A Phase 1-2 Randomized, Double-blind, Placebo-controlled Clinical Trial of Clade C ALVAC-HIV (vCP2438) and Bivalent Subtype C gp120/MF59® in HIV-uninfected Adults at Low Risk of HIV Infection
Phase: PHASE1
Conditions: HIV Infection
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
PROTOCOL 
HVTN 100 
A phase 1-2 randomized, double-blind, placebo-
controlled clinical trial of clade C ALVAC-HIV 
(vCP2438) and Bivalent Subtype C gp120/MF59® in 
HIV-uninfected adults at low risk of HIV infection 
DAIDS DOCUMENT ID 11913 
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 
Sanofi-Pasteur 
Swiftwater, Pennsylvania, USA 
GlaxoSmithKline Biologicals, S.A.  
Rixensart, Belgium  
May 23, 2017 
HVTN 100 
Version 3.0 
 
 

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Version 2.0 of HVTN 100 added booster vaccinations and extended follow-up to evaluate 
the capacity of different boost regimens and schedules to maintain or enhance vaccine-
elicited immune responses. Version 3.0 of the protocol implements a single booster 
vaccination at Month 30 with follow-up to Month 36 and reduces group sizes. A visit 1-
week postvaccination has been added to facilitate additional immunogenicity evaluations. 
Mucosal secretion sampling has been added along with associated STI testing. Additional 
corrections, clarifications, and updates have been made to consent form language 
concerning sample testing, to laboratory procedure tables, and to some clinic procedure 
timepoints. Version 3.0 of HVTN 100 also incorporates changes and corrections 
implemented through a previous modification to Version 2.0 of the protocol. 
 
 
 

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Contents 
1 
Ethical considerations .............................................................................................. 6 
2 
IRB/EC review considerations ................................................................................. 8 
2.1 
Minimized risks to participants ..................................................................... 8 
2.2 
Reasonable risk/benefit balance .................................................................... 9 
2.3 
Equitable subject selection ............................................................................ 9 
2.4 
Appropriate informed consent ....................................................................... 9 
2.5 
Adequate safety monitoring ........................................................................... 9 
2.6 
Protect privacy/confidentiality ..................................................................... 10 
3 
Overview ................................................................................................................ 11 
3.1 
Protocol Team .............................................................................................. 14 
4 
Background ............................................................................................................ 16 
4.1 
Rationale for trial concept ........................................................................... 16 
4.2 
ALVAC-HIV (vCP2438)............................................................................. 21 
4.3 
Bivalent Subtype C gp120/MF59® .............................................................. 23 
4.4 
Trial design rationale ................................................................................... 25 
4.5 
Plans for future product development and testing ....................................... 28 
4.6 
Nonclinical studies....................................................................................... 28 
4.7 
Clinical studies ............................................................................................ 31 
4.8 
Potential risks of study products and administration ................................... 46 
5 
Objectives and endpoints ....................................................................................... 48 
5.1 
Primary objectives and endpoints ................................................................ 48 
5.2 
Secondary objectives and endpoints ............................................................ 49 
5.3 
Exploratory objectives ................................................................................. 51 
6 
Statistical considerations ........................................................................................ 52 
6.1 
Accrual and sample size calculations .......................................................... 52 
6.2 
Randomization ............................................................................................. 56 
6.3 
Blinding ....................................................................................................... 56 
6.4 
Statistical analysis ........................................................................................ 56 
7 
Selection and withdrawal of participants ............................................................... 61 
7.1 
Inclusion criteria for Part A ......................................................................... 61 
7.2 
Exclusion criteria for Part A ........................................................................ 63 
7.3 
Eligibility criterion for Part B ...................................................................... 66 
7.4 
Participant departure from vaccination schedule or withdrawal .................. 66 
8 
Study product preparation and administration ....................................................... 69 
8.1 
Vaccine regimen .......................................................................................... 69 
8.2 
Study product formulation ........................................................................... 70 
8.3 
Preparation of study products ...................................................................... 72 
8.4 
Administration ............................................................................................. 76 
8.5 
Acquisition of study products ...................................................................... 76 
8.6 
Pharmacy records......................................................................................... 77 
8.7 
Final disposition of study products .............................................................. 77 
9 
Clinical procedures ................................................................................................ 78 
9.1 
Informed consent ......................................................................................... 78 
9.2 
Pre-enrollment procedures ........................................................................... 80 
9.3 
Enrollment and vaccination visits ................................................................ 82 

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9.4 
Follow-up visits ........................................................................................... 83 
9.5 
Mucosal sampling ........................................................................................ 84 
9.6 
HIV counseling and testing ......................................................................... 86 
9.7 
Contraception status..................................................................................... 87 
9.8 
Urinalysis ..................................................................................................... 88 
9.9 
Assessments of reactogenicity ..................................................................... 88 
9.10 Visit windows and missed visits .................................................................. 89 
9.11 Early termination visit ................................................................................. 90 
9.12 Pregnancy .................................................................................................... 90 
10 
Laboratory .............................................................................................................. 91 
10.1 HVTN CRS laboratory procedures .............................................................. 91 
10.2 Total blood volume ...................................................................................... 91 
10.3 Primary immunogenicity timepoint ............................................................. 91 
10.4 Endpoint assays: humoral ............................................................................ 91 
10.5 Endpoint assays: cellular ............................................................................. 92 
10.6 Genotyping .................................................................................................. 92 
10.7 Lab assay algorithm ..................................................................................... 92 
10.8 Exploratory studies ...................................................................................... 93 
10.9 Other use of stored specimens ..................................................................... 93 
10.10 Biohazard containment ................................................................................ 93 
11 
Safety monitoring and safety review ..................................................................... 94 
11.1 Safety monitoring and oversight .................................................................. 94 
11.2 Safety reporting ........................................................................................... 95 
11.3 Safety pause and prompt PSRT AE review ................................................. 97 
11.4 Review of cumulative safety data ................................................................ 98 
11.5 Study termination......................................................................................... 99 
12 
Protocol conduct .................................................................................................. 100 
12.1 Social impacts ............................................................................................ 100 
12.2 Compliance with NIH guidelines for research involving products containing 
recombinant DNA ..................................................................................... 101 
12.3 Specific regulatory considerations for South Africa .................................. 101 
12.4 Emergency communication with study participants .................................. 101 
13 
Version history ..................................................................................................... 102 
14 
Document references (other than literature citations) .......................................... 106 
15 
Acronyms and abbreviations ................................................................................ 108 
16 
Literature cited ..................................................................................................... 111 
Appendix A Sample informed consent form .................................................................. 120 
Appendix B Addendum to Sample informed consent form (for Part B) ....................... 135 
Appendix C Approved birth control methods (for sample informed consent form) ...... 143 
Appendix D Tables of procedures (for sample informed consent forms) ...................... 144 
Appendix E Sample consent form for use of samples and information in other studies 145 
Appendix F Laboratory procedures for Part A .............................................................. 149 
Appendix G Laboratory procedures for Part B .............................................................. 150 
Appendix H Procedures at HVTN CRS for Part A ........................................................ 151 
Appendix I Procedures at HVTN CRS for Part B ........................................................ 152 

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Appendix J Protocol Signature Page ............................................................................. 154 
 

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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 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 (CABs) are required by DAIDS and supported at 
all HVTN research sites to ensure community input in accordance with Good 
Participatory Practices (GPP) and all local and national guidelines. The HVTN 
leadership is aware of the Guidelines for Good Clinical Practice in the Conduct 
of Clinical Trials with Human Participants in South Africa Section 2.4 
“Communication and Community Involvement” and the South African Medical 
Research Council’s Guidelines on Ethics for Medical Research: HIV Preventive 
Vaccine Research (particularly section 5, Community Participation) and works to 
implement both guidelines generally and those sections specifically. 
 
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. 
 
The HVTN requires that all international HVTN sites lacking national plans for 
providing antiretroviral therapy (ART) develop plans for the care and treatment 
of participants who acquire HIV infection during a trial. Each plan is developed 
in consultation with representatives of host countries, communities from which 
potential trial participants will be drawn, sponsors, and the HVTN. Participants 
will be referred to programs for ART provision when the appropriate criteria for 
starting ART are met. If a program is not available at a site and ART is needed, a 
privately established fund will be used to pay for access to treatment to the fullest 
extent possible. 
 
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. 
 
Prior to implementation, HVTN trials are rigorously reviewed by scientists who 
are not involved in the conduct of the trials under consideration.  

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 
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) and Ethics Committees (ECs) 
as custodians responsible for ensuring the ethical conduct of research in each 
setting. 

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

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2.2 
Reasonable risk/benefit balance 
45 CFR 46.111 (a) 2 and 21 CFR 56 (a) 2: Risks to subjects are reasonable in 
relation to anticipated benefits, if any, to subjects, and the importance of the 
knowledge that may reasonably be expected to result. 
In all public health research, the risk-benefit ratio may be difficult to assess because the 
benefits to a healthy participant are not as apparent as they would be in treatment 
protocols, where a study participant may be ill and may have exhausted all conventional 
treatment options. However, this protocol is designed to minimize the risks to participants 
while maximizing the potential value of the knowledge it is designed to generate.  
2.3 
Equitable subject selection  
45 CFR 46.111 (a) 3 and 21 CFR 56.111 (a) 3: Subject selection is equitable 
This protocol has specific inclusion and exclusion criteria for investigators to follow in 
admitting participants into the protocol. Participants are selected because of these criteria 
and not because of positions of vulnerability or privilege. Investigators are required to 
maintain screening and enrollment logs to document volunteers who screened into and 
out of the protocol and for what reasons. 
2.4 
Appropriate informed consent 
45 CFR 46.111 (a) 4 & 5 and 21 CFR 56.111 (a) 4 & 5: Informed consent is sought 
from each prospective subject or the subject’s legally authorized representative as 
required by 45 CFR 46.116 and 21 CFR Part 50; informed consent is appropriately 
documented as required by 45 CFR 46.117 and 21 CFR 50.27. 
The protocol specifies that informed consent must be obtained before any study 
procedures are initiated and assessed throughout the trial (see 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 (see Section 11). Safety is 
monitored daily by HVTN Core and routinely by the HVTN 100 Protocol Safety Review 
Team (PSRT). In addition, the HVTN Safety Monitoring Board (SMB) or a Data and 
Safety Monitoring Board (DSMB) 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 addition, each staff member at each study site in this protocol signs a 
Confidentiality Agreement with the HVTN and each study site participating in the 
protocol is required to have a standard operating procedure on how the staff members 
will protect the confidentiality of study participants. 

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3 
Overview 
Title  
A phase 1-2 randomized, double-blind, placebo-controlled clinical trial of clade C 
ALVAC-HIV (vCP2438) and Bivalent Subtype C gp120/MF59® in HIV-uninfected 
adults at low risk of HIV infection 
Primary objective(s) for Part A 
 
To evaluate the safety and tolerability of 2 doses of ALVAC-HIV (vCP2438) 
followed by 2 doses of ALVAC-HIV (vCP2438) + Bivalent Subtype C 
gp120/MF59® in HIV-seronegative low risk South African adults  
 
To evaluate the immunogenicity of 2 doses of ALVAC-HIV (vCP2438) followed by 
2 doses of ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59® in HIV-
seronegative low risk South African adults at the month 6.5 timepoint (2 weeks after 
completion of the primary immunization series) 
Primary objective(s) for Part B 
 
To evaluate the safety and tolerability of Bivalent Subtype C gp120/MF59 and of 
ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59 when given as boosts 
in participants previously vaccinated  in Part A  
 
To evaluate the immunogenicity of Bivalent Subtype C gp120/MF59 and of 
ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59 when given as boosts at 
Month 30 in participants previously vaccinated in Part A at 2 weeks following 
vaccination 
Study products and routes of administration 
 
ALVAC-HIV (vCP2438) expresses the gene products ZM96 gp120 (clade C strain) 
linked to the sequences encoding the HIV-1 transmembrane anchor (TM) sequence of 
gp41 (28 amino acids clade B LAI strain) and gag and pro (clade B LAI strain). It is 
formulated as a lyophilized vaccine for injection at a viral titer ≥ 1 × 106 cell culture 
infectious dose (CCID)50 and < 1 × 108 CCID50 (nominal dose of 107 CCID50) and is 
reconstituted with 1mL of sterile sodium chloride solution (NaCl 0.4%) for 
intramuscular (IM) injection as a single dose  
 
Bivalent Subtype C gp120/MF59® consists of 2 subtype C recombinant monomeric 
proteins, TV1.C gp120 Env and 1086.C gp120 Env, each at a dose of 100 mcg, 
mixed with MF59® adjuvant (an oil-in-water emulsion) delivered as a 0.5 mL IM 
injection  
 
ALVAC-HIV placebo (Part A): a sterile, lyophilized product that consists of a 
mixture of virus stabilizer, and freeze drying medium and is reconstituted with 1mL 
of sterile sodium chloride solution (NaCl 0.4%) for injection as a single dose IM 
 
ALVAC-HIV placebo (Part B): sodium chloride for injection, 0,9% delivered as 
a 1.0 mL IM injection 

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 
Bivalent gp120/MF59® placebo: sodium chloride for injection, 0,9% delivered as 
a 0.5 mL IM injection 
Table 3-1 Schema 
Group 
N 
Primary vaccine regimen 
Booster* 
Month 0 
Month 1 
Month 3 
Month 6 
Month 12 
1 
210 
ALVAC-HIV 
(vCP2438) 
ALVAC-HIV 
(vCP2438) 
ALVAC-HIV 
(vCP2438) + 
Bivalent Subtype C 
gp120/MF59® 
ALVAC-HIV 
(vCP2438) + 
Bivalent Subtype C 
gp120/MF59® 
ALVAC-HIV 
(vCP2438) + 
Bivalent Subtype C 
gp120/MF59® 
2 
42 
Placebo 
Placebo 
Placebo + Placebo 
Placebo + Placebo 
Placebo + Placebo 
Total  
252 
 
*For booster dose evaluations, see secondary objectives.  
Table 3-2 Schema for Part B 
 
Booster vaccination 
Part A Group 
Part B Group† 
N 
Month 30 
1 
1a 
~30 
ALVAC-HIV (vCP2438) + 
Bivalent Subtype C gp120/MF59 
1b 
~30 
Placebo +  
Bivalent Subtype C gp120/MF59  
2 
2 
~12 
Placebo + Placebo 
                                       Total     72 
 
† Vaccine recipients in Part A (Group 1) are randomized to Group 1a or 1b. Part A 
placebo recipients (Group 2) continue to receive placebo injections in Part B. 
Numbers shown for each Part B group are approximate and will depend on how many 
Part A vaccine recipients and placebo recipients are enrolled in Part B.  
Participants 
Part A: 252 healthy, HIV-1–uninfected volunteers aged 18 to 40 years; 210 vaccinees, 42 
placebo recipients 
Part B: 72 HVTN 100 study participants who have not met discontinuation of vaccination 
criteria described in Section 7.4.3 and termination from study criteria as described in 
7.4.4 and who agree to provide mucosal secretion samples, as described in Section 9.5. 
Design 
Multicenter, randomized, placebo controlled, double-blind trial 
Duration per participant 
36 months 

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Estimated total study duration 
40 months  
Study sponsor 
DAIDS, NIAID, NIH, DHHS (Bethesda, Maryland, USA) 
Study product providers 
 
ALVAC-HIV (vCP2438): Sanofi-Pasteur (Swiftwater, Pennsylvania, USA ) 
 
Bivalent subtype C gp120/MF59®: GlaxoSmithKline Biologicals, S.A. (Rixensart, 
Belgium) [formerly Novartis Vaccines and Diagnostics (Cambridge, Massachusetts, 
USA)] 
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 laboratory 
HIV Molecular and Serology Laboratory, National Institute for Communicable Diseases 
(Johannesburg, South Africa) 
Endpoint assay laboratories 
 
HIV Sero-Molecular Laboratory–National Institute for Communicable Diseases 
(HSML-NICD) (Johannesburg, South Africa) 
 
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) 
Study sites 
HVTN Clinical Research Sites (HVTN CRSs) in South Africa to be specified in the Site 
Announcement Memo 
Safety monitoring 
 
HVTN 100 PSRT; NIAID Data and Safety Monitoring Board (DSMB) 

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3.1 
Protocol Team 
Protocol leadership 
Chair 
Linda-Gail Bekker 
The Desmond Tutu HIV 
Centre, Institute of Infectious 
Disease and Molecular 
Medicine, University of 
Cape Town, South Africa 
011-27-21-650-6959  
linda-gail.bekker@hiv-
research.org.za  
Statistician 
Zoe Moodie 
SCHARP, FHCRC 
206-667-7077 
zoe@scharp.org 
Cochair 
Fatima Laher 
Perinatal HIV Research Unit, 
Chris Hani Baragwanath 
Hospital, Soweto, South 
Africa 
011-27-11-989-9720 
laherf@phru.co.za 
Medical officer 
Mary Allen 
DAIDS, NIAID 
240-627-3036 
mallen@niaid.nih.gov 
Protocol Team 
leader 
Nicole Grunenberg 
HVTN Core, FHCRC 
206-667-2043 
ngrunenb@fhcrc.org  
Laboratory lead 
Georgia Tomaras 
HVTN Laboratory 
Program 
919-681-5598 
gdt@duke.edu 
Other contributors to the original protocol 
Core medical monitor 
Nicole Grunenberg 
HVTN Core, FHCRC 
DAIDS protocol 
pharmacist 
Katherine Shin 
DAIDS, NIAID 
240-627-3047 
Regional medical liaison 
Simba Takuva 
HCRISA 
Clinical safety specialist 
Jill Zeller 
HVTN Core, 
FHCRC 
Vaccine developer 
representatives 
Carlos DiazGranados 
Sanofi Pasteur 
Clinical trials manager 
Carissa Karg 
HVTN Core, 
FHCRC 
 
Sanjay Phogat 
Sanofi Pasteur 
SCHARP Clinical data 
manager 
Huguette Redinger 
SCHARP, FHCRC 
 
Niranjan Kanesa-thasan 
Novartis Vaccines and 
Diagnostics 
 
Jennifer Schille  
SCHARP, FHCRC 
 
Susan Barnett 
Novartis Vaccines and 
Diagnostics 
SCHARP Senior clinical 
data manager 
Gina Escamilla 
SCHARP, FHCRC 
 
Marguerite Koutsoukos 
GSK 
SDMC Associate director 
of lab science 
April Randhawa 
SCHARP, FHCRC 
 
Olivier van der Meeren 
GSK 
Statistical research 
associate 
Shannon Grant 
SCHARP, FHCRC 
 
Francois Roman 
GSK 
DAIDS Project Officer 
Michael Pensiero 
DAIDS, NIAID 
 
 

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Laboratory Program 
representatives 
On Ho 
HVTN Laboratory 
Program, FHCRC 
Protocol development 
manager 
Carter Bentley 
HVTN Core, FHCRC 
 
Eva Chung 
HVTN Laboratory 
Program, FHCRC 
Community engagement 
unit representative 
Genevieve Meyer  
HVTN Core, FHCRC 
 
John Hural 
HVTN Laboratory 
Program, FHCRC 
Community 
educator/recruiter 
Mluleki Nompondwana 
Emavundleni CRS, UCT 
CTU 
 
Erica Anderson-Nissen 
HVTN Cape Town HIV 
Immunology Laboratory  
Technical editor 
Erik Schwab 
HVTN Core, FHCRC 
Regulatory affairs 
Elizabeth Briesemeister 
HVTN Core, FHCRC 
Community Advisory 
Board (CAB) members 
Jerry Phore 
Klerksdorp CRS 
Clinic coordinator 
Dorothie Van der Vendt 
Cape Town CRS 
 
Goduka Mfana 
Soweto CRS 
 
 
 
Mzwandile Phanziso 
Emavundleni CRS, UCT 
CTU 
 
 
 
 
 

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4 
Background 
4.1 
Rationale for trial concept 
The RV144 HIV vaccine trial in Thailand, which evaluated a heterologous regimen of 2 
doses of ALVAC-HIV (vCP1521) followed by the 2 doses of ALVAC-HIV plus 
AIDSVAX® clades B/E gp120 protein, was the first clinical HIV vaccine trial to 
demonstrate efficacy in the prevention of HIV acquisition [4]. The RV144 trial results 
have triggered a suite of clinical trials designed to deepen understanding of the 
mechanism of protection and ultimately to develop a licensable product appropriate to 
regions with significant HIV burden. This is the first phase in the clinical testing of an 
HIV vaccine regimen similar to that tested in RV144 but adapted for the Southern 
African region, that is, with a clade C viral vector vaccine insert and clade C subunit 
proteins. As a ‘first-in-human’ test of this particular vaccine regimen, the trial will be 
conducted in South Africa among individuals at low risk of HIV infection.  
With approximately 6.1 million people living with HIV as of 2012 [5], South Africa’s 
epidemic remains the largest in the world and the Sub-Saharan region bears the 
preponderant burden of the HIV epidemic with almost 70% of all infections worldwide 
[6]. The vast majority of newly acquired infections in this region occur during 
unprotected heterosexual intercourse. Clearly, effective methods for preventing the 
acquisition and transmission of HIV-1 are urgently needed for this region.  
ART was introduced into the public sector in South Africa in 2003 and, as of 2012, 
approximately 2.2 million people were on treatment, representing 80% of people 
requiring ART [7]. While universal access to antiretroviral HIV treatment is a global 
ideal and progress toward this goal has been made [7], in many regions of Sub-Saharan 
Africa limited access and other barriers to care continue to undermine the prevention 
potential of widespread ART [8]. Moreover, the cost and health care burden of delivering 
ever-increasing amounts of treatment in resource constrained settings pose significant 
challenges and drives the quest for effective prevention of infection [9-12]. In addition, 
while studies conducted over the past few years have confirmed the promise of 
antiretroviral chemoprophylaxis, adherence to drug regimens, a critical factor in their 
effectiveness, has proved problematic in several recent clinical trials [13-15]. In sum, it 
remains well recognized that the way to eradicate a global viral epidemic is to design, 
mass produce, and then systematically vaccinate the target population with an effective 
prophylactic vaccine (see, eg, [16,17]). This protocol and overall plan takes into 
consideration that the predominant clade circulating in the Southern African region is 
HIV-1 subtype C [18-28].  
Although the results of the RV144 trial are modest, these provide the first indications that 
a prophylactic vaccine can reduce HIV acquisition risk [4]. This protocol describes a 
“next step” phase 1-2 study and is the first in a set of clinical trials which test vaccine 
products relevant to this region, and in a regimen that will build on and potentially 
enhance the level of the protection seen in the RV144 trial. 

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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 
pro, 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 (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 one year post vaccination (estimated 
60.5%, p = 0.02) with the vaccine effect waning over time to 31% cumulative through 3.5 
years [29].  
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 but 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 RV 144 clinical trial to identify CoR [30]. Among the 6 primary 
immunological variables selected for the correlates analysis (5 different antibody [Ab] 
responses and CD4+ T cell cytokine production) that were measured at the 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 [30]. 
4.1.3 
Rationale for the proposed vaccine regimen for South Africa 
This clinical trial will be conducted in South Africa, where clade C is the predominant 
circulating subtype [31] and will evaluate the safety and immunogenicity of the 
regionally adapted next-generation ALVAC/protein vaccine regimen. The regimen will 
comprise 2 administrations of ALVAC-HIV (vCP2438) containing clade C ZM96 gp120 
env along with clade B (LAI) gag, pro and gp41 env TM at Months 0 and 1 followed by 3 
administrations of the same ALVAC-HIV along with Bivalent Subtype C gp120/MF59®, 
comprising recombinant TV1.C and 1086.C gp120 Env proteins mixed with MF59® 
adjuvant, at Months 3, 6, and 12.  
The vaccine regimen in this trial strikes a balance between maintaining a close link to the 
RV144 vaccine regimen and the need to target the HIV strains circulating in the region of 

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the world where deployment of the vaccine is envisioned. In addition, the vaccine design 
and vaccination schedule have been altered in ways that aim at improving the magnitude 
and duration of vaccine-elicited immune responses beyond those observed in RV144. 
These changes have been made under the scientific assumption that improvements or 
extensions of immune responses will translate into improvements in vaccine efficacy. 
The gag, pro, and gp41 env components of ALVAC-HIV (vCP2438) are the same as in 
ALVAC-HIV (vCP1521), the ALVAC-HIV used in the RV144 trial. Adaptations of the 
RV144 vaccine regimen to South Africa include use of the 96ZM651 gp120 env insert 
(subtype C) rather than the TH023 gp120 env insert (clade E) used in RV144, and 
inclusion of 2 subtype C gp120 Env proteins (TV1.C and 1086.C) in boost vaccinations 
(rather than the clade B and E proteins used in RV144). 
The TV1.C and 1086.C gp120 Env proteins comprising Bivalent Subtype C gp120 were 
selected from among a long list of candidate clade C gp120 proteins according to a 
predefined algorithm incorporating, among other factors: genetic relatedness to regional 
HIV strains, CCR5 binding, capacity in animal studies to elicit key epitope-specific Ab, 
percent monomer expression (associated with receptor and co-receptor binding and 
induction of nAb), expression/secretion levels in stable cell lines, stability, and 
immunogenicity in animal models (including evidence of recognition of key epitopes 
identified in the RV144 correlates studies) [32,33]. Use of gp120 monomers rather than 
trimers has been prioritized to support comparisons with the RV144 results [34]. 
MF59® was selected as the protein adjuvant for multiple reasons, including its established 
safety record and previous experience with this adjuvant in similar prime-boost HIV 
vaccine regimens [35,36]. In addition, this adjuvant is proprietary of Novartis Vaccines 
and Diagnostics, the developer of the gp120 protein vaccine components. Based on 
related human experience, it is expected that MF59® will provide significant dose sparing 
compared to proteins adjuvanted with alum, while potentially improving the magnitude 
and subsequent durability of the immune responses elicited by the RV144 regimen. In 
addition, it has capacity to provide a more balanced Th1/Th2 response than alum [37]. 
MF59® was originally approved in Europe to enhance the immunogenicity of seasonal 
influenza vaccine among the elderly [38]. MF59®-adjuvanted influenza vaccine is now 
licensed in more than 20 countries with more than 100 million doses having been 
distributed. Recently influenza vaccine formulated with MF59® has been shown to be 
safe in young children and to significantly enhance immune responses and efficacy in this 
group [39]. MF59® is also used in a prepandemic H5N1 influenza vaccine (Aflunov®) 
licensed in the European Union (EU) for use in adults, and in two pandemic H1N1 
influenza vaccines (Focetria® and Celtura®), licensed in EU and other countries for use in 
adults and children [40]. 
4.1.4 
Rationale for Part B 
Based on interim safety and immunogenicity data for the primary vaccination series (ie, 
Months 0, 1, 3, and 6), a decision has been made to advance the HVTN 100 vaccine 
regimen to a pivotal efficacy trial in South Africa (see Section 4.5) This trial is 
designated HVTN 702. In this context, understanding the durability of vaccine-elicited 
immune responses and the extent to which those responses can be maintained or 
enhanced by subsequent booster vaccinations has assumed great importance. Part B of 
HVTN 100 seeks to provide this understanding by characterizing the immune responses 
elicited by different booster vaccinations at Month 30. 

