV risk reduction 
counseling  
9. Assessed by the clinic staff as being at “low risk” for HIV infection and 
committed to maintaining behavior consistent with low risk of HIV exposure 
through the last required protocol clinic visit (see low risk guidelines in Appendix 
J and Appendix K).  
Laboratory Inclusion Values 
Hemogram/Complete blood count (CBC) 
10. Hemoglobin ≥ 11.0 g/dL for volunteers who were assigned female sex at birth, ≥ 
13.0 g/dL for volunteers who were assigned male sex at birth. For transgender 
participants who have been on hormone therapy for more than 6 consecutive 
months, determine hemoglobin eligibility based on the gender with which they 
identify (ie, a transgender female who has been on hormone therapy for more than 
6 consecutive months should be assessed for eligibility using the hemoglobin 
parameters for persons assigned female sex at birth). 
11. White blood cell count = 3,300 to 12,000 cells/mm3 
12. Total lymphocyte count ≥ 800 cells/mm3 
13. Remaining differential either within institutional normal range or with site 
physician approval 
14. Platelets = 125,000 to 550,000/mm3 
Chemistry 
15. Chemistry panel: ALT, AST, and ALP < 1.25 times the institutional upper limit 
of normal; creatinine ≤ institutional upper limit of normal. 
Virology 
16. Negative HIV-1 and -2 blood test: US volunteers must have a negative FDA-
approved enzyme immunoassay (EIA). Non-US sites may use locally available 
assays that have been approved by HVTN Laboratory Operations. 
17. Negative Hepatitis B surface antigen (HBsAg)  
18. Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV 
polymerase chain reaction (PCR) if the anti-HCV is positive 
Urine 
19. Normal urine: 

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• Negative urine glucose, and 
• Negative or trace urine protein, and 
• Negative or trace urine hemoglobin (if trace hemoglobin is present on 
dipstick, a microscopic urinalysis with red blood cells levels within 
institutional normal range). 
Reproductive Status 
20. Volunteers who were assigned female sex at birth: 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. 
21. Reproductive status:  
Africa 
A volunteer who was assigned female sex at birth must: 
• Agree to consistently use effective contraception (see Appendix B) for sexual 
activity that could lead to pregnancy from at least 21 days prior to enrollment 
through the last required protocol clinic visit. Effective contraception for 
participants in Africa is defined as using 2 methods of birth control. These 
include 1 of the following methods: 
▪ Condoms (male or female), or 
▪ Diaphragm or cervical cap, 
PLUS 1 of the following methods: 
▪ Intrauterine device (IUD), 
▪ Hormonal contraception (in accordance with applicable national 
contraception guidelines),  
▪ Successful vasectomy in any partner assigned male at birth (considered 
successful if a volunteer reports that a male partner has [1] documentation 
of azoospermia by microscopy, or [2] a vasectomy more than 2 years ago 
with no resultant pregnancy despite sexual activity after vasectomy); or 
▪ Any other contraceptive method approved by the HVTN 120 PSRT 
• Or not be of reproductive potential, such as having reached menopause (no 
menses for 1 year) or having undergone hysterectomy, bilateral 
oophorectomy, or tubal ligation; 

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• Or be sexually abstinent. 
United States 
A volunteer who was assigned female sex at birth must: 
• Agree to consistently use effective contraception (see Appendix C) for sexual 
activity that could lead to pregnancy from at least 21 days prior to enrollment 
through the last required protocol clinic visit. Effective contraception for 
participants in the United States is defined as using any 1 or more of the 
following  methods of birth control: 
▪ Condoms (male or female) with or without spermicide,  
▪ Diaphragm or cervical cap with spermicide, 
▪ IUD, 
▪ Hormonal contraception, or  
▪ Successful vasectomy in any partner assigned male at birth (considered 
successful if a volunteer reports that a male partner has [1] documentation 
of azoospermia by microscopy, or [2] a vasectomy more than 2 years ago 
with no resultant pregnancy despite sexual activity after vasectomy); or 
▪ Any other contraceptive method approved by the HVTN 120 PSRT 
• Or must not be of reproductive potential, such as having reached menopause 
(no menses for 1 year) or having undergone hysterectomy, bilateral 
oophorectomy, or tubal ligation; 
• Or must be sexually abstinent. 
22. Volunteers who were assigned female sex at birth must also agree not to seek 
pregnancy through alternative methods, such as artificial insemination or in 
vitro fertilization until after the last required protocol clinic visit 
Other 
23. Volunteers 21 years of age and older who were assigned female sex at birth 
consenting to provide cervical samples:  
• Pap smear within: 
▪ the 3 years prior to enrollment with the latest result reported as normal or 
ASCUS (atypical squamous cells of undetermined significance), OR 
▪ the 5 years prior to enrollment, with the latest result reported as normal, or 
ASCUS with no evidence of high risk HPV. 
• If no pap smear was done within the last 3 years prior to enrollment (or within 
the last 5 years, if high risk HPV testing was performed), the volunteer must 

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be willing to undergo a pap smear with the result reported as normal or 
ASCUS prior to sample collection. 
7.2 
Exclusion criteria 
General 
1. Blood products received within 120 days before first vaccination  
2. Investigational research agents received within 30 days before first vaccination 
3. Body mass index (BMI) ≥ 40; or BMI ≥ 35 with 2 or more of the following: 
systolic blood pressure > 140 mm Hg, diastolic blood pressure > 90 mm Hg, 
current smoker, known hyperlipidemia  
4. 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 120 study  
5. Pregnant or breastfeeding 
6. Active duty and reserve US military personnel 
Vaccines and other Injections 
7. HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have 
received control/placebo in an HIV vaccine trial, the HVTN 120 PSRT will 
determine eligibility on a case-by-case basis. 
8. Previous receipt of monoclonal antibodies (mAbs), whether licensed or 
investigational; the HVTN 120 PSRT will determine eligibility on a case-by-case 
basis. 
9. 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 120 PSRT will determine eligibility on a 
case-by-case basis. For volunteers who have received an experimental vaccine(s) 
more than 5 years ago, eligibility for enrollment will be determined by the HVTN 
120 PSRT on a case-by-case basis. 
10. Live attenuated vaccines received within 30 days before first study vaccination 
or scheduled within 14 days after first study vaccination (eg, measles, mumps, 
and rubella [MMR]; oral polio vaccine [OPV]; varicella; yellow fever; live 
attenuated influenza vaccine) 

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11. Any vaccines that are not live attenuated vaccines and were received within 14 
days prior to first study vaccination (eg, tetanus, pneumococcal, Hepatitis A or B) 
12. Allergy treatment with antigen injections within 30 days before first study 
vaccination or that are scheduled within 14 days after first study vaccination  
Immune System  
13. Immunosuppressive medications received within 168 days before first study 
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 prednisone or equivalent at doses ≤ 60 
mg/day and length of therapy < 11 days with completion at least 30 days prior to 
enrollment. 
14. 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 nonanaphylactic 
adverse reaction to pertussis vaccine as a child.)  
15. Immunoglobulin received within 60 days before first study vaccination (for mAb 
see criterion 8 above) 
16. Autoimmune disease  
17. Immunodeficiency 
Clinically significant medical conditions  
18. 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: 
• A process that would affect the immune response, 
• A process that would require medication that affects the immune response, 
• Any contraindication to repeated injections or blood draws, 
• 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, 
• A condition or process for which signs or symptoms could be confused with 
reactions to vaccine, or 
• Any condition specifically listed among the exclusion criteria below. 

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19. 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 
20. 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. 
21. Current anti-tuberculosis (TB) prophylaxis or therapy 
22. Asthma other than mild, well-controlled asthma. (Symptoms of asthma severity 
as defined in the most recent US National Asthma Education and Prevention 
Program (NAEPP) Expert Panel report).  
 
Exclude a volunteer who: 
• Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or 
• Uses moderate/high dose inhaled corticosteroids, or 
• In the past year has either of the following: 
▪ Greater than 1 exacerbation of symptoms treated with oral/parenteral 
corticosteroids; 
▪  Needed emergency care, urgent care, hospitalization, or intubation for 
asthma. 
23. Diabetes mellitus type 1 or type 2. (Not excluded: type 2 cases controlled with 
diet alone or a history of isolated gestational diabetes.) 
24. Thyroidectomy, or thyroid disease requiring medication during the last 12 
months 
25. Hypertension: 
• If a person has been found to have elevated blood pressure or hypertension 
during screening or previously, exclude for blood pressure that is not well 
controlled. Well-controlled blood pressure is defined as consistently ≤ 140 
mm Hg systolic and ≤ 90 mm Hg diastolic, with or without medication, with 
only isolated, brief instances of higher readings, which must be ≤ 150 mm Hg 
systolic and ≤ 100 mm Hg diastolic. For these volunteers, blood pressure must 
be ≤ 140 mm Hg systolic and ≤ 90 mm Hg diastolic at enrollment. 
• If a person has NOT been found to have elevated blood pressure or 
hypertension during screening or previously, exclude for systolic blood 
pressure ≥ 150 mm Hg at enrollment or diastolic blood pressure ≥ 100 mm Hg 
at enrollment. 

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26. Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or 
platelet disorder requiring special precautions) 
27. 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) 
28. Seizure disorder: History of seizure(s) within past 3 years. Also exclude if 
volunteer has used medications in order to prevent or treat seizure(s) at any time 
within the past 3 years. 
29. Asplenia: any condition resulting in the absence of a functional spleen 
30. 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 11.3. 
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: 
• Within 45 days prior to any study injection  
▪ Receipt of blood products or immunoglobulin 
• Within 30 days prior to any study injection 
▪ Receipt of live attenuated vaccines  
▪ Receipt of allergy treatment with antigen injections 
• Within 14 days prior to any study injection 
▪ Receipt of any vaccines that are not live attenuated vaccines (eg, 
pneumococcal)  
• Pre-vaccination abnormal vital signs or clinical symptoms that may mask 
assessment of vaccine reaction. 
• 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 2 negative urine pregnancy tests 

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taken from 2 different urine samples that may be collected on the same day; in 
this circumstance, the HVTN 120 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 120 Study Specific Procedures. 
In order to avoid vaccination delays and missed vaccinations, participants who 
plan to receive licensed vaccines or allergy treatments should be counseled to 
schedule receipt of these 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 interval 
between a study vaccination and completion of the 2 week postvaccination 
follow-up 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 (see 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 
temporarily or permanently discontinued. Specific events that will result in 
stopping a participant’s vaccination schedule include: 
• 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 120 PSRT). 
• 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, see Section 7.3.1); 
▪ HIV infection; 
▪ Any grade 4 local or systemic reactogenicity symptom, lab abnormality, or 
AE that is subsequently considered to be related to vaccination; 

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▪ Any grade 3 lab abnormality that is subsequently considered to be related 
to vaccination 
▪ Other grade 3 clinical AE (exception: fever or vomiting and subjective 
local and systemic symptoms) that is subsequently considered to be related 
to vaccination. For grade 3 injection site erythema and/or induration, upon 
review, the PSRT may allow continuation of vaccination 
▪ SAE that is subsequently considered to be related to vaccination  
▪ Clinically significant type 1 hypersensitivity reaction associated with 
study vaccination. Consultation with the HVTN 120 PSRT is required 
prior to subsequent vaccinations following any type 1 hypersensitivity 
reaction associated with study vaccination;  
• Investigator determination in consultation with Protocol Team leadership (eg, 
for repeated nonadherence to study staff instructions). 
A study participant who misses a study vaccination is permitted to continue with 
subsequent vaccinations that can still be scheduled within the time intervals 
specified for those procedures in the HVTN 120 Study Specific Procedures (SSP), 
unless there is a protocol-mandated reason for discontinuation.  
Participants discontinuing study product for reasons other than HIV infection 
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 (see 
HVTN 120 SSP). 
Participants diagnosed with HIV infection during the study should be encouraged 
to participate in follow-up visits as indicated in Section 9.14). 
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: 
• Participant refuses further participation, 
• Participant relocates and remote follow-up or transfer to another HVTN CRS 
is not possible, 
• HVTN CRS determines that the participant is lost to follow-up,  
• Investigator decides, in consultation with Protocol Team leadership, to 
terminate participation (eg, if participant exhibits inappropriate behavior 
toward clinic staff), or 

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• 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 Investigator’s Brochures 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 and 1; 
THEN 
ALVAC-HIV (vCP2438) to be administered as 1 mL IM in LEFT deltoid (unless 
medically contraindicated) at months 3 and 6; 
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 and 6; 
AND 
Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 
0.9%) to be administered as 0.75 mL IM in RIGHT deltoid (unless medically 
contraindicated) at months 3 and 6. 
Group 2 
Treatment 2 (T2): ALVAC-HIV (vCP2438) to be administered as 1 mL IM in 
LEFT deltoid (unless medically contraindicated) at months 0 and 1; 
THEN 
ALVAC-HIV (vCP2438) to be administered as 1 mL IM in LEFT deltoid (unless 
medically contraindicated) at months 3 and 6; 
AND 

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Bivalent Subtype C gp120 / AS01B (an admixture of 100 mcg of TV1.C gp120, 
100 mcg of 1086.C gp120, and AS01B) to be administered as 0.75 mL IM in the 
RIGHT deltoid (unless medically contraindicated) at months 3 and 6; 
AND 
Placebo for Bivalent Subtype C gp120/MF59 (Sodium Chloride for Injection, 
0.9%) to be administered as 0.5 mL IM in RIGHT deltoid (unless medically 
contraindicated) at months 3 and 6. 
Group 3 
Treatment 3 (T3): ALVAC-HIV (vCP2438) to be administered as 1 mL IM in 
LEFT deltoid (unless medically contraindicated) at months 0 and 1; 
THEN 
ALVAC-HIV (vCP2438) to be administered as 1 mL IM in LEFT deltoid (unless 
medically contraindicated) at months 3 and 6; 
AND 
Bivalent Subtype C gp120 / AS01B (an admixture of 20 mcg of TV1.C gp120, 20 
mcg of 1086.C gp120, and AS01B) to be administered as 0.75 mL IM in the 
RIGHT deltoid (unless medically contraindicated) at months 3 and 6; 
AND 
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 
0.9%) to be administered as 0.5 mL IM in RIGHT deltoid (unless medically 
contraindicated) at months 3 and 6. 
Group 4 
Placebo 4 (P4): 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 and 1; 
THEN 
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 3 and 6; 
AND 

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Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 
0.9%) to be administered as 0.75 mL IM in the RIGHT deltoid (unless medically 
contraindicated) at months 3 and 6; 
AND 
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 
0.9%) to be administered as 0.5 mL IM in RIGHT deltoid (unless medically 
contraindicated) at months 3 and 6. 
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. 
Diluent for ALVAC-HIV (vCP2438) (labeled as Diluent 0.4% NaCl) 
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 will be needed to reconstitute 
each vial of ALVAC-HIV (vCP2438). 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. 
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. 

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MF59® [labeled as MF59C.1] is supplied as an oil-in-water emulsion. The MF59 
adjuvant is an opaque whitish suspension 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, protected from light. 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 Bivalent 
Subtype C gp120/MF59®. Product must be stored as directed by the manufacturer. 
AS01B is produced as a liposomal formulation containing MPL and QS-21 
Stimulon®. It is provided as an opalescent colorless to yellowish liquid in pre-
filled vials. Each vial contains a volume to deliver 0.5 mL. The product must be 
stored refrigerated at 2 to 8° C. 
The study product is described in further detail in the IB. 
Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 
0.9%) 
Sodium Chloride for Injection, 0.9%, will be used as the placebo for Bivalent 
Subtype C gp120 / AS01B. 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 
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 

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contents are well dissolved. DO NOT SHAKE THE VIAL. (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, 
3 or 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 prefilled expired 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, 3, or 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 (an admixture of 100 mcg of TV1.C 
gp120, 100 mcg of 1086.C gp120, and MF59) 
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 pharmacist will remove the TV1.C gp120 and 1086.C 
gp120 from the freezer and allow to thaw at room temperature. (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°C – 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.) The pharmacist will also remove the 
MF59C.1 vial from the refrigerator and mix by repeated gentle swirling and 
inversion (do not shake vigorously).  
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 

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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 or 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 study product 
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  
Using aseptic technique, the pharmacist will withdraw 0.5 mL of Sodium 
Chloride for Injection, 0.9% into a 1 or 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 study product 
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.  
8.3.5 
Bivalent Subtype C gp120 / AS01B (an admixture of 100 mcg of TV1.C 
gp120, 100 mcg of 1086.C gp120, and AS01B)  
One vial of TV1.C gp120 protein, one vial of 1086.C gp120 protein, two vials of 
AS01B, and one empty sterilized vial (for admixing) will be needed to prepare the 
dose. Prior to dispensing, the pharmacist will remove the TV1.C gp120 and 
1086.C gp120 vials from the freezer and allow them to thaw at room temperature. 
(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°C – 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.) The pharmacist will also remove the 
AS01B vials from the refrigerator. 

