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

 
PROTOCOL 
HVTN 108 
A phase 1/2a clinical trial to evaluate the safety and 
immunogenicity of HIV clade C DNA, and of MF59®- 
or AS01B-adjuvanted clade C Env protein in various 
combinations, in healthy, HIV-uninfected adult 
participants 
DAIDS DOCUMENT ID 12007 
BB IND #17018 HELD BY DAIDS 
CLINICAL TRIAL SPONSORED BY 
Division of AIDS (DAIDS) 
National Institute of Allergy and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
Department of Health and Human Services (DHHS) 
Bethesda, Maryland, USA 
STUDY PRODUCTS PROVIDED BY 
IPPOX Foundation 
Lausanne, Switzerland 
 
Novartis Vaccines 
Cambridge, MA, USA  
 
GlaxoSmithKline Biologicals 
Rixensart, Belgium 
August 8, 2016 
 
HVTN 108, Version 2.0 

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Contents 
1 
Ethical considerations .............................................................................................. 5 
2 
IRB/EC review considerations ................................................................................. 7 
2.1 
Minimized risks to participants ..................................................................... 7 
2.2 
Reasonable risk/benefit balance .................................................................... 7 
2.3 
Equitable subject selection ............................................................................ 8 
2.4 
Appropriate informed consent ....................................................................... 8 
2.5 
Adequate safety monitoring........................................................................... 8 
2.6 
Protect privacy/confidentiality ...................................................................... 8 
3 
Overview ................................................................................................................ 10 
3.1 
Protocol Team ............................................................................................. 13 
4 
Background ............................................................................................................ 14 
4.1 
Rationale for trial concept ........................................................................... 14 
4.2 
The Global Burden of HIV .......................................................................... 15 
4.3 
Rationale for phase 1/2a vaccine regimen selections .................................. 16 
4.4 
Study product descriptions .......................................................................... 18 
4.5 
Trial design rationale ................................................................................... 22 
4.6 
Summary of preclinical safety studies ......................................................... 30 
4.7 
Preclinical immunogenicity studies ............................................................. 33 
4.8 
Clinical studies ............................................................................................ 38 
4.9 
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 ................................................................................. 49 
6 
Statistical considerations ........................................................................................ 50 
6.1 
Accrual and sample size calculations .......................................................... 50 
6.2 
Randomization ............................................................................................. 54 
6.3 
Blinding ....................................................................................................... 55 
6.4 
Statistical analyses ....................................................................................... 55 
7 
Selection and withdrawal of participants ............................................................... 60 
7.1 
Inclusion criteria .......................................................................................... 60 
7.2 
Exclusion criteria ......................................................................................... 63 
7.3 
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 ........................................................................... 74 
8.3 
Preparation of study products ...................................................................... 75 
8.4 
Administration ............................................................................................. 78 
8.5 
Acquisition of study products ...................................................................... 79 
8.6 
Pharmacy records ........................................................................................ 79 
8.7 
Final disposition of study products .............................................................. 79 
9 
Clinical procedures ................................................................................................ 80 
9.1 
Informed consent ......................................................................................... 80 
9.2 
Pre-enrollment procedures ........................................................................... 82 
9.3 
Enrollment and vaccination visits................................................................ 83 
9.4 
Follow-up visits ........................................................................................... 85 
9.5 
AESI contact ................................................................................................ 86 

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9.6 
Mucosal sampling ........................................................................................ 86 
9.7 
Stool sampling ............................................................................................. 87 
9.8 
HIV counseling and testing ......................................................................... 88 
9.9 
Contraception status .................................................................................... 89 
9.10 Urinalysis ..................................................................................................... 89 
9.11 Assessments of reactogenicity ..................................................................... 90 
9.12 Visit windows and missed visits .................................................................. 91 
9.13 Early termination visit ................................................................................. 91 
9.14 Pregnancy .................................................................................................... 92 
10 
Laboratory .............................................................................................................. 93 
10.1 HVTN CRS laboratory procedures.............................................................. 93 
10.2 Total blood volume ...................................................................................... 93 
10.3 Primary immunogenicity timepoint ............................................................. 93 
10.4 Endpoint assays: humoral ............................................................................ 93 
10.5 Endpoint assays: cellular ............................................................................. 94 
10.6 Genotyping .................................................................................................. 94 
10.7 Lab assay algorithm ..................................................................................... 94 
10.8 Exploratory studies ...................................................................................... 94 
10.9 Other use of stored specimens ..................................................................... 95 
10.10 Biohazard containment ................................................................................ 95 
11 
Safety monitoring and safety review ..................................................................... 96 
11.1 Safety monitoring and oversight.................................................................. 96 
11.2 Safety reporting ........................................................................................... 97 
11.3 Safety pause and prompt PSRT AE review ............................................... 100 
11.4 Review of cumulative safety data .............................................................. 101 
11.5 Study termination ...................................................................................... 102 
12 
Protocol conduct .................................................................................................. 103 
12.1 Social impacts ............................................................................................ 103 
12.2 Compliance with NIH guidelines for research involving products containing 
recombinant DNA ..................................................................................... 104 
12.3 Specific regulatory considerations for Republic of South Africa and other 
Southern African countries ........................................................................ 104 
12.4 Emergency communication with study participants .................................. 104 
13 
Version history ..................................................................................................... 105 
14 
Document references (other than literature citations) .......................................... 107 
15 
Acronyms and abbreviations ................................................................................ 109 
16 
Literature cited ..................................................................................................... 111 
Appendix A 
Sample informed consent form .............................................................. 120 
Appendix B 
Approved birth control methods (for sample informed consent form) for 
US sites 
142 
Appendix C 
Approved birth control methods (for sample informed consent form) for 
Southern African sites ..................................................................................................... 143 
Appendix D 
Sample consent form for use of samples and information in other studies
 
144 
Appendix E 
Injection schedule for sample informed consent form ........................... 148 
Appendix F 
Table of procedures (for sample informed consent form) ...................... 149 
Appendix G 
Laboratory procedures ........................................................................... 150 

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Appendix H 
Procedures at HVTN CRS ..................................................................... 152 
Appendix I 
AESI contact .......................................................................................... 154 
Appendix J 
Adverse events of special interest .......................................................... 155 
 

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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 (CAB) are required by DAIDS and supported at all 
HVTN research sites to ensure community input, in accordance with Good 
Participatory Practices (GPP) and all local and national guidelines.  
 
HVTN clinical trial staff counsel study participants routinely on how to reduce HIV 
risk. Participants who become HIV infected during the trial are provided counseling 
on notifying their partners and about HIV infection according to local guidelines. 
Staff members will also counsel them about reducing their risk of transmitting HIV to 
others. 
 
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.  
 
HVTN trials are reviewed by local and national regulatory bodies and are conducted 
in compliance with all applicable national and local regulations. 

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 
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 
US Food and Drug Administration (FDA) and other US federal regulations require 
IRBs/ECs to ensure that certain requirements are satisfied on initial and continuing 
review of research (Title 45, Code of Federal Regulations (CFR), Part 46.111(a) 1-7; 21 
CFR 56.111(a) 1-7). The following section highlights how this protocol addresses each of 
these research requirements. Each HVTN Investigator welcomes IRB/EC questions or 
concerns regarding these research requirements. 
This trial is also being conducted in Southern Africa, with partial funding from the US 
NIH. Due to this, the trial is subject to both US and local regulations and guidelines on 
the protection of human research subjects and ethical research conduct. Where there is a 
conflict in regulations or guidelines, the regulation or guideline providing the maximum 
protection of human research subjects will be followed. 
In compliance with international and local (as appropriate) Good Clinical Practice 
guidelines, each research location has a locally based Principal Investigator (PI) who is 
qualified to conduct (and supervise the conduct of) the research; and the research 
addresses an important local health need for an HIV vaccine. In addition, the 
investigators take responsibility for the conduct of the study and the control of the study 
products, including obtaining all appropriate regulatory and ethical reviews of the 
research. 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. 
2.2 
Reasonable risk/benefit balance 
45 CFR 46.111(a) 2 and 21 CFR 56.111(a) 2: Risks to subjects are reasonable in 
relation to anticipated benefits, if any, to subjects, and the importance of the 
knowledge that may reasonably be expected to result. 
In all public health research, the risk-benefit ratio may be difficult to assess because the 
benefits to a healthy participant are not as apparent as they would be in treatment 

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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 108 Protocol Safety Review 
Team (PSRT). In addition, the HVTN Safety Monitoring Board (SMB) periodically 
reviews study data. 
2.6 
Protect privacy/confidentiality 
45 CFR 46.111 (a) 7 and 21 CFR 56.111 (a) 7: There are adequate provisions to 
protect the privacy of subjects and maintain the confidentiality of data. 
Privacy refers to an individual’s right to be free from unauthorized or unreasonable 
intrusion into his/her private life and the right to control access to individually 
identifiable information about him/her. The term “privacy” concerns research participants 
or potential research participants as individuals whereas the term “confidentiality” is used 
to refer to the treatment of information about those individuals. This protocol respects the 
privacy of participants by informing them about who will have access to their personal 
information and study data (see Appendix A). The privacy of participants is protected by 
assigning unique identifiers in place of the participant’s name on study data and 

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specimens. In the United States, research participants in HVTN protocols are protected 
by a Certificate of Confidentiality from the US NIH, which can prevent disclosure of 
study participation even when that information is requested by subpoena. Participants are 
told of the use and limits of the certificate in the study consent form. In addition, each 
staff member at each study site in this protocol signs a Confidentiality Agreement 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 1/2a clinical trial to evaluate the safety and immunogenicity of HIV clade C 
DNA, and of MF59®- or AS01B-adjuvanted clade C Env protein in various 
combinations, in healthy, HIV-uninfected adult participants 
Primary objectives 
Primary objective 1 
 
To evaluate the safety and tolerability of DNA and/or different doses of clade C 
bivalent gp120 protein with either MF59® or AS01B adjuvant in various regimens in 
HIV uninfected healthy adults. 
Primary objective 2 
 
To evaluate the systemic immune responses at the Month 6.5 timepoint (2 weeks 
after the 4th vaccination) of clade C DNA, bivalent gp120 protein/MF59, and/or 
bivalent gp120 protein/AS01B in each vaccine regimen 
Study products and routes of administration 
 
DNA: DNA-HIV-PT123: containing a mixture of 3 DNA plasmids in a 1:1:1 ratio, 
each at 1.33 mg: 1) clade C 96ZM651 gag, 2) clade C 96ZM651 gp140, and 3) clade 
C CN54 pol-nef, delivered at a total dose of 4 mg, administered IM as a single 1 mL 
dose. 
 