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Participants in Part B will receive vaccinations at Month 30 with ALVAC-HIV 
(vCP2438) plus Bivalent Subtype C gp120/MF59, with Bivalent Subtype C gp120/MF59 
alone, or placebo. Vaccinees in Part A of HVTN 100 (ie, those assigned to Group 1) will 
be randomized to Group 1a or 1b (see Table 3-2) in 1:1 proportions. In order to maintain 
blinding throughout the trial, placebo recipients in Part A (Group 2) will also receive 
placebo vaccinations at Month 30. 
Part B of HVTN 100 thus provides an opportunity to characterize the immune responses 
elicited by booster vaccinations at Month 30 and, importantly, in the event that vaccine-
induced immune CoR or correlates of vaccine protection are identified in the planned 
HVTN 702 trial, samples from Part B of HVTN 100 can be evaluated to determine 
whether booster vaccinations can maintain or even enhance those correlates. This 
information may help inform investigation of boost strategies should the vaccine regimen 
be advanced toward an application for marketing authorization. 
Questions concerning boost intervals and vaccine product selection have been explored 
previously with respect to the RV144 ALVAC-gp120 protein vaccine regimen in follow-
on protocols RV305 and RV306. Since the HVTN 100 vaccine regimen was designed to 
mimic the efficacious vaccine in RV144 but with adaptations to the clade C epidemic in 
sub-Saharan Africa (see Section 4.1.3) and HVTN 097 demonstrated that the RV144 
vaccine regimen elicited responses in South African vaccinees similar to those seen 
among Thai vaccinees in RV144, information from the RV305 and RV306 studies may 
suggest what to expect with late boosts to the HVTN 100 vaccine regimen. 
Notwithstanding differences in boosting schedule and study products between these 
studies and HVTN 100, these results have been useful in informing the design of Part B 
in HVTN 100. 
In RV305, RV144 participants who had completed the RV144 vaccination series per 
protocol received ALVAC+AIDSVAX, AIDSVAX alone, or ALVAC alone 6-8 years 
after completing the primary RV144 vaccination sequence. Vaccinations took place at 
Weeks 0 and 24. The trial was planned to enroll 162 participants (45 vaccinees and 9 
placebo recipients in each of the 3 groups); 97% of those enrolled completed the planned 
vaccinations. Among the key findings in this study are the following: 
 
Boosts with AIDSVAX alone and with ALVAC/AIDSVAX boosted antibody 
responses to levels significantly higher than those attained by the primary vaccine 
regimen. Specifically, 
 
AIDSVAX and ALVAC/AIDSVAX boosts generated peak IgG responses to 
gp120 A244gD and to vaccine-matched 92TH023 gp70 V1V2 that were 
significantly superior (following the first boost) and at least as robust (following 
the second boost) to the peak responses observed in RV144 following the 4th 
vaccination; boosting with ALVAC alone did not boost these IgG responses; and, 
while IgG responses declined at a rate similar to that observed in RV144, 
responses remained substantially higher 6 and 12 months post final vaccination 
than in RV144 (Karasavvas and Akapirat, unpublished data). 
 
With respect to IgG subclass responses to gp120 A244gD and to vaccine-
matched 93TH023, late boosts in RV305 elicited IgG1 and IgG4 responses that 
were higher than those observed in RV144; IgG3 responses were not boosted to 
the levels observed in RV144 (Karasavvas and Akapirat, unpublished data).  

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 
Although it has been demonstrated previously that antibodies of the IgG3 and IgG1 
subclasses that target V1V2 gp70 antigens were associated with antibody-mediated 
effector functions (eg, ADCC) that were linked to a reduced risk of infection in 
RV144 [41-43] and, conversely, that IgG4 can interfere with such Fc-mediated 
effector functions, ADCC responses were boosted after each injection of either 
AIDSVAX or ALVAC/AIDSVAX, but not with ALVAC alone. TH023-specific 
ADCC responses were stronger with ALVAC/AIDSVAX combination boosts 
compared to AIDSVAX alone while MN-specific ADCC responses were similar 
between the 2 boosting regimens. (Ferrari, unpublished data). 
 
Mucosal cytokine profiles differed between the AIDSVAX and ALVAC/AIDSVAX 
regimen, although the implications for the differences are unclear. 
The RV306 trial enrolled 360 new Thai volunteers (327 vaccinees; 33 placebo recipients) 
in a study to evaluate the impact of the timing of an additional vaccine boosts to the 
RV144 regimen and to gather new immunogenicity data. Vaccinees in all groups were 
primed with the RV144 regimen (4 vaccinations), which elicited IgG responses to gp120 
and to scaffolded gp70 V1V2 similar to the peak levels observed in RV144. Three groups 
were boosted once with ALVAC+AIDSVAX at either 6, 9, or 12 months after 
completion of the primary regimen; a fourth group was boosted with AIDSVAX alone 6 
months after completion of the primary regimen; the 5th group did not receive a late 
boost. Note that the boosts in RV306 occur far sooner than the first boost in RV305. 
Preliminary (blinded) findings from this study included: 
 
AIDSVAX and ALVAC/AIDSVAX boosts 6 months after completion of the primary 
(RV144) vaccine regimen elicited IgG responses to vaccine-matched antigens and to 
scaffolded V1V2 antigens comparable to peak levels following the primary vaccine 
regimen.  
 
Booster vaccinations elicited IgA response levels substantially lower than those 
elicited by the primary (RV144) regimen. IgG geometric mean titers (GMT) 
following boosting were approximately 100-fold higher than IgA. Note that the ratio 
of IgG to IgA responses was observed to correlate with efficacy in the RV144 trial 
[44]. 
 
Booster vaccinations increased neutralizing antibody response rates and titers to 
levels above those observed following the primary (ie, RV144) vaccine regimen; to 
one vaccine-matched antigen, late boosts at 9 and 12 months after the primary 
regimen elicited statistically higher neutralizing antibody titers than a boost 6 months 
after the primary regimen (Polonis and Wieczorek, unpublished data). 
 
Late boosts increased the number of gp120-specific B cell responders with a 
significant increase in magnitude and in frequency of plasmablasts (Schuetz, 
unpublished data). 
 
There was no evidence of induction of activated CD4+/CCR5+ T cells following the 
late boost vaccinations. 
Based on the failure of boosting with ALVAC-HIV alone to boost antibody responses in 
RV305, Part B does not include a late boost with ALVAC-HIV alone. However, aside 
from notation that activated T cells were not induced by serial boosting in RV306, 

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information concerning the impact of boost vaccinations on the rate, magnitude, and 
quality of cellular immune responses is lacking at this point in time. Hence a critical 
factor that may distinguish boosts that include the vector from protein-only boosts is 
currently unknown. 
The results of late boosts in RV305 and RV306 suggest the hypothesis that a Month 30 
boost of the Part A regimen with Bivalent Subtype C gp120/MF59 with and without 
ALVAC-HIV (vCP2438) will elicit immune response levels 2 weeks following the boost 
that are similar to or better than the immune responses observed 2 weeks following the 
Month 6 vaccination. These include immune responses previously shown to be inversely 
correlated with risk of HIV infection in the RV144 efficacy trial.  
4.1.5 
Rationale for mucosal secretion sampling in Part B 
While it has long been understood that immune responses at mucosal surfaces are critical 
in prevention of viral infections (see, eg, [45-47]), until recently the immunogenicity of 
investigational HIV-1 vaccines has been evaluated primarily in the periphery. As 
observed in some NHP studies, vaccine-induced systemic immune responses may not 
necessarily predict or correlate with responses at the mucosa, highlighting the importance 
of assessing immune responses in both compartments [48,49]. In order to determine if 
key peripheral immune responses (especially V1V2 IgG responses) shown to be 
associated with a lowered risk of immune HIV infection [30] are also present in the 
genital mucosa and to assess whether these differences between systemic and mucosal 
immune responses observed in macaques are recapitulated in humans, mucosal secretion 
sampling has been added in Part B of the study. 
4.2 
ALVAC-HIV (vCP2438) 
ALVAC-HIV (vCP2438) is a preparation of live, attenuated recombinant canarypox-
derived virus expressing products from the HIV-1 env gp120 (clade C), env gp41 TM 
(clade B), gag (clade B), and protease (clade B) coding sequences and cultured in 
primary chicken embryo fibroblasts (CEFs). 
4.2.1 
Constructs 
The original strain of canarypox virus (Rentschler strain) was attenuated by serial 
passages on CEFs. The attenuated virus was plaque isolated and designated as ALVAC. 
Details of the manufacturing process are provided in the Investigator’s Brochure (IB). 
The 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. 

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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 
4.2.2 
Formulation characteristics 
ALVAC-HIV (vCP2438) is formulated as a lyophilized vaccine for injection and is 
reconstituted with 1.0 mL of sterile sodium chloride solution (NaCl 0.4%) for injection of 
1.0 mL as a single dose. The composition of one dose of ALVAC-HIV (vCP2438) is 
provided in Table 4-2. 
Table 4-2 Composition of ALVAC-HIV (vCP2438) 
Ingredient 
Amount in one dose 
Function 
ALVAC-HIV (vCP2438) 
> 1 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 
4.2.3 
Manufacturing 
For Part A of the study, ALVAC-HIV (vCP2438) Bulk Drug Substance and Drug 
Product are manufactured by IDT Biologika GmbH, Am Pharmapark, Dessau-Rosslau, 
Germany, under contract to Sanofi Pasteur.  
For Part B of the study, 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 viral seed lot into cultured 
primary CEFs derived from eggs produced by specific pathogen free (SPF) flocks 
The manufacturing process for ALVAC-HIV (vCP2438) is similar to the manufacturing 
process for ALVAC-HIV (vCP1521) used in RV144. 

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4.3 
Bivalent Subtype C gp120/MF59® 
4.3.1 
Constructs 
Bivalent Subtype C gp120/MF59®, manufactured by Renstchler Biotechnologie 
(Laupheim, Germany), consists of two subtype C recombinant monomeric proteins, 
TV1.C gp120 and 1086.C gp120. These recombinant gp120s represent the receptor 
binding domain of the HIV envelope glycoprotein. Each gp120 is modified from its wild 
type full-length form (gp160) by replacement of the native signal sequence and deletion 
of the entire gp41 C-terminal portion of the glycoprotein containing the TM and 
cytoplasmic domains. The combination of the 2 subtype C gp120 proteins and the MF59® 
is referred to as Bivalent Subtype C gp120/MF59®. 
4.3.2 
Manufacturing and formulation 
Each protein is expressed in CHO cells under conditions favorable for secretion of 
monomeric protein. Following fermentation, each protein is extensively purified from 
culture supernatants, including further enrichment for monomer.  
Following clone selection, a fed batch cell culture at 250L scale is employed for cell 
propagation. Once the cells reach optimum cell density, the culture is harvested and 
purified using standard methods. The conditioned media is concentrated by ultrafiltration. 
The manufacturing process utilizes a weak cation exchange chromatography step, CM-
Fractogel, which provides purification as well as viral reduction. Concentration (by 
ultrafiltration) is then used, followed by exchange into the formulation buffer.  
After these process steps, both subtype C gp120 protein processes include viral reduction 
filtration (nanofiltration) followed by 0.22 µm filtration and bulk fill. Both TV1.C and 
1086.C bulk drug substances are stored frozen at not more than -60°C. For both drug 
substances, the formulation is the same, containing 0.4 mg/mL Env antigen, sodium 
citrate, and sodium chloride, pH 6.0. 
The composition per dose of each subtype C gp120 vaccine protein is provided in Table 
4-3. 
Table 4-3 Qualitative composition of Subtype C gp120 drug substances vials 
Ingredient 
Function 
gp120 protein 
Sodium Citrate, Dihydrate 
Citric Acid, Monohydrate 
Sodium Chloride 
Water for injections 
active 
buffer 
buffer 
tonicity modifying agent 
diluting agent 
Additional information is provided in the IB. 
4.3.3 
MF59® adjuvant  
The Novartis MF59® adjuvant is an oil-in-water emulsion with a squalene internal oil 
phase and a citrate buffer external aqueous phase. Two non-ionic surfactants, sorbitan 
trioleate and polysorbate 80, serve to stabilize the emulsion. The bulk formula is shown 
in Table 4-4.  

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Table 4-4 Composition of MF59® per liter 
Name of Ingredients 
Quantity 
 per Litre* 
Function 
Reference to Standards 
Squalene 
39.0 g 
oil phase 
In-house specification 
Polysorbate 80 
4.7 g 
surfactant 
USP/NF 
Sorbitan Trioleate 
4.7 g 
surfactant 
USP/NF 
Sodium Citrate, dihydrate 
2.65 g 
buffer 
USP/NF 
Citric Acid, monohydrate 
0.17 g 
buffer 
USP/NF 
Water for Injection 
q.s. 1 L 
aqueous phase 
Ph.Eur. and USP/NF 
Nitrogen 
overlay 
inert gas 
USP/NF 
*An overage of up to 10% is included to compensate for manufacturing losses. 
The full dose of MF59® utilized in the marketed Fluad vaccine (containing 9.75 mg of 
squalene) will be utilized for formulation with subtype C recombinant envelope gp120 
proteins (described above). 
The MF59® (full name: MF59®C.1) manufacturing process consists of five 
manufacturing steps: raw materials dispensing and blending, premixing, emulsification, 
sizing filtration, and filling. 
The MF59® bulk resulting at the end of the process is filled into the vials with an overlay 
of nitrogen and stored protected from light at 2-8° C. 
Additional information is provided in the IB. 
4.3.4 
Bivalent Subtype C gp120/MF59® for injection 
A final dose of 100mcg of each recombinant Env protein will be mixed with MF59® 
adjuvant. The composition of one dose of the resulting vaccine is shown in Table 4-5. 
Table 4-5 Composition of 0.5 mL dose of Bivalent Subtype C gp120/MF59® for injection 
Ingredient  
Amount in one dose  
Function  
Drug Substances  
TV1.C gp120 protein  
1086.C gp120 protein  
100 mcg  
100 mcg  
active  
active  
Adjuvant (MF59®)  
Squalene  
9.75 mg  
oil phase  
Polysorbate 80  
1.175 mg  
surfactant  
Sorbitan Trioleate  
1.175 mg  
surfactant  
Excipients  
Sodium Citrate, Dihydrate  
Citric Acid, Monohydrate  
Sodium Chloride  
Water for injections  
1.39 mg 
0.051 mg 
4.38 mg 
qs to 0.5 mL 
buffer  
buffer  
tonicity modifying agent  
solvent  

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4.4 
Trial design rationale 
No preventive efficacy was demonstrated when AIDSVAX® rgp120 subunit vaccines 
(B/B’ in North America and the Netherlands, in high risk men who have sex with men; 
B/E in Thailand, in injection drug users) were administered alone [50,51]. However, the 
modified intention-to-treat results of the community-based RV144 trial in Thailand in 
individuals at low and high risk demonstrated safety and modest efficacy of an ALVAC-
HIV (vCP1521) plus AIDSVAX® B/E protein regimen. The promising findings of 
RV144 provide a compelling rationale for studies aimed at replicating or enhancing these 
results in other regions of the world.  
This trial is part of a program that tests a vaccine regimen similar to that used in RV144. 
It aims not only to compare data with RV144 results, but also to build upon that trial 
design in three important ways: adaptation to the clade C strains of HIV-1 predominant in 
South Africa, an additional booster dose at month 12 aimed at prolonging the durability 
of peak immunogenicity, and use of different adjuvant having the potential to enhance the 
magnitude and durability of the immune responses elicited by the vaccine (see Section 
4.1.3).  
Safety and immunogenicity data from this trial will inform a decision whether to advance 
the vaccine regimen to a pivotal phase 3 trial. Hence the primary immunogenicity 
endpoints have been selected to support evaluation of the hypothesis that 2 doses of 
ALVAC-HIV (vCP2438) followed by 2 doses of ALVAC-HIV (vCP2438) + Bivalent 
Subtype C gp120/MF59® will result in immune responses at least comparable to those 
induced by the RV144 vaccine regimen.  
For Part B see Section 4.1.4. 
4.4.1 
Dose (amount and number) 
ALVAC-HIV (vCP2438): Viral titer ≥ 1 × 106 CCID50 and < 1 × 108 CCID50 (nominal 
dose of 107 CCID50) lyophilized vaccine to be reconstituted for IM injection. 
This study will utilize 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. 
Titers of the ALVAC-HIV (vCP205) construct used in studies ranged from 105.6 CCID50 
to 106.85 CCID50. A dose response analysis was conducted with samples collected on 
Days 98 and 182 in the AIDS Vaccine Evaluation Group (AVEG) 022, 022A, 027, 032, 
033, 034 and 034A studies. In summary, these data indicate that while there is not a 
positive dose-response relationship between ALVAC-HIV and cytotoxic T lymphocyte 
(CTL) responses, use of the lower titer is not optimal for induction of nAb responses. 
Therefore, many clinical studies in humans have targeted an ALVAC dose > 106 CCID50. 
HVTN 039 is the only study that has compared the safety and immunogenicity of 
ALVAC-HIV (vCP1452) given at the standard dose (107.25 CCID50) to a dose 5.6 times 
higher (108 CCID50), and placebo. The high-dose ALVAC-HIV (vCP1452) resulted in 
unacceptable levels of reactogenicity, without evidence of immunogenicity 
improvements. Although extrapolation of these findings to other ALVAC-HIV vaccines 

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requires caution, the study suggested that an ALVAC-HIV dose < 108 CCID50 is 
desirable.  
The desired improvements in overall and protective immune responses will rely on the 
use of a more potent protein adjuvant and adjustment of the vaccination schedule. 
For the Bivalent Subtype C gp120/MF59® vaccine component, 100 mcg each of the two 
gp120 subtype C proteins (TV1 gp120 and 1086) will be admixed with the oil-in-water 
emulsion MF59® (9.75 mg squalene) by the Pharmacist at each CRS prior to IM 
administration. 
Bivalent Subtype C gp120/MF59® vaccine has not yet been administered to humans. The 
200 mcg total dose was selected based on previous clinical experience. Limited dose 
range studies performed with Novartis (formerly Chiron) subtype B SF2 gp120 and 
subtype E gp120 protein candidates indicated that 50 mcg and 100 mcg, totalling 150 
mcg, doses with MF59® adjuvant were immunogenic and well tolerated [52].  
4.4.2 
Schedule 
Safety and immunogenicity will be assessed for ALVAC-HIV (vCP2438) (months 0, 1, 
3, 6, 12) and for Bivalent Subtype C gp120/MF59® (months 3, 6, 12).  
The vaccine administration schedule encompasses the schedule used in RV144 but with 
an additional boost at month 12 in response to the apparent wane in efficacy observed in 
RV144 from 12 to 36 months. 
Addition of a booster vaccination at month 12 is supported by immunogenicity data from 
nonhuman primate (NHP) studies performed with another pox-protein regimen. Both 
neutralizing and binding Ab levels dropped after completion of the primary 
immunization, while the re-boost at week 49 was able to bring back the Ab responses to 
the higher level [53]. In addition, administration of a late ALVAC-HIV/AIDSVAX® 
boost (in RV 305) approximately 7-9 years after the final vaccination in RV144 
demonstrated that immune responses were restored or improved compared to the 
responses observed at the primary timepoint in RV144 [54]. 
The selected dose schedule is therefore a five-dose schedule of ALVAC-HIV (vCP2438), 
a four-dose primary vaccination schedule with ALVAC-HIV administered at 0, 1, 3 and 6 
months plus protein boost administered at 3 and 6 months (replicating the RV144 
schedule); and a single booster vaccination with both ALVAC-HIV (vCP2438) and 
protein boost administered at 12 months. 
For Part B see Section 4.1.4. 
4.4.3 
Choice of placebo 
Part A 
The placebo for ALVAC-HIV (vCP2438) is a sterile, lyophilized product that consists of 
a mixture of virus stabilizer, and freeze drying medium and is reconstituted with sterile 
sodium chloride (0.4% NaCl) for a single 1 mL dose, to administer IM. 
Placebo for Bivalent Subtype C gp120/MF59® is sodium chloride for injection, 0,9%. 

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Part B 
In Part B, the placebo for both ALVAC-HIV (vCP2438) and Bivalent Subtype C 
gp120/MF59® is sodium chloride for injection, 0,9%.  
4.4.4 
Prime-boost regimen 
The prime-boost strategy consists of ALVAC-HIV (vCP2438) prime with Bivalent 
Subtype C gp120/MF59® boost. 
The concept of priming with one HIV vaccine followed by boosting with another 
heterologous HIV vaccine emerged in the 1990s as a strategy to enhance vaccine 
immunogenicity and, potentially, vaccine efficacy. While Env glycoproteins elicit strong 
humoral responses, they have not been associated with potent cellular immunity, 
particularly CD8-specific cytotoxic T lymphocyte (CTL) responses. On the other hand, 
although viral vector constructs, including ALVAC, often elicit both Ab and cell-
mediated responses, it was observed that the level of Ab could be increased significantly 
by subsequent administration of Env glycoproteins. In addition, prime-boost vaccine 
regimens were explored as means of increasing the breadth of HIV strains to which 
vaccination might induce responses and also as a means of generating both potent CTL 
and potent Ab responses, a combination believed to be important in conferring protective 
immunity against HIV infection [55,56]. These desirable immune response characteristics 
were often observed in early phase clinical trials of a variety of prime-boost vaccine 
regimens [56-66].  
Among the many prime-boost vaccine regimens tested during this period were 
canarypox-derived (ALVAC) vector primes containing differing arrays of recombinant 
HIV genes and HIV Env glycoprotein boosts. By 1998, early phase clinical trials of 
ALVAC-protein regimens had shown:  
 
These regimens with glycoproteins adjuvanted with alum or MF59® were well 
tolerated in several hundred HIV-uninfected, healthy volunteers; 
 
HIV-specific immune responses were not dampened in vaccinia-experienced 
individuals;  
 
The prime-boost regimens induced large repertoires of HIV-specific Ab, neutralizing 
activity against some laboratory HIV isolates, Ab capable of inducing antibody-
dependent cellular cytotoxicity (ADCC), and HIV-specific CTL activity against a 
broad range of targets [56,67].  
In NHP studies, heterologous prime-boost regimens afforded better protection against 
viral challenge than did sequential injections of ALVAC-HIV vaccines alone, suggesting 
a potential connection between the characteristic responses elicited by the heterologous 
ALVAC-protein prime-boost regimens and protection from HIV infection [68].  
On the basis of results from nonclinical studies and early-phase clinical trials, ALVAC-
HIV (vCP1521) and HIV gp120 Env became the first heterologous prime-boost vaccine 
regimen to enter efficacy testing in humans in the RV144 trial in Thailand. Comparison 
of the immunogenicity observed in the RV144 trial to that from the VAX003 efficacy 
study previously conducted in Thailand, showed that the nAb response after two doses of 
gp120 protein following priming with ALVAC-HIV (vCP1521) [4] exceeded the nAb 

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response seen after two inoculations with the same bivalent gp120 protein without 
preceding ALVAC-HIV (vCP1521) administration [52], pointing to a priming effect by 
ALVAC-HIV (vCP1521) that benefited the immune response in the RV144 study [69]. 
Hence, one of the primary advantages to prime-boost regimens posited by nonclinical 
studies and supported in early phase clinical trials, was borne out in comparison of results 
from 2 large later-phase clinical trials conducted in the same country. 
Furthermore, recent data suggest that priming by ALVAC-HIV (vCP1521) may 
favourably influence the quality of Ab responses. The IgG3 HIV-1 Env responses 
induced by the ALVAC-protein prime-boost regimen were significantly higher than those 
induced by the homologous gp120 prime-boost regimen, which indicates that ALVAC 
priming before a protein boost modifies the IgG subclass profile in a manner that may 
substantially change the HIV-1 inhibitory functions of the vaccine-elicited IgG responses 
[41,42]. IgG1 and IgG3 are the most functional of the IgG subclasses in that they have 
been associated with HIV-1 neutralization, complement fixation, phagocytosis, ADCC, 
and antibody dependent cellular viral inhibition (ADCVI) [70]. 
4.5 
Plans for future product development and testing 
This phase 1-2 trial is designed to establish a preliminary safety record in the low risk 
South African adult population for priming vaccinations of ALVAC vector with HIV 
clade C (ZM96) gp120 env and clade B (LAI) gag, pro, and gp41 env inserts followed by 
boost vaccinations of the ALVAC vector in combination with gp120 Env proteins 
(TV1.C and 1086.C) with MF59® adjuvant. Safety and immunogenicity data from this 
trial will inform a decision whether to advance the vaccine to a pivotal phase 3 trial and, 
should the phase 3 trial demonstrate sufficient preventive efficacy, an application for 
marketing authorization in the Republic of South Africa (RSA) will follow. Such 
additional studies as are required by governing regulatory authorities to support such an 
application will also be performed. 
Should the HVTN 702 study demonstrate preventive efficacy sufficient to support an 
application for a marketing authorization, data generated by Part B of HVTN 100 may 
help to inform subsequent evaluation of boosting strategies to prolong the protective 
effects of the vaccine.  
4.6 
Nonclinical studies 
4.6.1 
IM local tolerability and systemic toxicity study in New Zealand White Rabbits 
(Study AB20670) 
The objective of the study was to determine the local tolerability and systemic toxicity of 
ALVAC-HIV (vCP2438)/ALVAC-HIV (vCP2438) with gp120+MF59 vaccines and 
DNA-HIV-PT123 with gp120+MF59 vaccines administered by the IM route to New 
Zealand White Rabbits 7 or 6 times, respectively, at 2-week intervals, followed by a 2-
week recovery period. 
There were no deaths during the study. No treatment-related clinical signs were reported 
during the study and treatment was locally well tolerated. Body temperature was slightly 
increased mostly after the 1st injection but returned to normal within 48 hours. There 

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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 hematological parameters. 
At necropsy, at the end of treatment, the only histologic changes due to the test items 
were in the injection sites and iliolumbar and sacral lymph nodes. In the sites injected 
with ALVAC or gp120s+MF59, the changes comprised inflammatory cell infiltrates, 
necrosis, fibrosis, hemorrhage, acellular material and mineralization. These findings were 
often only minimal or slight. In the lymph nodes which drained the injected sites, there 
was minimal or slight increased lymphoid follicle development, increased paracortex and 
granulocyte infiltrate. There was evidence of partial resolution of the described changes 
at both injection site and lymph nodes, based on necropsy observations after the recovery 
period. 
In conclusion, under the defined study conditions, 7 intramuscular administrations of 
ALVAC-HIV (vCP2438) vaccine associated with gp120s/MF59 (last 4 injections) to the 
New Zealand White Rabbit at two-week intervals were clinically and locally well 
tolerated. The study supports the use of this vaccine regimen in human clinical trials. 
4.6.2 
ALVAC-HIV 
Nonclinical safety data from a variety of other ALVAC constructs 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  
 
Hypersensitivity study with ALVAC-HIV (vCP125) in guinea pigs 
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. 