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Using aseptic technique, the pharmacist will withdraw 0.5 mL into a 1 mL syringe 
from the first vial of AS01B. This volume will be transferred into the empty 
sterilized vial (“preparation vial”). The pharmacist will then repeat this process 
using the second vial of AS01B. The preparation vial now contains 1 mL of 
AS01B. 
Using aseptic technique, the pharmacist will gently swirl the contents of the vial 
containing TV1.C gp120 and then withdraw 0.25 mL of TV1.C gp120 from the 
correct vial and inject it into the preparation vial containing AS01B. The 
pharmacist will then gently swirl the vial containing 1086.C gp120 after which, 
using aseptic technique, the pharmacist will withdraw 0.25 mL of 1086.C gp120 
from the correct vial and inject it into the preparation vial (which contains TV1.C 
gp120 and AS01B). After gentle swirling and inversion (do not shake vigorously) 
the pharmacist, using aseptic technique, will withdraw 0.75 mL of the mixed 
preparation (100 mcg of each protein mixed with AS01B Adjuvant) for dosing 
into a 3 mL syringe or smaller. The pharmacist will apply an overlay to the 
syringe. 
The syringe should be labeled as “Bivalent Subtype C gp120 / AS01B or Placebo 
0.75 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 study 
product 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 vials, preparation vials, or expired prefilled syringes 
should be disposed of in compliance with local health, safety and environmental 
requirements  
8.3.6 
Bivalent Subtype C gp120 / AS01B (an admixture of 20 mcg of TV1.C 
gp120, 20 mcg of 1086.C gp120, and AS01B) 
One vial of TV1.C gp120 protein, one vial of 1086.C gp120 protein, two vials of 
AS01B, one vial/IV bag/ampule of Sodium Chloride for Injection, 0.9%, and one 
empty sterilized vial (for admixing) will be needed to prepare the dose. Prior to 
dispensing, the pharmacist will remove the TV1.C gp120 and 1086.C gp120 from 
the freezer and allow them to thaw at room temperature. (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°C – 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.) The pharmacist will also remove the AS01B vial 
from the refrigerator. 
Using aseptic technique, the pharmacist will withdraw 0.5 mL into a 1 mL syringe 
from the first vial of AS01B. This volume will be transferred into the empty 
sterilized vial (“preparation vial”). The pharmacist will then repeat this process 

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using the second vial of AS01B. The preparation vial now contains 1 mL of 
AS01B. 
Using aseptic technique, the pharmacist will gently swirl the contents of the vial 
containing TV1.C gp120 and then withdraw 0.05 mL of TV1.C gp120 from the 
correct vial and inject it into the preparation vial containing AS01B. The 
pharmacist will then gently swirl the vial containing 1086.C gp120 after which, 
using aseptic technique, the pharmacist will withdraw 0.05 mL of 1086.C gp120 
from the correct vial and inject it into the preparation vial (which contains 
TV1.C gp120 and AS01B). The pharmacist will then withdraw 0.4 mL of Sodium 
Chloride for Injection, 0.9% and transfer it into the preparation vial (containing 
TV1.C gp120, 1086.C gp120 and AS01B). After gentle swirling and inversion (do 
not shake vigorously) the pharmacist, using aseptic technique, will withdraw 
0.75 mL of the mixed preparation (20 mcg of each protein mixed with AS01B and 
0.9% NaCl) for dosing into a 3 mL syringe or smaller. The pharmacist will apply 
an overlay to the syringe. 
The syringe should be labeled as “Bivalent Subtype C gp120 / AS01B or Placebo 
0.75 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 study 
product 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 reconstituted vials or expired prefilled syringes is disposed 
of in compliance with local health, safety and environmental requirements. 
8.3.7 
Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for 
Injection, 0.9%) 
Using aseptic technique, the pharmacist will withdraw 0.75 mL of Sodium 
Chloride for Injection, 0.9% into a 3 mL syringe or smaller. The pharmacist will 
apply an overlay to the syringe. 
The syringe should be labeled as “Bivalent Subtype C gp120 / AS01B or Placebo 
0.75 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. If this is not possible, the study product 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 will 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 Subtype C gp120 / MF59 or placebo or 
Bivalent Subtype C gp120 / AS01B or placebo, the person administering the 
injection should gently roll the syringe prior to administration of the study 
product. 
If an injection(s) needs to be administered in an alternate body site (eg, thigh) due 
to a medical contraindication, the injection(s) should not be administered in the 
same deltoid as the other injection(s). The appropriate study staff should 
document this clearly. Under this circumstance, this is NOT a protocol violation. 
8.5 
Acquisition of study products 
The ALVAC-HIV (vCP2438) and diluent (0.4% NaCl) will be supplied by Sanofi 
Pasteur and will be available through the NIAID Clinical Research Products 
Management Center (CRPMC).  
Bivalent Subtype C gp120, MF59®, and AS01B will be supplied by GSK 
Vaccines and will be available through the NIAID CRPMC.  
Placebo for ALVAC-HIV (Sodium Chloride for Injection, 0.9%), Placebo for 
Bivalent Subtype C gp120/MF59 (Sodium Chloride for Injection, 0.9%), and 
Placebo for Bivalent Subtype C gp120/AS01B (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 
For US clinical research sites, all unused study products must be returned to the 
CRPMC after the study is completed or terminated unless otherwise instructed by 
the study sponsor. For non-US clinical research sites, all unused study products 
must be destroyed after the study is completed or terminated unless otherwise 
instructed by the study sponsor. The procedures are included in the Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks.  

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9 
Clinical procedures 
The schedule of clinical procedures is shown in Appendix G. 
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 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 informed consent forms (ICFs) 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. 
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 

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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 E. 
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 and Appendix E. The consent form(s) must be developed in 
accordance with requirements of the following: 
• CRS’s IRB/EC and any applicable REs, 
• CRS’s institution, and 
• Elements of informed consent as described in Title 45 CFR Part 46 and Title 
21 CFR, Part 50, and in ICH E6, Good Clinical Practice: Consolidated 
Guidance 4.8.  
Study sites are strongly encouraged to have their local CABs review their site-
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 forms include 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. 
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 

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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. The participant must 
complete the Assessment of Understanding before enrollment. Staff may provide 
assistance in reading and understanding the questions and responses, if necessary. 
Participants must verbalize understanding of all questions answered incorrectly. 
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, unless otherwise specified in the 
eligibility criteria (or below in this section). 
After the appropriate informed consent has been obtained and before enrollment, 
the following procedures are performed: 
• Medical history, documented in the case history record; 
• Assessment of Understanding (see Section 9.1.3); 
• Assessment of whether the volunteer is at low risk for HIV infection (see low 
risk guidelines in Appendix J and Appendix K); 
• Complete physical examination, including height, weight, vital signs, and 
clinical assessments of head, ears, eyes, nose, and throat; neck; lymph nodes; 
heart; chest; abdomen; extremities; neurological function; and skin; 
• Assessment of concomitant medications the volunteer is taking, including 
prescription and nonprescription drugs, vitamins, topical products, 
alternative/complementary medicines (eg, herbal and health food 
supplements), recreational drugs, vaccinations, and allergy shots; 
• Laboratory tests, including: 
▪ Screening HIV test,  
▪ CBC with differential and platelet count,  

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▪ Chemistry panel (ALT, AST, ALP, and creatinine), 
▪ Urine dipstick (urinalysis if indicated, see Section 9.9), 
▪ HBsAg,  
▪ Anti-HCV Ab, 
▪ Urine or serum pregnancy test (volunteers who were assigned female sex 
at birth); 
▪ Pap smear (Only for volunteers who were assigned female sex at birth and 
who agree to provide cervical samples; not required if volunteer has had 
Pap smear within previous 3-5 years with most recent result normal or 
ASCUS or less than 21 years old (see Section 7.1, Criterion 23; 
• Syphilis test, 
• Administration of behavioral risk assessment questionnaire; 
• 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); 
• Counseling on HIV testing and risk reduction, performed in compliance with 
the US Centers for Disease Control and Prevention (CDC)’s current 
guidelines or other local guidelines for HIV counseling, testing, and referral as 
described in Section 9.7; and 
• 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. Discussion of 
pregnancy prevention includes advising a participant who was assigned 
female sex at birth and who reports no current sexual activity that could lead 
to that participant becoming pregnant to have a plan to begin adequate birth 
control. This plan would be put to use if, during the study, the participant 
becomes sexually active in a way that could lead to that participant becoming 
pregnant.  
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 (see Sections 7.1 and 7.2). 

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9.3 
Enrollment and vaccination visits 
Enrollment is simultaneous with first vaccination. The HVTN CRS requests the 
randomization assignment via a Web-based randomization system. In general, the 
time interval between randomization and enrollment should not exceed 4 working 
days. However, 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; 
• Assessment of concomitant medications (as described in Section 9.2); 
• Assessment of any new or unresolved AEs/intercurrent illnesses; and 
• Urine or serum pregnancy test (for participants who were assigned female sex 
at birth). 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. 
Following completion of all procedures in the preceding list, and if results 
indicate that vaccination may proceed, vaccination is prepared and administered 
(see 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 is given the Participant Diary and is instructed on how to 
complete it. The site will make arrangements to be in contact with the participant 
during the reactogenicity period (as described in Section 9.10). 
The following procedures will be performed at all vaccination visits. These 
procedures may be performed prior to or following vaccination:  
• Risk reduction counseling (as described in Section 9.7);  
• Pregnancy prevention assessment (as described in Section 9.2 and 9.8); and 

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• 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). 
Additional procedures will be performed at scheduled visits as specified in 
Appendix G:  
• HIV infection assessment including pretest counseling. A subsequent follow-
up contact is conducted to provide post-test counseling and to report results to 
participant; 
• Confirm that participants received HIV test results from previous visit. If not, 
provide test results and post-test counseling as appropriate; and 
• Administration of the social impact assessment questionnaire (types of 
impacts assessed involve personal relationships, health insurance, life 
insurance, educational or employment opportunities, housing, immigration, or 
travel); 
• Administration of behavioral risk assessment questionnaire; 
• Administration of a questionnaire that asks the participant about any HIV 
testing he or she may have received outside of the study. Participants will also 
be asked whether they believe they received the active vaccine or the control; 
• Specimen collection (blood and/or mucosal and/or stool) should be completed 
prior to vaccination; 
• For participants who agree to mucosal sampling collection (see Appendix G): 
▪ Urine test or swab for gonorrhea and chlamydia; 
▪ Vaginal swab for Trichomonas and bacterial vaginosis (for participants 
providing cervical samples); 
• Vaginal swab (if indicated) for hyphae/budding yeast (for participants 
providing cervical samples); 
• Syphilis serology; and 
• Mucosal specimen collection. 
9.4 
Follow-up visits 
The following procedures are performed at all scheduled follow-up visits: 
• Risk reduction counseling (as described in Section 9.7);  

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• Pregnancy prevention assessment (as described in Section 9.2 and 9.8); and 
• 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); 
• Assessment of new or continuing concomitant medications (as described in 
Section 9.2); and 
• Assessment of new or unresolved AEs/intercurrent illnesses.  
Additional procedures will be performed at scheduled follow-up visits as 
specified in Appendix G:  
• Administration of behavioral risk assessment questionnaire; 
• Administration of the social impact assessment questionnaire (types of 
impacts assessed involve personal relationships, health insurance, life 
insurance, educational or employment opportunities, housing, immigration, or 
travel); 
• Administration of a questionnaire that asks the participant about any HIV 
testing he or she may have received outside of the study. Participants will also 
be asked whether they believe they received the active vaccine or the control; 
• 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; 
• Confirm that participants received HIV test results from previous visit. If not, 
provide test results and post-test counseling as appropriate; 
• 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;  
• 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; and skin; 
• Specimen collection (blood and/or mucosal and/or stool); 
• Clinical laboratory tests including: 
▪ CBC with differential, 
▪ Chemistry panel (see Section 9.2), and 
▪ Urine dipstick (urinalysis if appropriate; see Section 9.9); and 

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• Urine or serum pregnancy test (for participants who were assigned female sex 
at birth). 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. 
• For participants who agree to mucosal sampling collection (see Section 9.5): 
▪ Urine test or swab for gonorrhea and chlamydia; 
▪ Vaginal swab for Trichomonas and bacterial vaginosis (for participants 
providing cervical samples); 
• Vaginal swab (if indicated) for hyphae/budding yeast (for participants 
providing cervical samples); 
• Syphilis serology; 
• Pregnancy test; and 
• Mucosal specimen collection. 
9.5 
Mucosal sampling 
Mucosal samples will be collected at the timepoints indicated in Appendix G from 
the study participants who agree to these procedures. 
Participants who consent to provide cervical, rectal, or semen samples will be 
tested for the following infections at the mucosal sampling visits: gonorrhea, 
chlamydia, and syphilis. Participants who consent to provide cervical fluid 
samples will be tested for trichomoniasis and for bacterial vaginosis and (if 
clinically indicated) for hyphae/budding yeast. Test results will be provided to 
participants and all participants who test positive for 1 or more of these infections 
will receive counseling as well as treatment (or referral for treatment) as 
appropriate. Sample collection may not be performed or may be deferred to a later 
date within the visit window if a contraindication to sampling (eg, active GTI) is 
present (as indicated below). 
Rectal fluid sampling (both sexes): For participants assigned female sex at birth, 
a pregnancy test must be performed and be negative prior to any rectal mucosal 
sampling. 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. Rectal secretion sampling 
should be deferred if a participant is menstruating, but should be performed as 
soon as possible, if still within the visit window. In addition, rectal sampling will 
not be performed (or may be deferred to a later date if still within the visit 
window) if there is a contraindication to rectal secretion sampling, such as an 
active infection or inflammation of the colorectal area [such as a herpes simplex 

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virus (HSV)-2 outbreak or inflamed hemorrhoids or colitis/diarrhea] or if the 
participant has any active genital tract infection (GTI). 
For 48 hours prior to sample collection, participants should abstain from: 
• Receptive anal sex,  
• Insertion of any foreign object or substance into the anus (including but not 
limited to cleaning products [creams, gels, lotions, pads, etc.], lubricant, 
enemas, and douching even with water), and  
• Using perianal or intra-anal steroid or other anti-inflammatory cream in or 
around the anus.  
Cervical fluid sampling (only for participants who were assigned female sex 
at birth): Participants who are 21 years of age and older must report having had a 
Pap smear within the 3-5 years prior to enrollment, with the latest result reported 
as normal or ASCUS (see Section 7.1). A pregnancy test must be performed on 
the day of cervical sampling. The pregnancy test can be performed after collection 
has taken place. 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. Cervical sampling should 
be deferred if a participant is menstruating, but should be performed as soon as 
possible, if still within the visit window. In addition, cervical sampling will not be 
performed (or may be deferred to a later date if still within the visit window) if a 
participant is known to have an active ulcerative genital lesion or an active GTI at 
the scheduled timepoint. Participants providing cervical secretion samples should 
be advised as follows: 
• Do not use anything with spermicide, lubricants, or topical/intravaginal 
medications (eg, topical yeast infection treatments) for 48 hours before the 
samples are collected;  
• Do not douche for 48 hours before the samples are collected;  
• Do not have vaginal sex and/or insert any foreign object or substance into the 
vagina for 48 hours before the samples are collected;  
Semen sampling (only for participants who were born male): Participants 
providing semen samples are asked to refrain from ejaculation for at least 48 
hours prior to specimen collection. In addition, mucosal sampling will not be 
performed (or may be deferred to a later date if still within the visit window) if a 
participant is known or believes to have an active GTI at the scheduled timepoint. 

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9.6 
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. 
9.7 
HIV counseling and testing 
HIV counseling will be performed in compliance with the CDC’s 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 Ab positive due to 
the vaccine. They will also be counseled on the risks of HIV Ab 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. 
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 
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. 
Potential participants identified as being HIV-infected during screening are not 
enrolled. Potential and enrolled participants identified as HIV infected will be 
referred for medical treatment, counseling, and management of the HIV infection. 
Participants who are found to be HIV-infected after enrollment will not receive 
any additional study product but will continue to be followed in the study for 
safety assessments. These individuals may also be referred to appropriate ongoing 
clinical trials or observational studies. 

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9.7.1 
Distinguishing intercurrent HIV infection from vaccine-induced 
positive serology 
The study product may elicit an Ab 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: 
• Participants will have physical examinations at visits specified in Appendix G. 
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. 
• HIV testing will be performed at multiple timepoints throughout the study 
(see Appendix F). The Laboratory Program (or approved diagnostic 
laboratory) will follow the HVTN HIV testing algorithm (as described in the 
HVTN 120 SSP), which is able to distinguish vaccine-induced Ab responses 
from actual HIV infections.  
• All participants can receive HIV-1 diagnostic testing from the site following 
their last scheduled visit until they are told that they did not receive an HIV 
vaccine or that they do not have vaccine-induced seropositivity. 
• All participants who received vaccine product and who have vaccine-induced 
positive or indeterminate HIV-1 serology (as measured by the standard anti-
HIV Ab 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.  
9.7.2 
VISP registry  
Experimental HIV vaccines may induce Ab production to HIV antigens, 
producing reactive results on commercially available HIV test kits. This is called 
“vaccine-induced seropositivity” (VISP) (see Section 9.7.1). 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.  