Protein/MF59: Bivalent Subtype C gp120/MF59: clade C TV1.C gp120 Env and 
clade C 1086.C gp120 Env, each at a dose of 100 mcg, mixed with MF59 adjuvant, 
administered IM as a single 0.5 mL dose. 
 
Protein/AS01B: Bivalent Subtype C gp120/AS01B: clade C TV1.C gp120 Env and 
clade C 1086.C gp120 Env, each at a dose of 20 mcg or 100 mcg, mixed with AS01B 
adjuvant, administered IM as a single 0.75 mL dose. 
 
Placebo: Sodium Chloride for Injection, 0.9%, administered IM at volumes to match 
the active products. 

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Table 3-1 Schema 
Group 
N 
Dose of each 
protein 
Deltoid 
Month 0 
(Day 0) 
Month 1 
(Day 28) 
Month 3 
(Day 84) 
Month 6 
(Day 168) 
1 
30 
100 mcg 
Left 
DNA 
DNA 
DNA 
DNA 
Right 
Placebo + 
Placebo* 
Placebo + 
Placebo* 
Protein/MF59 
+ Placebo* 
Protein/MF59 
+ Placebo* 
2 
50 
100 mcg 
Left 
DNA 
DNA 
DNA 
DNA 
Right 
Placebo + 
Placebo* 
Placebo + 
Placebo* 
Protein/AS01B 
+ Placebo* 
Protein/AS01B 
+ Placebo* 
3 
50 
20 mcg 
Left 
DNA 
DNA 
DNA 
DNA 
Right 
Placebo + 
Placebo* 
Placebo + 
Placebo* 
Protein/AS01B 
+ Placebo* 
Protein/AS01B 
+ Placebo* 
4 
30 
100 mcg 
Left 
DNA 
DNA 
Placebo 
DNA 
Right 
Protein/MF59 
+ Placebo* 
Protein/MF59 
+ Placebo* 
Placebo + 
Placebo* 
Protein/MF59 
+ Placebo* 
5 
50 
100 mcg 
Left 
DNA 
DNA 
Placebo 
DNA 
Right 
Protein/AS01B 
+ Placebo* 
Protein/AS01B 
+ Placebo* 
Placebo + 
Placebo* 
Protein/AS01B 
+ Placebo* 
6 
50 
20 mcg 
Left 
DNA 
DNA 
Placebo 
DNA 
Right 
Protein/AS01B 
+ Placebo* 
Protein/AS01B 
+ Placebo* 
Placebo + 
Placebo* 
Protein/AS01B 
+ Placebo* 
7 
50 
20 mcg 
Left 
Placebo 
Placebo 
Placebo 
Placebo 
Right 
Protein/AS01B 
+ Placebo* 
Protein/AS01B 
+ Placebo* 
Placebo + 
Placebo* 
Protein/AS01B 
+ Placebo* 
8 
24 
N/A 
Left 
Placebo 
Placebo 
Placebo 
Placebo 
Right 
Placebo + 
Placebo* 
Placebo + 
Placebo* 
Placebo + 
Placebo* 
Placebo + 
Placebo* 
* Two distinct placebo volumes for protein/adjuvant will be needed to maintain the blind since Protein/AS01B and Protein/MF59 
consist of different injection volumes. 
Participants 
334 healthy, HIV-uninfected volunteers aged 18 to 40 years; 310 vaccinees, 24 placebo 
recipients 
Design 
Multicenter, randomized, controlled, double-blind trial 
Duration per participant 
12 months of scheduled clinic visits (main study) followed by 1 phone, text message, or 
e-mail contact 6 months after the last scheduled clinic visit to monitor AESIs 
Estimated total study duration 
24 months (includes enrollment, follow-up, and AESI contact) 
Investigational New Drug (IND) sponsor 
DAIDS, NIAID, NIH, DHHS (Bethesda, Maryland, USA) 

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Study product providers 
 
DNA-HIV-PT123: IPPOX Foundation (Lausanne, Switzerland) 
 
Bivalent Subtype C gp120: Novartis Vaccines (Cambridge, MA, USA) 
 
MF59: Novartis Vaccines (Cambridge, MA, USA) 
 
AS01B: GlaxoSmithKline Biologicals (Rixensart, Belgium) 
Core operations 
HVTN Vaccine Leadership Group/Core Operations Center, Fred Hutchinson Cancer 
Research Center (FHCRC) (Seattle, Washington, USA) 
Statistical and data management center (SDMC) 
Statistical Center for HIV/AIDS Research and Prevention (SCHARP), FHCRC (Seattle, 
Washington, USA) 
DF/Net Research (Seattle, Washington, USA) 
HIV diagnostic laboratory 
University of Washington Virology Specialty Laboratory (UW-VSL) (Seattle, 
Washington, USA) 
HIV Sero-Molecular Laboratory, National Institute for Communicable Diseases (HSML-
NICD) (Johannesburg, South Africa) 
Endpoint assay laboratories 
 
Cape Town HVTN Immunology Laboratory (CHIL) (Cape Town, South Africa)  
 
Duke University Medical Center (Durham, North Carolina, USA)  
 
FHCRC/University of Washington (Seattle, Washington, USA) 
 
South Africa Immunology Laboratory and National Institute for Communicable 
Diseases (SAIL-NICD) (Johannesburg, South Africa) 
Study sites 
HVTN Clinical Research Sites (HVTN CRSs) in the US and Southern Africa to be 
specified in the Site Announcement Memo 
Safety monitoring 
HVTN 108 PSRT; HVTN Safety Monitoring Board (SMB) 

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3.1 
Protocol Team 
Protocol leadership 
Chair 
Nigel Garrett 
CAPRISA 
+27 (0)31 260-4453 
nigel.garrett@caprisa.org 
Statistician 
Barbara Metch 
SCHARP, FHCRC 
206-667-4656 
bmetch@fredhutch.org 
Cochair 
Danielle Crida 
Emavundleni Research 
Center 
+27 (0)21 650 5873 
danielle.crida@hiv-
research.org.za 
Statistician 
Allan deCamp 
SCHARP, FHCRC 
206-667-2569 
adecamp@fredhutch.org 
Protocol team leader and 
Core medical monitor 
Philipp Mann 
HVTN Core, FHCRC 
206-667-1651 
pmann@fredhutch.org 
Laboratory lead 
Nicole Frahm 
HVTN Lab, FHCRC 
206-667-6268 
nfrahm@fredhutch.org 
DAIDS medical officer 
Julia Hutter 
DAIDS, NIAID 
240-627-3039 
julia.hutter@nih.gov 
 
 
Other contributors to the original protocol 
Vaccine developer 
representatives 
Giuseppe Pantaleo 
IPPPOX Foundation 
Clinical safety specialist 
Maija Anderson 
HVTN Core, FHCRC 
 
Song Ding 
IPPOX Foundation 
Clinical trials manager 
Shelly Ramirez 
HVTN Core, FHCRC 
 
Susan Barnett 
Novartis Vaccines  
SDMC Project manager 
Gina Escamilla 
SCHARP, FHCRC 
 
Niranjan Kanesa-thasan 
Novartis Vaccines  
Laboratory Program 
representative 
On Ho 
HVTN Lab Program, 
FHCRC 
 
Marguerite Koutsoukos 
GlaxoSmithKline 
Regulatory affairs 
Liz Briesemeister 
HVTN Core, FHCRC 
 
Francois Roman 
GlaxoSmithKline  
Clinic coordinators 
Elaine Sebastian 
Desmond Tutu HIV 
Center 
DAIDS protocol 
pharmacist 
Scharla Estep 
DAIDS, NIAID 
240-627-3046 
 
Theresa Wagner 
SFDPH 
Statistical research 
associate 
Niya Gu 
SCHARP, FHCRC 
Protocol development 
coordinator 
Ryan Jensen 
HVTN Core, FHCRC 
Community Advisory 
Board (CAB) members 
Basil Mtungane 
Cape Town CAB 
Community engagement unit 
representatives 
Gail Broder  
HVTN Core, FHCRC 
 
Daniel Byrd 
Seattle CAB 
 
Genevieve Meyer 
HVTN Core, FHCRC 
Technical editor 
Erik Schwab 
HVTN Core, FHCRC 
Community 
educator/recruiter 
Nomampondo Barnabas 
PHRU 
Regional medical 
liaison 
Simba Takuva 
HVTN Core, PHRU 
 
 