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4.6.3 
Toxicity studies of HIV Env vaccines  
The nonclinical safety of 4 doses of the gp120 proteins when co-administered with 
ALVAC-HIV (vCP2438) as a boost after 3 doses of ALVAC-HIV (vCP2438) given 
alone (prime), was evaluated in study AB20670 in New Zealand White Rabbits, as 
mentioned in Section 4.6.1.1. Overall, the immunizations were clinically and locally well 
tolerated. 
The nonclinical safety of 6 doses of the gp120 proteins, when co-administered with 
DNA-HIV-PT123, was also evaluated in study AB20670 in New Zealand White Rabbits. 
There were no deaths during the study. No treatment-related clinical signs were reported 
during the study and treatment was locally well tolerated. There was no obvious effect on 
body temperature. A lower body weight gain was noted in males only over the study 
period. However this was not related with lower food consumption. No treatment-related 
ophthalmological findings were observed at the end of the treatment period. When 
compared to the control group, a slight transient increase in C-reactive protein 
concentration was noted mainly after the first administration. These effects correlated 
with the inflammatory findings observed histopathologically at the injection sites. An 
increase in creatine kinase was noted after the first administration only. At necropsy, at 
the end of treatment, the only histologic changes due to the test items were in the 
injection sites and iliolumbar lymph nodes. In the sites injected with DNA-HIV-PT123 or 
gp120s+MF59, changes comprised fibrosis, hemorrhage, acellular material and 
inflammatory cell infiltrate usually minimal or slight, but occasionally more severe. In 
the lymph nodes which drained the injected sites, there was minimal to moderate 
increased paracortex and increased lymphoid follicle development and minimal 
granulocyte infiltration. There was evidence of partial resolution of the described changes 
at both injection site and lymph nodes, based on necropsy observations after the recovery 
period. In conclusion, under the defined study conditions, 6 intramuscular administrations 
of DNA-HIV-PT123 vaccine associated with gp120 proteins adjuvanted with MF59 to 
New Zealand White Rabbits at two-week intervals were clinically and locally well 
tolerated. 
In addition, nonclinical in vivo Good Laboratory Practice (GLP) toxicology studies were 
conducted with early candidate subtype B and E gp120 Env protein vaccine candidates 
that were subsequently advanced to phase 1-2 clinical trials. More recently, similar 
subtype B gp140 and subtype C gp140 vaccine candidates with MF59® have been tested 
in nonclinical safety studies. The subtype C gp140 previously tested was from the same 
strain (HIV-1 TV1) as one of the components (TV1 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. 
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 

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 
Repeat dose toxicity of IM SAAVI DNA-C2 followed by IM SAAVI MVA-C with 
subtype C gp140/ MF59® in rabbits 
4.6.3.1 
Toxicity studies of MF59® 
MF59® is not associated with any potential for systemic toxicity and it has a low order of 
local reactogenicity. In repeat-dose rabbit studies, clinical pathology findings of increased 
fibrinogen and minor inflammatory and degenerative changes at the injection site are 
consistent with the effects of IM injections of an immunological adjuvant. These findings 
are readily reversible within days to 1 to 2 weeks. In repeat-dose toxicology studies in 
dogs, there were no effects on cardiovascular or central nervous system (safety 
pharmacology) parameters. MF59® is not genotoxic (Ames test) or clastogenic (mouse 
micronucleus), is not a dermal sensitizer (Guinea pig), and was not teratogenic (rat and 
rabbit) or a developmental toxicant (rat).  
Pivotal toxicology studies performed with MF59® include: 
 
single- and repeat-dose toxicity (including local tolerability),  
 
genotoxicity,  
 
sensitization, and  
 
embryofetal and developmental toxicity.  
4.7 
Clinical studies  
4.7.1 
HVTN 100 experience to date 
HVTN 100 protocol version 1.0 enrolled 252 participants between February and May 
2015. All Month 12 injections were completed by 2 June 2016. 
4.7.1.1 
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 was reported by 58% 
of participants for injections in the left deltoid and by 48% for injections in the right 
deltoid. Moderate pain and/or tenderness was reported by 18% of participants for 
injections in the left deltoid and by 11% for injections in the right deltoid. Severe pain 
and/or tenderness was reported from a left deltoid injection by 1 participant (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 

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reactions were reported by 4% of participants and grade 2 reactions by 2% of 
participants. Three participants have reported erythema and/or induration reactions 
meeting grade 3 criteria (severe) based on size (≥ 10cm diameter or ≥ 100cm2 surface 
area) with no complications (such as ulceration, secondary infection, phlebitis, sterile 
abscess, or drainage). One person reported a grade 3 right deltoid erythema reaction 
(> 100 cm2) occurring on Day 2 of the 4th injection timepoint, which resolved within 4 
days. This participant also self-reported severe induration on Day 3, which resolved 
within 1 day. The participant returned to clinic on Day 4 for examination, and clinic staff 
observed severe erythema alone without induration or swelling. Antibiotics, analgesics, 
and antihistamines were prescribed and the participant was discontinued from further 
vaccinations but continued in follow-up. Another person reported grade 3 induration and 
erythema in the right deltoid on Day 3 after the 5th vaccination timepoint, resolving by 
Day 5. Antibiotics, anti-inflammatory and analgesic medications were prescribed and 
were taken for 3 days. Another person reported severe erythema and induration reactions 
in the left deltoid occurring on Day 0 after the 5th vaccination timepoint and resolving by 
Day 3. Antihistamine, oral steroid and analgesic/anti-inflammatory medications were 
taken. In all 3 participants, the needle used for injection was < 1.5” long, consistent with 
weight-based guidance for needle length choice provided to sites in the SSPs [71,72].  
Systemic reactions have been reported in 69% of participants thus far, with the vast 
majority of those reactions being mild in intensity. Malaise and/or fatigue, headache, 
myalgia and arthralgia appear to be the most common reactions, occurring in 42%, 41%, 
37% and 30% of participants, respectively thus far. Other systemic reactogenicity 
symptoms have included nausea (15%), chills (10%), fever (8%), and vomiting (4%). 
Maximum severity of systemic symptoms of moderate intensity has been reported in a 
total of 19% of participants; 7% reported systemic symptoms of moderate intensity after 
the 1st injection, 3% after the 2nd, 5% after the 3rd, 2% after the 4th and 5% after the 5th. 
Severe systemic reactions have occurred in 2% of participants (4 participants): 2 
participants with severe arthralgia occurring after the 1st injection, 1 person with severe 
malaise and/or fatigue and 1 with severe headache, each after the 5th injection. 
4.7.1.2 
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. 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 injurie 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. 

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4.7.1.3 
Discontinued vaccinations and early terminations 
As of July 14, 2016, Seventeen 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 1st 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 pregnancy. One 
pregnancy has been reported to date and this participant is continuing in follow-up.  
4.7.1.4 
Summary of Interim Immunogenicity data from HVTN 100 
Section [6.1.2] of version 1.0 of HVTN 100 (Part A) describes the immunological criteria 
guiding the decision whether to advance development of the ALVAC-HIV (vCP2438), 
Bivalent Subtype C gp120/MF59® regimen. Except for the increased stringency of the 
V1V2 response rate criteria (LL of the 95% CI increased from ≥ 45% to ≥ 56%), these 
same criteria ultimately formed the basis of the decision to proceed forward with HVTN 
702, A pivotal phase 2b/3 multi-site, randomized, double-blind, placebo-controlled 
clinical trial to evaluate the safety and efficacy of ALVAC-HIV (vCP2438) and Bivalent 
Subtype C gp120/MF59 in preventing HIV-1 infection in adults in South Africa (Table 
4-6). Immunogenicity data from samples collected from HVTN 100 participants at the 
month 6.5 timepoint (2 weeks post 6 month vaccination) were compared to data from a 
new, randomly selected subset of stored samples from RV144 vaccine recipients who 
were HIV-1 uninfected upon completion of follow-up (the RV144 “comparator arm”). 
Samples from the RV144 comparator arm and HVTN 100 participants were analyzed 
contemporaneously using qualified assays in the same laboratories (along with placebo 
samples for blinding).  
All four immunogenicity Go criteria were met. 
Table 4-6 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% 

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*Non-inferior to RV144 response based on contemporaneous assessment of clade C vaccine samples vs. 
RV144 vaccinee samples by the same lab. 
Binding antibody responses to Env (criteria 1 and 2): 
At the month 6.5 timepoint, 100% of vaccinees in HVTN 100 part A developed binding 
antibodies to the gp120 Clade C strain Env antigens in the ALVAC vector, as well as the 
two Clade C strains in the bivalent gp120 protein boost (Figure 4-1). 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 4-7). 
Hence criteria 1 and 2 were met. 
 
Figure 4-1  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 4-7 HVTN 100 vs. RV144 Peak bAb magnitudes to gp120 among vaccinees 
Protocol 
Antigen 
n 
Geometric Mean Titer 
GMR 
(100/RV144) 
GMR  
95% CI 
100 
1086 
185 
26,257.5 
8.8 
(7.64, 10.2) 
RV144 
A244 
201 
2,968.9 
100 
TV1 
185 
10,726.7 
3.6 
(3.01, 4.34) 
RV144 
A244 
201 
2,968.9 
100 
ZM96 
185 
2,685.4 
3.6 
(2.95, 4.39) 
RV144 
92TH023 
201 
746.1 

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CD4 responses (criterion 3) 
The CD4+ T cell response rate to vaccine-matched Env sequences in ALVAC 
(vCP2438), (Env peptide pool ZM96) in HVTN 100 participants was 58%. This was 
compared to the CD4+ T cell response rate to vaccine-matched Env sequences in 
ALVAC (vCP1521), (Env peptide pool 92TH023) in RV144 participants of 41%. The 
response rate difference (100-RV144) was 16% (95% CI: 6, 16%; p value 0.0019). This 
exceeded the LL response rate difference of -30% and meeting criterion #3. 
V1V2 antibody response rates (criterion 4) 
The binding antibody response rate to the vaccine-matched 1086.C V1V2 antigen was 
71% (95% CI 64% - 77%), thereby meeting criterion #4 that the prevalence of IgG 
antibodies to the Clade C V1V2 loop in at least one vaccine antigen must be at a lower 
limit threshold of > 56% (which equates to a response rate of 63%) (Table 4-8). The 
cumulative V1V2 response is 80%; well above the 63% threshold that was established for 
modeling a 50% efficacy if V1V2 was the Sole Correlate of Protection. 
Table 4-8 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. 
4.7.2 
Other clinical studies with related ALVAC-HIV® vaccines 
The proposed ALVAC-HIV vaccine candidate specific for southern Africa is ALVAC-
HIV (vCP2438). The vaccine is closest to ALVAC-HIV (vCP1521) (the ALVAC-HIV 
used in the RV144 trial) since it contains the same gag, pro and gp41env TM 
components. However, it has been adapted to include ZM96 gp120 env insert (subtype C) 
(rather than the TH023 gp120 env insert [subtype E] used for the RV144 study regimen 
in Thailand). 
There is extensive previous experience with other ALVAC-HIV vaccines that inform the 
expected safety, tolerability, and immunogenicity profile of the new vaccine (see Table 
4-9). In all, more than 10,000 human subjects have received ALVAC-HIV vaccines in 
clinical trials. The majority of these trials have been performed with ALVAC-HIV 

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(vCP205), (vCP1452), or (vCP1521). In these vaccines, different HIV gene inserts are 
introduced into the ALVAC vector.  
Table 4-9 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 (Part A) 
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 a preparation of a modified recombinant canarypox 
virus expressing the products of the HIV-1 env (Env gp160 protein of the HIV-1 MN 
Strain [clade B]) and gag (HIV-1 LAI strain [clade B]) genes, the protease portion of the 
pol gene on a synthetic polynucleotide encompassing the known human CTL epitopes 
from the nef (BRU Strain) and the pol (LAI strain) gene products. The C3 locus was used 
for the insertion of the HIV-1 env and gag gene sequences and the C5 locus was used for 
the insertion of the sequences encoding the HIV-1 Nef and Pol CTL epitopes.  
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 

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sequences are: the region of the env gene encoding the extracellular Env gp120 moiety of 
TH023 strain of HIV-1 (clade E) linked to the sequences encoding the HIV-1 TM anchor 
sequence of gp41 HIV-1 LAI strain (clade B); the gag gene encoding the entire Gag p55-
polyprotein of the HIV-1 LAI strain; and a portion of the pol sequences of the LAI strain 
of HIV-1 sufficient to encode the protease function. 
4.7.3 
Clinical safety experience with related ALVAC-HIV vaccines 
4.7.3.1 
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 [73,74]. The most relevant data, however, come from the large 
efficacy study performed in Thailand [4,75], 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.  
De Bruyn et al [76] characterized the tolerability and safety profile of ALVAC-HIV 
(vCP205) and ALVAC-HIV (vCP1452) (along with other ALVAC vectors) based on 
data from more than 1,000 clinical trial subjects. The authors concluded that:  
1.  ALVAC-HIV vaccines were safe and well tolerated, with a reactogenicity 
profile comparable to that of existing vaccines licensed for use in adults; and  
2. Reactogenicity was similar for different ALVAC-HIV constructs, suggesting that 
reactogenicity is determined in greater measure by the vector than by the 
additional genetic material inserted into the vector.  
Of interest as well was the observation that reactogenicity seemed to differ according to 
certain demographic variables: Black, non-Hispanic participants reported significantly 
less reactogenicity than did White, non-Hispanic participants; and males reported less 
pain than females. 
Additional information is available in the ALVAC-HIV (vCP2438) IB. 
4.7.3.2 
Summary of pregnancy occurrence and outcomes 
In study RV144 a total of 967 (30.6%) vaccine (vCP1521) and 955 (30.1%) placebo 
recipients reported a pregnancy during the study while 139 vaccine and 116 placebo 
recipients reported more than one pregnancy. Birth was reported for 1843 infants, 14 of 
them representing 7 twin pairs. Of these, 277 births (137 vaccine and 140 placebo 

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recipients; 1 twin pair per treatment) occurred within 450 days of study entry. For these 
infants, birth weight, gestational age, and Apgar scores were similar between the vaccine 
and placebo groups. Three congenital abnormalities (1 vaccine and 2 placebo recipients) 
were reported among these 277 births, the vaccine group abnormality being a respiratory 
distress syndrome with patent ductus arteriosus. Abnormal pregnancy outcomes were 
experienced in 165 out of 3165 (5.2%) vaccine female recipients and 139 out of 3169 
(4.4%) placebo female recipients (p = 0.13), and in 17.1% and 14.6% (p = 0.13) of 
vaccine and placebo pregnancies, respectively [75]. 
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 [77] 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. 
4.7.3.3 
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 (see also Section 4.7.1), and 
HVTN 097.  
HIVNET 007 [78] was a randomized, double-blind, placebo-controlled clinical trial 
conducted in Kampala, Uganda. In this study, 40 HIV-seronegative Ugandan volunteers 
were randomly assigned to receive ALVAC-HIV (vCP205) (n = 20), control ALVAC 
containing the rabies virus glycoprotein G gene (n = 10), or saline placebo (n = 10). 
Adverse reactions to immunizations were similar to those in previous trials with these 
vaccines in HIV-seronegative volunteers in the United States. No severe (grade 3 or 4) 
adverse reactions attributable to receipt of the vaccine were observed. 
HPTN 027 [79] was a phase 1 randomized, single center, double-blind, placebo-
controlled trial that evaluated the safety and immunogenicity of ALVAC-HIV (vCP1521) 
in infants born to HIV-1 infected women in Uganda. 60 infants were enrolled with 48 in 
the active group and 12 in the placebo group. Forty-seven infants received all 4 
vaccinations and completed follow-up (38 in the vaccine 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 

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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 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. 
4.7.3.4 
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 all, 
440 human subjects have received this combination across 7 clinical trials (Table 4-10). 
No safety signal of concern was identified in these studies (see also Section 4.7.1).  

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Table 4-10 Clinical studies performed with ALVAC-HIV and gp120+MF59® 
Study 
(Country) 
ALVAC-HIV 
Protein 
Subjectsa 
RV132 [74] 
(Thailand) 
vCP1521 
gp120 + MF59®  
clades B/E  
made in Chinese hamster ovary (CHO) cells 
n = 45 
AVEG 022A [80] 
(USA) 
vCP205 
gp120 + MF59®  
clade B 
made in CHO cells 
n = 47 
AVEG 029 [81] 
(USA) 
vCP205 
gp120 + MF59®  
clade B 
made in CHO cells 
n = 22 
AVEG 202/HIVNET 
014 [82] 
(USA) 
vCP205 
gp120 + MF59®  
clade B 
made in CHO cells 
n = 145 
AVEG 032 [83] 
(USA) 
vCP205 
gp120 +/- p24 + MF59®  
clade B  
gp120 made in CHO cells  
p24 made in S. cerevisiae 
n = 56 
AVEG 026 [84] 
(USA) 
vCP300b 
gp120 + MF59® 
clade B  
made in CHO cells 
n = 85 
AVEG 012A 012B 
[85] 
(USA) 
vCP125c 
gp120 + MF59® 
clade B  
made in CHO cells 
n = 40 
Total 
 
 
N = 440 
a Number of subjects who received both the ALVAC-HIV prime and the gp120/MF59® boost. 
b ALVAC-HIV (vCP300) is similar to vCP205 and contains additional sequences encoding Pol and Nef epitopes. 
c ALVAC-HIV (vCP125) contains the gene for gp160 from clade B. 
4.7.4 
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 (see Section 4.1.2 above [30]). 
As the development of assays for measuring immunogenicity has evolved during more 
than 20 years of testing in humans, immunogenicity data cannot be fully integrated. 
However, extensive data from previous studies with ALVAC-HIV can inform many 
relevant immunogenicity-related issues as described below.  
4.7.4.1 
ALVAC-protein schedule and immunogenicity  
The selection of a vaccination schedule for the large efficacy trial in Thailand (RV144) 
was based on existing scientific knowledge at the time [86]. 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 

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believed to have contributed to vaccine protection, even when the mechanism of 
protection has not been definitely established. The following paragraphs summarize the 
considerations that were taken into account in the selection of a vaccine regimen and 
schedule for the RV144 study. Section 4.4.2 explains the rationale for schedule 
modifications to address the goal of improving upon the RV144 results.  
Prior to RV144, several schedules of administration with ALVAC and protein boost were 
examined in multiple clinical trials [67,80,82,87,88]. 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 [88]. 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, two doses of the protein 
boost were proposed at months 3 and 6 to maximize Ab responses. The RV144 study 
implemented this vaccination schedule.  
4.7.4.2 
Immunogenicity of ALVAC used in combination with protein boost plus MF59® 
The vaccine regimen proposed for development in South Africa combines ALVAC-HIV 
(vCP2438) with a bivalent recombinant gp120 protein (total of 200mcg, 100mcg of each 
protein) adjuvanted with MF59®. Both vaccine components have been adapted to target 
the predominant HIV clade circulating in South Africa (clade C). Interim 
immunogenicity data from HVTN 100 are summarized in Section 4.7.1.4. 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 [74] used ALVAC-HIV (vCP1521) in the same dose and schedule as in 
study RV144 but 45 subjects in one of the study arms received a bivalent recombinant 
gp120 protein manufactured in CHO cells by Novartis Vaccines and Diagnostics and 
adjuvanted with MF59® as a protein boost. The dose of the proteins was 150 mcg in total 
(100 mcg of the CM235 protein and 50 mcg of the SF2 protein). Study RV135 [73] used 
ALVAC-HIV (vCP1521) in the same dose and schedule as in study RV144, and 97 
subjects in two study arms received a bivalent recombinant gp120 protein manufactured 
in CHO cells by VaxGen/Global Solutions for Infectious Diseases (GSID) and 
adjuvanted with alum as a protein boost. The study explored two doses of the proteins: a 
total dose of 200 mcg (100 mcg for the A244 protein and 100 mcg for the MN protein) 
and a total dose of 600 mcg (300 mcg each of the same proteins in the lower dose 
formulation). The vaccine regimen with ALVAC-HIV and 600 mcg of gp120 protein 
adjuvanted with alum was utilized in study RV144. Table 4-11 summarizes the nAb 
response rates for the pertinent study arms from these studies.  

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Table 4-11 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 
[74] 
100mcg CM235* 
50 mcg SF2** 
MF59® 
45 
89% 
61% 
95% 
19% 
100% 
RV135 
[73] 
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 4-12. 
Table 4-12 nAb GM titers to clade E strains 
Study 
gp120 dose 
Adjuvant 
N 
NPO3 
Strain 
CM244 
Strain 
RV132 
[74] 
100mcg CM235* 
50 mcg SF2** 
MF59® 
45 
45 
32.66 
RV135 
[73] 
100mcg A244* 
100mcg MN** 
alum 
50 
12.3 
7 
300mcg A244* 
300mcg MN** 
alum 
47 
14.8 
5.4 
* clade E Strain 
** clade B Strain 
Although the data should be interpreted with caution, they suggest that 100mcg of gp120 
protein adjuvanted with MF59® can induce Ab responses after ALVAC prime at least 
comparable to and possibly greater than 300mcg of gp120 protein adjuvanted with alum 
after ALVAC prime. These data suggest that MF59® allows for protein dose sparing 
compared with the less potent alum adjuvant. 
4.7.5 
Clinical studies with Novartis HIV-1 subunit protein vaccines  
For description of interim safety/tolerability and immunogenicity results from Part A of 
HVTN 100, see Section 4.7.1. 
In addition, recombinant monomeric (gp120) subunit vaccine formulations closely related 
to Subtype C gp120/MF59® from Novartis Vaccines and Diagnostics (formerly Chiron) 
have been tested in many clinical trials. In addition, recombinant oligomeric (o-gp140) 
Env proteins for subtypes B and C from Novartis have been or are currently in clinical 
trials. Overall, in these studies, recombinant HIV-Env proteins manufactured by Novartis 
were well tolerated and immunogenic. In most cases, recombinant HIV-Env proteins 
(either gp120 or gp140) were CHO-based and administered with MF59®, Novartis’ 
proprietary oil-in-water emulsion adjuvant [38]. 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 EU and other countries for use in the 
elderly. MF59® is also used in a prepandemic H5N1 influenza vaccine (Aflunov®) 
licensed in EU for use in adults, and in two pandemic H1N1 influenza vaccines 
(Focetria® and Celtura®), licensed in EU and other countries for use in adults and 

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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 [52,74,84,89-91]. Two clinical trials were conducted using 
Novartis CHO-based subtype B gp140 recombinant Env protein with MF59®. There are 
three 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 4-13 summarizes 
clinical trial experience with Novartis gp120 and gp140 recombinant vaccine candidates. 
Table 4-13 Novartis recombinant gp120 and gp140 vaccines in human clinical trials [90] 
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 
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 [4,51,52,74,84,89-92]. 

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4.7.5.1 
Summary of safety, reactogenicity, and tolerability from recent human experience 
For description of interim safety/tolerability results from Part A of HVTN 100, see 
Section 4.7.1. 
In addition, two other clinical trials have been conducted recently using Novartis CHO-
based subtype B gp140 with MF59®. In addition there are four ongoing 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, 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 [93]. During the study, there was one SAE reported 
of Bell’s Palsy (facial nerve paralysis) considered possibly related to the study vaccine 
LTK63 in a subject who never received any subtype B gp140 protein or any protein with 
MF59® adjuvant. IN vaccination was reactogenic resulting in upper respiratory tract 
symptoms including nasal congestion, nasal discomfort, pharyngolaryngeal pain and 
rhinorrhea. The subtype B gp140 MF59® was well tolerated following IM boost.  
The other completed study with Novartis subtype B gp140 MF59® was a multicenter, 
placebo-controlled trial (HVTN 049) conducted by the HVTN in the United States [94]. 
Subjects received one of three doses of a DNA/PLG vaccine (subtype B gag DNA/PLG 
and subtype B env DNA/PLG microparticles, at doses of 250/250, 500/500, or 
1000/1000mcg) or placebo (5 to 1 ratio) as a single IM injection at 0, 1 and 2 months, 
followed by a boost of subtype B gp140 with MF59® (or placebo) at 6 and 9 months. An 
additional group of 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 four events reported as SAEs that were 
not considered related to the study vaccine. A death attributed to cocaine overdose 
occurred in one subject, 10 days after receipt of the second dose of the placebo. One 
subject had a Grade 3 increase in creatine phosphokinase (CPK) to 2311 U/L, 14 days 
after the first DNA prime vaccination, which resolved within a week. Another subject 
had a Grade 4 increase in CPK to 4806 U/L 15 days after the first DNA prime 
vaccination, which resolved within two weeks. Both subjects reported to have initiated 
new exercise programs. One subject experienced severe fatigue 20 days after the fourth 
immunization (including one dose of subtype B gp140/MF59®), attributed to working 
two jobs and long hours. Overall, the regimens were generally well tolerated.  
There are three ongoing phase 1 studies with Novartis subtype C gp140/MF59® being 
conducted by the HVTN in the US and the RSA as well as one phase 1 trial being 
conducted by the Istituto Superiore di Sanità (ISS) in Italy. One of these trials, HVTN 
088, is being conducted in the United States in order to evaluate the safety and 
immunogenicity of a long-interval, cross-clade subtype C gp140/MF59® boost in subjects 
previously administered subtype B gp120/MF59® or subtype B gp140/MF59® in previous 
trials. This included subjects from the HVTN049 DNA/PLG prime, gp140/MF59® boost 
study described above. The study is fully enrolled with 16 previously vaccinated subjects 

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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 HVTN088 to receive a clade C protein boost in 
an open label phase 1 trial. There have been 3 SAEs reported in this trial, one involving 
traumatic injury, one instance of gastroenteritis, and one of appendicitis. All of these 
were assessed as unrelated to study agents.  
Another ongoing study, HVTN 073E, is being conducted in the US and RSA as an 
extension to the previous HVTN 073/SAAVI03 study. This extension study examines the 
safety and immunogenicity of two boosting doses of Novartis subtype C gp140/MF59® or 
placebo in subjects who previously received 3 vaccinations of SAAVI DNA-C2 and two 
vaccinations of SAAVI MVA-C. This study is fully enrolled, with 27 subjects. There was 
one report of endometrial intra-epithelial neoplasia resulting in hospitalization for 
hysterectomy, which was assessed as unrelated to study agents. 
The third ongoing HVTN study, HVTN 086, is being conducted in the RSA. It is 
evaluating the safety and immunogenicity of various combinations of SAAVI DNA-C2, 
SAAVI MVA-C, and Novartis subtype C gp140/MF59®. This study enrolled 184 
subjects. To date, 6 SAEs have been reported in this study, one case of acute tonsillitis 
that required hospitalization, one of schizophrenia requiring hospitalization (later 
determined to be a pre-existing condition), one of pelvic inflammatory disease, one soft-
tissue injury, one instance of anemia, and one instance of alcohol-related 
cardiomyopathy. All were assessed as not related to the study products. 
The ISS study (ISS P-002) is being conducted in Italy examining 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 does not include MF59®. 
There have been no SAEs reported in this study. 
4.7.5.2 
Summary of immunogenicity from recent human experience 
The immunogenicity of Novartis recombinant proteins has been demonstrated 
consistently in all clinical trials and in both of the recently completed studies using 
Novartis CHO-based subtype B gp140 MF59®. In the HVTN 049 DNA/PLG prime 
protein boost study, the primary cellular immunogenicity endpoints included interferon 
gamma (IFN-γ) enzyme-linked immunospot (ELISpot) and ICS responses. 
Immunogenicity was assessed 14 days after each vaccination. Env-specific IFN-γ 
ELISpot response rates did not increase substantially compared to baseline after the three 
DNA/PLG prime vaccinations, but did rise after the first protein/MF59® boost. nAb titers 
against the homologous SF162 isolate were detectable in two subjects after the third 
DNA/PLG priming vaccination and in 13 subjects after the first protein boost. 
Neutralization was boosted to high titer in all but one 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 one 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 

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subjects following IN administration of subtype B gp140 with the adjuvant LTK63 and 
an IM boost with subtype B gp140 and M59 adjuvant. nAb responses against the 
homologous SF162 were also detected in all groups following IM boost with subtype B 
gp140 and MF59® adjuvant. 
In addition, although the subtype C gp140/MF59® HVTN 088 long interval boost study is 
currently ongoing in the long term safety follow up stage, all vaccine administrations 
have been completed and preliminary results are available. Sixteen previously primed 
volunteers and 20 naïve volunteers each received 2 doses of the subtype C gp140/MF59® 
given 6 months apart. HIV-1 specific CD4+ and CD8+ T-cell responses were measured 
by an ICS assay. Ab responses were measured with a Luminex binding Ab assay and a 
nAb assay in TZM-bl Cells. Despite the long interval (4-17 years from prior 
protein/MF59® administration), 31% of primed participants demonstrated CD4+ T-cell 
responses to Env at baseline, which increased to 75% after a single protein boost. IgG 
and IgA responses to subtype C gp140/MF59® were present in 64% (IgG) and 7% (IgA) 
of primed participants at baseline, and rose to 93% and 85%, respectively, after one dose 
of protein. 71% of primed participants demonstrated nAb against Tier 1 clade B isolate 
MN at baseline. After a single booster dose of protein, 100% of the primed participants 
neutralized MN and 93% showed neutralizing activity against a clade C isolate, 
MW965.26. Unprimed participants did not demonstrate CD4+ responses or Ab responses 
to Env until after the second dose, which elicited IgG and IgA responses to TV1 trimeric 
Env in 88% and 50%, respectively. nAbs developed to MN in 38% and to MW965.26 in 
88% of the unprimed participants. 
See also Section 4.7.1. 
4.8 
Potential risks of study products and administration 
Table 4-14 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®.  