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9.8 
Contraception status 
Contraception status is assessed and documented at every scheduled clinic visit 
for a participant who was assigned female sex at birth and who is sexually active 
in a way that could cause that participant to become pregnant. Prior to enrollment 
and throughout the study, staff will ask participants to verbally confirm their use 
of adequate contraceptive methods. A participant who was assigned female sex at 
birth and is sexually active in a way that could cause that participant to become 
pregnant 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. (Specific contraception requirements are listed in Section 
7.1). This reminder should be documented in the participant’s study record. 
Self-reported infertility—including having reached menopause (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 
Urinalysis 
Dipstick testing may be performed in the clinic or the lab, as long as the required 
elements (glucose, protein, and hemoglobin) are tested. The examination is 
performed on urine obtained by clean catch. 
If the screening dipstick is transiently abnormal due to menses or infection, 
document this issue in the participant’s source documentation. For infection, 
provide appropriate treatment and/or referral. Following resolution, repeat the 
dipstick and, if within the eligibility limits specified in the protocol, the 
participant may be enrolled. 
Follow-up urinalysis should be deferred if a participant is menstruating, but 
should be performed as soon as possible. If a follow-up dipstick is abnormal due 
to a participant’s menstrual period, document in the comment section of the case 
report form (CRF) and repeat the dipstick once the participant is no longer 
menstruating. A micro-urinalysis is not required. 
9.10 
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 (DAIDS AE 
Grading Table), Corrected Version 2.1, July 2017, except as noted in Section 
11.2.2. 
The reactogenicity assessment period is 7 full days following each vaccination per 
the assessment schedule shown in Table 9-1. Participants are instructed to record 

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symptoms using a Participant Diary. Contacts between the participant and the site 
staff should take place at least once between 1-3 days postvaccination . 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 completely resolved. Clinic staff will follow new or unresolved 
reactogenicity symptoms present at day 7 to resolution. 
Reactogenicity events are reported using CRFs that correspond to the time of 
assessment in Table 9-1. Reactogenicity assessments include assessments of 
systemic and local symptoms, vaccine-related lesions. Events not listed on a CRF, 
or with an onset after the reactogenicity assessment period (day of vaccination 
and 7 full days after), or those meeting criteria for SAE/adverse events requiring 
expedited reporting to regulatory authorities, are recorded on an adverse 
experience log form.  
Table 9-1 Schedule of reactogenicity assessments 
Day 
Time 
Performed by 
0a 
Baseline: before vaccination 
HVTN CRS clinician 
 
Early: 25-60 minutes after vaccination 
HVTN CRS clinician 
 
Between early assessment and 11:59 pm day 0 
HVTN CRS clinician or participant 
1-7 b 
Between 12:00 am and 11:59 pm on the respective 
day 1-7 
HVTN CRS clinician or participant 
a Day of vaccination 
b New or unresolved reactogenicity symptoms present on day 7 are followed until resolution 
9.10.1 
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 at the injection site. The daily maximum severity 
reached for each symptom during the assessment period is reported.  
Body temperature is measured by oral or infrared thermometry. All temperatures 
must be measured by non-axillary thermometry. This includes temperatures taken 
in the clinic, as well as temperatures taken by participants during the 
reactogenicity period. 
Temperature is 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. 
9.10.2 
Assessment of injection site  
Typical injection site reactions are erythema or redness and induration or 
swelling. The maximum horizontal and maximum vertical measurements for all 
injection site reactions are recorded. 

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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. 
9.11 
Visit windows and missed visits 
Visit windows are defined in HVTN 120 Study Specific Procedures. For a visit 
not performed within the window period, a Missed Visit form is completed. If the 
missed visit is one that required safety assessments or local safety labs, 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 
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. 
9.12 
Early termination visit 
In the event of early participant termination, site staff should consider if the 
following assessments are appropriate: a final physical examination, clinical 
laboratory tests (including urine dipstick, CBC with differential, and chemistry 
panel), pregnancy testing, social impact assessment, and HIV test. For participants 
who have a confirmed diagnosis of HIV infection, see Section 9.14. 
9.13 
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. 
For participants who are no longer pregnant, see Section 7.3.1. In case of required 
termination from the study, enrollment in an observational study should be 
offered to the participant, if available. 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. Pregnancies and 
pregnancy outcomes will be reported. 

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9.14 
HIV infection during the study 
If a participant becomes HIV-infected during the course of the study, no 
additional study product will be administered. Participants will be encouraged to 
continue scheduled study visits for up to 24 weeks following their last study 
product administration. Follow-up duration for participants diagnosed with HIV 
infection may be adjusted in consultation with the CRS investigator and the 
HVTN 120 PSRT (eg, to avoid interference with participant initiation of HIV 
treatment). At post-infection follow-up visits, only specimens required for 
protocol-specified safety laboratory tests, urinalysis and pregnancy tests will be 
collected; in addition, some clinic procedures may be modified or discontinued 
(see Appendix F and Appendix G). 
 

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10 
Laboratory 
10.1 
HVTN CRS laboratory procedures 
The HVTN Site Lab Instructions and SSP provide further guidelines for 
operational issues concerning the clinical and processing laboratories. These 
documents include 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. 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. 
Of note, all assays described below are performed as research assays to evaluate 
the ability of the vaccine to induce immune responses in the context of the 
participants’ genetic background, and are not approved for use in medical care. 
Results from these assays are not made available to participants or medical 
professionals to guide treatment decisions. 
10.2 
Total blood volume 
Required blood volumes per visit are shown in Appendix F. 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. 
10.3 
Primary immunogenicity timepoints 
The primary immunogenicity timepoints in this study are at month 6.5 and at 
month 12. Endpoint assays for humoral and cellular responses are performed on 
participants at the appropriate primary immunogenicity timepoints and may be 
performed on samples collected at baseline. Depending on the initial results, 
assays for humoral and cellular responses may be performed on samples collected 
from participants at other timepoints; the schedule is shown in Appendix F. 

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10.4 
Endpoint assays: humoral 
10.4.1 
Binding antibody multiplex assay (BAMA) 
HIV-1–specific total binding IgG antibodies will be assessed on serum samples 
from study participants taken at the primary immunogenicity timepoints and 
baseline. In addition, HIV-1–specific total binding IgA antibodies and binding to 
IgG subclasses (IgG1, IgG2, IgG3, and IgG4) may also be assessed.  Specimens 
from other timepoints as well as other HIV antigens and Ab isotypes may also be 
assayed based on the results of the initial assay. 
10.4.2 
Neutralizing Ab (nAb) assay 
HIV-1–specific nAb assays may be performed on serum samples from study 
participants taken at the primary immunogenicity timepoint(s). 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 timepoints. The TZM-bl assay will test neutralization of 
the vaccine strains (96ZM651, TV1.C, 1086.C) and a single highly neutralization-
sensitive tier 1 virus as a positive control (MW965.26). The global panel and 
clade C panel may be used to assess tier 2 neutralization [81,82]. 
10.4.3 
Antibody-dependent cell-mediated cytotoxicity (ADCC) assay 
ADCC activity may be assessed using serum samples from study participants 
taken at the primary immunogenicity timepoints. 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 timepoints. For the Granzyme B flow-based cytotoxicity assay, 
participant sera are incubated with effector cells and gp120-coated target. ADCC 
is quantified as net percent granzyme B activity which is the percent of target 
cells positive for GranToxiLux (GTL), an indicator of granzyme B uptake, minus 
the percent of target cells positive for GTL when incubated with effector cells but 
without sera. For the Luciferase-based cytotoxity assay, participant sera are 
incubated with IMC-infected cells and percent killing is measured through the use 
of Viviren luminescence. 
10.5 
Endpoint assays: cellular 
10.5.1 
Flow cytometry 
Flow cytometry will 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 will 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. Data will be reported as percentages of CD4+ or 

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CD8+ T cells responding to a specific peptide pool. Additional cell surface 
markers, cytokines, or functional markers may also be analyzed. 
10.6 
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 genes, including those associated with 
immune responses (eg, immunoglobulin, or T cell receptor genes), or HIV-1 
disease progression may also be assessed.  
10.7 
Lab assay algorithm 
The Lab Assay Algorithm lists assays to characterize cellular, humoral, and innate 
immune responses as well as host genetics that may be conducted to determine 
endpoints in HVTN vaccine trials. The type of assay(s) employed will be 
dependent on the response obtained by the primary immunogenicity assays at 
relevant timepoints. Please note that the Lab Assay Algorithm will be updated 
periodically to include new assays. 
10.8 
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.  
10.8.1 
Microbiome analysis 
Swabs of stool will be shipped to a central laboratory at the FHCRC where they 
will be stored at -80oC prior to DNA extraction. DNA extraction will be 
performed with bead-beating and chaotropic lysis of bacteria. Bacterial 
communities in stool samples will be assessed using broad-range 16S rRNA gene 
PCR followed by high throughput sequencing and phylogenetic/taxonomic 
analysis of the sequences. Associations identified by broad range PCR may be 
confirmed using taxon-directed quantitative PCR assays. 
10.9 
Specimen storage and other use of 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.  

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Other use of specimens is defined as studies not covered by the protocol or the 
informed consent form for the main study (see Appendix A).  
This research may relate to HIV, vaccines, the immune system, and other 
diseases. This could include 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 research on 
specimens (“other use”) 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/REs if required.  
As part of consenting for the study, participants document their initial decision to 
allow or not allow their specimens to be used in other research, and they may 
change their decision at any time. The participant’s initial decision about other 
use of their specimens, and any later change to that decision, is recorded by their 
CRS in a Web-based tool that documents their current decisions for other use of 
their specimens. The HVTN will only allow other research to be done on 
specimens from participants who allow such use.  
CRSs must notify HVTN Regulatory Affairs if institutional or local governmental 
requirements pose a conflict with or impose restrictions on specimen storage or 
other use of specimens. 
10.10 
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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11 
Safety monitoring and safety review 
11.1 
Safety monitoring and oversight 
11.1.1 
HVTN 120 PSRT 
The HVTN 120 PSRT is composed of the following members: 
• DAIDS medical officer representative, 
• Protocol chair and cochair, 
• Protocol Team leader, 
• Core medical monitor,  
• Clinical safety specialist (CSS),  
• Regional medical liaison (RML) /Regional Clinical Safety Liaison (RCSL), 
and 
• A medical officer from an organization in Africa designated by the study 
sponsor will also participate in the PSRT.  
The clinician members of the HVTN 120 PSRT are responsible for decisions 
related to participant safety. 
The Protocol Team clinic coordinator, clinical data manager, vaccine developer 
representative, clinical trial manager, and others may also be included in HVTN 
120 PSRT meetings. 
11.1.2 
HVTN SMB 
The SMB is a multidisciplinary group consisting of biostatisticians, clinicians, 
and experts in HIV vaccine research that, collectively, has experience in the 
conduct and monitoring of vaccine trials. Members of the SMB are not directly 
affiliated with the protocols under review.  
The SMB reviews safety data, unblinded as to treatment arm, approximately 
every 4 months. The reviews consist of evaluations of cumulative reactogenicity 
events, AEs, laboratory safety data, and individual reports of adverse events 
requiring expedited reporting to DAIDS and pertinent national regulatory 
authorities. To increase the sensitivity for detecting potential safety problems, the 
SMB will review safety data aggregated across multiple protocols that use the 
same or similar vaccine candidates. The SMB conducts additional special reviews 
at the request of the HVTN 120 PSRT.  

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Study sites will receive SMB summary minutes and are responsible for 
forwarding them to their IRB/EC and any applicable RE. 
11.1.3 
SDMC roles and responsibilities in safety monitoring  
The roles and responsibilities of the SDMC in relation to safety monitoring 
include: 
• Maintaining a central database management system for HVTN clinical data; 
• Providing reports of clinical data to appropriate groups such as the HVTN 120 
PSRT and HVTN SMB (see Section 11.1.2). 
11.1.4 
HVTN Core roles and responsibilities in safety monitoring 
• Daily monitoring of clinical data for events that meet the safety pause and 
HVTN 120 PSRT AE review criteria (see Section 11.3); 
• Notifying HVTN CRSs and other groups when safety pauses or planned holds 
are instituted and lifted (see Section 11.3); 
• Querying HVTN CRSs for additional information regarding reported clinical 
data; and 
• Providing support to the HVTN 120 PSRT. 
11.2 
Safety reporting 
11.2.1 
Submission of safety forms to SDMC 
Sites must submit all safety forms (eg, reactogenicity, adverse experience, 
urinalysis, local lab results, and concomitant medications) before the end of the 
next business day, excluding federal or bank holidays. 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. For the case of a longer site holiday closure, site staff must submit 
the data by the end of the 5th day (local time) after receiving the information even 
if this day is a holiday.  
For example: If the site becomes aware of an AE on Thursday (Day 0), the site 
must submit the data by the end of the next business day, on Friday. If there is a 
longer site holiday closure, then this AE must be reported no later than the end of 
the fifth day, Monday (Day 4). If Monday is a holiday as well, all safety forms 
still need to be submitted by the end of Monday (Day 4). 

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11.2.2 
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 (DAIDS 
AE Grading Table), Corrected Version 2.1, July 2017, available on the RSC 
website at http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-
grading-tables, except:  
• 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 (see HVTN 
120 Study Specific Procedures); 
• Injection Site Erythema or Redness and Injection Site Induration or Swelling 
will not consider interference with usual social and functional activities such 
that: 
▪ 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); 
Unsolicited AEs will be collected over a period of 30 days after 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 (Section 11.2.3), (2) if the AE meets the criteria for a 
safety pause/prompt AE review (Section 11.3), and (3) if the AE is a potential 
immune-mediated disease that may be listed as an AE of special interest (AESI). 
A sample list of AESI is provided in Appendix H. 
Certain AEs will be collected and reported throughout the entire study:  
• SAEs/EAEs,  
• AESIs, 
• New chronic conditions requiring medical intervention for ≥ 30 days, 
• Newly diagnosed or treated STIs, 

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• AEs leading to early participant withdrawal or early discontinuation of study 
product(s) administration. 
CRSs are expected to notify HVTN clinical safety staff of any serious safety 
concern requiring their attention (see Table 11-1). Telephone numbers and email 
addresses are found on the Protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/HVTN 120). Concerns requiring immediate 
attention should be communicated by calling the clinical safety phone. 
In the case of email notification HVTN clinical safety staff will reply during 
working hours (local time) to confirm that the email has been received and 
reviewed. If email service is not available, the HVTN CRS should notify the 
HVTN clinical safety staff of the event by telephone, then submit CRFs. 
In addition, site investigators or their designees are required to submit AE 
information in accordance with IRB/EC and any applicable RE requirements. 
11.2.3 
Expedited reporting of AEs to DAIDS 
Requirements, definitions, and methods for expedited reporting of AEs 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 http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual. 
The SAE Reporting Category will be used for this study. 
The internet-based DAIDS Adverse Experience Reporting System (DAERS) must 
be used for expedited AE (EAE) 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 on the DAIDS RSC website at 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids/paper-eae-
reporting. 
For questions about DAERS, please contact DAIDS-
CRMSsupport@niaid.nih.gov or from within the DAERS application itself.  
For questions about EAE reporting, please contact the DAIDS RSC Safety Office 
at DAIDSRSCSafetyOffice@tech-res.com.  
Under ICH E2A (Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting), an SAE is defined as any untoward medical occurrence 
that at any dose:  
▪ results in death, 
▪ is life-threatening (Note: 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 event; it does not refer to an event, which hypothetically might 
have caused death, if it were more severe), 
▪ requires patient hospitalization or prolongation of existing hospitalization,  

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▪ results in persistent or significant disability/incapacity,  
▪ is a congenital anomaly/birth defect, or 
▪ is a medically important event or reaction*  
*Medical and scientific judgment should be exercised when deciding if other situations are 
serious. 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 the outcomes listed in the definition above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions not resulting in hospitalization, or development of drug dependency or 
drug abuse. 
The expedited reporting period for this study comprises the entire study period for 
each individual participant (from study enrollment until study completion or 
discontinuation from the study). After the expedited reporting period for the 
study, unless otherwise noted, only Suspected, Unexpected Serious Adverse 
Reactions 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. 
The NIAID/DAIDS will report all unexpected SAEs related to the study products 
observed in this clinical trial to the FDA in accordance with 21 CFR 312.32 (IND 
Safety Reports). However, because safety is a primary study endpoint, the 
Sponsor Medical Officer will not routinely be unblinded to study treatment 
assignment when there is an assessment of relatedness of the SAE with the study 
product(s); and the safety report will be sent to the FDA based on the blinded 
attribution assessment. 
In some cases, the PSRT or CRS may believe unblinding of the site PI and 
participant would be appropriate to facilitate the clinical management of an AE or 
SAE. The HVTN MOP specifies procedures for emergency unblinding, and for 
early unblinding for medical reasons. 
The study products that must be considered in determining relationships of AEs 
requiring expedited reporting to DAIDS and pertinent national regulatory 
authorities are: 
▪ ALVAC-HIV (vCP2438)/placebo 
▪ Bivalent Subtype C gp120/MF59/placebo 
▪ Bivalent Subtype C gp120/AS01B/placebo  
11.2.4 
Expedited reporting of AEs to pertinent national regulatory 
authorities  
The study sponsor or designee(s) prepares and files expedited reports to 
appropriate regulatory authorities within the timelines required by pertinent 
national regulatory authorities.  

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Site IoRs/designees will submit AE information and any other relevant safety 
information to their ECs/IRBs in accordance with EC/IRB requirements. 
11.3 
Safety pause and prompt PSRT AE review 
When a 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. The AEs that will lead to a safety pause or prompt HVTN 120 PSRT AE 
review are summarized in Table 11-1. Vaccinations may be suspended for safety 
concerns other than those described in the table, or before pause rules are met, if, 
in the judgment of the HVTN 120 PSRT, participant safety may be threatened. 
Criteria for an individual participant’s departure from the schedule of vaccinations 
are listed in Section 7.3. 
Table 11-1 AE notification and safety pause/AE review rules 
Event and 
relationship to study 
products 
Severity 
HVTN CRS actiona 
HVTN Core action 
SAE, related 
Grade 5 or 
Grade 4 
Phone immediately, email 
and submit forms 
immediately 
Immediate pause 
SAE, not related 
Grade 5 
Phone immediately, email 
and submit forms 
immediately 
Immediate HVTN 120 PSRT 
notification 
SAE, related 
Grade 3, 2, 
or 1 
Email and submit forms 
immediately 
Immediate PSRT notification and 
prompt PSRT AE review to 
consider pause 
AEb, related 
Grade 4 or 
3 
Email and submit forms 
immediately 
Immediate PSRT notification and 
prompt PSRT AE review to 
consider pause 
 a Phone numbers and email addresses are found on the Protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/HVTN 120). 
b Does not include the following Grade 3 subjective reactogenicity symptoms [injection site pain, tenderness, 
fatigue/malaise, myalgia, arthralgia, chills, headache, nausea (unless IV rehydration required)].  
For all safety pauses, HVTN Core notifies the HVTN 120 PSRT, HVTN 
Regulatory Affairs, DAIDS Pharmaceutical Affairs Branch (PAB), DAIDS 
Regulatory Affairs Branch (RAB), DAIDS Safety and Pharmacovigilance Team 
(SPT), and participating HVTN CRSs. When an immediate safety pause is 
triggered, HVTN Core notifies the SMB.  
Once a trial is paused, the HVTN 120 PSRT reviews safety data and decides 
whether the pause can be lifted or permanent discontinuation of vaccination is 
appropriate, consulting the SMB 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 
study vaccinations. Based on the HVTN 120 PSRT assessment, the trial sponsor 
or designee(s) notifies FDA and other pertinent national regulatory authorities as 
needed. 