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4 
Background 
4.1 
Rationale for trial concept 
Following the RV144 study in Thailand that demonstrated modest (31%) preventive 
efficacy for an HIV vaccine regimen comprising ALVAC-HIV (vCP1521) and clade B/E 
gp120 Env protein (AIDSVAX B/E) [4], a large number of consultations with 
independent groups of scientists collected through the NIH, MHRP, and the Global 
Vaccine Enterprise were held providing input into the next steps for the field. Several 
consensus concepts emerged: (1) the need to evaluate the RV144 pox-protein prime-
boost approach in a higher incidence population in a region of the world most affected by 
the HIV epidemic (ie, southern Africa); (2) the consequent need to manufacture vaccines 
that more closely match those clades/subtypes that circulate in the proposed trial 
population (clade C); (3) at least 1 of the vaccine concepts to be tested should be 
analogous to the ALVAC/gp120 regimen used in RV144; and (4) the program to be 
developed should build upon the “correlates” analysis done post-RV144 [5] to confirm 
the correlates identified in RV144 and to continue to define additional correlates of risk 
(CoR) for HIV vaccines. These recommendations led to the formation of the Pox Protein 
Public Private Partnership (P5), a group of vaccine developers, funders, and 
implementers, which was created to build on the RV144 results with the goal of 
improving the pox-protein regimen and enhancing the level and/or duration of protection 
seen in the RV144 study, with the hope of producing an effective prophylactic HIV 
vaccine with the potential to have a major public health impact.  
The P5 partnership is committed to evaluating multiple vaccine regimens and will 
address this goal by assessing regimens containing combinations of next-generation 
vaccine products as well as different adjuvant systems to identify those exhibiting potent 
yet diverse immunological profiles, thus providing the greatest potential to confirm 
previous and identify new CoR in an efficacy trial. More than a dozen different vaccine 
regimens will be evaluated in several phase 1/2a trials; and a number of these candidate 
vaccine regimens will be selected based on safety and immunogenicity data collected 
through the primary immunogenicity timepoint of Month 6.5 to advance to phase 2b 
proof-of-concept efficacy testing.  
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 
pol, followed by the AIDSVAX® clades B/E gp120 protein boost. These products were 
based on viruses commonly circulating in Thailand at the time. This vaccine regimen 
demonstrated 31.2% efficacy when compared with placebo (n = 51 vs. n = 74, 
respectively; p = 0.04) at 3.5 years [4]. Although evaluation of vaccine efficacy at 12 
months post vaccination was not included in the pre specified analysis, substantially 
greater reduction in acquisition was observed 1 year postvaccination (estimated 60.5%, 
95% CI 22-80) with the vaccine effect waning over time to 31% cumulative through 3.5 
years [6].  

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4.1.2 
Correlates of risk (CoR) in RV144 
To better understand how the RV144 vaccine regimen reduced the risk of HIV infection, 
a large consortium of independent laboratories worked together systematically to ensure 
maximal information could be derived from samples obtained from participants who 
were vaccinated and became infected compared with those vaccinated but uninfected at 
the end of the trial. A case control study was performed on 41 infected vaccine recipients, 
205 uninfected vaccine recipients (5:1) and 40 placebo recipients (20 infected and 20 
uninfected) within the RV 144 clinical trial to identify CoR [5]. Among the 6 primary 
immunological variables selected for the correlates analysis (5 different antibody [Ab] 
responses and CD4+ T cell cytokine production) that were measured at 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 [5]. 
Recently, several studies have further enhanced our understanding of the efficacy seen in 
RV144. Rolland and colleagues demonstrated a sieve effect in the vaccine recipients, 
specifically that the vaccine induced better protection against viruses that matched the 
vaccine sequence at position 169 in the V2 loop of Env [7]. These data further 
substantiate the importance of antibodies directed against this region in protecting against 
infection [5]. Yates and colleagues noted that Env V1V2-specific IgG3 was the 
immunoglobulin subclass showing the strongest correlation with prevention of HIV 
acquisition in RV144 [8]. Chung and colleagues demonstrated that the IgG3 subclass was 
much better at engaging Fc-mediated effector responses when compared to the other 
subclasses, thereby providing a possible mechanism explaining the association of Env 
V1V2 IgG3 with a lower rate of HIV acquisition [9]. In sum, these CoR studies point to 
the importance of Ab responses, directed against a specific region of Env, in mediating 
the differing rates of HIV acquisition observed in RV144. They lay the groundwork for 
directing immune analyses planned for future HIV vaccine clinical trials. 
4.2 
The Global Burden of HIV 
According to the most recent Gap Report of the Joint United Nations Program on 
HIV/AIDS, there were an estimated 35 million people living with HIV globally in 2013. 
There were 2.1 million new HIV infections globally and 1.5 million AIDS deaths in 
2013. Therefore, despite the well-recognized benefits from scaling-up ART and certain 
HIV prevention strategies, the global burden of HIV remains enormous [10]. 
4.2.1 
HIV in sub-Saharan Africa 
While universal access to ART is a global ideal, in many regions of sub-Saharan Africa 
limited access undermines the prevention potential of widespread ART. Moreover, the 
costs and health care burden of delivering ever-increasing amounts of treatment in 
resource constrained settings pose significant challenges. In addition, while studies 
conducted over the past few years have confirmed the promise of antiretroviral 
chemoprophylaxis, it is well recognized that one way to eradicate a global viral epidemic 
is to design, mass produce, and then systematically immunize the target population with 

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an effective prophylactic vaccine. Although the results of the RV144 trial are modest, 
these provide the first indications that a prophylactic vaccine can reduce HIV acquisition 
risk.  
With approximately 6.3 million people living with HIV as of 2013, South Africa’s 
epidemic remains the largest in the world and the Sub-Saharan region bears the 
preponderant burden of the HIV epidemic with approximately 70% of all infections 
worldwide. Ten countries (Ethiopia, Kenya, Malawi, Mozambique, Nigeria, South 
Africa, Uganda, United Republic of Tanzania, Zambia and Zimbabwe) account for 81% 
of all people living with HIV in the region and half of those are in only 2 countries—
Nigeria and South Africa. The vast majority of newly acquired infections in this region 
occur during unprotected heterosexual intercourse and subsequent transmission to 
newborns and breastfed babies. Approximately 340,000 new HIV infections and 200,000 
HIV-related deaths occurred in South Africa in 2013 [10]. These statistics give strong 
support to recent statements from top scientists and opinion leaders who have voiced the 
persistent unmet need for a preventive HIV vaccine [11]. 
4.2.2 
HIV in the United States 
Approximately 1 million people are living with HIV in the United States. Access to 
potent and safe ART has transformed a life-threatening disease into a manageable chronic 
condition for many of these individuals. Life expectancy has risen steadily, to the point 
where individuals, diagnosed early in infection and at a high CD4 count, may have a 
similar life-expectancy to the general population. Better tolerated treatment is now often 
provided as early as possible to reduce the contribution of HIV on non-AIDS related 
morbidity, and to prevent onward transmission.  
However, despite these advances in HIV care, HIV morbidity remains high and 
prevention efforts for the highest risk groups have had only partial success. The estimated 
incidence rates remain high at 15.8/100,000 overall, and 4 times as high among African 
Americans. Concernedly, the rates for young Americans, aged 20-29 years, increased 
between 2008 and 2011. In addition, 65% of new infections were estimated to be among 
men who have sex with men, and rates were increasing. It is unlikely that early treatment 
strategies and the availability of pre-exposure prophylaxis alone will be able to stop this 
epidemic, and that therefore an effective vaccine will be essential [12].  
The P5 partnership will investigate new vaccine products and vaccination strategies in 
populations from the US and Sub-Saharan Africa. This will ensure the study of correlates 
of risk and protection is representative of the global HIV epidemic, resulting in the 
greatest impact on populations at risk in the US and globally. 
4.3 
Rationale for phase 1/2a vaccine regimen selections 
The vaccine regimens included in the multiple phase 1/2a trials were selected based on 
the rationale that they will have robust yet distinct immune profiles for selection of future 
phase 2b efficacy testing and to address specific questions in the field that are pertinent 
for identifying CoR. These questions include the following:  
 
What are the immune responses elicited by vaccine regimens containing DNA and 
adjuvanted protein without a pox vector? 
 
When DNA is administered alone as a prime followed by DNA plus 
protein/adjuvant boost? 

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 
When DNA and protein/adjuvant are co-administered at each vaccination? 
 
What immune responses are elicited by the Bivalent Clade C gp120 + AS01B alone 
regimen? 
 
How do the adjuvants MF59 versus AS01B affect the immune responses elicited by 
each vaccine regimen? 
 
Does a higher dose (100 mcg) of each Env protein in the Bivalent Clade C gp120 
vaccine product adjuvanted with AS01B dampen immune responses as compared to a 
lower dose (20mcg) within each vaccine regimen? 
 
How does priming with DNA versus priming with ALVAC versus priming with 
NYVAC affect HIV-specific immune responses when followed by ALVAC or 
NYVAC + protein/adjuvant boosting? 
 