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Table 4-14 Summary of potential risks of study products and administration 
Common (> 10%) 
Mild to moderate injection site pain, tenderness, 
erythema, or swelling/induration/edema 
Malaise/fatigue, myalgia, arthralgia, 
nausea/vomiting, lymphadenopathy, asthenia, 
fever, or headache in the first few days 
following injection 
Arm movement limitation 
A vaccine-induced positive HIV antibody test 
result 
Less common (1% to 10%) 
Severe injection site pain or tenderness 
Chills, flu-like syndrome, diarrhea, rash, or 
dizziness in the first few days following 
injection  
Vasovagal reaction/lightheadedness/dizziness 
related to the injection procedure 
Transient changes in clinical laboratory values 
Injection site hematoma, bruising/ecchymosis, 
laceration, other transient lesions, or bleeding 
related to the injection procedure 
Uncommon (< 1%) or rare (< 0.1%) 
Severe localized injection site reaction, such as 
> 10 cm diameter erythema or induration, sterile 
abscess or secondary bacterial infection  
Allergic reaction, including rash, urticaria, 
angioedema, eyelid swelling, bronchospasm, or 
anaphylaxis 
Injection site pruritus, warmth or other non-
specific injection site reaction 
Generalized pruritus 
Oral paresthesia 
Syncope, insomnia 
Abdominal pain, anorexia, gastritis, dysgeusia 
Skin disorder, acne 
Unknown frequency or theoretical risks 
Muscle damage at the injection site 
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 
Part A 
Primary objective 1:  
To evaluate the safety and tolerability of 2 doses of ALVAC-HIV (vCP2438) followed 
by 2 doses of ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59® in HIV-
seronegative low risk South African adults  
Primary endpoints 1:  
Severe local and systemic reactogenicity signs and symptoms (pain, tenderness, 
maximum severity of pain and/or tenderness, erythema, induration, fever, 
malaise/fatigue, myalgia, headache, nausea, vomiting, chills, arthralgia) to 3 days after 
each vaccine/placebo dose 
AEs by body system, Medical Dictionary for Regulatory Activities (MedDRA) Preferred 
Term, severity, and assessed relationship to study products to 30 days after each 
vaccine/placebo dose 
SAEs 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 product(s) 
administration throughout the study 
Primary objective 2:  
To evaluate the immunogenicity of 2 doses of ALVAC-HIV (vCP2438) followed by 2 
doses of ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59® in HIV-
seronegative low risk South African adults at the month 6.5 timepoint (2 weeks after 
completion of the primary immunization series) 
Primary endpoints 2:  
Occurrence and level of vaccine-induced IgG Ab binding to the 3 gp120 Env proteins 
contained in the vaccine regimen (ZM96, TV1.C, and 1086.C)  
Vaccine-induced IgG Ab binding to 3 V1V2-scaffolded Env proteins  
Vaccine-induced CD4+ T cell responses to the HIV proteins included in the vaccine  
Part B 

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Primary objective 3: 
To evaluate the safety and tolerability of Bivalent Subtype C gp120/MF59 and of 
ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59 when given as boosts at 
Month 30 in participants previously vaccinated  in Part A 
Primary endpoints 3:  
Number and frequency of severe local and systemic reactogenicity signs and symptoms 
(pain, tenderness, maximum severity of pain and/or tenderness, erythema, induration, 
fever, malaise/fatigue, myalgia, headache, nausea, vomiting, chills, arthralgia) occurring 
within 3 days of each vaccine/placebo dose 
AEs by body system, Medical Dictionary for Regulatory Activities (MedDRA) Preferred 
Term, severity, and assessed relationship to study products occurring within 30 days of 
each vaccine/placebo dose 
SAEs throughout the study 
AEs leading to early participant withdrawal or early discontinuation of study product(s) 
administration 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 
Primary objective 4: 
To evaluate the immunogenicity of Bivalent Subtype C gp120/MF59 and of ALVAC-
HIV (vCP2438) + Bivalent Subtype C gp120/MF59 when given as boosts at Month 30 in 
participants previously vaccinated in Part A at 2 weeks following vaccination 
Primary endpoints 4:  
Occurrence and level of vaccine-induced IgG Ab binding to Env proteins contained in the 
vaccine  
Vaccine-induced IgG Ab binding to V1V2-scaffolded Env proteins  
Vaccine-induced CD4+ T cell responses to the HIV proteins included in the vaccine  
5.2 
Secondary objectives and endpoints 
Part A 
Secondary objective 1: 
To evaluate the safety and tolerability of 2 doses of ALVAC-HIV (vCP2438) followed 
by 3 doses of ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59® in HIV-
seronegative low risk South African adults  

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Secondary endpoint 1: 
Endpoints as indicated in primary endpoints 1 
Secondary objective 2: 
To further characterize the HIV-1 specific immunogenicity of ALVAC-HIV (vCP2438) 
followed by ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59®  
Secondary endpoints 2: 
Contingent upon results from the primary immunogenicity objective described above 
(primary objective 2), additional immunogenicity assays may be conducted at the Month 
6.5 timepoint, such as occurrence and level of various vaccine-induced immunoglobulin 
isotypes and HIV-1 nAb 
Secondary objective 3: 
To compare the immunogenicity of ALVAC-HIV (vCP2438) and ALVAC-HIV 
(vCP2438) + Bivalent Subtype C gp120/MF59® in HIV-seronegative low risk South 
African adults at the Month 12.5 timepoint (2 weeks after booster immunization) to the 
immunogenicity of the primary regimen at the Month 6.5 timepoint 
Secondary endpoint 3: 
Endpoints as in primary endpoints 2, and secondary endpoints 2 as applicable, at the 
Month 6.5 and Month 12.5 timepoints 
Part B 
Secondary objective 4: 
To evaluate the durability of immune responses at Months 30 and 36 
Secondary endpoint 4: 
Endpoints as in primary endpoints 4 and secondary endpoints 5, as applicable 
Secondary objective 5: 
To further characterize the HIV-1 specific immunogenicity of ALVAC-HIV (vCP2438) 
followed by ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59® at 2 weeks 
following vaccination at Month 30  
Secondary endpoints 5: 
Additional immunogenicity assays based on the HVTN Laboratory Assay Algorithm and 
as informed by correlates analyses in HVTN 702 (as applicable) 

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5.3 
Exploratory objectives 
Exploratory objective 1: 
To describe self-reported risk behavior of male and female participants and perceived 
treatment assignment 
Exploratory objective 2: 
Additional immunogenicity assays may be performed on blood samples and mucosal 
samples, including samples from other timepoints, based on the HVTN Laboratory Assay 
Algorithm 
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 252 healthy, HIV-uninfected participants aged 18 to 40 years at 
low risk of HIV infection. 210 participants will receive the ALVAC-HIV (vCP2438) + 
Bivalent Subtype C gp120/MF59® regimen and 42 will receive placebos, randomized in a 
5:1 ratio in Part A. To ensure a relative balance in participants of each sex at birth, no 
more than approximately 60% of trial participants of either sex will be enrolled into the 
trial in Part A and Part B. Hence, when approximately 150 participants of either sex have 
been enrolled in Part A (approximately 43 in Part B), recruitment for that sex will stop. In 
Part B, eligible participants who were randomized to the vaccine (Group 1) in Part A will 
be randomized to Group 1a or 1b while eligible participants who were randomized to 
placebo (Group 2) in Part A will continue to receive placebo injections in Part B. The 
sample sizes for Part B are estimated to be ~30 for each of Groups 1a and 1b and ~12 for 
Group 2. The availability of immunogenicity data at the later study visits in Part B may 
be somewhat lower than the projected sample sizes due to dropout over time. Differential 
dropout across the groups in Part B is not expected due to randomization and blinding. 
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 background. Immunogenicity data from 9 phase 1 
and 1 phase 2a HVTN trials, which began enrolling after June 2005 (data as of June 
2011) indicate that 14% is a reasonable estimate for the rate of immunogenicity missing 
data at Month 6.5. For this reason, the sample size calculations in Section 6.1.2 account 
for 14% of enrolled participants having missing data for the primary immunogenicity 
endpoints as well as for immunogenicity endpoints for Part B.  
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 (see Section 11.2.3) 
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 the vaccine arm of the study (n = 210), there is a 90% chance of 
observing at least 1 event if the true rate of such an event is 1.1% or more; and there is a 
90% chance of observing no events if the true rate is 0.05% or less. For the combined 
vaccine Groups 1a and 1b in Part B of the study with n = 60 in total, there is a 90% 
chance of observing at least 1 event if the true rate of such an event is 3.8% or more; and 
there is a 90% chance of observing no events if the true rate is 0.17% or less. As a 
reference, in HVTN vaccine trials from December 2000 through September 2010, about 
4% of participants who received placebos experienced an SAE. 
Probabilities of observing 0, 1 or more, and 2 or more events for arms of size 42 and 210 
are presented in Table 6-1 for a range of possible true AE rates. These calculations 
provide a more complete picture of the sensitivity of this study design to identify 
potential safety problems with the vaccine. 

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Table 6-1 Probability of observing 0 events, 1 or more events, and 2 or more events, for 
vaccine groups of size 60, (Groups 1a and 1b in Part B) and 210 (Group 1 in Part A), for 
different true event rates 
True event rate (%) 
Pr(0/60) 
Pr(1+/60) 
Pr(2+/60) 
Pr(0/210) 
Pr(1+/210) 
Pr(2+/210) 
0.1 
0.942 
0.058 
0.002 
0.810 
0.190 
0.019 
0.5 
0.740 
0.260 
0.037 
0.349 
0.651 
0.283 
1 
0.547 
0.453 
0.121 
0.121 
0.879 
0.622 
4 
0.086 
0.914 
0.698 
< 0.001 
> 0.999 
0.998 
10 
0.002 
0.998 
0.986 
< 0.001 
> 0.999 
> 0.999 
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 AE 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 [95]. If none of the 210 
participants receiving a vaccine regimen experience a safety event, the 95% 2-sided 
upper confidence bound for the true rate of such events in the total vaccinated population 
is 1.8%. If none of the 60 participants from Part B Groups 1a and 1b combined 
experience a safety event, the 95% 2-sided upper confidence bound for the true rate of 
such events in the total vaccinated population is 6.02%. 
Table 6-2 Two-sided 95% CIs based on observing a particular rate of safety endpoints for 
vaccine groups of size 60 (Groups 1a and 1b combined in Part B) and 210 (Group 1 in Part 
A)  
Observed event rate 
CI (%) 
0/60 
(0.00, 6.02) 
1/60 
(0.29, 8.86) 
2/60 
(0.92, 11.36) 
0/210 
(0.00, 1.80) 
1/210 
(0.02, 2.65) 
2/210 
(0.26, 3.41) 
6.1.2 
Sample size calculations for immunogenicity 
The primary immunogenicity objective of this trial is to provide data to guide the 
decision of whether to advance development of the ALVAC-HIV (vCP2438), Bivalent 
Subtype C gp120/MF59® regimen. Immunogenicity data from the study regimen will be 
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 this phase 1-2 trial 
will be analyzed contemporaneously using qualified assays in the same laboratories 
(along with placebo samples for blinding).  
Computer simulations (details provided below) were run to determine the sample size of 
the vaccine regimen for this trial and the RV144 comparator arm based on estimates of 
the power to conclude the vaccine regimen has potential for clinical development and the 
probability of incorrectly drawing this conclusion. 
With n = 180 evaluable samples for the vaccine regimen under study in this trial and 
n = 180 for the comparator RV144 arm, there is 91% power to conclude the vaccine 
regimen has potential for clinical development and there is a 3% probability of 
erroneously concluding the regimen has potential for clinical development (Figure 6-1). 
The regimen in this study is assumed to have potential for clinical development if the 
following conditions hold for the LL of the 95% CI: 

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Env Ab response rate ≥ 75% for at least 2 of the 3 env inserts 
GM titer ratio of ≥ 0.5 relative to RV144 samples for at least 2 of the 3 env inserts (and 
above response rate threshold is met for these) 
Difference in ALVAC Env-specific CD4 response rate in HVTN 100 and RV144 
samples ≥ -30%  
Env V1V2 response rate ≥ 45% for at least 1 of the 3 env inserts 
In the simulation study, seven binary responses, corresponding to 3 Env inserts, 1 CD4+ 
T cell and 3 V1V2 variables, were simulated with underlying multivariate normal 
variables with correlations equal to Spearman correlations estimated from RV144 data. 
Other correlations were considered but had minimal effect on the results. The RV144 
comparator arm results were simulated with underlying multivariate normal variables 
with parameters estimated in the RV144 correlates analysis [30] with response rates of 
92%, 94%, 98%, 71.5%, 63.8% for the 3 Env Ab, 1 CD4+ T cell, and 1 V1V2 variables 
respectively. The GM titers for the Env insert responses in the RV144 comparator arm 
were set equal to those estimated in RV144 with GMs=6.31, 6.42, and 8.05 with 
variance-covariance matrix with rows = (2.02 1.92 1.30), (1.92 1.89 1.32), (1.30 1.32 
2.06). For scenarios in which the regimen has the potential for clinical development, the 
V1V2 and Env insert response rates were set equal to those observed in RV144; the Env 
insert GMs were set equal to 90% of the responses observed in RV144, and the CD4+ T 
cell response was set equal to 5% less than the RV144 response rate. For scenarios in 
which the regimen does not have potential, the response rates for the Env inserts were set 
equal to 74% (with GMs set equal to 49% of those seen in RV144), the CD4+ T cell 
response rate was set equal to 31% less than that seen in RV144, and the V1V2 response 
rates were set equal to 44%, just failing to meet the above conditions. The error rate is 
then computed as the maximum probability of concluding potential for further 
development under scenarios where in truth not all 3 of the above conditions are met. The 
power is computed as the minimum probability of concluding potential for further 
development under scenarios where in truth all of the above conditions are met. 
 

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Figure 6-1 Plots display the maximum probability of erroneously concluding the vaccine 
regimen has potential for clinical development (left panel) and the minimum probability of 
correctly concluding the vaccine regimen has potential for clinical development (right panel) 
over a range of sample sizes (n = 100-200). 
To provide a sense of the level of precision with which the true immune responses can be 
estimated with this sample size, CIs for various hypothetical observed response rates are 
provided in Table 6-3. No adjustment for multiple comparisons will be made for the use 
of multiple assays. Two-sided 95% CIs for the response rate based on observing a 
particular rate of responses in the vaccinees is shown in Table 6-3; calculations are done 
using the score test method [95]. Note, n = 180 assumes a 14% rate of missing data. 
Table 6-3 Two-sided 95% CIs for the true response rate based on observing a particular rate 
of responses in the vaccinees (n = 180) 
No. of responses 
Observed response rate (%) 
CI 
90 
50 
(42.8, 57.2) 
108 
60 
(52.7, 66.9) 
126 
70 
(62.9, 76.2) 
144 
80 
(73.6, 85.2) 
162 
90 
(84.7, 93.6) 
CIs for various hypothetical observed response rates are provided in Table 6-4 for the 
sample sizes of Groups 1a and 1b in Part B. Table 6-5 contains CIs for the pooled Part B 
vaccine Groups 1a and 1b. No adjustment for multiple comparisons will be made for the 
use of multiple assays. Two-sided 95% CIs for the response rate based on observing a 
particular rate of responses in the vaccinees is shown in Table 6-4 and Table 6-5; 
calculations are done using the score test method [95]. Note, n = 26 (52) assumes a 14% 
rate of missing data. 
Table 6-4 Two-sided 95% CIs for the true response rate based on observing a particular rate 
of responses in the Part B Groups 1a and 1b vaccinees (n = 26 each group) 
No. of responses 
Observed response rate (%) 
CI 

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13 
50 
(32.1, 67.9) 
16 
60 
(42.5, 77.6) 
18 
70 
(50.0, 83.5) 
21 
80 
(62.1, 91.5) 
23 
90 
(71.0, 96.0) 
Table 6-5 Two-sided 95% CIs for the true response rate based on observing a particular rate 
of responses in the pooled vaccinees in Part B (Groups 1a and 1b combined, n = 52 in total) 
No. of responses 
Observed response rate (%) 
CI 
26 
50 
(36.9, 63.1) 
31 
60 
(46.1, 71.8) 
36 
70 
(55.7, 80.1) 
42 
80 
(68.1, 89.2) 
47 
90 
(79.4, 95.8) 
6.2 
Randomization  
The randomization sequence for Parts A and B will be obtained by computer-generated 
random numbers and provided to each HVTN CRS through the SDMC’s Web-based 
randomization system. The randomization will be done in blocks to ensure balance across 
arms. At each institution, the pharmacist with primary responsibility for dispensing study 
products is charged with maintaining blinding of the treatment assignments (except in 
emergency situations as specified in the HVTN Manual of Operations [MOP]). 
6.3 
Blinding 
Participants and site staff (except for site pharmacists) will be blinded as to participant 
treatment arm assignments (eg, vaccine or placebo). Study product assignments are 
accessible to those HVTN CRS pharmacists, DAIDS protocol pharmacists and contract 
monitors, and SDMC staff who are required to know this information in order to ensure 
proper trial conduct. Any discussion of study product assignment between pharmacy staff 
and any other HVTN CRS staff is prohibited. The DSMB members 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.  
Emergency unblinding decisions will be made by the site investigator. If time permits, 
the HVTN 100 PSRT should be consulted before emergency unblinding occurs. 
6.4 
Statistical analysis 
This section describes the final study analysis, unblinded as to treatment arm assignment. 
All data from enrolled participants will be analyzed according to the initial randomization 
assignment regardless of how many vaccinations they received. The analysis is a 
modified intent-to-treat analysis in that individuals who are randomized but not enrolled 
do not contribute data and hence are excluded. Because of blinding and the brief length of 

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time between randomization and enrollment—typically no more than 4 working days—
very few such individuals are expected. 
Analyses for primary endpoints will be performed using SAS. 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 
discussed below, when the assay endpoint is viewed as a collection of hypotheses (eg, 
testing multiple peptide pools to determine a positive response). 
6.4.1 
Analysis variables 
The analysis variables consist of baseline participant characteristic, safety, and 
immunogenicity for primary- and secondary-objective analyses. 
6.4.2 
Baseline comparability 
Treatment arms 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 arm and the percentages 
displayed graphically by arm. For a given sign or symptom, each participant’s 
reactogenicity will be counted once under the maximum severity for all injection visits. 
In addition to the individual types of events, the maximum severity of local pain or 
tenderness, induration or erythema, and of systemic symptoms will be calculated. 
Wilcoxon rank sum tests will be used to test for differences in severity between arms. 
6.4.3.2 
AEs and SAEs 
AEs will be summarized using MedDRA System Organ Class and preferred terms. 
Tables will show by treatment arm the number and percentage of participants 
experiencing an AE within a System Organ Class or within Preferred Term 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 arms is not planned since interpretation of differences must rely heavily upon 
clinical judgment. 
A listing of SAEs will provide details of the events including severity, relationship to 
study product, time between onset and last vaccination, and number of vaccinations 
received.  

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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 arm 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 arm 
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 
9.9) will be tabulated by treatment arm 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 arm. 
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 will also be 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 postinfection 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 postenrollment, then all data from that participant may be 
excluded from the analysis.  
Discrete categorical assay endpoints (eg, response rates) will be analyzed by tabulating 
the frequency of positive response for each assay by antigen and treatment arm at each 
timepoint for which an assessment is performed. Crude response rates will be presented 
with their corresponding 95% CI estimates calculated using the score test method [95]. 
No adjustment will be made to the vaccine arm estimates for the false positive rates in the 
placebo arms.  
For quantitative assay data (eg, GM Ab titers from the binding Ab multiplex assay 
[BAMA]), graphical and tabular summaries of the distributions by antigen, treatment 
arm, and timepoint will be made. An appropriate data transformation (eg, log10 
transformation) may be applied to better satisfy assumptions of symmetry and 
homoscedasticity (constant variance). 
The 95% CIs for the primary immunogenicity endpoints will be examined to determine 
whether the conditions are met to indicate that the vaccine regimen has the potential for 
clinical development.  

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For the secondary objective regarding the comparison of immunogenicity at Month 6.5 
and Month 12.5, 95% CIs for the difference in response rates and in the quantitative 
responses will be provided. 
More sophisticated analyses employing repeated measures methodology (for example, 
repeated measures analysis of variance [ANOVA] or generalized estimating equations) 
may be utilized to incorporate immune responses over several timepoints and to test for 
differences over time. All statistical tests will be 2-sided and will be considered 
statistically significant if p  0.05. 
Based upon previous early phase HVTN trials in the RSA, missing up to 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 
nonparametric tests and generalized linear models fit by generalized estimating equation 
(GEE) methods, missing data need to be missing completely at random (MCAR). MCAR 
assumes that the probability of an observation being missing does not depend upon the 
observed responses or upon any unobserved covariates but may depend upon covariates 
included in the model (eg, missing more among whites than nonwhites). When missing 
data are minimal (specifically if no more than 20% of participants are missing any 
values), then nonparametric tests and GEE methods will be used, because violations of 
the MCAR assumption will have little impact on the estimates and hypothesis tests. 
These models will include as covariates all available baseline predictors of the missing 
outcomes.  
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 [96] will be used, because they accommodate 
the censoring. In addition, secondary analyses of repeated immunogenicity measurements 
may be done using weighted GEE [97] 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 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 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 only. 

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6.4.5.1 
Safety 
During the course of the trial, unblinded analyses of safety data will be prepared for 
review by the DSMB, which will evaluate the safety and integrity of the ongoing trial 
periodically.  
6.4.5.2 
Immunogenicity 
An unblinded statistical analysis by treatment assignment for the primary 
immunogenicity endpoints will be performed when all participants have completed the 
primary immunogenicity visit (Month 6.5) and the data are available for analysis from all 
of these participants. An unblinded statistical analysis by treatment assignment of a 
secondary or exploratory immunogenicity endpoint may be performed when all 
participants have completed the corresponding immunogenicity visit and data are 
available for analysis from at least 80% of these participants. However, such analyses for 
a secondary or exploratory immunogenicity endpoint will only take place after all of the 
primary immunogenicity analyses are complete. The Laboratory Program will review the 
analysis report prior to distribution to the protocol chairs, DAIDS, vaccine developer, and 
other key stakeholders. Distribution of reports will be limited to those with a need to 
know for the purpose of informing future trial-related decisions. 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 results of 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 for Part A 
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; 
completes 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 
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 
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 (per Low Risk 
Guidelines for South African sites, available on the HVTN 100 protocol web page) 

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and committed to maintaining behavior consistent with low risk of HIV exposure 
through the last required protocol clinic visit 
Laboratory Inclusion Values 
Hemogram/CBC 
10. Hemoglobin ≥ 11.0 g/dL for volunteers who were born female, ≥ 13.0 g/dL for 
volunteers who were born male 
11. WBC = 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: 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: 
 
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 born female: negative urine beta human chorionic 
gonadotropin (β-HCG) pregnancy test performed prior to vaccination on the day of 
initial vaccination or negative serum beta human chorionic gonadotropin (β-HCG) 

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pregnancy test within 24 hours prior to initial vaccination. Persons who are NOT of 
reproductive potential due to having undergone total hysterectomy with bilateral 
oophorectomy (verified by medical records), are not required to undergo pregnancy 
testing. 
21. Reproductive status: A volunteer who was born female 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 South Africa is defined as using 2 methods, including the 
following: 
 
Condoms (male or female), or 
 
Diaphragm or cervical cap, 
PLUS 1 of the following methods: 
 
Intrauterine device (IUD), 
 
Hormonal contraception (in accordance with Republic of South Africa: 
National Contraception Clinical Guidelines),  
 
Successful vasectomy in the male partner (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 postvasectomy); or 
 
Any other contraceptive method approved by the HVTN 100 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; 
 
Or be sexually abstinent. 
22. Volunteers who were born female 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 
7.2 
Exclusion criteria for Part A 
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  

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4. Intent to participate in another study of an investigational research agent or any 
study that includes HIV testing during the planned duration of the HVTN 100 study  
5. Pregnant, breastfeeding, or lactating 
Vaccines and other Injections 
6. HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have 
received control/placebo in an HIV vaccine trial, the HVTN 100 PSRT will 
determine eligibility on a case-by-case basis. 
7. 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 by the South Africa Medicines Control Council (MCC). For 
volunteers who have received control/placebo in an experimental vaccine trial, the 
HVTN 100 PSRT will determine eligibility on a case-by-case basis. For volunteers 
who have received an experimental vaccine(s) greater than 5 years ago, eligibility for 
enrollment will be determined by the HVTN 100 PSRT on a case-by-case basis. 
8. Live attenuated vaccines other than influenza vaccine received within 30 days 
before first vaccination or scheduled within 14 days after injection (eg, measles, 
mumps, and rubella [MMR]; oral polio vaccine [OPV]; varicella; yellow fever) 
9. Influenza vaccine or any vaccines that are not live attenuated vaccines and were 
received within 14 days prior to first vaccination (eg, tetanus, pneumococcal, 
Hepatitis A or B) 
10. Allergy treatment with antigen injections within 30 days before first vaccination or 
that are scheduled within 14 days after first vaccination  
Immune System  
11. Immunosuppressive medications received within 168 days before first vaccination. 
(Not excluded from participation: [1] corticosteroid nasal spray; [2] inhaled 
corticosteroids; [3] topical corticosteroids for mild, uncomplicated dermatitis; or [4] a 
single course of oral/parenteral corticosteroids at doses < 2 mg/kg/day and length of 
therapy < 11 days with completion at least 30 days prior to enrollment.) 
12. 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.) 
13. Immunoglobulin received within 60 days before first vaccination 
14. Autoimmune disease  
15. Immunodeficiency 
Clinically significant medical conditions  

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16. Untreated or incompletely treated syphilis infection 
17. 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. 
18. 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 
19. 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. 
20. Current anti-tuberculosis (TB) prophylaxis or therapy 
21. Asthma other than mild or moderate, well-controlled asthma. (Symptoms of asthma 
severity as defined in the most recent 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 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. 
22. Diabetes mellitus type 1 or type 2, including cases controlled with diet alone. (Not 
excluded: history of isolated gestational diabetes.) 