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If an immediate HVTN 120 PSRT notification or prompt HVTN 120 PSRT AE 
review is triggered, HVTN Core notifies the HVTN 120 PSRT as soon as possible 
during working hours (local time)—or, if the information was received during off 
hours, by the morning of the next work day. If a prompt HVTN 120 PSRT AE 
review cannot be completed within 72 hours of notification (excluding weekends 
and US federal holidays), an automatic safety pause occurs. 
The HVTN requires that each CRS submit to its IRB/EC and any applicable RE 
protocol-related safety information (such as IND safety reports, notification of 
vaccine holds due to the pause rules, unanticipated problems involving risks to 
participants or others, and notification of other unplanned safety pauses). CRSs 
must also follow all applicable RE reporting requirements. 
In addition, all other AEs are reviewed routinely by the HVTN 120 PSRT (see 
Section 11.4.2). 
11.4 
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.  
11.4.1 
Daily review 
Blinded daily safety reviews are routinely conducted by HVTN Core for events 
requiring expedited reporting to DAIDS, and events that meet safety pause criteria 
or prompt HVTN 120 PSRT AE review criteria. 
11.4.2 
Weekly review 
During the injection phase of the trial, the HVTN 120 PSRT reviews clinical 
safety reports on a weekly basis and conducts calls to review the data as 
appropriate. After the injections and the final 2-week safety visits are completed, 
less frequent reporting and safety reviews may be conducted at the discretion of 
the HVTN 120 PSRT. HVTN Core reviews reports of clinical and laboratory 
AEs. Events identified during the review that are considered questionable, 
inconsistent, or unexplained are referred to the HVTN CRS clinic coordinator for 
verification.  
11.5 
Study termination 
This study may be terminated early by the determination of the HVTN 120 PSRT, 
a pertinent national regulatory authority, NIH, Office for Human Research 

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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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12 
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, 
DAIDS Clinical Research Policies and Standard Procedures Documents including 
procedures for the following: 
▪ Protocol registration, activation, and implementation; 
▪ Informed consent, screening, and enrollment; 
▪ Study participant reimbursement; 
▪ Clinical and safety assessments; 
▪ Safety monitoring and reporting; 
▪ Data collection, documentation, transfer, and storage; 
▪ Participant confidentiality; 
▪ Study follow-up and close-out; 
▪ Unblinding of staff and participants; 
▪ Quality control; 
▪ Protocol monitoring and compliance; 
▪ Advocacy and assistance to participants regarding negative social impacts 
associated with the vaccine trial; 
▪ Risk reduction counseling;  
▪ Specimen collection, processing, and analysis; 
▪ Exploratory and ancillary studies and sub-studies, and 
▪ 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 120 Study Specific Procedures.  
12.1 
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.  

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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. 
12.2 
Compliance with NIH guidelines for research involving products 
containing recombinant DNA 
Because this study is evaluating products containing recombinant or synthetic 
DNA, it must comply with regulations set forth in the NIH’s Guidelines for 
Research Involving Recombinant or Synthetic Nucleic Acid Molecules (April 
2016). Information about the study must be submitted to site Institutional 
Biosafety Committees (IBC). Investigators at each site are responsible for 
obtaining IBC approval per NIH guideline section IV-B7-a-(1). IBC review and 
approval must be documented by the investigator and submitted as part of 
DAIDS’s initial protocol registration for this trial before participants are enrolled 
at the site. If this protocol is amended, investigators should follow the 
requirements of their IBC. 
12.3 
Regulatory considerations for African countries 
Any regulations specific to African countries containing CRSs at which HVTN 
120 will be implemented will be observed. 
12.4 
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 can contact the participant without IRB/EC approval if 
such communication is necessary to avoid imminent harm to the study participant. 
The CRS must notify the IRB/EC and any applicable RE of the matter as soon as 
possible. 

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13 
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 120 are described 
below. 
Protocol history and modifications 
Date: September 12, 2018 
Protocol version: Version 3.0 
Protocol modification: Full Protocol Amendment 2 
Item 1 
Revised in Sections 3 and 6 and Appendix A: Sample size reduced from 
320 to 160 
Item 2 
Updated in Sections 1, 14, and 15: ICH full name 
Item 3 
Updated in Section 3.1, Protocol Team: Other contributors to the protocol 
Item 4 
Revised in Section 6.4.4.1, General approach: Tests for comparing 
response rates between arms 
Item 5 
Clarified in Sections 2.1, 7.1, 9.2, 9.3, 9.4, 9.5, 9.8, and Appendices A, B, 
C, F, and G: Assignment of sex at birth 
Item 6 
Revised in Sections 7.3.3, 7.3.4, 9.7, 9.12, 9.14, and Appendices A, F, and 
G: Follow-up for participants diagnosed with HIV infection during study 
participation 
Item 7 
Clarified in Section 7.3.3, Discontinuing vaccination for a participant: 
Specified time intervals apply to entire vaccination procedure 
Item 8 
Clarified in Section 9.1.2, Protocol-specific consent forms: Local use 
consent forms 
Item 9 
Clarified in Section 9.2, Pre-enrollment procedures: Required laboratory 
tests 
Item 10 
Revised in Section 9.7.1, Distinguishing intercurrent HIV infection from 
vaccine-induced positive serology: Location of HVTN HIV testing 
algorithm 
Item 11 
Revised in Section 10.4.1: Description of the BAMA assay 
Item 12 
Clarified in Section 11.2.3, Expedited reporting of AEs to DAIDS: DAIDS 
EAE Manual source and DAERS contact information 
Item 13 
Removed in Section 11.3, Safety pause and prompt PSRT AE review: 
Reactogenicity symptom duration 
Item 14 
Clarified in Section 11.3, Safety pause and prompt PSRT AE review: 
Reporting of protocol-related safety information 
Item 15 
Revised in Sections 2, 3, 6.1, 7.1, 11.1.1, 12.3 and Appendices A, E, and 
K: References to Southern Africa 

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Item 16 
Updated in Appendix A, Sample informed consent form: Study related 
injury language 
Item 17 
Clarified in Appendices A, B, and C: Birth control requirements 
Item 18 
Clarified in Appendix I, Injection schedule for sample informed consent: 
Number of right-arm injections shown at Months 3 and 6 
Item 19 
Corrected: Typographical errors and stylistic deviations 
Date: April 16, 2018 
Protocol version: Version 2.0 
Protocol modification: Letter of Amendment 1 
Item 1 
Revised in Section 6.4.4.1: Tests for comparing response rates between 
arms 
Item 2 
Clarified in Appendix I: Injection schedule graphic for sample informed 
consent form 
Date: January 3, 2018 
Protocol version: Version 2.0 
Protocol modification: Full Protocol Amendement 1 
Item 1 
Added: enrollment in the United States 
Item 2 
Added in Section 3, Study product providers: diluent for ALVAC-HIV to 
list of products being provided in the study 
Item 3 
Updated in Section 3.1, Protocol Team: Protocol team leadership 
Item 4 
Updated in Section 4.5.1.3, Bivalent Subtype C gp120/AS01B dose: current 
safety data from HVTN 108, which is evaluating the same vaccine. 
Item 5 
Added in Section 6.4.5, Analyses and data sharing prior to end of 
scheduled follow-up visits: data sharing restrictions for interim blinded 
safety and immunogenicity data 
Item 6 
Clarified in Section 7.1, Inclusion criterion, Criterion 10: hemoglobin 
eligibility for transgender participants 
Item 7 
Revised in Section 7.2, Exclusion criterion 
Item 8 
Removed the eligibility requirement regarding untreated or incompletely 
treated syphilis infection 
Item 9 
Revised in Section 7.3.1, Delaying vaccinations for a participant: criteria 
for delaying any study vaccinations due to the timing of receipt of a live 
attenuated influenza vaccine 
Item 10 
Revised in Section 7.3.3, Discontinuing vaccination for a participant 
Item 11 
Updated in Section 8, Study product preparation and administration 
Item 12 
Revised in Section 9.3, Enrollment and vaccination visits: participant diary 
will now be used in place of the postvaccination memory tool 
Item 13 
Removed in Section 9.4, Follow-up visits: platelet counts from required 
clinical lab tests 

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Item 14 
Updated in Section 9.10,  Assessments of reactogenicity, 11.2.2, AE 
reporting, and Section 14, Document references (other than literature 
citations): version number for the DAIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events 
Item 15 
Deleted Section 9.10.3, Assessment of lymph nodes 
Item 16 
Updated in Section 11, Safety monitoring and safety review 
Item 17 
Updated: Section 13, Version history 
Item 18 
Revised in Appendix A, Sample informed consent form 
Item 19 
Revised in Appendix F, Laboratory procedures 
Item 20 
Added in Appendix G, Procedures at HVTN CRS 
Item 21 
Added Appendix J and Appendix K, Low Risk Guidelines for sites in US 
and sites in Southern Africa 
Item 22 
Added Appendix L, Protocol Signature Page 
Item 23 
Updated HVTN protocol template language throughout the protocol 
Item 24 
Replaced the terms “(fe)male” or “(wo)man” with “participant who was 
assigned (fe)male at birth” throughout the protocol. 
Date: October 25, 2017 
Protocol version: 1.0 
Protocol modification: Clarification memo 1 
Item 1 
References to the DAIDS table for grading of adverse events updated to 
current version 2.1 and clarifications to the protocol to be consistent 
with new version of the grading table 
Date: December 20, 2016 
Protocol version: 1.0 
Protocol modification: Original protocol 
 
 

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14 
Document references (other than literature 
citations) 
Other documents referred to in this protocol, and containing information relevant 
to the conduct of this study, include: 
• Assessment of Understanding. Accessible through the HVTN protocol-
specific website. 
• 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.  
• Revised Guidelines for HIV Counseling, Testing, and Referral. Available 
at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5019a1.htm 
• 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 
• Division of AIDS Protocol Registration Manual. Available at 
https://www.niaid.nih.gov/sites/default/files/prmanual.pdf 
• Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events. Corrected Version 2.1, July 2017. Available at http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
• 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 
• HVTN Certificate of Confidentiality. Accessible through the HVTN website. 
• HVTN 120 Special Instructions. Accessible through the HVTN protocol-
specific website. 
• HVTN 120 Study Specific Procedures. Accessible through the HVTN 
protocol-specific website. 
• HVTN 120 Site Lab Instructions. Accessible through the HVTN protocol-
specific website 
• HVTN Manual of Operations. Accessible through the HVTN website. 

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• Dangerous Goods Regulations (updated annually), International Air Transport 
Association. Available for purchase at 
http://www.iata.org/publications/dgr/Pages/index.aspx 
• Lab assay algorithm (available upon request) 
• International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E6, 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 
• Participants’ Bill of Rights and Responsibilities. Accessible through the 
HVTN website. 
• NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic 
Acid Molecules. Available at http://osp.od.nih.gov/office-biotechnology-
activities/biosafety/nih-guidelines 
• 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 
• Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks, 
July 2008. 
• Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials. Available at 
https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf  
• Title 21, Code of Federal Regulations, Part 50. Available at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFR
Part=50 
• Title 45, Code of Federal Regulations, Part 46. Available at 
http://www.hhs.gov/ohrp/humansubjects/regulations-and-
policy/regulations/45-cfr-46/index.html 
See Section 16 for literature cited in the background and statistics sections of this 
protocol. 

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15 
Acronyms and abbreviations 
Ab 
antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANOVA analysis of variance 
ART 
antiretroviral therapy 
AST 
aspartate aminotransferase 
ATP 
adequate take/potency 
AVEG 
AIDS Vaccine Evaluation Group 
β-HCG 
beta human chorionic gonadotropin 
BMI 
body mass index 
CAB 
Community Advisory Board 
CBC 
complete blood count 
CDC 
US Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CI 
confidence intervals 
CoR 
correlate of risk 
CRF 
case report form 
CRP 
C-reactive protein 
CRPMC 
NIAID Clinical Research Products Management Center 
CRS* 
clinical research site 
CTL 
cytotoxic T lymphocyte 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS (US NIH) 
DHHS 
US Department of Health and Human Services 
EAE 
adverse events requiring expedited reporting to DAIDS 
EC 
Ethics Committee 
ELISA 
enzyme-linked immunosorbent assay 
ELISpot 
enzyme-linked immunospot 
FDA 
US Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equation 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HVTN 
HIV Vaccine Trials Network 

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IB 
Investigator’s Brochure 
IBC 
Institutional Biosafety Committee 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ICS 
intracellular cytokine staining 
IFN-γ 
interferon gamma 
IND 
Investigational New Drug 
IoR 
Investigator of Record 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
MAR 
missing at random 
MCAR 
missing completely at random 
MMR 
measles, mumps, and rubella 
nAb 
neutralizing antibody 
NHP 
nonhuman primate 
NIAID 
National Institute of Allergy and Infectious Diseases (US NIH) 
NICD 
National Institute for Communicable Diseases (Johannesburg, South 
Africa) 
NIH 
US National Institutes of Health 
OHRP 
US Office for Human Research Protections 
OPV 
oral polio vaccine 
PAB 
DAIDS Pharmaceutical Affairs Branch 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PI 
Principal Investigator 
PSRT 
Protocol Safety Review Team 
RAB 
DAIDS Regulatory Affairs Branch 
RE 
regulatory entity 
RSC 
DAIDS Regulatory Support Center 
SAE 
serious adverse event 
SCHARP Statistical Center for HIV/AIDS Research and Prevention 
SDMC 
statistical and data management center 
SHIV 
simian-human immunodeficiency virus 
SMB 
Safety Monitoring Board 
SPT 
DAIDS Safety and Pharmacovigilance Team 
TB 
tuberculosis 
UW-VSL University of Washington Virology Specialty Laboratory 
VISP 
Vaccine induced seropositivity 
VRC 
Dale and Betty Bumpers Vaccine Research Center (NIAID) 

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* 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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HVTN 120 Version 3.0 / September 12, 2018 
Appendix A 
Sample informed consent form 
A phase 1/2a clinical trial to evaluate the safety and immunogenicity of ALVAC-
HIV (vCP2438) and of MF59®- or AS01B-adjuvanted clade C Env protein, in 
healthy, HIV-uninfected adult participants 
HVTN protocol number: HVTN 120 
Site: [Insert site name] 
Thank you for your interest in our research study. Please read this consent form or 
ask someone to read it to you. If you decide to join the study, we will ask you to 
sign or make your mark on this form. We will offer you a copy to keep. We will 
ask you questions to see if we have explained everything clearly. You can also 
ask us questions about the study.  
Research is not the same as treatment or medical care. The purpose of a research 
study is to answer scientific questions. 
About the study 
The HIV Vaccine Trials Network (HVTN) and [Insert site name]  are doing a 
study to test HIV vaccines. HIV is the virus that causes AIDS. 
About 160 people will take part in this study at multiple sites in Africa and the 
United States. The researcher in charge of this study at this clinic is 
[Insert name of site PI]. The United States National Institutes of Health (NIH) and 
the Bill & Melinda Gates Foundation are paying for the study.  
1. We are doing this study to answer several questions. 
• Are the study vaccines safe to give to people? 
• Are people able to take the study vaccines without becoming too 
uncomfortable? 
• How do people’s immune systems respond to different combinations and 
doses of the study vaccines? (Your immune system protects you from 
disease.) 
2. The study vaccines cannot give you HIV. 
The study vaccines are not made from actual HIV. It is impossible for the study 
vaccines to give you HIV. Also, they cannot cause you to give HIV to someone 
else. 

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3. We do not know if the study vaccines will decrease, increase, or not change 
your chance of becoming infected with HIV if you are exposed to the virus. 
Several studies have tested whether HIV vaccines can reduce the risk of getting 
HIV from another person. In some studies, people who got the vaccine seemed to 
have the same risk of getting HIV as people who did not get the vaccine. In one 
study, people who got the vaccine seemed to have a lower risk of getting HIV 
than people who did not get the vaccine. In other studies, some people who got 
the vaccine had a higher risk of getting HIV than people who did not get the 
vaccine.  
This study differs from the studies in which people who got the vaccine had a 
higher or lower risk of getting HIV. The clinic staff can tell you about the 
differences.  
We do not know whether the vaccines in this study will affect your risk of getting 
HIV from another person. The risk could be higher, lower, or unchanged. It is 
very important to avoid exposure to HIV during and after the study. We will tell 
you how to avoid HIV. 
4.  These study vaccines are experimental. 
There are 3 study vaccines being tested in this study. They are all experimental 
vaccines. That means we do not know whether the vaccines will be safe to use in 
people, or whether they will work to prevent HIV infection. These vaccines are 
used only in research studies. The study vaccines are called ALVAC-HIV 
(vCP2438), Bivalent Subtype C gp120/MF59, and Bivalent Subtype C 
gp120/AS01B. From here on, we will call them the ALVAC vaccine, the 
protein/MF59 vaccine, and the protein/AS01B vaccine, or the study vaccines.  
The ALVAC vaccine 
The ALVAC vaccine is made out of canarypox virus. Canarypox virus infects 
birds but cannot infect humans. This virus has small bits of man-made DNA 
inserted into it. DNA is a natural substance found in all living things, including 
people and some viruses. The canarypox virus helps get the DNA into the body’s 
cells. The DNA then tells those cells to make small amounts of proteins that look 
like some of the ones found in HIV. 
The Protein/MF59 vaccine: 
The Protein/MF59 vaccine has man-made pieces of a protein found on the outside 
of HIV. These proteins will be mixed with an adjuvant. An adjuvant is a 
substance added to the vaccine to help the immune system respond better. In this 
study vaccine the adjuvant is called MF59. MF59 is commonly used in licensed 
flu vaccines in many countries. It has also been in other vaccines that have been 
given to over 50,000 people in research studies without causing any serious health 
problems. 