What are the immune responses elicited by a vaccine regimen comprising ALVAC 
and Bivalent Subtype C gp120 when the protein component is administered with 
MF59 and with alum adjuvants, or without adjuvant? 
Including all vaccine regimens in a single phase 1/2a trial would be prohibitively 
complex. Therefore a suite of studies has been developed, allowing the opportunity to 
address the pertinent questions in a programmatically feasible manner. The MF59 versus 
AS01B question will be addressed in several of these studies – HVTN 108 among them – 
as it applies to several vaccine product regimens. Similarly, since the AS01B/protein dose 
question may provide different results depending upon the full vaccine regimen 
evaluated, this question will be addressed in several studies as well. However, only 1 
AS01B adjuvanted Env protein dose for each vaccine regimen will be considered for 
advancement to phase 2b testing. 
HVTN 108 is one of the phase 1/2a studies planned within this program. Evaluation of 
DNA/protein and protein only regimens will provide an opportunity to compare the 
immunogenicity of these simpler, non-vector vaccine regimens. This study has 7 active 
arms and 1 placebo arm and will compare DNA priming administered at Months 0 and 1, 
followed by DNA + Protein + MF59 or AS01B boosting at Months 3 and 6, versus DNA 
+ Protein + MF59 or AS01B co-administered at Months 0, 1, and 6. In addition, this study 
will evaluate Protein + AS01B administered at Months 0, 1, and 6. Furthermore, to assess 
whether too high a protein dose in the presence of AS01B adjuvant may overstimulate the 
immune system and thereby suppress responses, 2 different doses of each of the bivalent 
Env proteins will be evaluated: 20 mcg versus 100 mcg for each of the DNA containing 
regimens (see section 4.5.4). 
How to identify the regimens which will be further assessed in a future efficacy trial will 
depend on the ‘adequate take/potency’ (ATP) as defined in Section 6.1.2. Meeting the 
ATP criteria is a necessity to move forward to efficacy testing, however in itself does not 
suffice for a regimen to qualify for further evaluation. Because many or all of the 
regimens of this study could hypothetically meet the ATP, further down-selection will be 
performed using secondary and exploratory objectives as described in Sections 5.2 and 
5.3. In this way, those individual regimens which are able to elicit an immune response 
with a unique profile, and therefore warrant further evaluation, can be moved forward 
into a future efficacy trial. Such an efficacy trial could potentially include 1 or more of 
the vaccine regimens evaluated in this study, together with regimens from other phase 
1/2a studies. 

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4.4 
Study product descriptions 
4.4.1 
DNA: DNA-HIV-PT123 
The investigational DNA-HIV-PT123 vaccine to be evaluated in this protocol has a DNA 
plasmid backbone that was developed by the Dale and Betty Bumpers Vaccine Research 
Center (VRC), NIAID, NIH (Bethesda, MD, USA). The CMV/R promoter consists of the 
translational enhancer region of the CMV immediate early region 1 enhancer substituted 
with the 5'-untranslated human T-cell leukemia virus type 1 (HTLV-1) R-U5 region of 
the long terminal repeat (LTR) to optimize gene expression. Other elements of the 
plasmid include a bovine growth hormone polyadenylation signal termination sequence 
(Tbgh) and a kanamycin resistance cassette (Kan.). A schematic of the plasmid map is 
shown in Figure 4-1. 
 
Figure 4-1 Example DNA-HIV-PT123 plasmid map 
The DNA-HIV-PT123 vaccine contains a mixture of 3 DNA plasmids in a 1:1:1 ratio, 
each at 1.33 mg: 1) a plasmid encoding clade C ZM96 Gag, 2) a plasmid encoding clade 
C ZM96 gp140 Env, and 3) a plasmid encoding clade C CN54 Pol-Nef polypeptide, 
delivered at a total dose of 4 mg, administered IM. A schematic of the inserts is included 
in Figure 4-2. 
 
Figure 4-2 DNA-HIV-PT123 plasmid inserts schematics 

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Additional information on the construction of these plasmids is provided in the DNA-
HIV-PT123 Investigator’s Brochure (IB). 
4.4.2 
Bivalent Subtype C gp120 proteins 
4.4.2.1 
Constructs 
Bivalent Subtype C gp120, manufactured by Rentschler Biotechnologie (Laupheim, 
Germany), consists of 2 separate subtype C recombinant monomeric proteins, TV1.C 
gp120 and 1086.C gp120. These recombinant gp120s represent the 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.  
4.4.2.2 
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 as 
described in the following paragraph.  
Following clone selection, a fed batch cell culture at 500L or 1000L scale is employed for 
cell propagation. Once the cells reach optimum cell density, the culture is harvested and 
purified using standard methods. Harvest clarification was performed using a series of 
depth filters followed by bioburden reduction using a sterilizing-grade filter. The harvest 
was collected in single use disposable bags and purified including further enrichment for 
monomer. Additional processing utilizes multiple filtration steps and a series of 
chromatography steps that remove process related impurities.  
Both TV1.C and 1086.C bulk drug substances are stored frozen at not more than -61°C. 
The formulations are similar for both drug substances, containing Env antigen, sodium 
citrate, and sodium chloride, pH 6.5-7.0. Each of the HIV gp120 proteins as final 
products are tested for pH, appearance, identity, strength (concentration), purity, potency, 
as well as safety and content uniformity following US Pharmacopoeia methods where 
applicable. 
The composition per dose of each subtype C gp120 vaccine protein is provided in Table 
4-1. 
Table 4-1 Qualitative composition of Subtype C gp120 drug substances vials 
Ingredient 
Function 
gp120 protein 
Sodium Citrate, Dihydrate 
Citric Acid, Monohydrate 
Sodium Chloride 
Water for injections 
active 
buffer 
buffer 
tonicity modifying agent 
solvent 
Additional information is provided in the IB. 
4.4.3 
MF59 adjuvant  
The Novartis MF59 adjuvant is an oil-in-water emulsion with a squalene internal oil 
phase and a citrate buffer external aqueous phase. Two non-ionic surfactants, sorbitan 

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trioleate and polysorbate 80, serve to stabilize the emulsion. The bulk formula is shown 
in the Table 4-2.  
Table 4-2 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  
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). 
Additional information is provided in the Bivalent Subtype C gp120/MF59 IB. 
4.4.4 
AS01B adjuvant  
The AS01B Adjuvant System component, which consists of a liposomal formulation 
containing two immunoenhancers, 3-O-desacyl-4’-monophosphoryl lipid A (MPL) and 
QS-21, is a proprietary current Good Manufacturing Practice (cGMP)-grade adjuvant 
developed by GlaxoSmithKline (GSK) Biologicals. 
Additional information is provided in Section 4.5.3 and in the Bivalent Subtype C 
gp120/AS01B IB. 
4.4.5 
Bivalent Subtype C gp120/MF59 for injection 
The combination of the 2 subtype C gp120 proteins and the MF59 is referred to as 
Bivalent Subtype C gp120/MF59. A final dose of 100mcg of each recombinant Env 
protein will be mixed with MF59 adjuvant. The composition of 1 dose of the resulting 
vaccine is shown in Table 4-3. 

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Table 4-3 Composition of 0.5 mL dose of Bivalent Subtype C gp120/MF59 for injection 
Ingredient  
Amount in 1 dose  
Function  
Drug Substances  
TV1.C gp120 protein  
100 mcg  
active  
1086.C gp120 protein  
100 mcg  
active  
Adjuvant (MF59)  
Squalene  
9.75 mg  
oil phase  
Polysorbate  
1.175 mg  
surfactant  
Sorbitan Trioleate  
1.175 mg  
surfactant  
Excipients  
Sodium Citrate, Dihydrate  
1.39 mg  
buffer  
Citric Acid, Monohydrate  
0.051 mg  
buffer 
Sodium Chloride  
4.38 mg  
tonicity modifying agent  
Water for injection 
qs to 0.5 mL 
solvent 
4.4.6 
Bivalent Subtype C gp120/AS01B for injection 
The combination of the 2 subtype C gp120 proteins and the AS01B adjuvant is referred to 
as Bivalent Subtype C gp120/AS01B. A final dose of 20mcg of each recombinant Env 
protein will be mixed with AS01B adjuvant and a final dose of 100mcg of each 
recombinant Env protein will be mixed with AS01B adjuvant. The composition of 1 dose 
of each of the resulting vaccines are shown in Table 4-4 and Table 4-5. 
Table 4-4 Composition of 0.75 mL dose of Bivalent Subtype C gp120/AS01B for injection with 
20 mcg of each gp120 protein 
Ingredient  
Amount in 1 
dose  
Function  
Drug Substances  
TV1.C gp120 protein  
20 mcg  
active  
1086.C gp120 protein 
20 mcg 
active 
Adjuvant (AS01B)  
Liposome 
 
Vesicles for MPL and QS-21 
MPL 
50 mcg 
 
Immunoenhancer  
QS21 
50 mcg 
Immunoenhancer 
Excipients  
Sodium citrate, dihydrate 
0.07 mg 
buffer 
Citric acid, monohydrate 
<0.01 mg 
buffer 
Sodium chloride 
7.06 mg 
tonicity modifying agent 
Sodium phosphate dibasic (Na2HPO4) 
0.15 mg 
buffer 
Potassium phosphate monobasic (KH2PO4) 
0.54 mg 
buffer 
Water for injection 
q.s. ad 0.75 mL 
solvent 

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Table 4-5 Composition of 0.75 mL dose of Bivalent Subtype C gp120/AS01B for injection with 
100 mcg of each gp120 protein 
Ingredient  
Amount in 1 
dose  
Function  
Drug Substances  
TV1.C gp120 protein  
100 mcg  
active  
1086.C gp120 protein 
100 mcg 
active 
Adjuvant (AS01B)  
Liposome 
 