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23. Thyroidectomy, or thyroid disease requiring medication during the last 12 months 
24. 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. 
25. Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or 
platelet disorder requiring special precautions) 
26. Malignancy (Not excluded: 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) 
27. Seizure disorder: History of seizure(s) within past three years. Also exclude if 
volunteer has used medications in order to prevent or treat seizure(s) at any time 
within the past 3 years. 
28. Asplenia: any condition resulting in the absence of a functional spleen 
29. History of hereditary angioedema, acquired angioedema, or idiopathic angioedema. 
7.3 
Eligibility criterion for Part B 
HVTN 100 study participants who have met neither discontinuation of vaccination 
criteria described in Section 7.4.3 nor criteria for termination from the study as described 
in Section 7.4.4. For those participants who experienced a prior SAE, consultation with 
the HVTN 100 PSRT is required prior to subsequent vaccinations in Part B.  
Participants who enter Part B under protocol Version 3.0 must agree to provide mucosal 
samples, as described in Section 9.5. 
7.4 
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. 

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7.4.1 
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 other than influenza vaccine  
 
Receipt of allergy treatment with antigen injections 
 
Within 14 days prior to any study injection 
 
Receipt of influenza vaccine or any vaccines that are not live attenuated vaccines 
(eg, pneumococcal)  
 
Prevaccination 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 two negative urine pregnancy tests taken from two 
different urine samples; in this circumstance, the HVTN 100 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 100 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. 
7.4.2 
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 7.4.1 and 7.4.3).  
7.4.3 
Discontinuing vaccination for a participant 
Under certain circumstances, an individual participant’s vaccinations will be permanently 
discontinued. Specific events that will result in stopping a participant’s vaccination 
schedule include: 

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 
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 100 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: 
 
Any grade 4 local or systemic reactogenicity symptom, lab abnormality, or AE 
that is subsequently considered to be related to vaccination; 
 
Any grade 3 lab abnormality or other clinical AE (exception: fever or vomiting 
and subjective local and systemic symptoms) that is subsequently considered to 
be related to vaccination; upon review, the PSRT may allow continuation of 
vaccination if the participant has grade 3 erythema and/or induration; or 
 
Clinically significant type 1 hypersensitivity reaction associated with study 
vaccination. Consultation with the HVTN 100 PSRT is required prior to 
subsequent vaccinations following any type 1 hypersensitivity reaction associated 
with study vaccination; or 
 
Investigator determination in consultation with Protocol Team leadership (eg, for 
repeated nonadherence to study staff instructions). 
Such participants should be counseled on the importance of continuing with the study and 
strongly encouraged to participate in follow-up visits and protocol-related procedures per 
the protocol for the remainder of the trial, unless medically contraindicated. 
In addition, vaccinations will be stopped for participants diagnosed with HIV infection. 
HIV-infected participants will not continue in the trial (see Sections 7.4.4 and 9.6). 
7.4.4 
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,  
 
Participant becomes HIV infected, or  
 
Investigator decides, in consultation with Protocol Team leadership, to terminate 
participation (eg, if participant exhibits inappropriate behavior toward clinic staff). 
 
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 and Table 3-2 (Part B). See the IBs for further information about 
study products. 
8.1 
Vaccine regimen 
The schedule of vaccination is shown in Section 3 and additional information is given 
below.  
8.1.1 
Part A 
Group 1 
Treatment 1 (T1): ALVAC-HIV (vCP2438) to be administered as 1 mL IM in LEFT 
deltoid (unless medically contraindicated) at months 0, 1, 3, 6 and 12 
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 0.5mL IM in RIGHT deltoid 
(unless medically contraindicated) at Months 3, 6 and 12 
Group 2 
Placebo 2 (P2): Placebo for ALVAC-HIV to be administered as 1 mL IM in LEFT 
deltoid (unless medically contraindicated) at months 0, 1, 3, 6 and 12 
AND 
Placebo for Bivalent Subtype C gp120/MF59® administered as 0.5mL IM in RIGHT 
deltoid (unless medically contraindicated) at Months 3, 6 and 12. 
8.1.2 
Part B 
Group 1a 
Treatment 1a (T1a): ALVAC-HIV (vCP2438) to be administered as 1 mL IM in LEFT 
deltoid (unless medically contraindicated) at Month 30  
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 0.5mL IM in RIGHT deltoid 
(unless medically contraindicated) at Month 30  

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Group 1b 
Treatment 1b (T1b): Placebo for ALVAC-HIV (Sodium Chloride for Injection, 0.9%) 
to be administered as 1 mL IM in LEFT deltoid (unless medically contraindicated) at 
Month 30  
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 0.5mL IM in RIGHT deltoid 
(unless medically contraindicated) at Month 30  
Group 2 
Placebo 2 (P2): Placebo for ALVAC-HIV (Sodium Chloride for Injection, 0.9%) to be 
administered as 1 mL IM in LEFT deltoid (unless medically contraindicated) at Month 30 
AND 
Placebo for Bivalent Subtype C gp120/MF59® (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.5mL IM in RIGHT deltoid (unless medically contraindicated) at 
Month 30  
8.2 
Study product formulation  
8.2.1 
Part A 
ALVAC-HIV (vCP2438) [Labeled as ALVAC-HIV Active (vCP2438)]  
ALVAC-HIV (vCP2438) is provided as a lyophilized, white to beige product. It must be 
stored refrigerated (2-8°C). DO NOT FREEZE. Once reconstituted with 1mL of Diluent 
0.4% NaCl, it appears as a clear to slightly opalescent solution, colorless with possible 
presence of particles or filaments. 
Placebo for ALVAC-HIV [Labeled as ALVAC-HIV Placebo]  
Placebo for ALVAC-HIV is a sterile, lyophilized product that consists of a mixture of 
virus stabilizer, and freeze drying medium. It is provided as a lyophilized, white to beige 
product. It must be stored refrigerated (2-8°C). DO NOT FREEZE. Once reconstituted 
with 1mL of Diluent 0.4% NaCl, it appears as a clear to slightly opalescent solution, 
colorless with possible presence of particles or filaments. 
Diluent for ALVAC-HIV (vCP2438) and Diluent for Placebo for ALVAC-HIV 
[Labeled as Diluent 0.4% NaCl]  
The diluent is provided in a vial filled with 1.2 -1.3 mL of sterile sodium chloride 
solution (NaCl 0.4%). It must be stored refrigerated (2-8°C). DO NOT FREEZE. 
Bivalent gp120 composed of two different proteins:  

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TV1.C gp120 protein [labeled as TV1.C gp120]: The TV1.C gp120 protein will be 
provided in a glass vial containing approximately 0.55 mL (440 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 0.55 mL (440 mcg) of protein in buffer. 
The protein is a clear colorless to slightly yellow liquid when thawed. The product must 
be stored frozen at -61°C or colder.  
The study product is described in further detail in the IB.  
MF59® [labeled as MF59C.1] is supplied as an oil-in-water emulsion. The MF59 
adjuvant has a milky white opaque appearance and is provided in a glass vial containing a 
total volume of 0.7 mL. The product must be stored refrigerated at 2 - 8° C. Do not 
freeze.  
The study product is described in further detail in the IB.  
Placebo for Bivalent Subtype C gp120/MF59® (Sodium Chloride for Injection, 0,9%)  
Sodium Chloride for Injection, 0,9% will be used for the Bivalent Subtype C 
gp120/MF59®. Product must be stored as directed by the manufacturer. 
8.2.2 
Part B 
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 1mL 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).  
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. 

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1086.C gp120 protein [labeled as 1086.C gp120]: The 1086.C gp120 protein will be 
provided in a glass vial containing approximately 0.58 mL (462 mcg) of protein in buffer. 
The protein is a clear colorless to slightly yellow liquid when thawed. The product must 
be stored frozen at -61°C or colder. 
The study product is described in further detail in the IB. 
MF59® [labeled as MF59C.1] is supplied as an oil-in-water emulsion. The MF59 
adjuvant has a milky white opaque appearance and is provided in a glass vial containing a 
total volume of 0.7 mL. The product must be stored refrigerated at 2 - 8°C. Protect 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 for the Bivalent Subtype C 
gp120/MF59®. Product must be stored as directed by the manufacturer. 
8.3 
Preparation of study products 
Pharmacists should refer to USP 38 General Chapter Physical Tests / <797> 
Pharmaceutical Compounding - Sterile, and should follow the requirements of their 
country, their institution, and their pharmacy regulatory authority regarding these 
procedures. At a minimum, study products must be prepared in a biological safety 
cabinet/isolator by appropriately trained/qualified pharmacy personnel using aseptic 
technique. 
8.3.1 
ALVAC-HIV (vCP2438) 
8.3.1.1 
Part A 
One vial of ALVAC-HIV (vCP2438) and 1 vial 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 1 mL from the vial 
containing diluent (NaCl 0.4%) and slowly inject (the diluent) into the vial containing the 
lyophilized ALVAC-HIV. The pharmacist will then set the vial aside and allow the vial 
to sit for up to 3 minutes to allow for dissolution of the vaccine. The pharmacist will 
gently swirl the vial to assure the contents are well dissolved. DO NOT SHAKE. (Note: 
Presence of particles or filaments in the dissolved solution is possible). 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”. The study product should be administered within 2 hours of the time the 
vaccine is reconstituted. 
Any unused portion of reconstituted vials or expired prefilled syringes is disposed of in 
accordance with institutional or pharmacy policy for a biological safety level 1 product. 

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8.3.1.2 
Part B 
One vial of ALVAC-HIV (vCP2438) and 2 vials of diluent (NaCl 0.4%) are needed to 
prepare this dose.  
Before reconstitution, the pharmacist will allow the vials to equilibrate to room 
temperature. The pharmacist, using aseptic technique, will withdraw a total of 1 mL from 
the 2 vials containing diluent (NaCl 0.4%) and slowly inject (the 1 mL of diluent) into the 
vial containing the lyophilized ALVAC-HIV. The pharmacist will then set the vial aside 
and allow the vial to sit for up to 3 minutes to allow for dissolution of the vaccine. The 
pharmacist will gently swirl the vial to assure the contents are well dissolved. DO NOT 
SHAKE THE VIAL. (Note: Presence of particles or filaments in the dissolved solution is 
possible). 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 expired prefilled syringes is disposed of in 
accordance with institutional or pharmacy policy for a biological safety level 1 product. 
8.3.2 
Placebo for ALVAC-HIV  
8.3.2.1 
Part A 
One vial of Placebo for ALVAC-HIV and 1 vial of diluent (NaCl 0.4%) is 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 1 mL from the vial 
containing diluent (NaCl 0.4%) and slowly inject the diluent into the vial containing the 
lyophilized placebo. The pharmacist will then set the vial aside and allow the vial to sit 
for up to 3 minutes to allow for dissolution. The pharmacist will gently swirl the vial to 
assure the contents are well dissolved. DO NOT SHAKE. (Note: Presence of particles or 
filaments in the dissolved solution is possible). Using aseptic technique, the pharmacist 
will then withdraw the entire contents for the Placebo for 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”. The study product should be administered within 2 hours of the time the 
vaccine is reconstituted. Any unused portion of reconstituted vials or expired prefilled 
syringes is disposed of in accordance with institutional or pharmacy policy for a 
biological safety level 1 product. 
8.3.2.2 
Part B 
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. 

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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 reconstituted vials or expired prefilled syringes is disposed of in 
accordance with institutional or pharmacy policy.  
8.3.3 
Bivalent Subtype C gp120/MF59 vaccine 
8.3.3.1 
Part A 
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. 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 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 syringe should be labeled as “Bivalent Subtype C gp120/MF59 or Placebo” and have 
an overlay to maintain blinding. The syringe must also be labeled for administration in 
RIGHT deltoid. This study product should be administered as soon as possible after 
preparation. 
8.3.3.2 
Part B 
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. 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 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 
needle should be removed and the syringe capped. 

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The syringe should be labeled as “Bivalent Subtype C gp120/MF59 or Placebo” and have 
an overlay to maintain blinding. The syringe must also be labeled for administration 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 Immunization Action Coalition (IAC) 
recommendations. If this is not possible, the site pharmacist may be permitted to label the 
syringe with a DO NOT USE AFTER 2 hour date and time from preparation. In this case, 
the vaccine should be stored at 2°C-8°C until administration and if not used within 2 
hours, it should be discarded.  
8.3.4 
Placebo for Bivalent Subtype C gp120/MF59 vaccine 
8.3.4.1 
Part A 
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 syringe should be labeled as “Bivalent Subtype C gp120/MF59 or Placebo” and have 
an overlay to maintain blinding. The syringe must also be labeled for administration in 
RIGHT deltoid. This study product should be administered as soon as possible after 
preparation.  
Any unused portion of entered vials or expired prefilled syringes should be disposed of in 
accordance with institutional or pharmacy policy. 
8.3.4.2 
Part B 
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 needle should be removed and the syringe 
capped. 
The syringe should be labeled as “Bivalent Subtype C gp120/MF59 or Placebo” and have 
an overlay to maintain blinding. The syringe must also be labeled for administration in 
RIGHT deltoid. The syringe containing study product should be bagged for transport to 
the clinic where it will be administered. In order to maintain blinding and be consistent 
with the active product, this study product should be administered immediately, defined 
as within 30 minutes as per IAC recommendations. If this is not possible, the site 
pharmacist may be permitted to label the syringe with a DO NOT USE AFTER 2 hour 
date and time from preparation. In this case, 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 
Procedures to preserve blinding 
The pharmacist will prepare all doses for administration and dispense to the clinic. In 
order to preserve blinding, the pharmacist will place an overlay on ALL the syringes. 

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8.4 
Administration 
All injections are to be given IM in the deltoid indicated. At sites where registered 
pharmacists are legally authorized to administer injections, the HVTN CRS may choose 
to have the pharmacist administer vaccinations. 
When preparing a dose in a syringe and administering the dose, consideration should be 
given to the volume of solution in the needle before and after the dose is administered. 
Particularly, if the needle used to withdraw the product is replaced prior to vaccine 
administration, consideration should be given to conserving the full dose of product. The 
pharmacy and clinic staff members are encouraged to work together to administer the 
dose specified in the protocol.  
All injections are to be given using standard IM injection technique. 
For all syringes containing Bivalent gp120/MF59 or placebo, the person administering 
the injection should gently roll the syringe prior to administration of the study product. 
If an injection is administered in the contralateral deltoid due to a medical 
contraindication, the appropriate study staff should document this clearly. Under this 
circumstance, this is NOT a protocol violation. Two injections administered into the same 
deltoid should be at least 2.4 cm apart and should be documented in the participant’s 
study record. 
8.5 
Acquisition of study products 
Part A 
The ALVAC-HIV (vCP2438) or Placebo was manufactured by IDT Biologika for Sanofi 
Pasteur. It will be provided (along with the Diluent) by Sanofi Pasteur. 
Bivalent Subtype C gp120 and MF59® will be provided by Novartis Vaccines and 
Diagnostics, Inc. 
Placebo for Bivalent Subtype C gp120/MF59 (Sodium Chloride for Injection, 0,9%) will 
not be provided through the protocol and must be obtained by the site. 
Part B 
The ALVAC-HIV (vCP2438) and Diluent (0.4% NaCl) will be provided by Sanofi 
Pasteur.  
Bivalent Subtype C gp120 and MF59® will be provided GlaxoSmithKline Biologicals, 
S.A. 
Placebo for Bivalent Subtype C gp120/MF59 (Sodium Chloride for Injection, 0,9%) and 
Placebo for ALVAC-HIV (Sodium Chloride for Injection, 0,9%) will not be provided 
through the protocol and must be obtained by the site. 

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Once an HVTN CRS is protocol registered, the pharmacist can obtain study products 
from the NIAID Clinical Research Products Management Center (CRPMC) by following 
the ordering procedures given in 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 codes 
and randomization confirmation notices for each participant in a secure manner. 
8.7 
Final disposition of study products 
All unused study products must be returned to the CRPMC after the study is completed 
or terminated unless otherwise instructed by the CRPMC. The procedures and relevant 
form are included in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks.  

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9 
Clinical procedures 
The schedules of clinical procedures are shown in Appendix H and Appendix I. 
9.1 
Informed consent 
Informed consent is the process of ensuring that participants 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 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 Protocol Registration 
Office’s Regulatory Support Center (RSC). 
Some HVTN CRSs have approval from their IRB/EC and any applicable RE to use a 
general screening consent form that allows screening for an unspecified HIV vaccine 
trial. In this way, HVTN CRS staff can continually screen potential participants and, 
when needed, proceed quickly to obtain protocol-specific enrollment consent. Sites 
conducting general screening or prescreening approved by their IRB/EC and any 
applicable RE may use the results from this screening to determine eligibility for this 
protocol, provided the tests are conducted within the time periods specified in the 
eligibility criteria.  

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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 
consent addendum for participants who will enter Part B of the protocol is located in 
Appendix B. 
An optional separate consent form for other uses of samples is located in Appendix E. 
Note that participants need only sign the consent addendum in Appendix B in order to 
enter Part B of the study.  
Each HVTN CRS is responsible for developing protocol-specific consent forms for local 
use, based on the sample protocol-specific consent forms in Appendix A, Appendix B, 
and Appendix E. The consent forms must be developed in accordance with requirements 
of the following: 
 
CRS’s IRB/EC, 
 
CRS’s institution and any applicable REs, and 
 
Elements of informed consent as described in Title 45, Code of Federal Regulations 
(CFR) Part 46 and Title 21 CFR, Part 50, and in the International Conference on 
Harmonisation (ICH) E6, Good Clinical Practice: Consolidated Guidance 4.8.  
Study sites are strongly encouraged to have their local CABs review their sites-specific 
consent forms. This review should include, but should not be limited to, issues of cultural 
competence, local language considerations, and the level of understandability. 
The sample informed consent form includes instructions throughout the document for 
developing specific content. 
Sites should follow the instructions in the Protocol-specific Official Memo distributed 
along with this protocol regarding when they may begin using their site-specific protocol 
consent forms. 
Regarding protocol registration, sites should follow procedures outlined in the current 
version of the DAIDS Protocol Registration Manual. 
9.1.3 
Assessment of Understanding 
Study staff are responsible for ensuring that participants fully understand the study before 
enrolling them. This process involves reviewing the informed consent form with the 
participant, allowing time for the participant to reflect on the procedures and issues 
presented, and answering all questions completely.  
An Assessment of Understanding is used to document the participant’s understanding of 
key concepts in this HIV vaccine trial. 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. 

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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; 
 
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 as defined in the inclusion and exclusion criteria, including: 
 
Screening HIV test,  
 
CBC with differential and platelet count,  
 
Chemistry panel (ALT, AST, ALP, and creatinine), 
 
Urine dipstick (urinalysis if indicated, see Section 9.8), 
 
HBsAg,  
 
Anti-HCV Ab, 
 
Syphilis test, 
 
Urine or serum pregnancy test (volunteers who were born female); 
 
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 9.6; and 

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 
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 born female 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). 
9.2.2 
Part B eligibility visit 
Prior to administration of study injections at Month 30, the eligibility of Part A 
participants to continue into Part B of the study is assessed. This assessment can take 
place over the course of several contacts/visits, up to and including before vaccination at 
Month 30. 
After the appropriate informed consent has been obtained (see Appendix B) and before 
study product administration in Part B, the following procedures are performed: 
 
Assessment of Understanding (see Section 9.1.3); 
 
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 concomitant medications (as described in Section 9.2); 
 
Assessment of new or unresolved AEs/intercurrent illnesses; 
 
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); 
 
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 placebo; 
 
HIV infection assessment including pretest counseling. A subsequent follow-up 
contact is conducted to provide post-test counseling and to report results to 
participant; 
 
Laboratory tests, including: 
 
HIV diagnostic test,  

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 
CBC with differential and platelet count,  
 
Chemistry panel (ALT, AST, ALP, and creatinine), 
 
Urine dipstick (urinalysis if indicated, see Section 9.8), 
 
Urine or serum pregnancy test (volunteers who were born female); 
 
Risk reduction counseling (as described in Section 9.6); and 
 
Pregnancy prevention assessment (as described in Section 9.2 and 9.7). 
After eligibility has been confirmed, the participant may be randomized for Part B. 
9.3 
Enrollment and vaccination visits 
Enrollment is simultaneous with first vaccination. The time interval between 
randomization and enrollment should not exceed 4 working days. The HVTN CRS 
registers the participant by scheduling the day 0 visit (enrollment) via the Web-based 
randomization system, and requests the randomization assignment. Circumstances may 
require a participant’s enrollment visit to be changed. This may exceed the 4-day 
randomization time limit. 
At all vaccination visits, the following procedures are performed before vaccination: 
 
Abbreviated physical examination, including weight, vital signs, and a symptom-
directed evaluation by history and/or appropriate physical exam based on participant 
self-reported symptoms or complaints; 
 
Assessment of baseline reactogenicity parameters; 
 
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 born female). Persons who 
are NOT of reproductive potential due to having undergone total hysterectomy with 
bilateral oophorectomy (verified by medical records), are not required to undergo 
pregnancy testing. 
Following completion of all procedures in the preceding list and 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 postvaccination symptom log and is instructed on how to complete it. The site will 
make arrangements to obtain daily reports of reactogenicity events from the participant 
during the reactogenicity period (as described in Section 9.9). 

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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 9.6);  
 
Pregnancy prevention assessment (as described in Section 9.2 and 9.7); 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). 
Additional procedures will be performed at scheduled visits as specified in Appendix H 
and Appendix I:  
 
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 
 
Specimen collection, blood and/or mucosal (should be completed prior to 
vaccination) 
 
For participants entering Part B (see Appendix I): 
o Urine test or swab for gonorrhea and chlamydia; 
o Vaginal swab for Trichomonas and bacterial vaginosis (for participants providing 
cervical samples); 
o Vaginal swab (if indicated) for hyphae/budding yeast (for participants providing 
cervical samples); 
o Syphilis serology; and 
o 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 9.6);  
 
Pregnancy prevention assessment (as described in Section 9.2 and 9.7); 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 H and Appendix I:  

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 
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 placebo; 
 
Administration of behavioral risk assessment questionnaire; 
 
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; 
 
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); 
 
Clinical laboratory tests including: 
 
CBC with differential and platelet count, 
 
Chemistry panel (see Section 9.2), and 
 
Urine dipstick (urinalysis if appropriate; see Section 9.8). 
 
For participants entering Part B (see  Appendix I): 
 
Urine or serum pregnancy test (for participants who were born female). Persons 
who are NOT of reproductive potential due to having undergone total 
hysterectomy with bilateral oophorectomy (verified by medical records), are not 
required to undergo pregnancy testing. 
 
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. 
9.5 
Mucosal sampling 
Mucosal samples will be collected at the timepoints indicated in Appendix G and 
Appendix I from study participants who enter Part B under protocol Version 3.0. 

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Participants providing cervical, rectal, or semen samples will be tested for the following 
infections at visits specified in Appendix G and Appendix I: gonorrhea, chlamydia, and 
syphilis. Participants providing 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 born female, 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 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 born female): Participants who 
are 21 years of age and older must report having had a Pap smear within: 
 
the 3 years prior to sample collection with the latest result reported as normal or 
ASCUS (atypical squamous cells of undetermined significance), OR 
 
the 5 years prior to sample collection, 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 sample collection (or within the 
last 5 years, if high risk HPV testing was performed), the volunteer must have a Pap 
smear with the result reported as normal or ASCUS prior to sample collection. 
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 

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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. 
9.6 
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. 
All participants who become HIV infected during the study will be terminated from this 
study. Potential and enrolled participants identified as HIV infected will be referred for 

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medical treatment, counseling, and management of the HIV infection. These individuals 
may also be referred to appropriate ongoing clinical trials or observational studies. 
9.6.1 
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 H and 
Appendix I. 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 and Appendix G). The Laboratory Program (or approved diagnostic 
laboratory) will follow the HVTN HIV testing algorithm (as described in the HVTN 
100 Study Specific Procedures), 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).  
9.6.2 
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 9.6.1). 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. 
9.7 
Contraception status 
Contraception status is assessed and documented at every scheduled clinic visit for a 
participant who was born female 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 born female and is sexually active in a way that could cause that 

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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. 
9.8 
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. 
9.9 
Assessments of reactogenicity 
For all participants, baseline assessments are performed before and reactogenicity 
assessments are performed after each vaccination. All reactogenicity symptoms are 
graded according to the Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.1 [March 2017], except 
as noted in Section 11.2.2. 
The reactogenicity assessment period is 3 full days following each vaccination per the 
assessment schedule shown in Table 9-1. Participants are instructed to record symptoms 
using a postvaccination symptom log and to contact the site daily during the assessment 
period. Clinic staff will follow new or unresolved reactogenicity symptoms present at day 
3 to resolution. Participants are instructed to contact the clinic for events that arise during 
the period between vaccination and the next scheduled visit. In general, a participant who 
self-reports any postvaccination reaction greater than mild is seen by a clinician within 48 
hours after onset, unless the reaction is improving and/or has completely resolved.  
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, and lymph nodes. Events not listed on a CRF, or with 
an onset after the reactogenicity assessment period (day of vaccination and 3 full days 
after), or those meeting SAE/adverse events requiring expedited reporting to MCC 
criteria, are recorded on an adverse experience log form.  