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The ALVAC vaccine and the Protein/MF59 vaccine combination is currently 
being given in South Africa in 2 studies named HVTN 100 and HVTN 702. For 
HVTN 100, 210 participants have received this vaccine combination. It is also 
being given in South Africa and other African countries in a study named HVTN 
107. In addition, the Protein/MF59 is being given in 2 other studies named HVTN 
111 and HVTN 108. Similar Protein vaccines have been given to more than 
10,000 people in research studies. In these studies, the protein vaccines did not 
cause serious health problems.  
The Protein/AS01B vaccine: 
The Protein /AS01B vaccine has the same proteins used in the Protein/MF59 
vaccine. However, these protein pieces are mixed with a different adjuvant called 
AS01B. This adjuvant is also added to this vaccine to help the immune systems 
respond better.  
The Protein/AS01B is also being given in one of the studies mentioned above, 
named HVTN 108. Similar vaccines have been given to over 1400 people in past 
studies. In these studies, the vaccines did not cause serious health problems. 
This study will be the first time the ALVAC vaccine and the Protein/AS01B 
vaccine combination will be given to humans. 
General risks of vaccines: 
All vaccines can cause fever, chills, rash, aches and pains, nausea, headache, 
dizziness, and feeling tired. Vaccines can also cause pain, redness, swelling, or 
itching where you got the injection. Most people can still do their planned 
activities after getting a vaccine. Rarely, people have side effects that limit their 
normal activities or make them go to the doctor. 
Rarely, a vaccine can cause an allergic reaction, including a rash, hives, or trouble 
breathing. Allergic reactions can be life-threatening. You should tell us if you 
have ever had a bad reaction to any injection or vaccine. 
Rarely, people who have received vaccines with adjuvants have developed 
illnesses called autoimmune diseases. Autoimmune diseases have also occurred in 
people who have not been vaccinated. These diseases develop when immune cells 
that normally protect you from illness, attack your organs instead. Autoimmune 
diseases can be serious and can also be lifelong. They can involve for example 
your liver, kidneys, skin, joints, eyes, brain, as well as other parts of the body. 
Since no one knows for sure if vaccines with adjuvants might cause autoimmune 
diseases, we continue to monitor this situation closely. 
Risks of the study vaccines: 
The ALVAC vaccine and the Protein/MF59 vaccine: 

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In HVTN 100, the study vaccines have not caused serious health problems. About 
3 out of 4 participants had mild or medium pain or tenderness on the arm where 
they got the injections. Three participants had severe arm pain after one of their 
injections. About 1 out of 7 participants had a small area of redness or hardening 
of the skin on the arm where they got the injections. These side effects did not 
bother most people much and all went away within a few days. Three participants 
had larger areas of redness or swelling (more than 10 cm in diameter) where they 
got the injection that bothered them. They were treated with prescription 
medications and the symptoms went away within a few days. 
About 2 out of 3 participants felt weak or tired, or had a headache or body aches 
after an injection. A small number had nausea, chills, fever, or vomiting. These 
symptoms were mostly mild but in 4 participants their daily activities were 
affected (joint aches in 2, weakness/tiredness in 1 and headache in another 
person). All of these symptoms went away within a few days.  
A few participants had one of these side effects after an injection: lump where 
they got the injection, itching where they got the injection or all over, lymph node 
swelling, stomach pain, diarrhea, dizziness, brief tingling around the mouth. 
These symptoms were all mild or medium and all went away within a few days.  
Most of the symptoms participants had are common side effects of vaccines or of 
getting injections. We do not know yet which participants got the study vaccines 
and which got the placebo because the study is still “blinded”, so we do not know 
if the study vaccines caused these side effects.  
The Protein/AS01B vaccine: 
The Protein/AS01B is being given in HVTN 108 and we will give you any 
important information that may come out of that study that may affect your health 
or your participation.  
In studies with similar products some people had redness, swelling, pain, muscle 
tenderness, or itching in the area where they got the injection. Some people had 
headache, weakness, increased heart rate, and increased sensitivity to stimulation 
at the site of injection. A small number of people had flu-like symptoms, nausea, 
rash, vomiting, diarrhea, or swollen lymph nodes after getting an injection. A very 
small number of people had tiredness and difficulty sleeping. People who have 
these symptoms may only have a few of them and they usually go away within a 
few days.  
There may be other risks of the study vaccines that we do not yet know about. We 
will tell you if we learn anything new that may affect your participation in the 
study.  

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Joining the study 
5. It is completely up to you whether or not to join the study.  
Take your time in deciding. If it helps, talk to people you trust, such as your 
doctor, friends or family. If you decide not to join this study, or if you leave it 
after you have joined, your other care at this clinic and the benefits or rights you 
would normally have will not be affected. 
If you join this study, you may not be allowed to join other HIV vaccine or HIV 
prevention studies now or in the future. You cannot be in this study while you are 
in another study where you receive a study product. Also during the study, you 
should not donate blood or tissue. 
If you choose not to join this study, you may be able to join another study. 
Site: Remove item 6 if you use a separate screening consent that covers these 
procedures. 
6. If you decide to join the study, we will screen you to see if you are eligible. 
Screening involves a physical exam, HIV test and health history. A physical exam 
may include, but is not limited to: 
• Checking your weight, temperature and blood pressure 
• Looking in your mouth and throat 
• Listening to your heart and lungs 
• Feeling your abdomen (stomach and liver) 
We will also do blood and urine tests. These tests tell us about some aspects of 
your health, such as how healthy your kidneys, liver, and immune system are. We 
will also test you for Hepatitis B, Hepatitis C, and syphilis. We will ask you about 
medications you are taking. We will ask you about behaviors that might put you 
at risk for getting HIV. If you were assigned female sex at birth, we will test you 
for pregnancy. People who have had a hysterectomy or oophorectomy (removal of 
the uterus or ovaries, verified by medical records), are not required to have a 
pregnancy test. We will also ask if you have ever been allergic to eggs, egg 
products, or the antibiotic Neomycin. 
We will review the screening results with you. The screening results may show 
you are not eligible to join the study, even if you want to. Also, you might not be 
able to join if we have already enrolled enough people of your same sex. 
Site: adapt the following section so it is applicable to the care available at your site 

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7. If we find that you have a health problem during screening or during the 
study. 
We will tell you about the care that we can give here for free.  
For the care that we cannot give, we will explain how we will help you get care 
elsewhere.  
We will not be able to pay for care for health problems that are unrelated to this 
study. 
8. If you were assigned female sex at birth and could become pregnant, you 
must agree to use birth control to join this study. 
Site: If you want to include Appendix B, Approved birth control methods (for sample 
informed consent form), in this consent form, paste it below and delete paragraph 
below. 
You should not become pregnant during the study because we do not know how 
the study vaccines could affect the developing baby. You must agree to use 
effective birth control from 3 weeks before your first injection until 6 months 
after your last study injection. We will talk to you about effective birth control 
methods. They are listed on a handout that we will give to you.  
Being in the study 
If you meet the study requirements and want to join, here is what will happen: 
9. You will come to the clinic for scheduled visits about [#] times over 12 
months. 
Site: Insert number of visits and range of visit lengths. (There is site-specific variation 
in screening protocols and in the number of possible follow-up visits between 
protocol-mandated visits). 
Visits can last from [#] to [#] hours. 
You may have to come for more visits if you have a laboratory test result or 
health issue.  
We may contact you after the main study ends (for example, to tell you about the 
study results). 
10. We will give you [Site: Insert compensation] for each study visit you 
complete. 
This amount is to cover the costs of [Site: Insert text] 

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Site: Insert any costs to participants (eg, birth control costs for female participants 
who could become pregnant). 
US sites: Include the following paragraph: 
Payments you receive for being in the study may be taxable. We may need to ask 
you for your Social Security number for tax reasons. 
You do not have to pay anything to be in this study. 
11. Not everyone in this study will get the study vaccines.  
Everyone in this study will get some placebos. Placebos are substances that do not 
contain vaccine. Some people will get the study vaccines and also some placebos. 
Some people will get only placebos. We will compare the results from people 
who got the placebos with results from people who got the study vaccines.  
The placebo for the study vaccines is saline solution. We do not expect the 
placebo to cause any health problems in people. 
The clinic staff have no say in whether you get the study vaccines and/or the 
placebos. They will not know which study products you are getting, and neither 
will you. Only the pharmacist at your site will have this information while the 
study is going on.  
You will have to wait until everyone completes their final study visits to find out 
what study products you got. This could be 2-5 years. But, if you have a serious 
medical problem and need to know what you got before the end of the study, we 
can tell you. 
12. We will give you the study products on a schedule. 
There are 4 groups in this study. Each group will get a different combination of 
study products. The group you get assigned to is completely random. Each group 
will get 8 injections during the study. You will get the injections into your upper 
arms. At some visits you will get one injection. At other visits, you will get 3 
injections.  
The ALVAC vaccine or its placebo will go into the left arm. The Protein/MF59 
vaccine and Protein/AS01B vaccine and their placebos will go into the right arm.  

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Site: You may insert the picture version of the injection schedule (Appendix I) in 
place of (or in addition to) the text version or give it as a separate document to 
volunteers if you believe it will be helpful to them. You are not required to do either. 
 
 
 
 
 
Time after first injection visit 
Group 
Number 
of 
people 
Protein 
dose 
Arm 
First injection 
visit 
1 month 
3 months 
6 months 
1 
50 
High dose 
Left 
ALVAC-HIV 
ALVAC-HIV 
ALVAC-HIV 
ALVAC-HIV 
Right 
 
 
Protein/MF59 + 
Placebo 
Protein/MF59 + 
Placebo 
2 
50 
High dose 
Left 
ALVAC-HIV 
ALVAC-HIV 
ALVAC-HIV 
ALVAC-HIV 
Right 
 
 
Protein/AS01B 
+ Placebo 
Protein/AS01B 
+ Placebo 
3 
50 
Low dose 
Left 
ALVAC-HIV 
ALVAC-HIV 
ALVAC-HIV 
ALVAC-HIV 
Right 
 
 
Protein/AS01B 
+ Placebo 
Protein/AS01B 
+ Placebo 
4 
10 
N/A 
Left 
Placebo 
Placebo 
Placebo 
Placebo 
Right 
 
 
Placebo + 
Placebo 
Placebo + 
Placebo 
You will have to wait in the clinic for about a half hour after each set of injections 
to see if there are any problems. Then for that night and for 7 more days, you will 
need to keep track of how you are feeling and if you have any symptoms. Within 
3 days of vaccination, we will ask you to contact us or clinic staff will contact you 
to check on how you are doing. You should always contact us if you have any 
issues or concerns after receiving an injection. If you have a problem, we will 
continue to check on you until it goes away. 
13. In addition to giving you the study products, we will:  
• Do regular HIV testing, as well as counseling on your results and on how to 
avoid getting HIV; 
• Do physical exams; 
• Do pregnancy tests if you were assigned female sex at birth; 
• Ask questions about your health, including medications you may be taking;  
• Ask questions about any personal problems or benefits you may have from 
being in the study, and;  
• Take blood and urine samples. 
Each time we take blood, the amount will depend on the lab tests we need to do. It 
will be some amount between 10 mL and 200 mL (2 teaspoons to a little less than 
1 cup/ 14 tablespoons). Your body will make new blood to replace the blood we 
take out.  

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Site: You may want to add a sentence to the end of the previous paragraph 
contextualizing the blood volumes described (eg, “To compare, people who donate 
blood in the US can give a total of about 500 mL in an 8-week period.”). Modify the 
example for cultural relevance and alter blood volumes as necessary. 
Site: Insert Appendix D, Table of procedures (for informed consent form) in this 
section or distribute it as a separate sheet if it is helpful to your study participants. 
You are not required to do either. 
We will be looking for side effects. We will review the results of these procedures 
and tests with you at your next visit, or sooner if necessary. If any of the results 
are important to your health, we will tell you. 
Site: in the following section, delete references to semen if your site is not 
participating in semen collection. 
14. If you agree, we will also collect stool, rectal fluid and cervical fluid or semen.  
At the end of this form we will ask if you allow us to collect stool, rectal fluid and 
cervical fluid (if you were assigned female sex at birth) or semen (if you were 
assigned male at birth). You can decide not to give any of these samples and still 
be in the study.  
Stool  
We would like to collect a small sample of your stool to look at the bacteria living 
in your stomach. We want to learn if your immune response to the study vaccines 
is influenced by these bacteria. We will do this twice during this study. If you 
agree to give the rectal fluid sample described below, we can collect the stool 
sample at that time, or you may provide a stool sample at home or at the clinic. 
The clinic must receive the stool sample within 24 hours after it is collected. 
Rectal fluid, cervical fluid, or semen 
We want to see how the study vaccines affect the parts of the body where people 
may be exposed to HIV: their rectum, vagina, and penis.  
We would like to collect these samples at 3 visits. When we collect the samples, 
we will test you for gonorrhea, chlamydia and syphilis. If you were assigned 
female sex at birth, we will also test you for pregnancy, trichomoniasis, bacterial 
vaginosis and if needed, for a yeast infection. We will explain what these tests are 
for and we will give you the results. If you need care, we will tell you about the 
care we can give you at the clinic. We will also tell you about care we can help 
you get elsewhere. We will ask you to avoid some activities for 2 days before we 
collect these samples. This will help make sure your samples give accurate lab 
readings. 
Rectal fluid 

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Site: You may delete the units of measure that are not used at your site in the next 
sentence. We will collect rectal fluid by first inserting a plastic tube into your 
rectum that is about 10 cm (4 inches) long and a little less than 2.5 cm (1 inch) 
wide. The tube will go inside your bum about 7 cm (3 inches). Then we will insert 
up to 3 small absorbent sponges through the tube into the rectum. The sponges 
will be left in place for 5 minutes and then removed.  
For the 2 days before we collect your rectal fluid:  
• Do not have receptive anal intercourse 
• Do not put anything into your anus, including cleaning products (creams, gels, 
lotions, pads, etc.), lubricant, enemas or douches (even with water) 
• Do not use any anti-inflammatory creams in or around your anus.  
We will not collect rectal fluid if we learn that you are pregnant, or if we think 
you may have an anal or rectal infection. You should tell us if your rectal area is 
sore. 
Cervical fluid 
If you are 21 or older, you must have had a Pap smear within the last 3 to 5 years 
with the most recent result being normal. If you have not had a Pap smear within 
the last 3 years and would like to get one, we will tell you where you can get one. 
If you are younger than 21, you do not need a Pap smear because at that age it is 
not medically necessary. 
To collect cervical fluid, we will give you a menstrual cup  to insert into your 
vagina. The study staff will explain how to insert and remove the cup, or they can 
do it for you at the clinic. We will explain how many cups we will collect and 
how long you should wear them.  
For the 2 days before we collect your cervical fluid,  
• Do not use any spermicide, lubricants, douche (even with water), or 
medication in or around your vagina;  
• Do not have vaginal intercourse or insert anything into your vagina.  
Do not insert the menstrual cup:  
• if you think you may be pregnant. 
• if you think you may have a cervical or vaginal infection. We may ask you 
to collect this sample at a later date. 
Semen 

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You may provide the semen at home or here. We will give you a plastic cup and 
ask you to ejaculate into it. We must receive the semen sample within 2 hours or 
less after it is collected. For at least 2 days before providing the semen, we will 
ask you: 
• not to have sex, including oral sex 
• not to ejaculate 
• not to use anything with lubricants 
• not to put saliva on the penis 
You should tell us if you think you have an infection on your penis. If you have 
an infection, we may not use your sample.  
15. The HVTN will test your samples to see how your immune system responds 
to the study products. 
We will send your samples (without your name) to labs approved by the HVTN 
for this study, which are located in the United States and South Africa. 
Researchers at these labs will test your samples to see how your immune system 
responds to the study products. In rare cases, some of your samples may be sent to 
labs approved by the HVTN in other countries for research related to this study. 
Researchers may also do genetic testing related to this study on your samples. 
Your genes are passed to you from your birth parents. They affect how you look 
and how your body works. The differences in people’s genes can help explain 
why some people get a disease while others do not. The genetic testing will only 
involve some of your genes, not all of your genes (your genome). The researchers 
will study only the genes related to the immune system and HIV and those that 
affect how people get HIV. 
If you become HIV infected, the researchers may look at all of the genes of the 
virus found in your samples. If you give cervical, stool, or rectal fluid samples, 
the researchers may look at all of the genes of the bacteria found in your samples. 
In both cases the researchers will use this information to learn more about HIV 
and the study product(s). The researchers may put this information about the virus 
and/or bacteria into a protected database so that other researchers can access it. 
They would not be able to link the information to you.  
In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to contribute to this study.  
Tests done on your samples are for research purposes, not to check your health. 
The labs will not give the results to you or this clinic because their tests are not 
approved for use in making health care decisions. 