Vesicles for MPL and QS-21 
MPL 
50 mcg 
 
Immunoenhancer  
QS21 
50 mcg 
Immunoenhancer 
Excipients  
Sodium citrate, dihydrate 
0.34 mg 
buffer 
Citric acid, monohydrate 
0.02 mg 
buffer 
Sodium chloride 
8.77 mg 
tonicity modifying agent 
Sodium phosphate dibasic (Na2HPO4) 
0.15 mg 
buffer 
Potassium phosphate monobasic (KH2PO4) 
0.54 mg 
buffer 
Water for injection 
q.s. ad 0.75 mL 
solvent 
4.5 
Trial design rationale 
DNA, Protein, and the combination of the two, as well as the combination of each of 
these immunogens with other constructs have been widely evaluated. However, these 
investigations included a variety of different vaccine candidates in different 
combinations, doses, and with incongruent injection schedules. They were implemented 
in different populations and the immunological assessments were performed in a variety 
of different laboratories using different assays. HVTN 108, in the context of the suite of 
P5 trials, is in the unique position to compare the suggested regimens directly. 
Subsequently, the immunogenicity and safety profiles can also be compared 
unconditionally. In order to assess the impact of the different adjuvants in the respective 
doses on prime/boost versus simultaneous DNA/Protein injections, each individual 
combination is evaluated as its own regimen. This setup allows forming a rational 
decision on which regimen(s) warrant further evaluation in an efficacy trial. Furthermore, 
the overall number of participants will provide sufficient safety data to comfortably move 
into a phase 2b efficacy set up (see also Section 6.1). 
4.5.1 
Rationale for DNA prime, protein boost 
A variety of preclinical studies using the DNA prime followed by protein boost approach 
with HIV immunogens have been published since the 1990s. Quantitative and qualitative 
differences were found between the antibodies induced by Env-based DNA/protein vs. 
Env protein alone or DNA alone in rabbits [13,14]. In addition, nonhuman primate (NHP) 
SHIV challenge studies showed protective antibody responses [15,16]. 
DNA-protein combination vaccine regimens have recently been investigated in clinical 
trials. Two studies conducted by the NIAID Vaccine Research Center (VRC) in 2008-
2010 assessed influenza H5 DNA priming followed by boosting with H5/N1 monovalent 
inactivated vaccine (MIV) and showed that the combination approach enhanced the 
magnitude of hemagglutination inhibition antibodies to protective levels in 81% of 
vaccine recipients with geometric mean titers 4-fold higher than MIV given twice [17]. In 

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addition, this effect was most evident when the booster vaccination was given at least 12-
24 weeks after the prime as compared to 4-8 week intervals [18]. 
Three HIV vaccine clinical trials have been conducted using the DNA prime/Env protein 
boost platform. The first study was conducted by Lu and colleagues at the University of 
Massachusetts Medical School. In this study, participants who received 2 dose levels of a 
multi-clade HIV DNA prime followed by a multi-clade HIV gp120 protein with QS-21 
adjuvant boost demonstrated Env-specific interferon gamma (IFN-γ) enzyme-linked 
immunospot (ELISpot) responses in over 90% of participants 2 weeks after the final 
vaccination, which persisted at 1 year (5 months after the final vaccination) in over 80% 
of participants. Also, Env-specific binding antibodies were induced at a higher magnitude 
than those seen from recombinant envelope vaccine regimens alone and these responses 
persisted in most participants at 1 year with only a modest decrease in titer [19]. 
Furthermore, the DNA prime plus protein boost approach elicited a unique Ab profile 
compared to recombinant HIV envelope protein alone or a pox-vector prime plus protein 
boost, characterized by higher neutralizing antibodies against more resistant viral isolates 
and higher CD4 binding site antibodies [20]. 
HVTN 049 evaluated DNA priming at months 0, 1 and 2 followed by trimeric gp140 
clade B protein in MF59 boosting at months 6 and 9 versus protein only at months 0, 3 
and 9 and found that following the protein boost, the DNA plus gp140 protein prime-
boost regimen induced: 1) substantial levels of binding antibodies against Env in 100% of 
vaccinees; 2) significantly higher titers of homologous neutralizing antibodies (nAbs); 3) 
CD4+ T-cell responses to Env antigens of significantly greater magnitude (among the 
group that was primed with 1mg of env DNA), in comparison with the group that was 
immunized with gp140 protein alone, and 4) a polyfunctional CD4+ T cell response 
pattern that differed qualitatively from the CD4+ responses in the protein alone group, 
shifting towards a Th1 response by DNA priming [21]. In HVTN 049, antibodies were 
induced that were avid, reacted with envelopes of multiple clades (A, B, C, A/E, G) and 
mediated infectious virion capture [Georgia Tomaras, personal communication]. Also, in 
a comparison between multiple different vaccination strategies from several HVTN 
clinical trials with differing combinations of DNA, MVA, Ad5 vectors, and Env protein 
vaccinations, as well as RV144, the DNA/protein strategy in HVTN 049 led to the 
highest magnitude memory B cell responses [22]. 
HVTN 088 evaluated an HIV gp140 clade C protein in MF59 adjuvant administered to 
participants who had received HIV DNA boosted by HIV gp140 clade B protein in MF59 
as a part of HVTN 049 or other HVTN trials conducted 5-7 years earlier. Even before 
administration of the clade C gp140 boost, a significant portion of the HVTN 049 
participants still had detectable T-cell and binding Ab responses, suggesting remarkably 
durable memory responses induced by the DNA + protein combination. This impression 
was further confirmed by the finding of strong and rapid boosting responses after the 
administration of the clade C gp140 protein [23]. The findings from these clinical trials 
provide intriguing clues as to an approach that may facilitate the induction of nAbs and 
long-lasting memory B and T cell responses and provides justification to examine the 
DNA prime/ DNA+ protein boost regimen in this study. Co-administration of the DNA 
with the protein as a boost increases the number of DNA vaccinations beyond 2 priming 
doses, as 3 DNA primes have been shown to be beneficial in some clinical trials of other 
HIV DNA vaccine candidates [24]. While boosting with DNA that is co-administered 
with protein has not yet been investigated in humans, boosting with co-administration of 
vector and protein has been shown to enhance immunogenicity as compared to vector or 
protein boost alone [25]. By extrapolation, then, it is hypothesized that the combined 
DNA/protein boost will elicit strong humoral and cellular responses. Therefore, HVTN 
108 will evaluate DNA prime with DNA+ protein boost. 

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4.5.2 
Rationale for simultaneous administration of DNA and protein vaccines 
Co-administration of a protein from the initial vaccination timepoint has the potential 
benefits of more rapidly eliciting both Ab and T-cell responses from the first vaccination. 
The Pavlakis group demonstrated the potential immunologic advantages of co-
administration of protein with DNA in NHP. In this 4-arm study rhesus macaques 
received either DNA alone, DNA co-administered with protein, 2 DNA priming 
injections followed by 2 protein boosts, or sham DNA vaccination. The DNA vaccine 
plasmids expressed SIV Env, Gag, Pol, Nef, Tat, and Vif, were given with rhesus IL-12 
DNA adjuvant administered IM with electroporation. The protein vaccine consisted of 
inactivated SIVmac239 particles. Vaccinations were given at month 0, 2, 4 and 9, and 
followed by repeated low-dose mucosal challenge with heterologous SIVsmE660. The 2 
groups that received DNA vaccine (DNA alone, or DNA co-administered with protein) at 
all 4 timepoints had higher levels of vaccine-induced SIV-specific IFN-γ+ T cells. 
However, the group that received co-administered DNA and protein had the highest 
levels of Env binding Abs and higher avidity that persisted at a higher rate than the other 
groups. In addition, Env binding Abs and avidity correlated with slower SIV acquisition 
and cytotoxic CD4+ effector memory inversely correlated with peak viral load [26,27]. In 
addition, the Haigwood group recently demonstrated in rabbits that DNA plus protein co-
administration was superior to protein administration alone in terms of antibody kinetics, 
magnitude, avidity, and neutralization potency [28].  
These studies suggest that a qualitative difference in humoral and T-cell responses may 
result from co-administration of protein with DNA, as compared to the more common 
approach of priming with DNA or viral vector immunogens and provides justification for 
the systematic investigation of protein/DNA co-administration. 
Protein was co-administered with DNA or NYVAC in the NHP AUP512 study (see 
Section 4.7.3) and this approach induced earlier binding antibody immune responses. 
Protein co-administered with NYVAC, as well as protein co-administered with DNA-
HIV-PT123 is currently being evaluated in HVTN 096/EV04, and this is the only clinical 
trial of which we are aware that has co-administered DNA and protein (DNA-HIV-PT123 
and AIDSVAX B/E have been given simultaneously at months 0 and 1, followed by 
simultaneous boosting with a NYVAC-HIV and AIDSVAX B/E). This study is still 
blinded and final results are pending (see Section 4.8.1 for interim results). 
4.5.3 
Rationale for MF59 and AS01B 
An equally unique and scientifically compelling aspect of these trial designs is the use of 
2 different adjuvants with the HIV envelope (env) glycoproteins in the boosts. Adjuvants 
are known to enhance the potency, quality, and longevity of antigen-specific immune 
responses [29], and the availability of novel commercial adjuvants that are potent and 
safe has been heralded as an important contribution that may advance HIV vaccines 
[30,31]. The MF59 adjuvant, an oil-in-water emulsion, is licensed for several flu vaccines 
in multiple countries, and in pre-clinical models [32] has demonstrated recruitment of 
antigen presenting cells and up-regulation of cytokines, chemokines, and receptors. The 
adjuvant has improved antibody affinity maturation [33], improving both epitope breadth 
and binding affinity, and elicits a balanced Th1 and Th2 response. It also increases T-cell 
proliferation by enhanced surface expression of MHC class II and co-stimulatory 
molecules [34]. Remarkably durable memory responses (T-cell and binding and 
neutralizing Ab responses) were induced by a DNA-prime/gp120 and MF59 boost 
regimen in HVTN 049 and HVTN 088 (see results in Section 4.5.1). 