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Table 9-1 Schedule of reactogenicity assessments 
Day 
Time 
Performed by 
0a 
Baseline: before vaccination 
HVTN CRS staff 
 
Early: 25-60 minutes after 
vaccination 
HVTN CRS staff 
 
Between early assessment and 
11:59pm day 0 
HVTN CRS staff or 
participant 
1 
Between 12:00am and 11:59pm day 
1 
HVTN CRS staff or 
participant 
2 
Between 12:00am and 11:59pm day 
2 
HVTN CRS staff or 
participant 
3b 
Between 12:00am and 11:59pm day 
3 
HVTN CRS staff or 
participant 
a Day of vaccination 
b New or unresolved reactogenicity symptoms present on day 3 are followed until resolution 
9.9.1 
Assessment of systemic and local symptoms 
Systemic symptoms include increased body temperature, malaise and/or fatigue, myalgia, 
headache, chills, arthralgia, nausea, and vomiting. Local symptoms include pain and/or 
tenderness proximal to the injection site. The daily maximum severity reached for each 
symptom during the assessment period is reported.  
Body temperature is measured by oral or infrared thermometry and reported in degrees 
Celsius. If temperature is measured in Fahrenheit, the conversion to Celsius should be 
documented in the participant’s chart note. A measurement is taken once daily during the 
assessment period and should be repeated if participant is feeling feverish. 
9.9.2 
Assessment of injection site 
Typical injection site reactions are erythema/induration/swelling/edema. The maximum 
horizontal and maximum vertical measurements for all injection site reactions are 
recorded. 
All injection site reactions are monitored until resolution. Areas greater than 25 cm2 are 
followed daily; otherwise, the frequency of follow-up is based on clinician judgment. 
9.9.3 
Assessment of lymph nodes 
This assessment is required only when reactogenicity assessments are performed by 
HVTN CRS staff, not by the participant. 
Only the proximally draining lymph nodes are assessed (eg, axillary nodes on the same 
side of the body for injections given in the deltoid). Lymph nodes are first evaluated for 
enlargement and tenderness. If they are found to be enlarged, measurements are taken to 
determine the size (widest diameter) of the enlarged node(s). 
9.10 
Visit windows and missed visits 
Visit windows are defined in HVTN 100 Study Specific Procedures. For a visit not 
performed within the window period, a Missed Visit form is completed. If the missed 

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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 7.4.2 and Section 7.4.3 for 
resolution. 
9.11 
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, platelet count, and chemistry panel), 
pregnancy testing, social impact assessment, and HIV test. 
9.12 
Pregnancy 
If a participant becomes pregnant during the course of the study, no more injections of 
study product will be given during the pregnancy, but remaining visits and study 
procedures should be completed unless medically contraindicated. For participants who 
are no longer pregnant, see Section 7.4.1. If the participant terminates from the study 
prior to the pregnancy outcome, the site should make every effort to keep in touch with 
the participant in order to ascertain the pregnancy outcome. 

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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. The manual includes 
guidelines for general specimen collection, special considerations for phlebotomy, 
specimen labeling, whole blood processing, HIV screening/diagnostic testing, and 
general screening and safety testing. 
Tube types for blood collection are specified in Appendix F and Appendix G. 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. 
10.2 
Total blood volume 
Required blood volumes per visit are shown in Appendix F and Appendix G. 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 timepoint 
The primary immunogenicity timepoint for Part A is at visit 10 (day 182) (ie, 2 weeks 
after the fourth vaccination visit) and for Part B at visit 19 (ie, 2 weeks after the sixth 
vaccination visit). Endpoint assays for humoral and cellular responses are performed on 
participants at the primary immunogenicity timepoint and may be performed at baseline. 
Depending on the number of responders observed in the primary and secondary 
endpoints, assays for humoral and cellular responses may be performed on participants at 
other timepoints; the schedule is shown in Appendix F and Appendix G. 
10.4 
Endpoint assays: humoral 
10.4.1 
HIV-1 multiplex Ab assay 
Total binding IgG and IgA Ab to HIV Env proteins contained in the vaccine regimen will 
be assessed on plasma/serum samples from study participants taken at the primary 
immunogenicity timepoint and baseline. In addition, binding to cross-clade Env proteins 
and IgG isotypes will be assessed. Specimens from other timepoints as well as other HIV 
antigens may also be assayed based on the results of the initial assay. Mucosal samples 
collected at the M30 and M30.5 visits (Visits 17 and 19) may also be evaluated using this 
assay. 

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10.4.2 
HIV-1 nAb assays 
HIV-1–specific nAb assays may be performed on serum samples from study participants 
taken at the primary immunogenicity timepoint. Specimens from the baseline and other 
timepoints may also be analyzed at the discretion of the HVTN Laboratory Program, 
which may be contingent on the results of the primary immunogenicity timepoint. Tier 1 
assays will test neutralization of HIV-1 strains represented in the highly neutralization-
sensitive tier 1 viruses. The tier 2 assays will test neutralization of a panel of heterologous 
primary isolates. 
10.5 
Endpoint assays: cellular 
10.5.1 
Flow cytometry 
Flow cytometry will be used to examine vaccine-specific CD4+ T-cell responses 
following stimulation of PBMCs with synthetic HIV peptides that span the proteins in the 
vaccine. Data for CD8+ T-cell responses will also be collected in the same assay. ICS 
parameters will include cytokines such as IFN-γ, interleukin 2 (IL-2), and tumor necrosis 
factor alpha (TNF-α), and may include other cytokines to identify T cells of specific 
functionality (such as Th2 and Th17). Data will be reported as percentages of CD4+ T 
cells responding to a specific peptide pool. Additional cell surface markers, cytokines, or 
functional markers may also be analyzed to assess additional T and B cell phenotypes. 
Phenotyping of T cells (eg, T follicular helper [Tfh]), B cells (eg, plasmablasts), dendritic 
cells, monocytes, natural killer (NK) cells, or other leukocytes may be performed for 
lineage, maturation, homing, and activation markers using PBMC samples. 
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 placebo recipients) may be HLA-typed to 
support future studies of immunological interest at the discretion of the HVTN 
Laboratory Program. Other markers, such as genes associated with immune responses or 
HIV-1 disease progression may also be assessed.  
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. 

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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.  
10.9 
Other use of stored specimens 
The HVTN stores specimens from all study participants indefinitely, unless a participant 
requests that specimens be destroyed or if required by IRB/EC, or RE. 
Other use of specimens is defined as studies not described in the protocol. 
This research may relate to HIV, vaccines, the immune system, and other diseases. This 
could include limited genetic testing and, potentially, genome-wide studies. This research 
is done only to the extent authorized in each study site’s informed consent form, or as 
otherwise authorized under applicable law. Other testing on specimens will occur only 
after review and approval by the HVTN, the IRB/EC of the researcher requesting the 
specimens, and the CRS’s IRBs/ECs if required. 
The protocol sample informed consent form is written so that the participant either 
explicitly allows or does not allow their samples to be used in other research when they 
sign the form. Participants who initially agree to other use of their samples may rescind 
their approval once they enter the study; such participants will remain in this study and 
their samples will only be used for the studies described in this protocol. If a participant 
decides against allowing other research using his or her samples, or at any time rescinds 
prior approval for such other use, the study site investigator or designee must notify 
HVTN Regulatory Affairs in writing. In either case, HVTN Regulatory Affairs directs the 
HVTN Lab Program not to use samples from these participants for such other uses.  
CRSs must notify HVTN Regulatory Affairs if institutional or local governmental 
requirements pose a conflict with or impose restrictions on other use of specimens. 
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 100 PSRT 
The HVTN 100 PSRT is composed of the following members: 
 
DAIDS medical officer representative, 
 
Protocol chair and cochair, 
 
Protocol Team leader, 
 
Core medical monitor,  
 
Regional medical liaison, and 
 
Clinical safety specialist. 
The clinician members of HVTN 100 PSRT listed above are responsible for decisions 
related to participant safety. 
A medical officer from an in-country organization designated by the study sponsor will 
also participate in the PSRT.  
The Protocol Team clinic coordinator, project manager, vaccine developer representative, 
clinical trial manager, and others may also be included in HVTN 100 PSRT meetings. 
11.1.2 
DSMB review of cumulative safety data 
The DSMB assesses the effects of the study vaccine during the trial and may give advice 
to the HVTN 100 Protocol Team.  
The DSMB will periodically review accumulating unblinded safety data by group. Prior 
to each meeting, the SDMC will provide the DSMB with data as described in Section 
6.4.5.1. Reports will be cumulative, generated from an up-to-date data file.  
Based upon the reports, the DSMB will determine whether to recommend that the study 
should be continued, modified, or stopped for safety reasons.  
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 100 PSRT 
and DSMB (see Section 11.1.2); 

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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 
100 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 100 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, concomitant medications) before the end of the next business day after 
receiving the information. The forms should not be held in anticipation of additional 
information at a later date. If additional information is received at a later date, the forms 
should be updated and refaxed before the end of the next business day after receiving the 
new information. 
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), Version 2.1 [March 2017], available on the RSC 
website at http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-
tables, except that:  
 
Unintentional weight loss is required to be reported as an adverse event only if it is 
considered to be deleterious to the participant’s health (see HVTN 100 SSP); 
 
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 (e.g., abscess, exfoliative 
dermatitis, necrosis involving dermis or deeper tissue); 

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Unsolicited AEs will be collected over 30 days post-each vaccination visit. All collected 
AEs are reported to the SDMC on the appropriate CRF. Clinic staff should evaluate every 
AE to determine if (1) the AE meets the requirements for expedited reporting to MCC 
(Section 11.2.3) and (2) if the AE meets the criteria for a safety pause/prompt AE review 
(Section 11.3). 
AEs leading to early participant withdrawal or early discontinuation of study product(s) 
administration will be collected and reported throughout the study. 
Sites are expected to notify the CSS of any serious safety concern requiring their 
attention (see Table 11-1). Telephone numbers and email addresses are listed in the Key 
Resource Guide of the HVTN 100 Study Specific Procedures. Concerns requiring 
immediate attention should be communicated by calling the clinical safety phone. 
In the case of email notification the CSS will reply during working hours (US Pacific 
Time) to confirm that the email has been received and reviewed. If email service is not 
available, the HVTN CRS should notify the CSS of the event by telephone, then submit 
CRFs. 
In addition, site investigators 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/MCC  
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. 
The internet-based DAIDS Adverse Experience Reporting System (DAERS) must be 
used for expedited AE reporting to DAIDS. In the event of system outages or technical 
difficulties, expedited AE reports may be submitted via the DAIDS EAE Form. This 
form is available 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 CRMSSupport@niaid.nih.gov or from 
within the DAERS application itself.  
For questions about expedited AE reporting, please contact the RSC 
(DAIDSRSCSafetyOffice@tech-res.com).  
An AE is considered to be an SAE by the most recent version of the MCC guidelines as 
described in Reporting Adverse Drug Reactions in South Africa 
(http://www.mccza.com/documents/ae9635a42.11_ADR_reporting_May03_v1_2.pdf), if 
it: 
 
results in death, 
 
is life-threatening, 
 
requires patient hospitalisation or prolongation of existing hospitalisation,  
 
results in persistent or significant disability/incapacity,  

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 
is a congenital anomaly/birth defect, or 
 
is a medically important event or reaction. 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
Medical and scientific judgment should be exercised when deciding 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 include blood dyscrasias or convulsions not resulting in hospitalization, or 
development of drug dependency or drug abuse. 
The sponsor or designee(s) prepares and files expedited reports to appropriate regulatory 
authorities and ECs within the timelines required by the South African MCC guidelines, 
which are detailed in Reporting Adverse Drug Reactions in South Africa, Version 1.2, 
December 2012.  
Any SAE that is considered unexpected and for which the contribution of the study 
products cannot be ruled out will qualify for expedited reporting to the South African 
Medicines Control Council (MCC). The expedited reporting period for this study 
comprises the entire study period for each individual participant (from study enrolment 
until study completion or discontinuation from the study).  
The study products that must be considered in determining relationships of AEs requiring 
expedited reporting to DAIDS and MCC are: 
 
ALVAC-HIV (vCP2438) 
 
Placebo for ALVAC-HIV (vCP2438)  
 
Bivalent Subtype C gp120/MF59® 
 
Placebo for Bivalent Subtype C gp120/MF59® 
Clinic staff will report SAEs as indicated in Section 11.3, Safety pause and prompt PSRT 
AE review to HVTN Core or within 3 working days for SAEs not described in Table 
11-1, AE notification and safety pause/AE review rules, in addition to completing the 
standard AE form.  
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 100 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 100 
PSRT, participant safety may be threatened. Criteria for an individual participant’s 
departure from the schedule of vaccinations are listed in Section 7.3. 

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Table 11-1 AE notification and safety pause/AE review rules 
Event and 
relationship to study 
products 
Severity 
HVTN CRS action 
HVTN Core action 
SAE, related 
Grade 5 or 
Grade 4 
Phone immediately, email 
and fax forms immediatelya 
Immediate pause 
SAE, not related 
Grade 5 
Phone immediately, email 
and fax forms immediatelya 
Immediate HVTN 100 
PSRT notification 
SAE, related 
Grade 3 
Email and fax forms 
immediately 
Prompt HVTN 100 PSRT 
AE review to consider 
pause 
AEb, related 
Grade 4 or 
Grade 3 
Email and fax forms 
immediately 
Prompt HVTN 100 PSRT 
AE review to consider 
pause 
a Phone numbers and email addresses are listed in HVTN 100 Study Specific Procedures, Key Resource Guide. 
b Does not include subjective reactogenicity symptoms (injection site pain, tenderness, fatigue/malaise, myalgia, arthralgia, chills, 
headache, and nausea). 
For all safety pauses, HVTN Core notifies the HVTN 100 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 
DSMB.  
Once a trial is paused, the HVTN 100 PSRT reviews safety data and decides whether the 
pause can be lifted or permanent discontinuation of vaccination is appropriate, consulting 
the DSMB if necessary. HVTN Core notifies the participating HVTN CRSs, HVTN 
Regulatory Affairs, DAIDS PAB, DAIDS RAB, and DAIDS SPT of the decision 
regarding resumption or discontinuation of study vaccinations. Based on the HVTN 100 
PSRT assessment, the trial sponsor or designee(s) notifies the South Africa MCC as 
needed. 
If an immediate HVTN 100 PSRT notification or prompt HVTN 100 PSRT AE review is 
triggered, HVTN Core notifies the HVTN 100 PSRT as soon as possible during working 
hours (US Pacific Time)—or, if the information was received during off hours, by the 
morning of the next work day. If a prompt HVTN 100 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 protocol-related safety 
information (such as IND safety reports, notification of vaccine holds due to the pause 
rules, 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 100 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. 

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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 the HVTN Core for events 
requiring expedited reporting, and events that meet safety pause criteria or prompt HVTN 
100 PSRT AE review criteria. 
11.4.2 
Weekly review 
During the injection phase of the trial, the HVTN 100 PSRT review clinical safety reports 
on a weekly basis and conduct 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 100 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 100 PSRT, MCC, 
NIH, Office for Human Research Protections (OHRP), or vaccine developer(s). In 
addition, the conduct of this study at an individual HVTN CRS may be terminated by the 
determination of the IRB/EC and any applicable RE. 

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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; 
 
Ancillary 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 100 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 DNA, it must comply 
with regulations set forth in the NIH’s Guidelines for Research Involving Recombinant 
DNA Molecules. Information about the study must be submitted to site Institutional 
Biosafety Committees (IBC) and must be approved before participants are enrolled at the 
site. Investigators at each site are responsible for obtaining IBC approval and periodic 
review of the research per NIH guidelines section IV-B07-b-(6) and section IV-B-2-b. 
IBC review and approval must be documented by the investigator and submitted as part 
of initial protocol registration for this trial. If this protocol is amended, investigators 
should follow the requirements of their IBC. 
12.3 
Specific regulatory considerations for South Africa 
South Africa has laws regarding the use, manufacture, importation, and experimentation 
of products which are genetically modified. These are contained in the Genetically 
Modified Organism (GMO) Act 15 of 1997, administered by the South African National 
Department of Agriculture, Pretoria. The Registrar of GMO shall be consulted on all 
formal developments relating to this protocol and clinical trial, and as required, a formal 
application will be made to the Registrar of GMO to review the HVTN 100 clinical trial, 
to obtain approval for the proposed clinical trial and for the importation of the study 
products. 
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 should 
contact the participant first, and then notify the IRB/EC and any applicable RE of the 
matter as soon as possible. 

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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 100 are described below. 
Protocol history and modifications 
Date: May 23, 2017 
Protocol version: Version 3.0 
Protocol modification: Full Protocol Amendment 2 
Item 1 
Revised: Vaccination and visit schedules 
Item 2 
Added: Mucosal secretion sampling 
Item 3 
Added to Part B visit schedule: One week post-vaccination visit 
Item 4 
Revised: Appendix B, Addendum to Sample informed consent form (for Part B) 
Item 5 
Revised in Appendix D, Tables of procedures (for sample informed consent forms): 
Part B procedure tables 
Item 6 
Revised in Appendix G, Laboratory procedures for Part B: Mucosal sampling, STI, 
testing, and follow-up duration 
Item 7 
Revised in Appendices F and G: Endpoint laboratory designations 
Item 8 
Corrected in Appendices F and G: Neutralizing antibody assay 
Item 9 
Revised in Appendix I, Procedures at HVTN CRS for Part B: Mucosal sampling, 
STI, testing, and follow-up duration 
Item 10 Removed in Section 8.2.2, Part B: Do not freeze instruction 
Item 11 Revised in Sections 8.3.1.2 and 8.3.2.2: Time limit within syringe for administration 
of ALVAC-HIV study product or placebo 
Item 12 Clarified in Section 9.1.2, Protocol-specific consent forms: Participants entering Part 
B 
Item 13 Removed in Section 9.2, Pre-enrollment procedures: Requirement to record generic 
medication names 
Item 14 Updated in Section 9.6.1: Reference for HVTN HIV testing algorithm 
Item 15 Updated in Section 9.9, Assessments of reactogenicity, Section 11.2.2, AE reporting 
and Section 14, Document references (other than literature citations): AE grading 
table version and exceptions 
Item 16 Updated in Section 10.1: Source for site lab instructions 
Item 17 Clarified in footnotes to Appendices G and I: Window for specimen collection prior 
to Part B vaccination 
Item 18 Removed in Appendix I: Confirmation HIV results provided to participant at Month 
36 study visit 

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Item 19 Clarified in Appendix I footnote “e”: Pregnancy test results required prior to 
vaccination 
Item 20 Added as Appendix J: Protocol signature page 
Item 21 Updated in Sections 3.1, 11.1.1, and 15: Protocol team 
Item 22 Updated throughout protocol: Literature reference numbering, cross-references, and 
document URLs 
Item 23 Updated per Clarification Memo 1 to Version 2.0: Part B visit numbering 
Item 24 Corrected per Clarification Memo 1 to Version 2.0: Behavioral risk assessment 
timepoints 
Item 25 Corrected per Clarification Memo 1 to Version 2.0: UW-VSL removed from 
Appendix G footnote 
Item 26 Updated in boxed text: Summary of revisions 
Item 27 Updated in Section 13: Version history 
Item 28 Minor typographical and formatting errors have been corrected throughout the 
protocol document 
Date: December 20, 2016 
Protocol version: Version 2.0 
Protocol modification: Clarification Memo 1 
Item 1 Updated in Appendices G and I : Visit numbering 
Item 2 Corrected in footnote 2 to Appendix G, Laboratory procedures for Part B: UW-VSL 
removed 
Item 3 Corrected in Appendix I, Procedures at HVTN CRS for Part B: Behavioral Risk 
Assessment timepoints 
Date: September 9, 2016 
Protocol version: Version 2.0 
Protocol modification: Full Protocol Amendment 1 
Item 1 
Added as HVTN 100, Part B: Evaluation of booster vaccinations at Months 24 and 
36 
Item 2 
Added following Title page: Brief amendment description 
Item 3 
Version 1.0 content marked Part A 
Item 4 
Updated in Section 3, Overview: Part B primary objectives, schema, participants 
description, study duration, and endpoint assay laboratories 
Item 5 
Updated in Section 3, Overview, Section 4.4.3, Choice of placebo, and Section 8.2, 
Study product formulation: ALVAC-HIV placebo in Part B 
Item 6 
Updated in Section 3.1, Protocol team: Team members and team roles 
Item 7 
Updated on Title page and in Section 3, Overview: Study product provider 
Item 8 
Added: Section 4.1.4, Rationale for Part B 
Item 9 
Updated in Section 4.2, ALVAC-HIV (vCP2438): Formulation and manufacture 

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Item 10 Updated in Section 4.3.4, Bivalent Subtype C gp120/MF59® for injection: Buffer 
quantities 
Item 11 Added in Section 4.5, Plans for future product development and testing: Potential 
impact of Part B results 
Item 12 Added in Section 4.6, Nonclinical studies and Section 4.6.3, Toxicity studies of HIV 
Env vaccines: Study AB20670 
Item 13 Added as new Section 4.7.1, HVTN 100 experience to date: Summary of interim 
HVTN 100 safety and immunogenicity results 
Item 14 Updated in Sections 4.7.2 through 4.7.5: Clinical experience 
Item 15 Updated in Section 4.8, Potential risks of study products and administration: Table 
4-14 
Item 16 Added in Section 5, Objectives and endpoints: Part B primary and secondary 
objectives and endpoints 
Item 17 Added in Section 6.1, Accrual and sample size calculations and Section 6.2, 
Randomization for Part B 
Item 18 Added as Section 7.3: Eligibility criterion for Part B 
Item 19 Added in Section 7.4.3, Discontinuing vaccination for a participant: 
Item 20 Updated in Section 8, Study product preparation and administration: 
Item 21 Added in Section 9, Clinical procedures: Part B clinical procedures 
Item 22 Updated in Section 10, Laboratory: Primary timepoints and cross-references to 
Laboratory procedures appendices 
Item 23 Update in Section 13: Version history 
Item 24 Updated in Section 14: Document references 
Item 25 Updated in Section 16: Literature cited 
Item 26 Added as Appendix B: Addendum to Sample informed consent form 
Item 27 Added to Appendix D, Tables of procedures (for sample informed consent forms): 
Part B table of procedures 
Item 28 Added as Appendix G: Laboratory procedures for Part B 
Item 29 Clarified in Appendix H: Unblinding 
Item 30 Added as Appendix I: Procedures at HVTN CRS for Part B 
Item 31 Corrected per Clarification Memo 1: Study day for visit 13 Part A Laboratory and 
CRS procedures Appendices 
Item 32 Clarified per Clarification Memo 2: Serum pregnancy tests prior to vaccination, 
screening HIV infection assessment, and provision of test results to participants 
Item 33 Updated per Clarification Memo 3: DAIDS AE Grading Table version 
Item 34 Clarified per Clarification Memo 4: Exceptions to AE reporting 
Item 35 Minor typographical and formatting errors have been corrected throughout the 
protocol document 

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Date: April 2, 2015 
Protocol version: Version 1.0 
Protocol modification: Clarification Memo 4 
Item 1 Clarified: Exceptions to Version 2.0 of the DAIDS AE Grading Table 
Date: February 26, 2015 
Protocol version: Version 1.0 
Protocol modification: Clarification Memo 3 
Item 1 Updated: References to DAIDS AE Grading Table 
Date: February 5, 2015 
Protocol version: Version 1.0 
Protocol modification: Clarification Memo 2 
Item 1 Clarified: Time limit for pregnancy tests prior to vaccination 
Item 2 Corrected in Appendix F, Procedures at HVTN CRS: Confirm HIV test results 
provided to participant at Visit 15 
Date: November 13, 2014 
Protocol version: Version 1.0 
Protocol modification: Clarification Memo 1 
Item 1 Corrected in Appendix E, Laboratory Procedures and Appendix F, Procedures at 
HVTN CRS: Study day for Visit 13 
Date: May 5, 2014 
Protocol version: 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. 
 
ABPI. Guidelines for Phase 1 Clinical Trials 2012 Edition Available at 
http://www.abpi.org.uk/our-work/library/guidelines/Pages/phase-1-trials-2012.aspx   
 
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   
 
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 
 
U.S. Department of Health and Human Services, National Institutes of Health, 
National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 
2.1 [March 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 
 
Reporting Adverse Drug Reactions in South Africa. Available at 
http://www.mccza.com/documents/ae9635a42.11_ADR_reporting_May03_v1_2.pdf 
 
Guidelines for Good Practice in the Conduct of Clinical Trials in Human 
Participants in South Africa. Available at 
http://www.mccza.com/documents/7c21ba77SA_GCP_guidelines_second_edition_2
006.pdf 
 
Republic of South Africa: National Contraception Clinical Guidelines. December 
2012. 
 
Ethics in Health Research: Principles, Processes and Structures (Second edition, 
2015), Department of Health, Republic of South Africa. Available at 
http://www.nhrec.org.za/docs/Documents/EthicsHealthResearchFinalAused.pdf  
 
Declaration of Helsinki (last updated October 2013), World Medical Association. 
Available at http://www.wma.net/en/30publications/10policies/b3/ 
 
Guidelines on Ethics for Medical Research: HIV Preventive Vaccine Research. 
Available at http://www.mrc.ac.za//ethics/ethicsbook5.pdf  
 
South Africa Genetically Modified Organism (GMO) Act 15 of 1997. Available at 
http://www.saflii.org/za/legis/num_act/gmoa1997286/  

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 
HVTN Certificate of Confidentiality. Accessible through the HVTN website. 
 
HVTN 100 Special Instructions. Accessible through the HVTN protocol-specific 
website. 
 
HVTN 100 Study Specific Procedures. Accessible through the HVTN protocol-
specific website. 
 
HVTN 100 Site Lab Instructions. Accessible through the HVTN protocol-specific 
website. 
 
HVTN Manual of Operations. Accessible through the HVTN website. 
 
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  
 
International Conference on Harmonisation (ICH) E6 (R1), Guideline for Good 
Clinical Practice: Section 4.8, Informed consent of trial subjects. Available at 
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html  
 
Participants’ Bill of Rights and Responsibilities. Accessible through the HVTN 
website. 
 
NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid 
Molecules (NIH Guidelines), April 2016. Available at 
http://osp.od.nih.gov/sites/default/files/resources/NIH_Guidelines.pdf  
 
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/documents/daids-sourcedocpolicy.pdf 
 
Title 21, Code of Federal Regulations, Part 50. Available at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=50 
 
Title 45, Code of Federal Regulations, Part 46. Available at 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html  
 
Immunization Action Coalition, Vaccines with Diluents: How to Use Them. 
Available at http://www.immunize.org/catg.d/p3040.pdf 
 
US Centers for Disease Control and Prevention. Vaccine Storage & Handling 
Toolkit, June 2016. Available at 
http://www.cdc.gov/vaccines/hcp/admin/storage/toolkit/storage-handling-toolkit.pdf  
See Section 16 for literature cited in the background and statistics sections of this 
protocol. 