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When your samples are no longer needed for this study, the HVTN will continue 
to store them.  
16. We will counsel you on avoiding HIV infection.  
We will ask you personal questions about your HIV risk factors such as sexual 
behavior, alcohol, and drug use. We will talk with you about ways to keep your 
risk of getting HIV low. 
Site: Delete next section if using separate consent for use of samples and information 
in other studies. 
17. When samples are no longer needed for this study, the HVTN wants to use 
them in other studies and share them with other researchers. The HVTN 
calls these samples “extra samples.” 
The HVTN will only allow your extra samples to be used in other studies if you 
agree to this. You will mark your decision at the end of this form. If you have any 
questions, please ask. 
Do I have to agree? No. You are free to say yes or no, or to change your mind 
after you sign this form. At your request, we will destroy all extra samples that we 
have. Your decision will not affect your being in this study or have any negative 
consequences here.  
Where are the samples stored? Extra samples are stored in a secure central place 
called a repository. [Site: choose one of the following two sentences. African sites 
should choose the sentence referencing the repository in South Africa. All other 
sites should choose the sentence referencing the repository in the United States.] 
Your samples will be stored in the HVTN repository in South Africa. Your 
samples will be stored in the HVTN repository in the United States. 
How long will the samples be stored? There is no limit on how long your extra 
samples will be stored. [Site: Revise the previous sentence to insert limits if your 
regulatory authority imposes them.] 
Will I be paid for the use of my samples? No. Also, a researcher may make a new 
scientific discovery or product based on the use of your samples. If this happens, 
there is no plan to share any money with you. The researcher is not likely to ever 
know who you are. 
Will I benefit from allowing my samples to be used in other studies? Probably not. 
Results from these other studies are not given to you, this clinic, or your doctor. 
They are not part of your medical record. The studies are only being done for 
research purposes. 

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Will the HVTN sell my samples and information? No, but the HVTN may share 
your samples with HVTN or other researchers. Once we share your samples and 
information, we may not be able to get them back. 
How do other researchers get my samples and information? When a researcher 
wants to use your samples and information, their research plan must be approved 
by the HVTN. Also, the researcher’s institutional review board (IRB) or ethics 
committee (EC) will review their plan. [Site: If review by your institution’s 
IRB/EC/RE is also required, insert a sentence stating this.] IRBs/ECs protect the 
rights and well-being of people in research. If the research plan is approved, the 
HVTN will send your samples to the researcher’s location.  
What information is shared with HVTN or other researchers? The samples and 
information will be labeled with a code number. Your name will not be part of the 
information. However, some information that we share may be personal, such as 
your race, ethnicity, sex, health information from the study, and HIV status. We 
may share information about the study product you received and how your body 
responded to the study product.  
What kind of studies might be done with my extra samples and information? The 
studies will be related to HIV, vaccines, the immune system and other diseases.  
Researchers may also do genetic testing on your samples.  
In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to do research with them. 
If you agree, your samples could also be used for genome-wide studies. In these 
studies, researchers will look at all of your genes (your genome). The researchers 
compare the genomes of many people, looking for common patterns of genes that 
could help them understand diseases. The researchers may put the information 
from the genome-wide studies into a protected database so that other researchers 
can access it, but your name and other personal information will not be included. 
Usually, no one would be able to look at your genome and link it to you as a 
person. However, if another database exists that also has information on your 
genome and your name, someone might be able to compare the databases and 
identify you. If others found out, it could lead to discrimination or other problems. 
The risk of this is very small. There may be other unknown risks. 
Who will have access to my information in studies using my extra samples?  
People who may see your information are: 
• Researchers who use your extra samples and information for other research 
• Government agencies that fund or monitor the research using your extra 
samples and information 

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• Any regulatory agency that reviews the research using your extra samples and 
information 
• The researcher’s Institutional Review Board or Ethics Committee 
• The people who work with the researcher  
All of these people will do their best to protect your information. The results of 
any new studies that use your extra samples and information may be published. 
No publication will use your name or identify you personally. 
18. We will do our best to protect your private information. 
US sites: Check HIPAA authorization for conflicts with this section. 
Your study records and samples will be kept in a secure location. We will label all 
of your samples and most of your records with a code number, not your name or 
other personal information. However, it is possible to identify you, if necessary. 
We will not share your name with the lab that does the tests on your samples, or 
with anyone else who does not need to know your name. 
Sites: Any change to the following highlighted text requires approval from HVTN 
Regulatory Affairs 
We do need to share your name with the HVTN in case you need proof in the 
future that you participated in an HIV vaccine study. The HVTN will keep your 
name in a secure file with these items:  
• The name of your study  
• Your age or date of birth  
• Your study ID number  
• What study product(s) you received  
There are no HIV test results kept in this file. The HVTN will not share any 
information that could identify you without your agreement. The HVTN will 
remove your name from the file if you do not want it there. 
Clinic staff will have access to your study records. Your records may also be 
reviewed by groups who watch over this study to see that we are protecting your 
rights, keeping you safe, and following the study plan. These groups include: 
• The US National Institutes of Health, its study monitors, and its chosen 
representatives, 
• The US Food and Drug Administration,  

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• Any regulatory agency that reviews clinical trials, 
• [Insert name of local IBC], 
• [Insert name of local IRB/EC] , 
• [Insert name of local and/or national regulatory authority as appropriate], 
• GlaxoSmithKline Biologicals S.A., Sanofi Pasteur and people who work for 
them, 
• The HVTN and people who work for them,  
• The HVTN Safety Monitoring Board; and 
• The US Office for Human Research Protections. 
All reviewers will take steps to keep your records private. 
We cannot guarantee absolute privacy. At this clinic, we have to report the 
following information:  
Site: Include any public health or legal reporting requirements. Bulleted examples 
should include all appropriate cases (reportable communicable disease, risk of harm 
to self or others, etc.). 
• [Item 1] 
• [Item 2] 
• [Item 3] 
US sites: Include the following boxed text. You can remove the box. 
We have a Certificate of Confidentiality from the US government, to help protect 
your privacy. With the certificate, we do not have to release information about 
you to someone who is not connected to the study, such as the courts or police. 
Sometimes we can’t use the certificate. Since the US government funds this 
research, we cannot withhold information from it. Also, you can still release 
information about yourself and your study participation to others. 
The results of this study may be published. No publication will use your name or 
identify you personally. 
We may share information from the study with other researchers. We will not 
share your name or information that can identify you. 

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 Sites: The text below may not be deleted or changed, per FDA requirement. It’s OK 
to remove the box around it. 
A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This website will not 
include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time. 
19. We may stop your injections or take you out of the study at any time. We 
may do this even if you want to stay in the study and even if you were 
scheduled for more injections.  
This may happen if: 
• you do not follow instructions, 
• we think that staying in the study might harm you, 
• you get HIV, 
• you enroll in a different research study where you get another study product, 
or 
• the study is stopped for any reason. 
If we stop your injections, we may ask you to stay in the study to complete other 
study procedures. 
20. We will stop your injections if you become pregnant before your last 
injection.  
We will encourage you to stay in the study if you choose. We will discuss your 
study options with you. 
If you leave the study while you are still pregnant, we will contact you after your 
due date to ask some questions about your pregnancy and delivery. 
21. If you get infected with HIV during the study, we will stop your injections, 
take fewer samples, and help you get care and support. 
We will encourage you to stay in this study for up to 6 months after your last 
study product administration if you choose. We will discuss your study options 
with you. We will counsel you about your HIV infection and about telling your 
partner(s). We will tell you where you can get support and medical care. Site: 
Modify the following sentence as appropriate. We will not provide or pay for any 
of your HIV care directly.  

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Other Risks 
22. There are other risks to being in this study. 
This section describes the other risks and restrictions we know about. There may 
also be unknown risks, even serious ones. We will tell you if we learn anything 
new that may affect your willingness to stay in the study. 
Risks of routine medical procedures:  
In this study, we will do some routine medical procedures. These are taking blood 
and giving injections. These procedures can cause bruising, pain, fainting, 
soreness, redness, swelling, itching, a sore, bleeding, and (rarely) muscle damage 
or infection where you got the injection. Taking blood can cause a low blood cell 
count (anemia), making you feel tired. 
Risks of collecting rectal and cervical fluids: 
You may have some discomfort and minor bleeding during these procedures. This 
does not usually last very long. 
Personal problems/discrimination/testing HIV antibody positive: 
About 10 to 20% of people who join HVTN studies report personal problems or 
discrimination because of joining an HIV vaccine study. Family or friends may 
worry, get upset or angry, or assume that you are infected with HIV or at high risk 
and treat you unfairly as a result. Rarely, a person has lost a job because the study 
took too much time away from work, or because their employer thought they had 
HIV.  
The body makes antibodies to fight or prevent infection. Most vaccines cause the 
body to make antibodies as a way of preventing infection. Your body may make 
antibodies to HIV because you received HIV study vaccines. The study vaccines 
are likely to cause you to test positive on some types of HIV tests, even if you are 
not infected with HIV. This is called vaccine-induced seropositivity (VISP). VISP 
means that after you get the study vaccines, a routine HIV test done outside this 
clinic is likely to say you have HIV, even if you don’t. For this reason, you should 
plan to get HIV tests only at this clinic during the study. Our tests can tell the 
difference between true HIV infection and a positive result that is caused by the 
study vaccines. 
If you receive a positive test result caused by the study vaccines at any time, we 
can arrange free HIV testing for as long as you need it. If this happens, we do not 
know how long you will test positive due to the study vaccines. If you receive a 
positive HIV test result and we determine it is because you have HIV, we will 
refer you for follow-up care. 

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It is unlikely, but you could test negative at the end of the study and positive some 
time later, even though you don’t have HIV. This could happen if different HIV 
tests come into use. We will give you a phone number to call for more 
information.  
Site: Modify the following paragraph if applicable. If someone believes you are 
infected with HIV even if you are not, you could face discrimination and other 
problems. For example, you could be denied medical or dental care, employment, 
insurance, a visa, or entry into the military in some countries. If you do have a 
positive HIV antibody test caused by the study vaccines, you will not be able to 
donate blood or organs. Your family and friends may treat you differently. We 
will give you a brochure that tells you more about testing HIV positive because of 
an HIV vaccine, and how you can avoid some of these problems. 
If you become pregnant during or after the study and have VISP, we don't know if 
the antibodies could be passed to your baby. We know that this happens with 
other vaccines, like tetanus vaccine. These antibodies from the mother are not a 
danger to the baby, and they go away over time. For most babies antibodies from 
the mother last for about six months. 
You should always tell the delivery staff if you have VISP. However, you may 
still be tested for HIV using the antibody test when you deliver your baby. If your 
test is positive and the delivery staff believes you have an HIV infection, your 
baby may be started on antiretroviral treatment when it is not needed. If this 
happens, we can arrange for you and the baby to have a test that can tell the 
difference between true HIV infection and a VISP result. If you or the baby 
continue to have VISP, we can arrange this testing for free for as long as it is 
needed. 
Embarrassment/anxiety:  
You may feel embarrassed when we ask about your HIV risks, such as having sex 
and using drugs. Also, waiting for your HIV test results or other health test results 
could make you feel anxious. You could feel worried if your test results show that 
you are infected with HIV. If you feel embarrassed or anxious, please tell us and 
we will try to help you. 
Risks of disclosure of your personal information: 
We will take several steps to protect your personal information. Although the risk 
is very low, it is possible that your personal information could be given to 
someone who should not have it. If that happened, you could face discrimination, 
stress, and embarrassment. We can tell you more about how we will protect your 
personal information if you would like it.  
Risks of genetic testing: 

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It is unlikely, but the genetic tests done on your samples could show you may be 
at risk for certain diseases. If others found out, it could lead to discrimination or 
other problems. However, it is almost impossible for you or others to know your 
test results from the genetic testing. The results are not part of your study records 
and are not given to you.  
U.S. Sites, include the following paragraph. In the very unlikely event that your 
genetic information becomes linked to your name, a federal law called the 
Genetic Information Nondiscrimination Act (GINA) helps protect you. GINA 
keeps health insurance companies and employers from seeing results of genetic 
testing when deciding about giving you health insurance or offering you work. 
GINA does not help or protect you against discrimination by companies that sell 
life, disability or long-term care insurance. 
Unknown risks:  
We do not know if the study vaccines will increase, decrease, or not change your 
risk of becoming infected with HIV if exposed. If you get infected with HIV, we 
do not know how the study vaccines might affect your HIV infection or how long 
it takes to develop AIDS. 
We do not know if getting these study vaccines will affect how you respond to 
any future approved HIV vaccine. Currently, no HIV vaccine has been approved 
for use.  
We do not know how the study vaccines will affect a pregnant participant or a 
developing baby.  
Benefits 
23. The study may not benefit you. 
We do not know whether getting the study vaccines might benefit you in any way. 
However, being in the study might still help you in some ways. The counseling 
that you get as part of the study may help you avoid getting HIV. The lab tests 
and physical exams that you get while in this study might detect health problems 
you don’t yet know about.  
This study may help in the search for a vaccine to prevent HIV. However, if the 
study vaccines later become approved and sold, there are no plans to share any 
money with you.  

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Your rights and responsibilities 
24. If you join the study, you have rights and responsibilities. 
You have many rights that we will respect. You also have responsibilities. We list 
these in the Participant’s Bill of Rights and Responsibilities. We will give you a 
copy of it. 
Leaving the study 
25. Tell us if you decide to leave the study.  
You are free to leave the study at any time and for any reason. Your care at this 
clinic and your legal rights will not be affected, but it is important for you to let us 
know.  
We will ask you to come back to the clinic one last time for a physical exam, and 
we may ask to take some blood and urine samples. We will also ask about any 
personal problems or benefits you have experienced from being in the study. We 
believe these steps are important to protecting your health, but it is up to you 
whether to complete them. 
Injuries 
Sites: Do not change text in the following section (except as prompted) without 
obtaining prior approval from HVTN Regulatory Affairs at vtn.core.reg@hvtn.org 
26. If you get sick or injured during the study, contact us immediately. 
Your health is important to us. (Sites: adjust the following 2 sentences if 
applicable to the care available at your site) We will tell you about the care that 
we can give you here. For the care that we cannot provide, we will explain how 
we will help you get care elsewhere. 
If you become sick or injured in this study, there is a process to decide if it is 
related to the study products and/or procedures. If it is, we call it a study-related 
injury. There are funds to pay for treatment of study-related injuries if certain 
conditions are met.  
Next paragraph for African sites: 
Sites: adjust the language in this paragraph so it is applicable to your site. Note: 
insurance is purchased for all African countries. In this study, our clinic has 
insurance to cover your medical treatment in the case of a study-related injury. In 
rare cases, the insurance funds may not be enough. The vaccine developers have 
agreed to pay medical costs for study-related injuries that are determined to be 
caused by their own study products.  

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The HVTN has limited funds to pay medical costs that it determines are 
reasonable. (Sites: insert locale-appropriate medical insurance language in the 
following sentence) If the injury is not study related, then you and your health 
insurance will be responsible for treatment costs.  
Some injuries are not physical. For example, you might be harmed emotionally by 
being in an HIV vaccine study. Or you might lose wages because you cannot go 
to work. However, there are no funds to pay for these kinds of injuries, even if 
they are study related. 
You may disagree with the decision about whether your injury is study related. If 
you wish, the HVTN will ask independent experts to review the decision. You 
always have the right to use the court system if you are not satisfied. 
Questions  
27. If you have questions or problems at any time during your participation in 
this study, use the following important contacts. 
If you have questions about this study, contact 
[name and telephone number of the investigator or other study staff]. 
If you have any symptoms that you think may be related to this study, contact 
[name and telephone number of the investigator or other study staff]. 
If you have questions about your rights as a research participant, or problems or 
concerns about how you are being treated in this study, contact 
[name/title/phone of person on IRB or other appropriate organization]. 
If you want to leave this study, contact 
[name and telephone number of the investigator or other study staff]. 
Your permissions and signature  
28. In section 14 of this form, we told you about collecting stool, rectal fluid and 
cervical fluid or semen. Please write your initials or make your mark in the 
boxes next to the options you choose. 
 
I agree to provide stool samples. 
I do not agree to provide stool samples. 
 
 

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I agree to provide rectal fluid. 
I do not agree to provide rectal fluid. 
 
For people assigned female sex at birth: 
I agree to provide cervical fluid. 
I do not agree to provide cervical fluid. 
N/A: assigned male sex at birth 
 
Site: Delete the following if your site is not participating in semen collection 
For people assigned male sex at birth: 
I agree to provide semen. 
I do not agree to provide semen. 
N/A: assigned female sex at birth 
 
Site: Delete this section if using a separate consent for use of samples and 
information in other studies 
29. In Section 17 of this form, we told you about possible other uses of your extra 
samples and information, outside this study. Please choose only one of the 
options below and write your initials or make your mark in the box next to it. 
Whatever you choose, the HVTN keeps track of your decision about how 
your samples and information can be used. You can change your mind after 
signing this form. 
 
 
I allow my extra samples and information to be used for other studies related 
to HIV, vaccines, the immune system, and other diseases. This may include 
genetic testing and keeping my cells growing over time.  
OR 
 

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I agree to the option above and also to allow my extra samples and 
information to be used in genome wide studies. 
OR 
 
 
I do not allow my extra samples to be used in any other studies. This includes 
not allowing genetic testing, growing more of my cells, or genome wide 
studies. 
30. If you agree to join this study, you will need to sign or make your mark 
below. Before you sign or make your mark on this consent form, make sure 
of the following: 
• You have read this consent form, or someone has read it to you. 
• You feel that you understand what the study is about and what will happen to 
you if you join. You understand what the possible risks and benefits are. 
• You have had your questions answered and know that you can ask more. 
• You agree to join this study. 
You will not be giving up any of your rights by signing this consent form. 
 