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The Adjuvant System AS01 is a liposome-based adjuvant which contains 2 
immunostimulants, 3-O-desacyl-4’-monophosphoryl lipid A (MPL) and QS-21 [35]. 
MPL is a non-toxic derivative of the lipopolysaccharide from Salmonella minnesota and 
is a TLR4 agonist [36]. It can stimulate NF-ĸB transcriptional activity and subsequent 
cytokine production [36]. MPL directly activates APCs such as dendritic cells (DCs) to 
produce cytokines and elevated levels of costimulatory molecules [37-39]. QS-21 is a 
natural saponin molecule extracted from the bark of the South American tree Quillaja 
saponaria Molina [40] (reviewed in [35,41]). The early evaluations of QS-21 as an 
adjuvant demonstrated that it could promote high Ag-specific Ab responses and CD8+ T-
cell responses in mice [42,43] and high Ag-specific Ab responses in humans [44]. 
However, specific receptors and signaling pathways induced by saponin-based adjuvants 
have yet to be clearly defined, most likely through the activation of the inflammasome as 
observed with QuilA [45]. AS01 has been selected in a number of human vaccine 
candidates because of its association with enhanced and durable immune responses, both 
humoral and cellular [35,46-54] and recently with protection [46,47]. The ability of AS01 
to improve adaptive immune responses was shown in mice to be linked to a transient 
stimulation of the innate immune system characterized by the induction of a specific 
pattern of cytokines and innate immune cell recruitment that occurred rapidly and 
transiently at the muscle injection site and draining lymph node postinjection, consistent 
with the rapid drainage of the vaccine components to the draining lymph node, and also 
linked to the generation of a high number and heterogeneous dendritic cell population in 
the draining lymph node that was efficient at priming T cells [55]. 
GSK PRO HIV-002 evaluated the gp120 20 mcg / NefTat 20 mcg (clade B) candidate 
HIV vaccine formulated with 1 of 3 different Adjuvant Systems (AS02A, AS02V and 
AS01B) each in 60 healthy HIV-seronegative adults. The vaccine candidates were 
administered at Month 0, Month 1, Month 3 and Month 6. All vaccine formulations 
induced strong HIV-specific CD4+ T-cell responses characterized by high 
lymphoproliferative capacity and IL-2 production that were still detectable 18 months 
after the last immunization, with significantly stronger responses seen in the AS01B 
group (Figure 4-3 A and B). Broad coverage of CD4+ T-cell responses was demonstrated 
against gp120, and to a lesser extent Nef, derived from the most common circulating 
clades (B, C and circulating recombinant form [CRF]-01) (Figure 4-3 C).  

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Figure 4-3 CD4+ T cell responses following vaccination with the gp120/NefTat vaccine 
candidate formulated with 1 of 3 different Adjuvant Systems (AS02A, AS02V and AS01B) in 
study PRO HIV-002 
Strong antibody responses against gp120, Nef and Tat were observed in all 3 groups. 
Responses were detected already after the second vaccine dose and peaked 2 weeks after 
the third or fourth vaccine dose.  
The demonstration of superior CD4+ T-cell induction by AS01B has guided selection of 
this Adjuvant System for further HIV vaccine evaluation [54]. 
Retrospective testing of the GSK PRO HIV-002 clinical study evaluating 
gp120W6.1D/NefTat in different Adjuvant Systems has been performed by Dr. Georgia 
Tomaras’ lab, which had conducted the correlate analysis of the RV144 trial. Samples 
collected at various timepoints from 30 subjects vaccinated with gp120W6.1D (20 mcg) 
/NefTat/AS01B were tested. The analysis of the isotype-specific responses showed that 
after the vaccination that all subjects had detectable IgG1 responses, however most of 
these subjects also had detectable IgA against gp120 vaccine protein [56].  
In all cases, IgG1 was found to have the highest serum concentration among the IgG 
subclasses (mean concentration of serum antibody to gp120 was 5 µg/ml). IgG2 vaccine-
induced antibodies were detected in a minority (8/30, 27%) of subjects. When IgG3 and 
IgG4 vaccine-induced antibodies were detected, they were found in concentrations less 
than IgG2 vaccine-induced antibodies.  
The V1V2 specificity was also assessed and the results showed that after vaccine dose 3, 
100% of the subjects had total anti-V1V2 concentrations comparable to the high levels 
seen in RV144 and that this response was persistent, with total IgG anti-V1V2 detected in 
87% of the subjects 18 months after the administration of the last vaccine dose (4-dose 
schedule) (see Figure 4-4) [57].  

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Figure 4-4 Total IgG Ab to gp70 V1V2 (Case A2, Clade B) elicited in GSK Pro HIV-002 and 
RV144 trials 
Vaccination with gp120W61D (AS01B) induces increased total IgG but not high IgG3 
response magnitude and half-life. IgG3 V1V2 response rates and magnitude significantly 
declined 12-18 months post last boost (see Figure 4-5) [57]. 
 
Figure 4-5 IgG3 Ab to gp70 V1V2 (Case A2, Clade B) elicited in GSK Pro HIV-002 and RV144 
trials 
A subset of GSK PRO HIV-005 (see Section 4.8.3) volunteers primed 3 years before with 
2 doses F4 10 mcg / AS01B received a booster dose of F4 10 mcg / AS01B (GSK ECR-
004). Before the administration of the booster dose, all participants were still seropositive 
for anti-F4 antibodies as well as high levels of CD4+ T-cell responses were still detected. 
The F4/ AS01B booster induced strong F4-specific CD4+ T-cell responses, with similar 
frequencies and polyfunctional phenotypes as following primary vaccination, and high 
anti-F4 antibody concentrations, reaching higher levels than those following primary 
vaccination (see Figure 4-6) [49]. 

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Figure 4-6 CD4+ T cell and antibody responses following primary and booster doses of the 
F4 / AS01B vaccine candidate in studies PRO HIV-005 and ECR-004.  
4.5.4 
Rationale for evaluation of protein plus AS01B alone arm and 2 protein doses with 
AS01B 
Clinical trials assessing gp120 with a GlaxoSmithKline Biologicals (GSK) Adjuvant 
System provide evidence that an Env protein with AS01B can elicit strong humoral and 
cellular responses. Currently, it is unclear whether too high a protein dose in the presence 
of the AS01B adjuvant leads to suboptimal vaccine responses. 
HVTN 041 evaluated a combination vaccine (NefTat and gp120W61D) formulated with 
AS02A (oil-in-water emulsion of a combination of MPL and QS-21) administered at 0, 1 
and 3 months with varying doses (5, 20 and 100 mcg in 20 subjects each) of the gp120 
vaccine component (the NefTat antigen dose was constant at 20mcg). The vaccine was 
safe and well tolerated at all dose amounts and Nef-, Tat-, and gp120-specific binding 
antibodies were induced in all individuals that received the respective antigen, lasting up 
to 9 months after the final immunization (Figure 4-7).  
 
Figure 4-7 Kinetic of binding IgG antibodies induced by the NefTat/gp120/AS02A vaccine 
candidate in study HVTN 041 
Antibodies able to neutralize the T-cell laboratory-adapted strain of HIV-1W6.1D were 
detected in the majority of vaccinees, but did not neutralize primary isolates. Envelope 
specific ADCC was detected in most of the individuals receiving gp120. Robust and 
persistent HIV-specific lymphoproliferative responses were detected against all subunits 
proteins in the majority of immunized participants. Most immune responses were similar 

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across all doses, except for a significant dampening effect on the CD4+ T-cell responses 
occurring at the highest gp120 dose (100mcg) measured by lymphoproliferative and ICS 
assays [52] (see Figure 4-8).  
 
Figure 4-8 gp120-specific CD4+ T cell responses (IFN- and/or IL-2) induced by the 
NefTat/gp120/AS02A vaccine candidate in study HVTN 041 
GSK PRO HIV-005 evaluated an HIV vaccine candidate consisting of a recombinant 
fusion protein (F4) containing 4 HIV-1 clade B antigens (Gag p24, Pol-RT, Nef, and Gag 
p17) adjuvanted with AS01B in 3 different doses: 10, 30, and 90 mcg. Each dose of the 
AS01B-adjuvanted vaccine candidate was administered twice in a group of 50 subjects, 
following a Month 0 and Month 1 schedule. Three control groups of 10 subjects received 
a dose of 10, 30 or 90 mcg without AS01B. The 10 mcg AS01B-dose elicited a 
statistically significantly higher CD4+ T-cell response as compared to the other doses (p 
< 0.0001 at 2 weeks post second vaccination), while anti-F4 IgG responses were elicited 
in 100% of vaccinees with no significant difference in GMC titers amongst the groups 
[58].  
The protein dose question with AS01B warrants evaluation within the context of the 
specific immunogens and vaccine regimens being tested using updated methodologies. 
The dampening effect of high protein doses on the immune response has not been 
observed with Env proteins adjuvanted with MF59 however, so this specific question is 
limited to the AS01B adjuvanted arms. These observations raise important hypotheses to 
test in this and other planned phase 1/2 trials. The protein plus AS01B alone question 
warrants testing as well in the context of immune responses as they relate to the 
correlates in RV144 (see Section 4.1.2).  
As mentioned in section 4.5.3 protein alone adjuvanted by AS01B induced anti-V1V2 
antibody concentrations comparable to RV144 and detectable levels of IgG1 in 100% of 
the subjects. 
4.5.5 
Dose rationale 
4.5.5.1 
DNA-HIV-PT123 dose 
The choice of the 4mg dose for the DNA-HIV-PT123 vaccine is based on: 1) the dose 
response study conducted by the Vaccine Research Center (VRC), NIAID [59] with a 
DNA vaccine using a similar backbone as DNA-HIV-PT123, that demonstrated that there 