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15 
Acronyms and abbreviations 
Ab 
antibody 
ADCC 
antibody-dependent cellular cytotoxicity 
ADCVI 
antibody dependent cellular viral inhibition  
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
ART 
antiretroviral therapy 
AST 
aspartate aminotransferase 
AVEG 
AIDS Vaccine Evaluation Group 
BAMA 
binding antibody multiplex assay 
β-HCG  
beta human chorionic gonadotropin 
BMI 
body mass index 
CAB 
Community Advisory Board 
CBC 
complete blood count 
CCID 
cell culture infectious dose 
CDC 
US Centers for Disease Control and Prevention 
CEF 
chick embryo fibroblast 
CFR 
Code of Federal Regulations 
CHIL 
Cape Town HVTN Immunology Laboratory 
CHO 
Chinese hamster ovary 
CI 
confidence intervals 
CoR 
correlate(s) of risk 
CPK 
creatine phosphokinase 
CRF 
case report form 
CRPMC 
NIAID Clinical Research Products Management Center 
CRS* 
clinical research site 
CSS 
Clinical safety specialist 
CTL 
cytotoxic T lymphocyte 
DAIDS 
Division of AIDS (US NIH) 
DHHS 
US Department of Health and Human Services 
DHVI 
Duke Human Vaccine Institute 
DOV 
discontinuation of vaccination 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
ELISA 
enzyme-linked immunosorbent assay 
ELISpot 
enzyme-linked immunospot 
EU 
European Union 
EMA 
European Medicines Agency 
FDA 
US Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 

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GCP 
Good Clinical Practice 
GEE 
generalized estimating equation 
GLP 
Good Laboratory Practice 
GM 
geometric mean 
GMO 
Genetically Modified Organism 
GMP 
Good Manufacturing Practice 
GPP 
Good Participatory Practice 
GSID 
Global Solutions for Infectious Diseases 
HBsAg 
hepatitis B surface antigen 
HCRISA 
Hutchinson Centre Research Institute of South Africa 
HCV 
hepatitis C virus 
HLA 
human leukocyte antigen 
HPTN 
HIV Prevention Trials Network 
HSML-NICD 
HIV Sero-Molecular Laboratory, National Institute for 
Communicable Diseases  
HVTN 
HIV Vaccine Trials Network 
IAC 
Immunization Action Coalition 
IB 
Investigator’s Brochure 
IBC 
Institutional Biosafety Committee 
ICH 
International Conference on Harmonisation 
ICS 
intracellular cytokine staining 
IFN-γ 
interferon gamma 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IL-2 
Interleukin 2 
IM 
intramuscular 
IN 
intranasal 
IRB 
Institutional Review Board 
ISS  
Istituto Superiore di Sanità 
IUD 
intrauterine device 
MAR 
missing at random 
MCAR 
missing completely at random 
MCC 
(South Africa) Medicines Control Council 
mcg 
microgram 
MedDRA Medical Dictionary for Regulatory Activities 
MMR 
measles, mumps, and rubella 
MOP 
Manual of Operations 
MUVAPRED 
Mucosal Vaccines for Poverty Related Diseases 
nAb 
neutralizing antibody 
NAEPP  
US National Asthma Education and Prevention Program  
NHP 
nonhuman primate 
NIAID 
(US) National Institute of Allergy and Infectious Diseases  

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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 
RSA 
Republic of South Africa 
RSC 
(DAIDS) Regulatory Support Center 
SAE 
serious adverse event 
SCHARP Statistical Center for HIV/AIDS Research and Prevention 
SDMC 
statistical and data management center 
SMB 
Safety Monitoring Board 
SPF 
specific pathogen free 
SPT 
(DAIDS) Safety and Pharmacovigilance Team 
TB 
tuberculosis 
TM 
transmembrane 
TNF-α 
tumor necrosis factor alpha 
VISP 
Vaccine induced seropositivity 
WBC 
white blood cells 
* 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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  82.   Gorse GJ, Patel GB, Mandava MD, Arbuckle JA, Doyle TM, Belshe RB. Cytokine 
responses to human immunodeficiency virus type 1 (HIV-1) induced by immunization 
with live recombinant canarypox virus vaccine expressing HIV-1 genes boosted by 
HIV-1(SF-2) recombinant GP120. Vaccine 2001;19:1806-19. 

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  83.   A study to test the safety of three experimental HIV vaccines. 
http://www.clinicaltrials.gov/ct2/show/NCT00000946?term=NCT00000946&rank=1. 
5-16-2012. Last accessed: 8-10-2012 
  84.   Evans TG, Keefer MC, Weinhold KJ, Wolff M, Montefiori D, Gorse GJ, Graham BS, 
McElrath MJ, Clements-Mann ML, Mulligan MJ, Fast P, Walker MC, Excler JL, 
Duliege AM, Tartaglia J. A canarypox vaccine expressing multiple human 
immunodeficiency virus type 1 genes given alone or with rgp120 elicits broad and 
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  85.   Clements-Mann ML, Weinhold K, Matthews TJ, Graham BS, Gorse GJ, Keefer MC, 
McElrath MJ, Hsieh RH, Mestecky J, Zolla-Pazner S, Mascola J, Schwartz D, Siliciano 
R, Corey L, Wright PF, Belshe R, Dolin R, Jackson S, Xu S, Fast P, Walker MC, 
Stablein D, Excler JL, Tartaglia J, Paoletti E, et al. Immune responses to human 
immunodeficiency virus (HIV) type 1 induced by canarypox expressing HIV-1MN 
gp120, HIV-1SF2 recombinant gp120, or both vaccines in seronegative adults. NIAID 
AIDS Vaccine Evaluation Group. J Infect Dis 1998;177:1230-46. 
  86.   Russell ND, Hudgens MG, Ha R, Havenar-Daughton C, McElrath MJ. Moving to human 
immunodeficiency virus type 1 vaccine efficacy trials: defining T cell responses as 
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  87.   Belshe RB, Gorse GJ, Mulligan MJ, Evans TG, Keefer MC, Excler JL, Duliege AM, 
Tartaglia J, Cox WI, McNamara J, Hwang KL, Bradney A, Montefiori D, Weinhold 
KJ. Induction of immune responses to HIV-1 by canarypox virus (ALVAC) HIV-1 and 
gp120 SF-2 recombinant vaccines in uninfected volunteers. NIAID AIDS Vaccine 
Evaluation Group. AIDS 1998;12:2407-15. 
  88.   Franchini G, Gurunathan S, Baglyos L, Plotkin S, Tartaglia J. Poxvirus-based vaccine 
candidates for HIV: two decades of experience with special emphasis on canarypox 
vectors. Expert Rev Vaccines 2004;3:S75-S88. 
  89.   Graham BS, Keefer MC, McElrath MJ, Gorse GJ, Schwartz DH, Weinhold K, Matthews 
TJ, Esterlitz JR, Sinangil F, Fast PE. Safety and immunogenicity of a candidate HIV-1 
vaccine in healthy adults: recombinant glycoprotein (rgp) 120. A randomized, double-
blind trial. NIAID AIDS Vaccine Evaluation Group. Ann Intern Med 1996;125:270-9. 
  90.   Gilbert PB, Chiu YL, Allen M, Lawrence DN, Chapdu C, Israel H, Holman D, Keefer MC, 
Wolff M, Frey SE. Long-term safety analysis of preventive HIV-1 vaccines evaluated 
in AIDS vaccine evaluation group NIAID-sponsored Phase I and II clinical trials. 
Vaccine 2003;21:2933-47. 
  91.   Kim JH, Pitisuttithum P, Kamboonruang C, Chuenchitra T, Mascola J, Frankel SS, 
DeSouza MS, Polonis V, McLinden R, Sambor A, Brown AE, Phonrat B, 
Rungruengthanakit K, Duliege AM, Robb ML, McNeil J, Birx DL. Specific antibody 
responses to vaccination with bivalent CM235/SF2 gp120: detection of homologous 
and heterologous neutralizing antibody to subtype E (CRF01.AE) HIV type 1. AIDS 
Res Hum Retroviruses 2003;19:807-16. 
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Tappero JW, Choopanya K. Randomized, Double-Blind, Placebo-Controlled Efficacy 

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Drug Users in Bangkok, Thailand. J Infect Dis 2006;194:1661-71. 
  93.   Lewis DJ, Huo Z, Barnett S, Kromann I, Giemza R, Galiza E, Woodrow M, Thierry-
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mutant of Escherichia coli heat labile toxin. PLoS One 2009;4:e6999. 
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Rosa SC, Sato A, Huang Y, Frey SE, Sato P, Donnelly J, Barnett S, Corey LJ. A 
trimeric, V2-deleted HIV-1 envelope glycoprotein vaccine elicits potent neutralizing 
antibodies but limited breadth of neutralization in human volunteers. J Infect Dis 
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non-response. Stat Med 1997;16:81-102. 
 

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Appendix A 
Sample informed consent form 
Title: A phase 1-2 randomized, double-blind, placebo-controlled clinical trial of clade C 
ALVAC-HIV (vCP2438) and Bivalent Subtype C gp120/MF59® in HIV-uninfected 
adults at low risk of HIV infection 
HVTN protocol number: HVTN 100 
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 a new HIV vaccine combination. HIV is the virus that causes AIDS. 
About 252 people will take part in this study at multiple sites. The researcher in charge of 
this study at this clinic is [Insert name of site PI]. The US National Institutes of Health 
(NIH) is 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 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. 
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 those who did not get the vaccine.  

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This study differs from the studies in which people who got the vaccine had a higher or 
lower risk of getting HIV. The study 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’s very important 
to avoid exposure to HIV during and after the study. We will tell you how to avoid HIV. 
4.  The study vaccines are experimental. 
The study uses 2 different vaccines. These are ALVAC-HIV (vCP2438) and bivalent 
gp120/MF59. From here on, we will call them ALVAC and Protein. These are 
experimental HIV 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. They were developed by Sanofi Pasteur and Novartis 
Vaccines and Diagnostics.  
The ALVAC vaccine is made out of canarypox virus. Canarypox virus infects birds but 
cannot grow in human cells. 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. 
A study in South Africa, HVTN 097, is giving a similar ALVAC vaccine to about 80 
participants. So far, no one has had serious health problems.  
The Protein vaccine has man-made pieces of a protein found on the outside of HIV. 
These protein pieces are mixed with an adjuvant called MF59. An adjuvant is something 
added to the vaccine to help the immune system respond better. MF59 has been included 
in flu vaccines licensed in many countries. It has also been included in other vaccines that 
have been given to over 50,000 people in clinical trials without causing any serious 
health problems.  
This combination of study vaccines has not been given to people before. However, 
similar ALVAC and Protein vaccines have been given to more than 10,000 people in 
clinical trials without causing any serious health problems. Also, over 300 people have 
received a similar combination of ALVAC and protein vaccines with the MF59 adjuvant 
in clinical trials without having any serious health problems. 
General risks of vaccines: 
Rarely, a vaccine can cause an allergic reaction, including a rash, hives, or difficulty 
breathing. Allergic reactions can be life-threatening. You should tell us if you have ever 
had a bad reaction to any injection or vaccine. 
All vaccines can cause fever, chills, rash, aches and pains, nausea, headache, dizziness, 
and feeling tired. Most people can still do their planned activities after getting a vaccine. 
Rarely, people experience side effects that limit their normal activities or make them go 
to the doctor. 
Very rarely, a vaccine causes an autoimmune disease in a person, or makes an 
autoimmune disease worse. An autoimmune disease happens when your immune 
system attacks your own body, instead of attacking an infection. 

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Risks of the study vaccines: 
In earlier studies with similar ALVAC and Protein vaccines, some people found it hard to 
move their arm for a short while after the injection(s). Also, some people felt tired or 
weakened, and some people had swollen lymph nodes. A small number of people had 
diarrhea after receiving the injections. An even smaller number had trouble sleeping, 
stomach pain, loss of appetite, an odd taste in their mouths, fainting, acne, eyelid 
swelling, or felt itching in the place on their arm where they got the injection. These 
problems usually happened within a couple of days of injection(s) and usually went away 
on their own within a few days. Not everyone has these problems. 
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 or HIV testing. 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 born female, we will test you for pregnancy. If you have had a complete 
hysterectomy (removal of the uterus and ovaries, verified by medical records), you 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.  

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We will review the screening results with you, and offer you counseling and referral if 
you need medical care. We will not pay for this medical care. The screening results may 
show you are not eligible to join the study, even if you want to.  
7. If you were born female and could become pregnant, you must agree to use birth 
control to join this study. 
Site: List approved birth control methods here if you do not want to hand out the separate 
Approved Birth Control Methods sheet. 
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 three 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. Site: Delete the preceding sentence if you include the birth 
control sheet in this consent form. If you join the study, we will test you for pregnancy at 
some visits, including before each study injection.  
Being in the study 
If you meet the study requirements and want to join, here is what will happen: 
8. You will come to the clinic for scheduled visits about 14 times over 18 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 lab or health issue. 
We may contact you after the study ends (for example, to tell you about the study 
results). 
9. We will give you [Site: Insert compensation] for each study visit you complete. 
This amount is to cover the costs of [Site: Insert text] 
Site: Insert any costs to participants (eg, birth control costs for female participants who 
could become pregnant). 
You do not have to pay anything to be in this study. 
10. We will give you either the study vaccines or placebos.  
Not everyone in this study will get the study vaccines. Some people will get placebos 
(non-vaccine). The ALVAC placebo has all the same ingredients as the vaccine but no 
HIV-related pieces. The Protein placebo is sterile salt water. We will compare the results 
from people who got the placebos with results from people who got the study vaccines.  

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You have a 5-in-6 chance of receiving the study vaccines. 
Site: Modify the randomization metaphor in the paragraph below as appropriate to your 
local culture. 
Whether you get the study vaccines or the placebos is completely random, like flipping a 
coin.  
The clinic staff have no say in whether you get the study vaccines or the placebos. They 
will not know which one 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 whether 
you got the study vaccines or the placebos. This could be several 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. 
11. We will give you the study products on a schedule. 
You will be in one of 2 groups. You will get 8 injections into the upper arms during the 
study. At some visits you will get one injection. At other visits, you will get two 
injections. The ALVAC vaccine or its placebo will go into the left arm. The Protein 
vaccine or its placebo will go into the right arm. 
 
You will have to wait in the clinic for about a half hour after each injection to see if there 
are any problems. Then for that night and for three more days, you will need to write 
down how you are feeling and if you have any symptoms. Contact the clinic staff 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. 

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12. 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; 
 
Perform physical exams; 
 
Take blood and urine samples; 
 
Do pregnancy tests if you were born female (If you have had a complete 
hysterectomy [removal of the uterus and ovaries, verified by medical records], you 
are not required to have pregnancy tests.); 
 
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. 
When 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 (a little less than 3 teaspoons to a little less 
than ¾ cup). Your body will make new blood to replace the blood we take out.  
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: Paste table of procedures in this section or distribute it as a separate sheet if it is 
helpful to your study participants. 
We will review the results of these procedures and tests with you at your next visit, or 
sooner if necessary. We will also offer you counseling and referral for needed care. 
13. We will counsel you on avoiding HIV infection.  
We will ask you personal questions about your HIV risk factors such as sexual behavior 
and drug use. We will talk with you about ways to keep your risk of getting HIV low. 
Some topics we may discuss include:  
 
What you think may cause risky behavior for you.  
 
Methods to avoid getting HIV.  
These may include not having sex, using condoms, or behavior changes, such as cutting 
down on alcohol. We will talk with you about which methods of HIV prevention may be 
right for you. 
14. We will test your samples for this study. 
We will send your samples (without your name) to a lab to see how your immune system 
responds to the study products. The researchers may:  

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 
Take cells from your samples and grow more of them. We may grow more of your 
cells over time, so that they can continue to contribute to this study.  
 
Do limited genetic testing. 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. Limited 
genetic testing involves only some of your genes, not all of your genes (your 
genome). The researchers will not look at all of your genes, only the genes related to 
the immune system and diseases. 
These tests are for research purposes only. The lab will not give the results to you or this 
clinic, and the results will not become part of your study record.  
Most of these tests will be done in labs in South Africa. Some blood samples may be 
shipped to US labs for testing. 
Site: Delete next section if using separate consent for use of samples and information in 
other studies  
15. When we take samples from you for this study, we take extra samples in case we 
have to repeat tests. When samples are no longer needed for this study, the HVTN 
wants to keep them for use in other studies. We will call these “extra samples.” 
This section gives you information so you can decide if you want your extra samples and 
information used in other studies. You will mark your decision at the end of the 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: insert specific information if your regulatory authority requires it.] The 
central repositories for the HVTN are located in the United States and South Africa. 
While most of your samples will be stored in South Africa, some may be shipped to the 
US for some tests, including genetic tests. 
How long will the samples be stored? There is no limit on how long your extra samples 
will be stored. [Site: 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 needed for your medical care. 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 other researchers. Once we share your samples and information, we will 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/or 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: insert review by your institution’s IRB/EC, if applicable.] 
IRBs/ECs protect the rights and well-being of people in research. The HVTN keeps track 
of your decision about how your samples and information can be used.  
What information is shared with other researchers? The samples and limited 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.  
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. The researchers 
may: 
 
Take cells from your samples and grow more of them. This means the researchers 
may keep your cells growing over time.  
 
Do limited genetic testing, which involves only looking at some of your genes, not all 
of your genes. 
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. 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. 
Who will have access to my information in studies using my extra samples?  
People who may see your information are: 
 
Researchers who use your stored samples and limited information for other research 
 
Government agencies that fund or monitor the research using your samples or 
information 
 
The researcher’s Institutional Review Board or Ethics Committee 
 
The people who work with the researcher  

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All of these people will do their best to protect your information. The results of any new 
studies that use your extra samples or information may be published. No publication will 
use your name or identify you personally. 
16. We will do our best to protect your private information. 
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. 
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 NIH, its study monitors, and its chosen South African representatives, 
 
[Insert name of local IBC], 
 
[Insert name of local IRB/EC] , 
 
The South African Medicines Control Council, 
 
Sanofi Pasteur and Novartis Vaccines and Diagnostics and people who work for 
them, 
 
The HVTN and people who work for them,  
 
The Data and Safety Monitoring Board, and 
 
The US Office for Human Research Protections. 
All reviewers will take steps to keep your records private. 

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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] 
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. 
17. 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 
additional injections.  
This may happen if: 
 
you do not follow instructions, 
 
the researcher thinks that staying in the study might harm you, 
 
you get HIV, 
 
you enroll in a different research study where you receive 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. 
18. We will stop your injections if you become pregnant during the study.  
We will encourage you to stay in the study if you choose. The clinic staff 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. 
19. If you get infected with HIV during the study, we will help you get care and support. 
You will not be able to stay in this study. 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 

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care, and about other studies you may want to join. We will not provide or pay for any of 
your HIV care directly.  
Other risks 
20. 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, muscle damage, and (rarely) infection where the needle was inserted. 
Taking blood can cause a low blood cell count (anemia), making you feel tired. 
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 an HIV study vaccine. 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 
provide you with 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. 
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.  
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 (outside 
of South Africa). 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 

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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. 
Site: Modify the preceding paragraph if applicable.  
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. If the baby continues to have VISP, we can do this testing for 
free for as long as it is needed. 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.  
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: 
The genetic testing 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.  
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. It could be that a future HIV vaccine may not work as well for 

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you because you got the study vaccines. 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 
21. 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. 
Your rights and responsibilities 
22. 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 
23. 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 
24. If you get sick or injured during the study, contact us immediately. 
Your health is important to us. We will help you get the medical care you need. 
We call an injury or illness study-related if it occurs as a direct result of the 
administration of the study products or study-related procedures. The clinic staff will 
treat you for study-related problems or tell you where you can get the treatment you need. 
If a study-related injury occurs you have not waived any of the legal rights which you 
otherwise would have as a participant in this study by signing this form. 

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If you get sick or injured because of the study vaccines, insurance has been purchased to 
cover your medical treatment. This policy will follow the guidelines for payment of 
study-related illness or injury approved by the Association of the British Pharmaceutical 
Industry (“ABPI Guidelines”). You can get a copy of these ABPI Guidelines from us if 
you wish.  
Some injuries are not physical. For example, someone might be harmed psychologically 
or emotionally by being in an HIV vaccine study. Or they might lose wages from injuries 
because they could not go to work. No funds have been set aside to pay for nonphysical 
injuries, even if they are related to participation in the study. 
You, your usual health care provider and/or your health insurance carrier will continue to 
be responsible for the cost of your usual medical care outside this study, and for medical 
expenses that are determined not directly related to study procedures or products.  
Questions  
25. 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  
26. In Section 15 of this form, we told you about possible other uses of your extra 
samples and limited information, outside this study. Please write your initials or 
make your mark in the box next to the option you choose. 
 

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I allow my extra samples combined with limited information to be used for other studies 
related to HIV, the immune system, and other diseases. This may include limited genetic 
testing and keeping my cells growing over time.  
 OR 
 
 
I agree to the option above and also to allow my extra samples combined with limited 
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 
limited genetic testing, growing more of my cells, or genome-wide studies. 
27. 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 consent process. 
 

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Appendix B 
Addendum to Sample informed consent 
form (for Part B) 
Title: A phase 1-2 randomized, double-blind, placebo-controlled clinical trial of clade C 
ALVAC-HIV (vCP2438) and Bivalent Subtype C gp120/MF59® in HIV-uninfected 
adults at low risk of HIV infection 
HVTN protocol number: HVTN 100 
Site: [Insert site name] 
Thank you for your participation in the HVTN 100 study. Please read this consent form 
or ask someone to read it to you. The study staff will talk with you about the information 
in it. You are free to ask questions at any time. 
The HIV Vaccine Trials Network (HVTN) and [Insert site name]  are continuing HVTN 
100 by adding a second part to the study with more clinic visits and injections. We will 
now call the first part of the study that you were in Part A, and we will call the second 
part of the study Part B. We are inviting you to join Part B because you have participated 
in the HVTN 100 study already.  
The body’s immune response to vaccines gets weaker as time passes. For this reason, 
most vaccines need to be given again to build up the immune responses again. This is 
called “boosting.” We want to learn about how the body responds to boosting with the 
study vaccines.  
If you decide to continue in 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.  
Review of study information 
The study is testing 2 experimental vaccines. One is ALVAC-HIV (vCP2438) and we 
call it the ALVAC vaccine. The other is Bivalent Subtype C gp120/MF59 and we call it 
the Protein vaccine. There is also a placebo of sterile salt water in this study.  
The study was designed to look at 3 main 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 the study vaccines? (Your immune 
system protects you from disease.) 
The study opened on 2 February 2015. On 26 May 2015 the study was fully enrolled with 
252 participants.  

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New information about the study vaccines 
All study injections were complete by 2 June 2016. As of July 2016, about 225 
participants were still in the study.  
In the Part A consent form, we told you that the Protein vaccine was developed by 
Novartis Vaccines and Diagnostics and that this company may review your study records. 
The Protein vaccine is now owned by GlaxoSmithKline (GSK). This means that GSK 
may review your study records, not Novartis. 
In Part A, the study products 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 were severe in 4 participants (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.  
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. We will not know this until part B is complete. 
So far the study vaccines have produced the immune responses we hoped to see. We 
don’t know yet if the study vaccines will protect people from HIV. A larger study is 
being started to answer that question. 
Part B of the study 
We are continuing the study to learn how well boosting the study vaccines improves 
immune responses. About 72 participants will be enrolled in Part B of the study. 
It is completely up to you whether or not to continue in the study. If you decide not to 
continue, or if you leave it after you have agreed to continue, your other care at this clinic 
and the benefits or rights you would normally have will not be affected. 
If you decide to continue in Part B of the study, we will check to make sure you are 
eligible. This involves: 

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 
A brief physical exam 
 
An HIV test 
 
Blood and urine tests 
 
Questions about medications you are taking 
 
Questions about any problems you may have experienced from being in the study 
 
 Questions about any HIV testing you have had outside the study 
 
A pregnancy test if you were born female. 
We will review the test results with you, and offer you counseling and referral if you 
need medical care. We will not pay for this medical care. The screening results may show 
you are not eligible to join Part B of the study, even if you want to.  
Also, to be in Part B of the study, you must be willing to give samples of your rectal 
fluids and also cervical fluid or semen. The collection procedures are described below. 
Being in Part B of the study 
If you are eligible and want to join Part B, here is what will happen: 
You will come to the clinic for scheduled visits about [#] times over 6 months. 
Site: Insert number of visits and range of visit lengths. (There is site-specific variation 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 lab or health issue. 
At these study visits, we will do the same things we did at the study visits in Part A. We 
will review with you the consent form for Part A. The information in it about what we 
will do at study visits remains correct.  
Site: Paste table of procedures for Part B (Appendix D) in this section or distribute it as 
a separate sheet if it is helpful to your study participants. 
We will give you [Site: Insert compensation] for each study visit you complete. This 
amount is to cover the costs of [Site: Insert text] 
Site: Insert any costs to participants (eg, birth control costs for female participants who 
could become pregnant). 
You do not have to pay anything to be in Part B. 
If you were born female and could become pregnant, you will need to continue using 
birth control in Part B of the study. 

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In Part A, the clinic staff did not know whether you got the study vaccines or the placebo, 
and neither did you. It will be the same in Part B. Only the pharmacist at your site will 
have this information while the study is going on. 
In Part A, we told you that you would have to wait until everyone completed their final 
study visits to find out which study products you got. Because we are continuing this 
study, we will not tell you which study products you got in Part A until after everyone in 
Part B completes their final study visits. This could be several more years. If you have a 
serious medical problem and need to know what you got before the end of Part B, we can 
tell you. 
In Part B you will get 2 injections into the upper arms. The ALVAC vaccine or its 
placebo will go into the left arm. The Protein vaccine or its placebo will go into the right 
arm. 
People who got the study vaccines in Part A will get one or both of the study vaccines in 
Part B.  
 
Some will get the ALVAC vaccine and the Protein vaccine.  
 
Some will get the Protein vaccine and placebo.  
 
Some will get placebos. 
People who got placebos in Part A will continue to get placebos in Part B.  
When we take blood, the amount will depend on the lab tests we need to do. It will be 
some amount between 20 mL and 220 mL (about 1½ tablespoons to a little less than 1 
cup). Your body will make new blood to replace the blood we take out.  
Sampling of rectal fluid and 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 especially want to see whether the 
immune system makes antibodies in these parts of the body.  
Collecting rectal fluid along with cervical fluid (if you were born female) or semen (if 
you were born male) is required in Part B of this study. If you do not want to give these 
samples, you cannot join Part B of the study.  
We will collect these samples 2 times:  at your injection visit and at the visit 2 weeks 
after the injection visit.  
When we collect these samples, we will test you for gonorrhea, chlamydia, and syphilis. 
And if you were born female, 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 this 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. 