 
 
 
 
 
 
 
Participant’s name (print) 
 
Participant’s signature or mark 
 
Date 
 
Time 
 
 
 
 
 
 
 
Clinic staff conducting consent 
discussion (print) 
 
Clinic staff signature 
 
Date 
 
Time 
For participants who are unable to read or write, a witness should complete the signature 
block below: 
 
 
 
 
 
 
 
Witness’s name (print) 
 
Witness’s signature  
 
Date 
 
Time 
 
*Witness is impartial and was present for the entire discussion of this consent form. 
 

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Appendix B 
Approved birth control methods for persons 
assigned female sex at birth (for sample informed 
consent form) for African sites 
You should not become pregnant during the study because we do not know how 
the study vaccines could affect the developing baby.  
You must agree to use effective birth control, from 3 weeks before your first 
study injection until 6 months after your last study injection.  
Effective birth control for participants in Africa is defined as using 2 methods of 
birth control every time you have sex. These include 1 of the following methods: 
• Male or female condoms; or, 
• Diaphragm or cervical cap; 
PLUS 1 of the following methods: 
• Birth control drugs that prevent pregnancy—given by pills, shots, patches, 
vaginal rings, or inserts under the skin;  
• Intrauterine device (IUD); or 
• You are only having sex with a partner who has had a vasectomy. (We will 
ask you some questions to confirm that the vasectomy was successful.).  
You do not have to use birth control if: 
• You have reached menopause, with no menstrual periods for one year; 
• You have had a hysterectomy (your uterus removed); 
• You have had your ovaries removed; 
• You have a tubal ligation (your “tubes tied”) or confirmed successful 
placement of a product that blocks the fallopian tubes;  
• You are sexually abstinent (no sex at all) 
Sites may delete the bullets below, if desired. 
• You are having sex only with a female partner or partners; 
• You only have oral sex.  
Remember: If you are having sex, male and female condoms are the only birth 
control methods that also provide protection against HIV and other sexually 
transmitted infections. 

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Appendix C 
Approved birth control methods for persons 
assigned female sex at birth (for sample informed 
consent form) for US sites 
You should not become pregnant during the study because we do not know how 
the study vaccines could affect the developing baby.  
You must agree to use effective birth control, from 3 weeks before your first 
study injection until 6 months after your last study injection.  
Effective contraception for participants in the US means using any of the 
following methods every time you have sex: 
• Birth control drugs that prevent pregnancy—given by pills, shots, patches, 
vaginal rings, or inserts under the skin; 
• Male or female condoms, with or without a cream or gel that kills sperm; 
• Diaphragm or cervical cap with a cream or gel that kills sperm; or 
• Intrauterine device (IUD); 
You do not have to use birth control if: 
• You are only having sex with a partner or partners who have had a vasectomy. 
(We will ask you some questions to confirm that the vasectomy was 
successful.); 
• You have reached menopause, with no menstrual periods for one year; 
• You have had a hysterectomy (your uterus removed); 
• You have had your ovaries removed; 
• You have a tubal ligation (your “tubes tied”) or confirmed successful 
placement of a product that blocks the fallopian tubes; 
• You are having sex only with a female partner or partners; 
• You only have oral sex; or, 
• You are sexually abstinent (no sex at all). 
Remember: If you are having sex, male and female condoms are the only birth 
control methods that also provide protection against HIV and other sexually 
transmitted infections. 

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Appendix D 
Table of procedures (for sample informed 
consent form) 
 
 
 
Time after first injection visit (in months) 
Procedure 
Screening 
visit(s) 
First 
injection 
visit 
½  
1 
1½  
3 
3½  
6 
6¼  
6½ 
9 
12 
Injection 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
√ 
 
 
 
 
 
 
 
 
 
 
√ 
Brief physical 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Urine test 
√ 
 
√ 
 
 
 
 
 
 
√ 
 
 
Blood drawn 
√ 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Pregnancy testa 
(participants assigned 
female sex at birth) 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√c 
√ 
√c 
HIV testing & pretest 
counseling 
√ 
 
 
 
 
√ 
 
√ 
 
 
√ 
√ 
Risk reduction counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Interview/questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Pap smearb 
√ 
 
 
 
 
 
 
 
 
 
 
 
Rectal fluids/cervical 
fluids/semen samples 
(optional) 
 
√ 
 
 
 
 
 
 
 
√ 
 
√ 
Genital Tract Infection 
testing (urine, blood and 
swab for females) for 
people who agree to 
provide the optional 
samples 
 
√ 
 
 
 
 
 
 
 
√ 
 
√ 
Stool sample and/or swab 
(optional) 
 
√ 
 
 
 
 
 
 
 
√ 
 
 
Not shown in this table is a time after all study participants have completed their last scheduled visit when 
you can find out what products you received.  
a People who are NOT of reproductive potential due to having had total hysterectomy or bilateral 
oophorectomy are not required to have pregnancy tests  
b For participants who were assigned female sex at birth and who agree to provide cervical and/or rectal 
fluids samples and are ≥ 21 years of age. 
c For participants who were assigned female sex at birth and who agree to provide cervical and/or rectal 
fluids sample 

HVTN 120 Version 3.0 / September 12, 2018 
HVTN120_v3.0_FINAL.docx / Page 171 of 184 
Appendix E 
Sample consent form for use of samples and 
information in other studies 
A phase 1/2a clinical trial to evaluate the safety and immunogenicity of ALVAC-
HIV (vCP2438) and of MF59®- or AS01B-adjuvanted clade C Env protein, in 
healthy, HIV-uninfected adult participants  
HVTN protocol number: HVTN 120 
Site: [Insert site name] 
When samples are no longer needed for this study, the HVTN wants to use them 
in other studies and share them with other researchers. The HVTN calls these 
samples “extra samples”. The HVTN will only allow your extra samples to be 
used in other studies if you agree to this. You will mark your decision at the end 
of this form. If you have any questions, please ask.  
1. Do I have to agree?  
No. You are free to say yes or no, or to change your mind after you sign this form. 
At your request, we will destroy all extra samples that we have. Your decision 
will not affect your being in this study or have any negative consequences here.  
2. Where are the samples stored?  
Extra samples are stored in a secure central place called a repository. [Site: 
choose one of the following two sentences. African sites should choose the 
sentence referencing the repository in South Africa. All other sites should choose 
the sentence referencing the repository in the United States.] Your samples will 
be stored in the HVTN repository in South Africa. Your samples will be stored in 
the HVTN repository in the United States. 
3. How long will the samples be stored?  
There is no limit on how long your extra samples will be stored. [Site: Revise the 
previous sentence to insert limits if your regulatory authority imposes them.] 
4. Will I be paid for the use of my samples?  
No. Also, a researcher may make a new scientific discovery or product based on 
the use of your samples. If this happens, there is no plan to share any money with 
you. The researcher is not likely to ever know who you are. 
5. Will I benefit from allowing my samples to be used in other studies?  
Probably not. Results from these other studies are not given to you, this clinic, or 
your doctor. They are not part of your medical record. The studies are only being 
done for research purposes. 

HVTN 120 Version 3.0 / September 12, 2018 
HVTN120_v3.0_FINAL.docx / Page 172 of 184 
6. Will the HVTN sell my samples and information?  
No, but the HVTN may share your samples with HVTN or other researchers. 
Once we share your samples and information, we may not be able to get them 
back. 
7. How do other researchers get my samples and information?  
When a researcher wants to use your samples and information, their research plan 
must be approved by the HVTN. Also, the researcher’s institutional review board 
(IRB) or ethics committee (EC) will review their plan. [Site: If review by your 
institution’s IRB/EC/RE is also required, insert a sentence stating this.] IRBs/ECs 
protect the rights and well-being of people in research. If the research plan is 
approved, the HVTN will send your samples to the researcher’s location. 
8. What information is shared with HVTN or other researchers?  
The samples and information will be labeled with a code number. Your name will 
not be part of the information. However, some information that we share may be 
personal, such as your race, ethnicity, gender, health information from the study, 
and HIV status. We may share information about the study product you received 
and how your body responded to the study product.  
9. What kind of studies might be done with my extra samples and information?  
The studies will be related to HIV, vaccines, the immune system and other 
diseases.  
Researchers may also do genetic testing on your samples. 
In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to do research with them. 
If you agree, your samples could also be used for genome wide studies. In these 
studies, researchers will look at all of your genes (your genome). The researchers 
compare the genomes of many people, looking for common patterns of genes that 
could help them understand diseases. The researchers may put the information 
from the genome-wide studies into a protected database so that other researchers 
can access it, but your name and other personal information will not be included. 
Usually, no one would be able to look at your genome and link it to you as a 
person. However, if another database exists that also has information on your 
genome and your name, someone might be able to compare the databases and 
identify you. If others found out, it could lead to discrimination or other problems. 
The risk of this is very small. There may be other unknown risks. 

HVTN 120 Version 3.0 / September 12, 2018 
HVTN120_v3.0_FINAL.docx / Page 173 of 184 
10. What are the risks of genetic testing?  
It is unlikely, but the genetic tests done on your samples could show you may be 
at risk for certain diseases. If others found out, it could lead to discrimination or 
other problems. However, it is almost impossible for you or others to know your 
test results from the genetic testing. The results are not part of your study records 
and are not given to you.  
US Sites, include the following paragraph  
In the very unlikely event that your genetic information becomes linked to your 
name, a federal law called the Genetic Information Nondiscrimination Act 
(GINA) helps protect you. GINA keeps health insurance companies and 
employers from seeing results of genetic testing when deciding about giving you 
health insurance or offering you work. GINA does not help or protect you against 
discrimination by companies that sell life, disability or long-term care insurance.  
11. Who will have access to my information in studies using my extra samples? 
People who may see your information are: 
• Researchers who use your extra samples and information for other research 
• Government agencies that fund or monitor the research using your extra 
samples and information 
• Any regulatory agency that reviews the research using your extra samples and 
information 
• The researcher’s Institutional Review Board or Ethics Committee 
• The people who work with the researcher  
All of these people will do their best to protect your information. The results of 
any new studies that use your extra samples and information may be published. 
No publication will use your name or identify you personally. 
Questions  
12. If you have questions or problems about allowing your samples and 
information to be used in other studies, use the following important contacts. 
If you have questions about the use of your samples or information or if you want 
to change your mind about their use, contact 
[name or title and telephone number of the investigator or other study staff]. 

HVTN 120 Version 3.0 / September 12, 2018 
HVTN120_v3.0_FINAL.docx / Page 174 of 184 
If you think you may have been harmed because of studies using your samples or 
information, contact 
[name or title and telephone number of the investigator or other study staff]. 
If you have questions about your rights as a research participant, contact 
[name or title and telephone number of person on IRB/EC . 
13. Please choose only one of the options below and write your initials or make 
your mark in the box next to it. Whatever you choose, the HVTN keeps track 
of your choice about how your samples and information can be used. You can 
change your mind after signing this form. 
 
I allow my extra samples and information to be used for other studies related to HIV, 
vaccines, the immune system, and other diseases. This may include genetic testing and 
keeping my cells growing over time.  
OR 
 
 
I agree to the option above and also to allow my extra samples and information to be 
used in genome wide studies. 
OR 
 
 
I do not allow my extra samples to be used in any other studies. This includes not 
allowing genetic testing, growing more of my cells, or genome wide studies.  
 
 
 
 
 
 
 
 
 
Participant’s name (print) 
 
Participant’s signature or mark 
 
Date 
 
Time 
 
 
 
 
 
 
 
Clinic staff conducting consent 
discussion (print) 
 
Clinic staff signature 
 
Date 
 
Time 
For participants who are unable to read or write, a witness should complete the 
signature block below: 
 
 
 
 
 
 
 
Witness’s name (print) 
 
Witness’s signature  
 
Date 
 
Time 
*Witness is impartial and was present for the entire discussion of this consent form. 
.

HVTN 120 Version 3.0 / September 12, 2018 
HVTN120_v3.0_FINAL.docx / Page 175 of 184 
Appendix F 
Laboratory procedures 
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
Day:
D0
D14
D28
D42
D84
D98
D168
D175
D182
D273
D364
Weeks
W0
W2
W4
W6
W12
W14
W24
W25
W26
W39
W52
Month
M0
M0.5
M1
M1.5
M3
M3.5
M6
M6.25
M6.5
M9
M12
VAC1
VAC2
VAC3
VAC4
ALVAC OR 
Placebo
ALVAC OR 
Placebo
ALVAC + Protein
w/ MF59 OR 
AS01B OR 
Placebo
ALVAC + Protein
w/ MF59 OR 
AS01B OR 
Placebo
Procedure
Ship to1
Assay 
location2
Tube 
Type4
Tube size
(vol. capacity)4
 
Total
BLOOD COLLECTION
Screening/Diagnostic
Screening HIV test
Local lab
Local lab
EDTA
5mL
5
—
—
—
—
—
—
—
—
—
—
—
5
HBsAg/anti-HCV
Local lab
Local lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
5
HIV diagnostics 9
HSML-NICD /
UW-VSL
HSML-NICD /
UW-VSL
EDTA
10mL
—
—
—
—
—
10
—
10
—
—
10
209
50
Safety labs15
CBC/ Diff/ platelets
Local lab
Local lab
EDTA
5mL
5
—
5
—
5
—
5
—
—
5
—
—
25
Chemistry panel5
Local lab
Local lab
SST
5mL
5
—
5
—
5
—
5
—
—
5
—
—
25
STI Serology
Syphilis11
Local lab
Local lab
SST
5mL
5
5 11
—
—
—
—
—
—
—
5 11
—
5 11
20
Immunogenicity & Virologic assays 6
HLA host genetics 7
CSR
HVTN Labs
ACD
8.5mL
—
17
—
—
—
—
—
—
—
—
—
—
17
Cellular assays
ICS
CSR
HVTN Labs
ACD
8.5mL
—
68
—
—
—
—
68
—
—
68
—
68
272
pTfh and Plasmablast
CSR
HVTN Labs
ACD
8.5mL
—
17
—
—
—
—
—
—
17
—
—
—
34
Humoral assays
Binding Ab Assay
CSR
HVTN Labs
SST
8.5mL
—
8.5
—
—
—
—
8.5
—
—
8.5
—
8.5
34.0
Neutralizing Ab Assay
CSR
HVTN Labs
SST
8.5mL
—
8.5
—
—
—
—
8.5
—
—
8.5
—
8.5
34.0
Ab Avidity
CSR
HVTN Labs
SST
8.5mL
—
y
—
—
—
—
—
—
—
y
—
y
0
ADCC
CSR
HVTN Labs
SST
8.5mL
—
y
—
—
—
—
—
—
—
y
—
y
0
STORAGE
Serum storage
CSR
—
SST
8.5mL
—
17
—
—
25.5
—
8.5
25.5
8.5
8.5
25.5
8.5
128
PBMC storage
CSR
—
ACD
8.5mL
—
42.5
—
—
25.5
—
17
—
34
17
—
17
153
Visit total
25
184
10
0
61
10
121
36
60
126
36
136
802
56-Day total
 
25
209
219
219
280
71
192
36
95
221
36
136
URINE COLLECTION
Urinalysis15
Local lab
Local lab
X
—
X
—
—
—
—
—
—
X
—
—
Pregnancy Test8, 15
Local lab
Local lab
X
X
—
X
—
X
—
X
—
X10
X
X10
Chlamydia/Gonorrhea11
Local lab
Local lab
—
X
—
—
—
—
—
—
—
X
—
X
CERVICAL/VAGINAL SWAB COLLECTION12
Trichomonas vaginalis
Local lab
Local lab
—
X
—
—
—
—
—
—
—
X
—
X
Bacterial vaginosis
Local lab
Local lab
—
X
—
—
—
—
—
—
—
X
—
X
Yeast
Local lab
Local lab
—
X
—
—
—
—
—
—
—
X
—
X
MUCOSAL COLLECTION (OPTIONAL)13 
Semen
CSR
HVTN Labs
—
X
—
—
—
—
—
—
—
X
—
X
Cervical Secretions
CSR
HVTN Labs
—
X
—
—
—
—
—
—
—
X
—
X
Rectal Secretions
CSR
HVTN Labs
—
X
—
—
—
—
—
—
—
X
—
X
STOOL COLLECTION (OPTIONAL)
Stool 
CSR
HVTN Labs
—
X14
—
—
—
—
—
—
—
X
—
—
Screening 
visit3
 

HVTN 120 Version 3.0 / September 12, 2018 
HVTN120_v3.0_FINAL.docx / Page 176 of 184 
Footnotes for Laboratory procedures  
 
1 CSR = Central Specimen Repository; HSML-NICD = HIV Sero-Molecular Laboratory-National 
Institute for Communicable Diseases (Johannesburg, South Africa); UW-VSL = University of 
Washington Virology Specialty Laboratory (Seattle, Washington, USA). 
2 HVTN Laboratories include: Cape Town HVTN Immunology Laboratory (CHIL, Cape Town, 
South Africa); South African Immunology Laboratory–National Institute for Communicable 
Diseases (SAIL-NICD, Johannesburg, South Africa); Fred Hutchinson Cancer Research Center 
(Seattle, Washington, USA); Duke University Medical Center (Durham, North Carolina, USA).  
3 Screening may occur over the course of several contacts/visits up to and including day 0 prior to 
vaccination.  
4 Local labs may assign appropriate alternative tube types for locally performed tests. 
5 Chemistry panels are defined in Section 9.2 (pre-enrollment) and Section 9.3 (postenrollment). 
 