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is a trend toward a greater magnitude and frequency of T cell responses in recipients of 
the 4-or 8-mg dose than in the recipients of the 2-mg dose; 2) the previous clinical studies 
with the DNA-HIV-PT123 and NYVAC-HIV combination [24,60,61]; 3) the preclinical 
immunogenicity studies NHP with DNA-HIV-PT123 (see Section 4.7.1); and 4) the 
repeated-dose toxicity study of DNA-HIV-PT123 and NYVAC-HIV (see Section 4.6.1) 
that used the same clinical material at the same dose as this study and demonstrated that 
the selected dose was safe and well tolerated in animals.  
4.5.5.2 
Bivalent Subtype C gp120 dose 
For the Bivalent Subtype C gp120/MF59 vaccine component, 100 mcg each of the 2 
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, totaling 150 
mcg, doses with MF59 adjuvant were immunogenic and well tolerated [62].  
As discussed in 4.5.3, the Bivalent Subtype C gp120 dose for evaluation with AS01B is 
based on previous dose escalation studies. Both a 20mcg and 100mcg per Env component 
will be tested to determine if the higher dose results in suppression of any immune 
parameters when administered with this adjuvant system. 
The dose of the AS01B / Bivalent Subtype C gp120 administered alone will be 20mcg of 
each Env component for consistency with the PRO HIV-002 trial described in 4.5.4. 
4.5.6 
Schedule 
The vaccination schedule of the DNA prime followed by DNA+protein boost regimens is 
based upon the schedule used in RV144, but replaces the canarypox (ALVAC) vector 
immunogen with a DNA plasmid construct. The schedule for the DNA and protein co-
administration and protein alone regimens is similar to the prime/boost regimens, yet 
administers placebo instead of active product at month 3. In previous trials with 
adjuvanted protein, peak immunogenicity is obtained after 3 doses of protein, while a 
longer rest between the 2nd and 3rd vaccinations is preferred for antibody maturation. 
4.5.7 
Choice of control 
Sodium Chloride for Injection, 0.9% delivered IM will serve as the placebo for the DNA 
vaccine, the Bivalent Subtype C gp120/MF59 vaccine, and the Bivalent Subtype C gp120 
+ AS01B vaccine. 
4.6 
Summary of preclinical safety studies 
4.6.1 
Preclinical safety study of DNA-HIV-PT123 in combination with NYVAC-HIV-PT1 
and NYVAC-HIV-PT4 
A toxicity study (SVT11-02) in rabbits was conducted in 2011-2012 to determine and 
assess systemic (short-term and persistent) and local site reactogenicity of DNA-HIV-
PT123 followed by a boost with attenuated vaccinia, NYVAC-HIV-PT1 and NYVAC-

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HIV-PT4 (see Table 4-6). The study was conducted at Spring Valley Laboratories, Inc. in 
Sykesville, MD, US.  
Table 4-6 Study design of the toxicity study with DNA-HIV-PT123 and NYVAC-HIV-PT1 and 
NYVAC-HIV-PT4 
Group 
Test/Control 
Article Days 
0, 14, 28 and 
42 
Dose 
(mg) 
Volume 
(mL) 
Test/Control 
Article Days 56 
and 701 
Dose 
(PFU) 
Volume 
(mL)1 
Main 
Study 
Necropsy 
(Day 72) 
Recovery 
Study 
Necropsy 
(Day 84) 
Total # 
Animals 
1 
Saline 
N/A 
1 
Saline 
N/A 
2 
5M, 5F 
5M, 5F 
10M/10
F 
2 
DNA-HIV-
PT123  
1 
1 
NYVAC-HIV-PT1 
and NYVAC-HIV-
PT41 
≥ 5 × 106 
PFU per 
NYVAC 
2 
5M, 5F 
5M, 5F 
10M/10
F 
1 Two separate types of NYVAC (HIV-PT-1 and HIV-PT-4) were administered separately in 2 separate injections of 1 mL each. Saline 
control was delivered as 2 separate injections of 1 mL each. 
New Zealand White rabbits (20/sex, total 40 rabbits) were randomly assigned to receive 
IM injections of either DNA-HIV-PT123 on Days 0, 14, 28 and 42 followed by NYVAC- 
HIV-PT-1 and NYVAC-HIV-PT-4 on Days 56 and 70 or to saline control on the same 
days. NYVAC-HIV-PT1 and NYVAC-HIV-PT4 were administered separately (right and 
left hind limbs) in 2 separate injections of 1 ml each on Days 56 and 70. The control 
group received saline control delivered as a single injection on Days 0, 14, 28 and 42, and 
delivered as 2 separate injections of 1 mL each on Days 56 and 70.  
Clinical symptoms, body weight, temperature, ophthalmology, injection site reactions 
and safety laboratory parameters were assessed. Five animals/sex/group were sacrificed 2 
days or 2 weeks following the final vaccination (Day 72 or 84). Each animal underwent a 
complete necropsy with organ weights. All tissues collected from animals assigned to the 
main study (Day 72 necropsy) were examined microscopically. For those animals 
assigned to the recovery study (Day 84 necropsy) only the injection site with surrounding 
muscle and gross lesions was microscopically examined.  
In accordance with the toxicity report, all animals survived to scheduled sacrifice. No 
abnormal findings or statistically significant changes in physical and cageside 
examinations, ophthalmological examination, body weights, administration site, 
urinalysis and gross necropsy considered to be related to treatment were observed. Body 
temperatures were briefly elevated following the NYVAC administration. Some changes 
were observed in clinical pathology and microscopic observations, most of which could 
be correlated to an acute inflammatory and immune response that is expected with 
administration of a test material intended for use as a vaccine. Most changes were 
temporary and reversible and therefore not considered to constitute a safety concern. 
Overall, it was concluded that the study results demonstrated that administration of DNA-
HIV-PT123 in combination with NYVAC-HIV-PT1 and NYVAC-HIV-PT4 was safe and 
well-tolerated in New Zealand White Rabbits. The vaccine was immunogenic in all 
treated animals following the complete immunization schedule. 
4.6.2 
Toxicity studies of HIV Env vaccines  
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, 

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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 
 
Repeat dose toxicity of IM SAAVI DNA-C2 followed by IM SAAVI MVA-C with 
subtype C gp140/ MF59 in rabbits 
4.6.3 
Toxicity studies of MF59  
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) [63].  
Pivotal toxicology studies performed with MF59 include [63]: 
 
single- and repeat-dose toxicity (including local tolerability),  
 
genotoxicity,  
 
sensitization, and  
 
embryofetal and developmental toxicity.  
4.6.4 
Toxicity studies of AS01B  
Toxicology studies performed with AS01B included: 
 
Repeated dose studies (Rabbit, Rat) 
 
Local tolerance studies (Rabbit) 
 
Safety/pharmacology studies (Rat, Dog) 
 
Genotoxicity (micronucleus) studies (Rat) 
The pre-clinical toxicity studies indicated that no treatment-related systemic toxicity was 
associated with single or repeated IM injection of AS01B, alone or in combination with 

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antigens. In addition, no adverse treatment-related effects on male mating performance, 
fertility, early embryonic development, pre- and post-natal survival, growth or 
development of the offspring up to Day 25 of age were associated with repeated IM 
injection of AS01B, alone or in combination with antigens. AS01B was considered safe 
with regard to cardio-respiratory side effects in two different animal species. Moreover, 
single or repeated IM injection of AS01B did not adversely affect RBC production in the 
bone marrow. The only treatment-related effects of vaccine administration were mild 
local injection site reactions. Hematology parameters such as increased WBC and 
neutrophil counts, both related to the local inflammation reaction, were transiently 
affected. 
Details of these studies and more information are included in the Bivalent Subtype C 
gp120/AS01B IB. 
4.7 
Preclinical immunogenicity studies 
4.7.1 
Preclinical immunogenicity studies with DNA-HIV-PT123 
The immunogenicity of the DNA-HIV-PT123 product has been tested in NHP studies in 
combination with NYVAC and/or HIV protein. The vaccine used in these studies is the 
research grade material equivalent to DNA-HIV-PT123. The gp120 protein was 
formulated with MF59 adjuvant. Results from the following 2 studies summarized below 
demonstrate that the DNA-HIV-PT123 is immunogenic and also primes the immune 
response when combined with a boost. Further information regarding the preclinical 
immunogenicity studies; please refer to the DNA-HIV-PT123 IB. 
4.7.2 
AUP444: Immunogenicity study comparing the priming ability of DNA-HIV-PT123 
vs NYVAC followed by NYVAC and/or protein boost in NHP 
The immunogenicity and safety of DNA-HIV-PT123 in combination with NYVAC or 
NYVAC-KC and protein was evaluated in this non-human primate study. The results 
discussed below focus on the safety and immunogenicity results from groups that 
received DNA prime. Groups 1-3 are therefore also referred to as DNA prime groups and 
groups 4-5 are also referred to as No-DNA prime groups.  
The study design is provided in Table 4-7. The study was initially designed with 6 
vaccinations for groups 1, 2 and 3 (last vaccination at week 32) and 4 vaccinations for 
groups 4 and 5 (last vaccination at week 24). This is also referred to as “Primary 
Vaccination” in this study. Based on the initial immunogenicity data, a late boost at week 
49 was added. 