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Rectal fluid 
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 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 (a small flexible plastic cup, 
shaped like a bell) to insert into your vagina. We will explain how to insert and remove 
the cup, or we can do it for you here. 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: 
 
Do not have sex, including oral sex; 
 
Do not ejaculate; 
 
Do not use anything with lubricants; 
 
Do not put saliva on your 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.  
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.  
New information about testing your samples 
In Part A, we told you that we will send your samples (without your name) to a lab to see 
how your immune system responds to the study products. We said that the researchers 
may do limited genetic testing on your samples. Limited genetic testing involves only 
some of your genes, not all of your genes (your genome).   
We are now adding the following information about the use of your samples in this study: 
If you become HIV infected, the researchers may look at all the genes of the virus found 
in your samples. The researchers will use this information to learn more about HIV and 
the study products. The researchers may put this information about the virus into a 
protected database so that other researchers can access it. They would not be able to link 
the information from your samples to you. 
Use of your samples in other studies 
When you joined Part A, you signed a separate consent form about using your extra 
samples and information in other studies. The information in that consent form still 
applies to your samples and information from Part B. In that consent form you told us 
whether or not you allowed use of your samples and information in other studies. We will 
continue to follow your decision in that consent form unless you tell us you have changed 
your mind. We can review it with you if you would like.  
Other information 
The rest of the information in the consent forms you signed when you joined Part A has 
not changed. This includes: 

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 
the information about study procedures,  
 
birth control,  
 
stopping your injections,  
 
the risks and benefits of being in the study,  
 
your rights and responsibilities,  
 
how your privacy is protected,  
 
how study-related injuries would be handled and whom to contact if you have 
questions or problems during the study.  
Questions  
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 or title 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 or title and telephone number of the investigator or other study staff]. 
This study has been reviewed and approved by a committee called the 
[name of local IRB/EC]. 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 or title and telephone number of person on IRB or other appropriate organization], 
at the committee. 
The study has been structured in accordance with the Declaration of Helsinki (last 
updated October 2013) which deals with the recommendations guiding doctors in 
biomedical research involving human participants, the Ethics in Health Research: 
Principles, Structures and Processes, Second Edition 2015, and Guidelines for Good 
Practice in the Conduct of Clinical Trials in Human Participants in South Africa. We can 
provide you with copies of these guidelines if you wish to review them. 
If you want to leave this study, contact 
[name or title and telephone number of the investigator or other study staff]. 
You can reach a study staff member 24-hours a day at [telephone number]. 
If you have questions about this trial you should first discuss them with your doctor or the 
ethics committee (contact details as provided on this form). After you have consulted 
your doctor or the ethics committee and if they have not provided you with answers to 
your satisfaction, you should write to the South African Medicines Control Council 
(MCC) at: 
 
The Registrar of Medicines 

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Medicines Control Council 
Department of Health 
Private Bag X828 
PRETORIA 
0001 
 
Fax: (012) 395 9201 
e-mail: gouwsj@health.gov.za  
Your permissions and signature  
If you agree to continue in Part B of 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 continue. 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 provide rectal fluid samples. 
 
If you were born female, you agree to provide cervical fluid samples. 
 
If you were born male, you agree to provide semen samples. 
 
You agree to continue in 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 consent process. 
 

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Appendix C 
Approved birth control methods (for sample 
informed consent form) 
You should not become pregnant during the study because we do not know how the study 
vaccines could affect the developing baby.  
If you were born female and are sexually active in a way that could lead you to get 
pregnant, 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 means using any of the following methods every time you have 
sex: 
 
Male or female condoms; or, 
 
Diaphragm or cervical cap; 
PLUS 1 of the following methods: 
 
Birth control drugs that prevent pregnancy—given by pills, 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 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, you need to use male or female condoms to protect 
yourself from HIV infection. 

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Appendix D 
Tables of procedures (for sample informed 
consent forms) 
Part A 
 
 
 
 
Time after 1st injection visit (in months) 
Procedure 
Screening 
visit(s) 
First 
injection visit 
½ 
1 
1.5 
2 
3 
3.5 
6 
6.5 
9 
12 
12.5 
15 
18 
Injection 
 
√ 
 
√ 
 
 
√ 
 
√ 
 
 
√ 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
Brief physical 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Urine test 
√ 
 
√ 
 
 
 
 
 
 
√ 
 
 
√ 
 
 
Blood drawn 
√ 
√ 
√ 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Pregnancy test 
(participants born 
female)* 
√ 
√ 
 
√ 
 
 
√ 
 
√ 
 
 
√ 
 
√ 
 
HIV testing and pretest 
counseling 
√ 
 
 
 
 
 
√ 
 
√ 
 
√ 
√ 
 
√ 
√ 
Risk reduction 
counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Interview/questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
* Persons who have had a complete hysterectomy (removal of the uterus and ovaries, verified by medical 
records), are not required to have a pregnancy test. 
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.  
Part B  
 
 
 
 
Time after enrollment in 
Part A (in months) 
Procedure 
Eligibility 
visit(s) 
30 
30.25 
30.5 
36 
Injection 
 
√ 
 
 
 
Complete physical 
 
 
 
 
√ 
Brief physical 
√ 
√ 
√ 
√ 
 
Urine test 
√ 
 
 
√ 
 
Blood drawn 
√ 
√ 
√ 
√ 
√ 
Pregnancy test (participants born female)* 
√ 
√ 
 
√ 
√ 
HIV testing and pretest counseling 
√ 
√ 
 
 
√ 
Risk reduction counseling 
√ 
√ 
√ 
√ 
√ 
Questions/questionnaire 
√ 
√ 
√ 
√ 
√ 
Mucosal sampling  
 
√ 
 
√ 
 
Sexually transmitted infection (STI) testing 
 
√ 
 
√§ 
 
* Persons who have had a complete hysterectomy (removal of the uterus and ovaries, verified by medical 
records), are not required to have a pregnancy test. 
§ STI testing only if the participant has new STI symptoms since the month 30 visit. 
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.  
 

HVTN 100 Version 3.0 / May 23, 2017 
HVTN100_v3.0_FINAL.docx / Page 145 of 154 
Appendix E 
Sample consent form for use of samples and 
information in other studies 
Title: A phase 1-2 randomized, double-blind, placebo-controlled clinical trial of clade C 
ALVAC-HIV (vCP2438) and Bivalent Subtype C gp120/MF59® in HIV-uninfected 
adults at low risk of HIV infection 
HVTN protocol number: HVTN 100 
Site: [Insert site name] 
When samples are no longer needed for this study, the HVTN wants to keep them for use 
in other studies. We will call these “extra samples.” 
This form gives you information so you can decide if you want your extra samples and 
information used in other studies. You will mark your decision at the end of the 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: insert specific 
information if your regulatory authority requires it.] The central repositories for the 
HVTN are located in the South Africa and in the United States.  
While most of your samples will be stored in South Africa, some may be shipped to the 
US for some tests, including genetic tests. 
3. How long will the samples be stored?  
There is no limit on how long your extra samples will be stored. [Site: 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 needed for your medical care. They are not part of your medical 
record. The studies are only being done for research purposes. 

HVTN 100 Version 3.0 / May 23, 2017 
HVTN100_v3.0_FINAL.docx / Page 146 of 154 
6. Will the HVTN sell my samples and information?  
No, but the HVTN may share your samples with other researchers. Once we share your 
samples, we will 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/or 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: insert review by your institution’s 
IRB/EC, if applicable.] IRBs/ECs protect the rights and well-being of people in research. 
The HVTN keeps track of your decision about how your samples and information can be 
used.  
8. What information is shared with other researchers?  
The samples and limited 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. The 
researchers may: 
 
Take cells from your samples and grow more of them. This means the 
researchers may keep your cells growing over time.  
 
Do limited genetic testing, which involves only looking at some of your genes, 
not all of your genes. 
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. 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. 
10. What are the risks of limited genetic testing?  
The genetic testing 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.  

HVTN 100 Version 3.0 / May 23, 2017 
HVTN100_v3.0_FINAL.docx / Page 147 of 154 
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 stored samples and limited information for other 
research 
 
Government agencies that fund or monitor the research using your samples or 
information 
 
The researcher’s IRB or EC 
 
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 or 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 and telephone number of the investigator or other study staff]. 
If you think you may have been harmed because of studies using your samples or 
information, contact [name and telephone number of the investigator or other study staff]. 
If you have questions about your rights as a research participant, contact 
[name/title/phone of person on IRB or other appropriate organization]. 
13. Please write your initials or make your mark in the box next to the option you 
choose. 
 
 
I allow my extra samples combined with limited information to be used for other 
studies related to HIV, the immune system, and other diseases. This may include 
limited genetic testing and keeping my cells growing over time.  
 OR 
 
 
I agree to the option above and also to allow my extra samples combined with limited 
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 limited genetic testing, growing more of my cells, or genome-wide studies.  
 

HVTN 100 Version 3.0 / May 23, 2017 
HVTN100_v3.0_FINAL.docx / Page 148 of 154 
 
 
 
 
 
 
 
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 consent process. 

HVTN 100 Version 3.0 / May 23, 2017 
HVTN100_v3.0_FINAL.docx / Page 149 of 154 
Appendix F 
Laboratory procedures for Part A 
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Day:
D0
D14
D28
D42
D56
D84
D98
D168
D182
D273
D364
D378
D455
D546
Weeks
W0
W2
W4
W6
W8
W12
W14
W24
W26
W39
W52
W54
W65
W78
Month
M0
M0.5
M1
M1.5
M2
M3
M3.5
M6
M6.5
M9
M12
M12.5
M15
M18
ALVAC
ALVAC
ALVAC+prot
ALVAC+prot
ALVAC+prot
Procedure
Ship to1
Assay location2
Tube 
Type4
Tube size          
(vol. capacity)4
placebo
placebo
placebo
placebo
placebo
Total
BLOOD COLLECTION
Screening/Diagnostic
Screening HIV test
Local lab
Local lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
HBsAg/anti-HCV/Syphilis
Local lab
Local lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
HIV in-study diagnostic test9
HMSL-NICD
HSML-NICD
EDTA
10mL
—
—
—
—
—
—
10
—
10
—
10
10
—
10
20
70
Safety labs
CBC/ Diff/ platelets
Local lab
Local lab
EDTA
5mL
5
—
5
—
5
—
—
5
—
5
—
—
5
5
—
35
Chemistry panel5
Local lab
Local lab
SST
5mL
5
—
5
—
5
—
—
5
—
5
—
—
5
5
—
35
Immunogenicity & Virologic assays 6
HLA host genetics 7
BARC
HVTN Labs
ACD
8.5mL
—
17
—
—
—
—
—
—
—
—
—
—
—
—
—
17
Cellular assays
ICS
BARC
HVTN Labs
ACD
8.5mL
—
85
—
—
85
—
—
85
—
85
—
85
85
—
85
595
Humoral assays
Binding Ab Assay
BARC
HVTN Labs
SST
8.5mL
—
8.5
—
—
8.5
—
—
8.5
—
8.5
—
8.5
8.5
8.5
8.5
68
Neutralizing Ab Assay
BARC
HVTN Labs
SST
8.5mL
—
y
—
—
y
—
—
y
—
y
—
y
y
y
y
0
Storage
PBMC
BARC
ACD
8.5mL
—
59.5
—
—
59.5
—
—
59.5
—
59.5
—
59.5
59.5
—
59.5
417
Serum
BARC
SST
8.5mL
—
17
—
—
17
—
—
17
—
17
—
17
17
17
17
136
Visit total
20
187
10
0
180
0
10
180
10
180
10
180
180
46
190
1383
56-Day total
20
207
217
217
397
377
190
370
10
190
10
180
360
46
190
URINE COLLECTION
Urinalysis
Local lab
Local lab
X
—
X
—
—
—
—
—
—
X
—
—
X
—
—
Pregnancy Test8
Local lab
Local lab
X
X
—
X
—
—
X
—
X
—
—
X
—
X
—
Screening 
visit3
 
1 BARC = Bio Analytical Research Corporation South Africa (Pty) Ltd. (Johannesburg, South Africa); HSML-NICD = HIV Sero-Molecular Laboratory–National Institute for Communicable Diseases (Johannesburg, South Africa) 
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 Human Vaccine Institute, 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 9.4 (postenrollment). 
 
6 Immunogenicity assays will be performed at M0 (for binding Ab assay) and M6.5. 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 Pregnancy tests may be performed on blood specimens. 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. 
9At an early termination visit for a withdrawn or terminated participant (see Section 9.11), blood should be drawn for HIV diagnostic testing, as shown for visit 15 above.  
y = SST blood collected for binding Ab assays and serum storage will also cover specimen needs for neutralizing Ab assays; no separate blood draw is needed. 
 
 

HVTN 100 Version 3.0 / May 23, 2017 
HVTN100_v3.0_FINAL.docx / Page 150 of 154 
Appendix G 
Laboratory procedures for Part B 
Visit:
16
1714
18
19
20
Day:
D910
D917
D924
D1092
Weeks:
W130
W131
W132
W156
Month:
M30
M30.25
M30.5
M36
Procedure
Ship to1
Assay location2
Tube 
Type4
Tube size                (vol. 
capacity)4
Total
BLOOD COLLECTION
Diagnostic
HIV diagnostics 8
HSML-NICD
HSML-NICD
EDTA
10mL
10
10
—
—
208
40
Safety labs
CBC/ Diff/ platelets
Local lab
Local lab
EDTA
5mL
5
—
—
5
—
10
Chemistry panel5
Local lab
Local lab
SST
5mL
5
—
—
5
—
10
STI Serology
Syphilis10
Local lab
Local lab
SST
5mL
—
5
—
513
—
10
Immunogenicity & Virologic assays 6
Cellular assays
ICS
BARC
HVTN Labs
ACD
8.5mL
—
59.5
—
59.5
85
204
pTfh and plasmablasts
BARC
HVTN Labs
ACD
8.5mL
—
42.5
42.5
—
—
85
Humoral assays
Binding Ab Assay
BARC
HVTN Labs
SST
8.5mL
—
8.5
—
8.5
8.5
26
Neutralizing Ab Assay
BARC
HVTN Labs
SST
8.5mL
—
y
—
y
y
0
Storage
PBMC
BARC
ACD
8.5mL
—
59.5
—
59.5
59.5
179
Plasma
BARC
ACD
8.5mL
—
—
z
—
—
0
Serum
BARC
SST
8.5mL
—
17
—
17
17
51
Visit total
20
202
43
160
190
614
56-Day total
20
222
265
424
190
URINE COLLECTION
Urinalysis
Local lab
Local lab
X
—
—
X
—
Pregnancy Test7
Local lab
Local lab
X
X
—
X9
X
Chlamydia/Gonorrhea10
Local lab
Local lab
—
X
—
X13
—
CERVICAL/VAGINAL SWAB COLLECTION11
Trichomonas vaginalis
Local lab
Local lab
—
X
—
X13
—
Bacterial vaginosis
Local lab
Local lab
—
X
—
X13
—
Yeast
Local lab
Local lab
—
X
—
X13
—
MUCOSAL COLLECTION
Semen
BARC
HVTN Labs
—
X12
—
X
—
Cervical Secretions
BARC
HVTN Labs
—
X12
—
X
—
Rectal Secretions
BARC
HVTN Labs
—
X12
—
X
—
Part B 
eligibility
visit3
Vacc #6
 
1 BARC = Bio Analytical Research Corporation South Africa (Pty) Ltd. (Johannesburg, South Africa); HSML-NICD = HIV Sero-Molecular Laboratory, National Institute for Communicable Diseases (Johannesburg, South Africa) 
2 HVTN Laboratories include: Cape Town HVTN Immunology Laboratory (CHIL, Cape Town, South Africa); South African Immunology Laboratory–National Institute for Communicable Diseases (SAID-NICD, Johannesburg, South Africa); Fred 
Hutchinson Cancer Research Center (Seattle, Washington, USA); Duke University Medical Center (Durham, North Carolina, USA). 
3 Eligibility visit applies to participants who terminated from the study. It is not needed for participants who are currently in study. The eligibility visit may occur over the course of several contacts/visits up to and including the visit day for visit 17. 
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 9.4 (postenrollment). 
6 Immunogenicity assays will be performed at M0 from Part A (for binding Ab assay) and M30.5. 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 For a participant who was born female (ie, assigned female sex at birth), pregnancy test must be performed on urine or blood specimens on the day of vaccination with negative results received prior to vaccination. Persons who have undergone total 
hysterectomy or bilateral oophorectomy (verified by medical records) are not required to undergo pregnancy testing. 
8 At an early termination visit (see Section 9.11), blood should be drawn for HIV diagnostic testing, as shown for visit 20 above. 
9 Pregnancy testing at the indicated visit is only required of participants who are born female and are providing a cervical and/or rectal secretion sample. 
10 Syphilis testing by serology and Chlamydia and gonorrhea testing by urine will only be performed for participants providing mucosal samples. 
11 Cervical/vaginal swabs will only be collected from participants who agree to provide a cervical secretion sample and for yeast if clinically indicated. 
12 Mucosal specimens must be collected prior to vaccination once the participant is confirmed to have met mucosal specimen collection criteria specified in Section 9.5. 
13 STI tests at M30.5 will only be performed if the participant is symptomatic following their STI tests at M30. 
14 Specimens collected at the vaccination visit may be obtained within the 14 days prior to vaccination, except for a pregnancy test (see footnote “7” above). 
y = SST blood collected for binding Ab assays and serum storage will also cover specimen needs for neutralizing Ab assays; no separate blood draw is needed. 
z = Up to 10 × 1mL aliquots of ACD plasma will be harvested for storage during PBMC processing; no separate blood draw is needed. 

HVTN 100 Version 3.0 / May 23, 2017 
HVTN100_v3.0_FINAL.docx / Page 151 of 154 
Appendix H 
Procedures at HVTN CRS for Part A 
Visit: 
01a  
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
15 
Post 
Day: 
 
D0 
D14 
D28 
D42 
D56 
D84 
D98 
D168 
D182 
D273 
D364 
D378 
D455 
D546 
 
Week 
 
W0 
W2 
W4 
W6 
W8 
W12 
W14 
W24 
W26 
W39 
W52 
W54 
W65 
W78 
 
Month: 
 
M0 
M0.5 
M1 
M1.5 
M2 
M3 
M3.5 
M6 
M6.5 
M9 
M12 
M12.5 
M15 
M18 
 
Procedure 
Scr. 
VAC1 
 
VAC2 
 
 
VAC3 
 
VAC4 
 
 
VAC5 
 
 
 
 
Study proceduresb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed screening consent (if used) 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Signed protocol consent  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Assessment of understanding 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Medical history  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Complete physical exam 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
Screening for low risk of HIV infection 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Confirm eligibility, obtain demographics, randomize  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Abbreviated physical exam 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Risk reduction counseling 
X 
X 
X 
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 
X 
X 
X 
— 
Behavioral risk assessment questionnaire 
X 
— 
— 
— 
— 
— 
X 
— 
X 
— 
X 
— 
— 
X 
X 
— 
Social impact assessment 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Social impact assessment questionnaire 
— 
— 
— 
— 
— 
X 
— 
— 
— 
X 
— 
— 
— 
X 
X 
— 
Outside testing and belief questionnaire 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
X 
X 
— 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Intercurrent illness/adverse experience 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
HIV infection assessmentd 
X 
— 
— 
— 
— 
— 
X 
— 
X 
— 
X 
X 
— 
X 
X 
— 
Confirm HIV test results provided to participant 
— 
X 
— 
— 
— 
— 
— 
X 
— 
X 
— 
X 
X 
— 
X 
X 
Local lab assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening HIV test 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Urine dipstick 
X 
— 
X 
— 
— 
— 
— 
— 
— 
X 
— 
— 
X 
— 
— 
— 
Pregnancy (urine or serum HCG)e 
X 
X 
— 
X 
— 
— 
X 
— 
X 
— 
— 
X 
— 
X 
— 
— 
CBC, differential, platelet 
X 
— 
X 
— 
X 
— 
— 
X 
— 
X 
— 
— 
X 
X 
— 
— 
Chemistry panel (see Section 9.2) 
X 
— 
X 
— 
X 
— 
— 
X 
— 
X 
— 
— 
X 
X 
— 
— 
Syphilis, Hepatitis B, Hepatitis C 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Vaccination procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccinationf 
— 
X 
— 
X 
— 
— 
X 
— 
X 
— 
— 
X 
— 
— 
— 
— 
Reactogenicity assessmentsg 
— 
X 
— 
X 
— 
— 
X 
— 
X 
— 
— 
X 
— 
— 
— 
— 
Poststudy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblind participant  
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Xh 
 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 born female and are capable of becoming pregnant. 
d Includes pre-test counseling. A subsequent follow-up contact is conducted to provide post-test counseling and to report results to participant. See Section 9.6. 
e For a participant who was born female, pregnancy test must be performed on the day of vaccination prior to vaccination (serum pregnancy tests may be performed within 24 hours preceding vaccination). Pregnancy test to 
determine eligibility may be performed at screening or on day 0 prior to first vaccination. Persons who are NOT of reproductive potential due to having undergone total hysterectomy with bilateral oophorectomy (verified 
by medical records), are not required to undergo pregnancy testing. Serum pregnancy tests may be used to confirm the results of, or substitute for, a urine pregnancy test. 
f Blood draws required at vaccination visits must be performed prior to administration of study product; however, it is not necessary to have results prior to administration. Lab tests may be drawn within the 3 days prior to 
vaccination. 
g Reactogenicity assessments performed daily for at least 3 days postvaccination (see Section 9.9). 
h Unblinding of all participants will occur after Part B has been completed. 

HVTN 100 Version 3.0 / May 23, 2017 
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Appendix I 
Procedures at HVTN CRS for Part B 
 
Visit: 
16 
17k 
18 
19 
20 
Post 
Day: 
Part B 
eligibility 
visita 
D910 
D917 
D924 
D1092 
 
Week 
W130 
W131 
W132 
W156 
 
Month: 
M30 
M30.25 
M30.5 
M36 
 
Procedure 
VAC6 
 
 
 
 
Study proceduresb 
 
 
 
 
 
 
Signed screening consent (if used) 
— 
— 
— 
— 
— 
— 
Signed Part B protocol consent  
X 
— 
— 
— 
— 
— 
Assessment of understanding 
X 
— 
— 
— 
— 
— 
Complete physical exam 
— 
— 
— 
— 
X 
— 
Confirm eligibility, randomize  
X 
— 
— 
— 
— 
— 
Abbreviated physical exam 
X 
X 
X 
X 
— 
— 
Risk reduction counseling 
X 
X 
X 
X 
X 
— 
Pregnancy prevention assessmentc 
X 
X 
X 
X 
X 
— 
Behavioral risk assessment questionnaire 
— 
X 
— 
— 
X 
— 
Social impact assessment 
X 
X 
X 
X 
X 
— 
Social impact assessment questionnaire 
X 
— 
— 
— 
X 
— 
Outside testing and belief questionnaire 
X 
— 
— 
— 
X 
— 
Concomitant medications 
X 
X 
X 
X 
X 
— 
Intercurrent illness/adverse experience 
X 
X 
X 
X 
X 
— 
HIV infection assessmentd 
X 
X 
— 
— 
X 
— 
Confirm HIV test results provided to participant 
— 
X 
— 
X 
— 
X 
Local lab assessment 
 
 
 
 
 
 
Urine dipstick 
X 
— 
— 
X 
— 
— 
Pregnancy (urine or serum HCG)e 
X 
X 
— 
Xf 
X 
— 
CBC, differential, platelet 
X 
— 
— 
X 
— 
— 
Chemistry panel (see Section 9.2) 
X 
— 
— 
X 
— 
— 
Pap smearg 
X 
— 
— 
— 
— 
— 
Syphilish 
— 
X 
— 
Xi 
— 
— 
Chlamydia/gonorrheah 
— 
X 
— 
Xi 
— 
— 
Trichomonas vaginalisj 
— 
X 
— 
Xi 
— 
— 
Bacterial vaginosisj 
— 
X 
— 
Xi 
— 
— 
 a May occur over the course of several contacts/visits up to and including day 910 prior to vaccination 
b For specimen collection requirements, see Appendix G. 
c Pregnancy prevention compliance occurs only with participants who were born female and are capable of becoming pregnant. 
d Includes pre-test counseling. A subsequent follow-up contact is conducted to provide post-test counseling and to report results to participant. See Section 9.6. 
e For a participant who was born female, pregnancy test must be performed on the day of vaccination prior to vaccination with negative results received prior to vaccination (serum pregnancy tests may be performed within 24 hours preceding 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.  
f Pregnancy testing at the indicated visit is only required of participants who were born female and who are providing a cervical and/or rectal secretion sample.  
g Only for participants who were born female and who enter Part B under protocol Version 3.0. Pap smear is not required if volunteer has had a Pap smear within the previous 3-5 years with most recent result normal or ASCUS, or if participant is less than 
21 years old. See Section 9.5. 
h Syphilis testing by serology and urine testing for Chlamydia and gonorrhea will be done only for participants who enter Part B under protocol Version 3.0 . Specimen collection for this testing will take place at the time of mucosal sampling, prior to 
vaccination (if scheduled). 
i Test at M30.5 will only be performed if the participant is symptomatic following their STI tests at M30. 
j Cervical/vaginal swabs will only be collected from participants who enter Part B under protocol Version 3.0 and who provide a cervical secretion sample. Swabs for bacterial vaginosis and yeast will only be collected if clinically indicated. Specimen 
collection for this testing will take place at the time of mucosal sampling prior to vaccination.   

HVTN 100 Version 3.0 / May 23, 2017 
HVTN100_v3.0_FINAL.docx / Page 153 of 154 
Visit: 
16 
17k 
18 
19 
20 
Post 
Day: 
Part B 
eligibility 
visita 
D910 
D917 
D924 
D1092 
 
Week 
W130 
W131 
W132 
W156 
 
Month: 
M30 
M30.25 
M30.5 
M36 
 
Procedure 
VAC6 
 
 
 
 
Yeastj 
— 
X 
— 
Xi 
— 
— 
Mucosal sample collection  
 
 
 
 
 
 
Rectal secretions, cervical secretions, semen 
— 
X 
— 
X 
— 
— 
Vaccination procedures 
 
 
 
 
 
 
Vaccination 
— 
X 
— 
— 
— 
— 
Reactogenicity assessmentsl 
— 
X 
— 
— 
— 
— 
Poststudy 
 
 
 
 
 
 
Unblind participant  
— 
— 
— 
— 
— 
X 
 
k Specimens collected at the vaccination 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.. 
 
l Reactogenicity assessments performed daily for at least 3 days postvaccination (see Section 9.9). 

HVTN 100 Version 3.0 / May 23, 2017 
HVTN100_v3.0_FINAL.docx / Page 154 of 154 
Appendix J 
Protocol Signature Page 
 
A phase 1-2 randomized, double-blind, placebo-controlled clinical trial of clade C 
ALVAC-HIV (vCP2438) and Bivalent Subtype C gp120/MF59® in HIV-uninfected 
adults at low risk of HIV infection 
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 100 
DAIDS Protocol Version: Version 3.0 
Protocol Date: May 23, 2017