6 Immunogenicity assays will be performed at M0 (for binding Ab assay), M6.5, and M12. Based on 
the number of responders observed at these timepoints, lab assays may be performed on 
participants for humoral and cellular responses at other timepoints. 
7 Genotyping may be performed on enrolled participants using cryopreserved PBMC collected at 
baseline, initially in participants who demonstrate vaccine-induced T-cell responses at 
postvaccination timepoints. 
8 For a participant who was assigned female sex at birth, pregnancy test must be performed on urine 
or blood specimens within 24 hours of vaccination with negative results received prior to 
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. 
9 At an early termination visit for a withdrawn or terminated participant who is not HIV-infected (see 
Section 9.12), blood should be drawn for HIV diagnostic testing, as shown for visit 12 above. If a 
participant has a confirmed diagnosis of HIV infection, do not collect blood for HIV diagnostic 
testing (see Section 9.14). 
10 Pregnancy testing at the indicated visit is only required of participants who were assigned female 
sex at birth and are providing a cervical and/or rectal secretion sample. 
11 Syphilis testing by serology and Chlamydia and gonorrhea testing by urine will only be performed 
if the participant agrees to provide a mucosal sample. 
12 Cervical/vaginal swabs will only be collected from participants who agree to provide a cervical 
secretion sample and for yeast if clinically indicated. 
13 Optional mucosal specimens may be collected as part of screening and prior to the enrollment visit 
once the participant has been found to have met mucosal specimen collection criteria specified in 
Section 9.5. 
14 Optional stool specimen must be collected prior to first vaccination. 
15 For participants with confirmed diagnosis of HIV infection, only specimens required for protocol-
specified safety laboratory tests, urinalysis, and pregnancy tests will be collected. 
y = 17 mL of SST blood collected for the Binding Ab and Neutralizing Ab assays will also cover 
specimen needs for the Ab avidity and ADCC assays; no separate blood draw is needed. 
 

HVTN 120 Version 3.0 / September 12, 2018 
HVTN120_v3.0_FINAL.docx / Page 177 of 184 
Appendix G 
Procedures at HVTN CRS  
Visit:
01a  
02m 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
Post 
Day:
 
D0 
D14 
D28 
D42 
D84 
D98 
D168 
D175 
D182 
D273 
D364 
 
Month:
 
M0 
M0.5 
M1 
M1.5 
M3 
M3.5 
M6 
M6.25 
M6.5 
M9 
M12 
 
Procedure
Scr. 
VAC1 
 
VAC2 
 
VAC3 
 
VAC4 
 
 
 
 
 
Study proceduresb 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed screening consent (if used) 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Assessment of understanding 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Signed protocol consent 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Medical history  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Complete physical exam 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
Abbreviated physical exam 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Risk reduction counselingr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Pregnancy prevention assessmentc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Behavioral risk assessments 
X 
— 
— 
— 
— 
X 
— 
X 
— 
— 
X 
X 
— 
Confirm eligibility, obtain demographics, randomize  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Social impact assessment 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Social impact assessment questionnaire 
— 
— 
— 
— 
— 
X 
— 
X  
— 
— 
— 
X 
— 
Outside testing and belief questionnaire 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
X 
— 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Intercurrent illness/adverse experienced 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
HIV infection assessmente 
X 
— 
— 
— 
— 
X 
— 
X 
— 
— 
X 
X 
— 
Confirm HIV test results provided to participant 
— 
X 
— 
— 
— 
— 
X 
— 
X 
— 
— 
X 
X 
Local lab assessmentt 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine dipstick 
X 
— 
X 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
Pregnancy (urine or serum HCG)f 
X 
X 
— 
X 
— 
X 
— 
X 
— 
Xo 
X 
Xo 
— 
CBC, differential, platelet 
X 
— 
X 
— 
X 
— 
X 
— 
— 
X 
— 
— 
— 
Chemistry panel (see Section 9.2)  
X 
— 
X 
— 
X 
— 
X 
— 
— 
X 
— 
— 
— 
Hepatitis B, Hepatitis C 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Syphilis 
X 
Xn 
— 
— 
— 
— 
— 
— 
— 
Xn 
— 
Xn 
— 
Pap smearg 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Chlamydia/gonorrhea (urine)h 
— 
X 
— 
— 
— 
— 
— 
— 
— 
X 
— 
X 
— 
Trichomonas vaginalisi 
— 
X 
— 
— 
— 
— 
— 
— 
— 
X 
— 
X 
— 
Bacterial vaginosisi 
— 
X 
— 
— 
— 
— 
— 
— 
— 
X 
— 
X 
— 
Yeastj 
— 
X 
— 
— 
— 
— 
— 
— 
— 
X 
— 
X 
— 
Mucosal and stool sample collection (optional) 
Rectal secretions, cervical secretions, semen 
— 
X 
— 
— 
— 
— 
— 
— 
— 
X 
— 
X 
— 
Stoolq 
— 
Xp 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
Vaccination procedures 
Vaccinationk 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
— 
— 
— 
Reactogenicity assessmentsl 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
— 
— 
— 
Poststudy 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblind participant  
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 

HVTN 120 Version 3.0 / September 12, 2018 
HVTN120_v3.0_FINAL.docx / Page 178 of 184 
Footnotes for Procedures at HVTN CRS  
 
a Screening may occur over the course of several contacts/visits up to and including day 0 prior to 
vaccination. 
b For specimen collection requirements, see Appendix F. 
c Pregnancy prevention compliance occurs only with participants who were assigned female sex at birth and 
are capable of becoming pregnant. 
d AEs to be collected and reported through 30 days after each vaccination (see Section 11.2.2). 
e Includes pre-test counseling. A subsequent follow-up contact is conducted to provide post-test counseling 
and to report results to participant. If a participant has a confirmed diagnosis of HIV infection, do not 
perform HIV infection assessment. 
f For a participant who was assigned female sex at birth, pregnancy test must be performed on urine or blood 
specimens within 24 hours of vaccination with negative results received prior to vaccination. Pregnancy 
test to determine eligibility may be performed at screening, but must also be done on day 0 prior to 
vaccination. Persons who have undergone total hysterectomy or bilateral oophorectomy (verified by 
medical records), are not required to undergo pregnancy testing. 
g Only for volunteers who were assigned female sex at birth and who agree to provide cervical samples. Per 
Section 7.1, Criterion 23; Pap smear not required if volunteer has had Pap smear within previous 3-5 years 
with most recent result normal or ASCUS or less than 21 years old. 
h Urine testing for Chlamydia and gonorrhea will be done only if the participant consents to provide mucosal 
samples. Specimen collection for this testing will take place at the time of mucosal sampling, prior to 
vaccination (if scheduled). 
i This testing will be done for participants providing cervical mucosal samples. Specimen collection for this 
testing will take place at the time of mucosal sampling, prior to vaccination (if scheduled). 
j This testing will be done for participants providing cervical mucosal samples only if clinically indicated. 
Specimen collection for this testing will take place at the time of mucosal sampling, prior to vaccination (if 
scheduled). 
k Blood draws required at vaccination visits must be performed prior to vaccination; however, it is not 
necessary to have results prior to vaccination, except for results of a urine or serum pregnancy test, if 
indicated. 
l Reactogenicity assessments performed daily for at least 7 days postvaccination (see Section 9.10). 
 
m Specimens collected at the enrollment visit may be obtained within the 14 days prior to vaccination, except 
for a pregnancy test which must be performed on urine or blood specimens on the day of vaccination with 
negative results received prior to vaccination 
n Syphilis testing will only be performed at the indicated visit if the participant agrees to provide mucosal 
samples. 
o Pregnancy testing at the indicated visit is only required of participants who were assigned female sex at 
birth and are providing a cervical and/or rectal secretion sample. 
p Optional stool specimen must be collected prior to first vaccination. 
q Collect dietary, antibiotic use, and gastrointestinal symptom information from participants providing stool 
specimen. 
r Includes transmission risk reduction counseling for HIV-infected participants. 
s Not applicable to HIV-infected participants. 
t For participants with a confirmed diagnosis of HIV infection, only specimens listed under “Safety labs” in Appendix F, 
urinalysis, and urine pregnancy tests will be collected per the protocol schedule. 
 

HVTN 120 Version 3.0 / September 12, 2018 
HVTN120_v3.0_FINAL.docx / Page 179 of 184 
Appendix H 
Adverse events of special interest 
AEs of special interest (AESI) for this protocol include but are not limited to 
potential immune-mediated diseases; representative examples of AESI are listed 
below.  
 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve disorders, including 
paralyses/paresis (eg Bell’s palsy)  
• 
Optic neuritis 
• 
Multiple sclerosis 
• 
Transverse myelitis 
• 
Guillain-Barré syndrome, including 
Miller Fisher syndrome and other 
variants 
• 
Acute disseminated 
encephalomyelitis, including site 
specific variants: eg non-infectious 
encephalitis, encephalomyelitis, 
myelitis, myeloradiculoneuritis 
• 
Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome  
• 
Immune-mediated peripheral 
neuropathies and plexopathies, 
(including chronic inflammatory 
demyelinating polyneuropathy, 
multifocal motor neuropathy and 
polyneuropathies associated with 
monoclonal gammopathy). 
• 
Narcolepsy 
• 
Systemic lupus erythematosus and 
associated conditions 
• 
Systemic scleroderma (Systemic 
sclerosis), including diffuse 
systemic form and CREST 
syndrome 
• 
Idiopathic inflammatory 
myopathies, including 
dermatomyositis  
• 
Polymyositis  
• 
Antisynthetase syndrome 
• 
Rheumatoid arthritis, and 
associated conditions including 
juvenile chronic arthritis and Still’s 
disease 
• 
Polymyalgia rheumatica 
• 
Spondyloarthritis, including 
ankylosing spondylitis, reactive 
arthritis (Reiter's Syndrome) and 
undifferentiated spondyloarthritis  
• 
Psoriatic arthropathy 
• 
Relapsing polychondritis 
• 
Mixed connective tissue disorder 
• 
Psoriasis 
• 
Vitiligo 
• 
Erythema nodosum 
• 
Autoimmune bullous skin 
diseases (including pemphigus, 
pemphigoid and dermatitis 
herpetiformis) 
• 
Alopecia areata 
• 
Lichen planus 
• 
Sweet’s syndrome 
• 
Localized Scleroderma 
(Morphea)  
• 
Cutaneous lupus erythematosus 
 
Metabolic disorders 
• 
Addison’s disease 
• 
Autoimmune thyroiditis 
(including Hashimoto thyroiditis) 
• 
Diabetes mellitus type I 
• 
Grave's or Basedow’s disease 
Vasculitides 
Blood disorders 
Others 
• 
Large vessels vasculitis including: 
giant cell arteritis such as 
Takayasu’s arteritis and temporal 
arteritis.  
• 
Medium sized and/or small vessels 
vasculitis including: polyarteritis 
nodosa, Kawasaki's disease, 
microscopic polyangiitis, Wegener’s 
granulomatosis, Churg-Strauss 
syndrome (allergic granulomatous 
angiitis), Buerger’s disease 
(thromboangiitis obliterans), 
necrotizing vasculitis and anti-
neutrophil cytoplasmic antibody 
(ANCA) positive vasculitis (type 
unspecified), Henoch-Schonlein 
purpura, Behcet’s syndrome, 
leukocytoclastic vasculitis. 
• 
Autoimmune hemolytic anemia 
• 
Autoimmune thrombocytopenia 
• 
Antiphospholipid syndrome 
• 
Pernicious anemia 
• 
Autoimmune aplastic anemia 
• 
Autoimmune neutropenia  
• 
Autoimmune pancytopenia 
 
Gastrointestinal disorders 
• 
Celiac disease 
• 
Crohn’s disease 
• 
Ulcerative colitis 
• 
Ulcerative proctitis 
 
Liver disorders 
• 
Autoimmune cholangitis 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing cholangitis 
• 
Autoimmune glomerulonephritis 
(including IgA nephropathy, 
glomerulonephritis rapidly 
progressive, membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and 
mesangioproliferative 
glomerulonephritis) 
• 
Ocular autoimmune diseases 
(including autoimmune uveitis 
and autoimmune retinopathy) 
• 
Autoimmune 
myocarditis/cardiomyopathy 
• 
Sarcoidosis 
• 
Stevens-Johnson syndrome 
• 
Sjögren’s syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Goodpasture syndrome 
• 
Raynaud’s phenomenon 

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Appendix I 
Injection schedule for sample informed 
consent 
 
 

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Appendix J 
Low Risk Guidelines for the United States 
The following are intended as guidelines for the investigator to help identify 
potential vaccine trial participants at “low risk” for HIV infection in the US.  
These guidelines are based on behaviors within the last 6-12 months prior to 
enrollment; however, it may be appropriate to consider a person’s behavior over a 
longer period of time than specified to assess the person’s likelihood of 
maintaining low risk behavior. Some volunteers may not be appropriate for 
enrollment even if they meet these guidelines. These guidelines should be 
supplemented and interpreted with local epidemiologic information about HIV 
prevalence in your area and community networks.  The investigator may review 
the risk level of any volunteer with the site PI and/or protocol safety review team. 
A volunteer may be appropriate for inclusion if he/she meets these guidelines: 
1. SEXUAL BEHAVIORS 
In the last 12 months did not: 
• Have oral, vaginal or anal intercourse with an HIV-infected partner, or  
a partner who uses injection drugs  
• Give or receive money, drugs, gifts or services in exchange for oral, 
vaginal or anal sex 
AND 
In the last 6 months has abstained from penile/anal or penile/vaginal 
intercourse, OR 
In the last 6 months: 
• Had 4 or fewer partners of the opposite birth sex for vaginal and/or 
anal intercourse, OR 
Is an MSM (person born male with partner(s) born male) who, in the last 12 
months: 
• Had 2 or fewer MSM partners for anal intercourse and had no 
unprotected anal sex with MSM, OR 
• Had unprotected anal intercourse with only 1 MSM partner, within a 
monogamous relationship lasting at least 12 months (during which 
neither partner had any other partners). If the monogamous 
relationship ended, the volunteer may then have had protected anal 
intercourse with 1 other MSM partner (total 2 or fewer partners in the 
last 12 months).  
Is a transgender person, regardless of the point on the transition spectrum, 
having sex with men (born male) and/or other transgender persons, who in the 
last 12 months: 

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• Had 2 or fewer partners for anal or vaginal intercourse, and had no 
unprotected anal or vaginal sex, OR  
• Had unprotected anal or vaginal intercourse sex with 1 partner only 
within a monogamous relationship lasting at least 12 months (during 
which neither partner had any other partners). If the monogamous 
relationship ended, may then have had protected anal or vaginal sex 
with 1 other partner (total 2 or fewer partners in the last 12 months). 
AND 
Uses or intends to use condoms in situations which may include penile/anal or 
penile/vaginal intercourse with new partners of unknown HIV status, 
occasional partners, partners outside a primary relationship, and/or partners 
known to have other partners. 
2. NON-SEXUAL BEHAVIORS 
In the last 12 months did not: 
• Inject drugs or other substances without a prescription 
• Use cocaine, methamphetamine, or excessive alcohol, which in the 
investigator’s judgment rendered the participant at greater than low 
risk for acquiring HIV infection. The investigator’s judgment should 
consider local epidemiologic information about HIV prevalence in the 
area and community networks. 
A volunteer is NOT appropriate for inclusion if he/she: 
Acquired an STI (i.e. new infection) in the last 12 months: 
• Syphilis  
• Gonorrhea  
• Non-gonococcal urethritis  
• Herpes Simplex Virus type 2 (HSV2)  
• Chlamydia  
• Pelvic inflammatory disease (PID)  
• Trichomonas  
• Mucopurulent cervicitis  
• Epididymitis  
• Proctitis  
• Lymphogranuloma venereum  
• Chancroid  
• Hepatitis B 
 

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Appendix K 
Low Risk Guidelines for Africa 
The following are intended as guidelines for the investigator to help identify 
potential vaccine trial participants at “low risk” for HIV infection. These 
guidelines are based on behaviors within the last 12 months prior to enrollment; 
however, it may be appropriate to consider a person’s behavior over a longer 
period of time than specified to assess the person’s likelihood of maintaining low 
risk behavior. Some volunteers may not be appropriate for enrollment even if they 
meet these guidelines. These guidelines should be supplemented and interpreted 
with local epidemiologic information about HIV prevalence in your area and 
community networks. The investigator may review the risk level of any volunteer 
with the site PI and/or protocol safety review team. 
ASSESSMENT OF SEXUAL BEHAVIORS 
Consider whether a volunteer would be appropriate for inclusion if, within 12 
months prior to enrollment, the person: 
• Abstained from penile/vaginal and penile/anal intercourse, or 
• Was in a mutually monogamous relationship with a partner with a 
known HIV-uninfected status, or 
• Had one partner believed to be HIV-uninfected with whom he/she 
regularly used condoms for penile/vaginal and penile/anal intercourse. 
Exclude a volunteer if: 
Within the 12 months prior to enrollment: a history of newly acquired syphilis, 
gonorrhea, chlamydia, trichomoniasis, active HSV lesions, chancroid, pelvic 
inflammatory disease (PID), genital sores or ulcers, cervicitis, genital warts of the 
labia minora, vagina, or cervix, or any other symptomatic genital warts. 

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Appendix L 
Protocol Signature Page 
A phase 1/2a clinical trial to evaluate the safety and immunogenicity of ALVAC-
HIV (vCP2438) and of MF59®- or AS01B-adjuvanted clade C Env protein, in 
healthy, HIV-uninfected adult participants 
I will conduct the study in accordance with the provisions of this protocol and all 
applicable protocol-related documents. I agree to conduct this study in 
compliance with United States (US) Health and Human Service regulations (45 
CFR 46); applicable U.S. Food and Drug Administration regulations; standards of 
the International Conference on Harmonization Guideline for Good Clinical 
Practice (E6); Institutional Review Board/Ethics Committee determinations; all 
applicable in-country, state, and local laws and regulations; and other applicable 
requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies 
 
 
 
 
 
 
 
 
 
Investigator of Record Name (print) 
 
Investigator of Record Signature 
 
Date 
 
 
DAIDS Protocol Number: HVTN 120 
DAIDS Protocol Version: Version 3.0 
Protocol Date: September 12, 2018