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Table 4-7 AUP444 study design 
Gp 
Size 
Wk 0 
Wk 4 
Wk 8 
Wk 12 
Wk20 
Wk 24 
Wk28 
Wk32 
Wk 49 
1 
8 
DNA1 
(IM) 
DNA 
(IM) 
DNA 
(IM) 
 
NYVAC 
–KC2 
(Scarifica
tion) 
 
Protein4 
(IM) 
protein 
(IM) 
protein 
(IM) 
2 
8 
DNA 
(IM) 
DNA 
(IM) 
DNA 
(IM) 
 
NYVAC 
-KC 
(IM) 
 
protein 
(IM) 
protein 
(IM) 
protein 
(IM) 
3 
8 
DNA 
(IM) 
DNA 
(IM) 
DNA 
(IM) 
 
NYVAC3 
(IM) 
 
protein 
(IM) 
protein 
(IM) 
protein 
(IM) 
4 
8 
NYVAC 
-KC 
(IM) 
NYVAC 
-KC 
(IM) 
 
NYVAC 
–KC + 
protein 
(IM) 
 
NYVAC 
–KC + 
protein 
(IM) 
 
 
NYVAC 
–KC + 
protein 
(IM) 
5 
8 
NYVAC 
(IM) 
NYVAC 
(IM) 
 
NYVAC 
+ protein 
(IM) 
 
NYVAC 
+ protein 
(IM) 
 
 
NYVAC 
+ protein 
(IM) 
1 DNA: DNA-HIV-PT123 with a total dose of 4mg 
2 NYVAC-KC: NYVAC-KC-HIV-PT1 and NYVAC –KC-HIV-PT4 with a final dose of 2x108pfu/mL 
3 NYVAC: NYVAC-HIV-PT1 and NYVAC –HIV-PT4 with a final dose of 2x108pfu/mL 
4 Protein: TV1gp120 with a final dose of 100µg plus MF59 adjuvant 
4.7.2.1 
Summary of AUP444 cellular responses 
 
DNA-HIV-PT123 was greatly immunogenic with an average of 0.5% cytokine 
secreting cells after DNA immunization; 
 
The DNA-HIV-PT123 prime groups induced balanced CD4 and CD8 T-cell 
responses as shown by flow cytometry after the 3 DNA immunizations; 
 
DNA-HIV-PT123 prime induced broad T-cell responses as indicated by the large 
number of targeted peptide pools encompassing Env, Gag, Pol and Nef HIV proteins; 
 
The DNA-HIV-PT123 prime groups induced more balanced Env and Gag/Pol 
responses; while the No-DNA prime groups (Group 4-5) induced predominantly Env 
T-cell responses; 
 
The DNA-HIV-PT123 prime groups induced more potent CD4 and CD8 T-cell 
responses both in terms of magnitude and polyfunctionality. 
4.7.2.2 
Summary of AUP444 humoral responses 
Prior to the late protein only boost at week 49, the no-DNA prime groups induced 
significantly greater Nab activity against Tier 1 viruses and SHIVs (TZM.bl assay), and 
significantly greater titers of ADCC activity as well as a trend to greater cross clade 
binding IgG Ab titers, as compared to DNA prime groups. Post the week 49 late boost, 
DNA prime groups showed a substantial increase in Ab responses, comparable to the No-
DNA prime groups. In contrast, no significant increase in T-cell responses was observed 
with the DNA.  
In summary, no apparent toxicity was observed during the course of the AUP444 study 
and the vaccines were well tolerated. Dose site observations were generally mild in 
nature and quickly resolved. The immunogenicity data obtained in this study 
demonstrated that DNA-HIV-PT123 combined with NYVAC or NYVAC-KC were 
highly immunogenic in terms and CD4 and CD8 T-cell responses as assessed by 
qualitative and quantitative endpoints. The immunogenicity profile of the DNA, NYVAC 

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and protein regimen is distinctively different from the regimen with NYVAC and protein 
combination. 
4.7.3 
AUP512: protein schedule vaccination study 
The objective of the AUP512 NHP study is to compare the safety and immunogenicity 
among: 1) DNA or NYVAC prime / NYVAC + protein boost versus DNA or NYVAC in 
combination with gp120 protein prime followed by NYVAC/gp120 protein boost; 2) 
DNA+gp120 protein at all timepoints versus Groups 1-4. Groups 1-4 are being studied in 
HVTN 096 (see Section 4.8.1).  
In order to better understand the kinetics of the antibody response, the study was 
amended by adding the week 36 and 48 boost. The study design is provided in Table 4-8. 
Table 4-8 Study design of AUP512  
Gp 
Size 
Wk 0 
Wk 4 
Wk12 
Wk 24 
Wk 36 
Wk 48 
1 
12 
NYVAC 
NYVAC 
NYVAC + 
protein 
NYVAC + 
protein 
NYVAC + 
protein 
NYVAC + 
protein 
2 
12 
NYVAC + 
protein 
NYVAC + 
protein 
NYVAC + 
protein 
NYVAC + 
protein 
NYVAC + 
protein 
NYVAC + 
protein 
3 
12 
DNA + 
protein 
DNA + 
protein 
NYVAC + 
protein 
NYVAC + 
protein 
NYVAC + 
protein 
NYVAC + 
protein 
4 
8 
DNA 
DNA 
NYVAC + 
protein 
NYVAC + 
protein 
NYVAC + 
protein 
NYVAC + 
protein 
5 
8 
DNA + 
protein 
DNA + 
protein 
DNA 
+protein 
DNA + 
protein 
DNA + 
protein 
DNA + 
protein 
Total 
52 
 
 
 
 
 
 
DNA: DNA-HIV-PT123 used in the study was 2mg/mL in 2 injections (total dose 4mg) 
NYVAC: NYVAC-HIV-PT1 and NYVAC-HIV-PT4 were formulated together at the concentration of 2×108 PFU/mL (1×108 
PFU/mL each). 
Protein is bivalent gp120 protein (clade C TV1 and 1086) formulated with MF59. The total dose of 100 mcg (50 mcg of each protein). 
Preliminary immunogenicity data demonstrated that: 
 
IgG binding antibody responses against Env are detectable in Groups #2, #3 and #5 at 
week 6 (after 2 immunizations and co-administration with gp120 proteins). These 
responses are further boosted at week 14 after the 3rd immunization. IgG binding 
antibody responses against Env are detectable in Groups #1 and #4 only at week 14 
(after the first protein co-administration); 
 
Peptide microarray for mapping of linear epitope has been completed on a subset of 
15 AUP512 animals (3 from each of the 5 groups) that are among the top binders for 
Env and/or gp70-V1V2 binding in the Luminex assay. For each animal week 0 and 
week 26 samples were tested. The results obtained indicate: 
 
Animals in AUP 512 developed binding Abs targeting multiple epitopes:  
 
C1, C1-V1, V2, C3, V3, C5 of gp120. 
 
No binding was seen in gp41.  
 
V3-response dominated in most animals, followed by C5, C3, and C1.  
 
No significant difference was seen among the groups for binding patterns. 

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 
Appearance of neutralizing antibodies followed the same kinetics of the IgG binding 
antibodies; 
 
T-cell responses were greater in the DNA prime/NYVAC boost group. 
AUP512 demonstrated that earlier immunization with protein (week 0 vs week 14) 
induces earlier IgG binding and neutralizing antibody responses, and heterologous DNA 
prime and NYVAC boost regimens induces greater T-cell responses compared to 
homologous NYVAC or DNA prime boost regimens. 
With regard to safety, no apparent toxicity was observed during the course of this study 
and the vaccines were well-tolerated. Minimal dose site reactions were observed and any 
changes in clinical pathology were generally mild in nature, often preexisting conditions 
or incidental findings. Overall, the study animals were devoid of any signs of clinical 
abnormality. The only scorable reporting was inappetence and occasional Grade 1 local 
reactions. The days with the most inappetence correlate with anticipated recovery times 
from either fasting or sedation. 
4.7.4 
Dose-range Immunogenicity study of Bivalent Clade C gp120 (TV1.C and 1086) / 
AS01B in mice 
The objective of this experiment was to assess the dose response relationship of bivalent 
Clade C gp120 (TV1.C and 1086) antigens in CB6F1 mice when formulated in 
combination with AS01B, in terms of antigen-specific cellular and humoral responses. 
Animals were immunized intramuscularly on Day 0, 14, and 28 with 10 mcg, 2 mcg, 0.4 
mcg, or 0.08 mcg of bivalent (TV1.C and 1086) gp120 antigens formulated with 50 mcL 
of AS01B. The induced T cell and antibody responses were characterized at 7 and 14 days 
post third dose, respectively. 
The bivalent 1086-TV1.C / AS01B vaccine formulation elicited 1086C and TV1.C-
specific CD4+ T cell responses for all tested doses. No statistically significant differences 
were observed between doses, however, a trend for higher 1086C-specific CD4+ T cell 
responses was observed with lower doses of 1086-TV1.C / AS01B (Figure 4-9-Panel A). 
This was not observed when measuring the TV1.C-specific CD4+ T cell responses 
(Figure 4-9-Panel B). The vaccine-induced CD8+ T cell responses at 7 days after third 
immunization were low to undetectable for both, TV1 and 1086 responses. The bivalent 
(1086C-TV1.C) gp120 antigens adjuvanted in AS01B induced dose-dependent high levels 
of 1086C and TV1.C-specific antibody responses at 14 days post second and third 
immunization (Figure 4-9-Panel C). Moreover, for all antigen doses tested, similar levels 
of 1086C and TV1.C specific total immunoglobulin (Ig) responses were observed, 
suggesting that there is no negative impact on the humoral responses when combining 
1086C and TV1.C antigens in AS01B. Anti-V1V2 total Ig responses were also detected in 
all the groups (Figure 4-9-Panel D). 

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Figure 4-9: Animals were intramuscularly immunized with 10 μg, 2 μg, 0.4 μg or 0.08 g of 
bivalent (TV1 and 1086) antigen formulated in 50 μL of AS01B at Days 0, 14 and 28. 
Percentage of CD4+ T cells secreting IFN-and/or IL-2 and/or TNFα was measured at 7 days 

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post-third immunization (Panels A and B). Intracellular staining performed on peripheral 
blood lymphocytes after a 6-hour re-stimulation with TV1 and 1086 clade C gp120 antigens. 
4 pools of 6 mice with median are represented. Anti-TV1 and anti-1086 (Panel C) and anti-
gp70-V1V2 (Clade B/Case A2) (Panel D) binding antibody titers measured by ELISA 14 days 
post-third immunization (Blue dots=14 days post-dose 2; Red dots=14 days post-dose 3). 
4.8 
Clinical studies 
4.8.1 
Clinical studies with DNA-HIV-PT123 
HVTN 096/EV04: DNA-HIV-PT123, NYVAC (NYVAC-HIV-PT1 and NYVAC-HIV-
PT4), and AIDSVAX B/E are currently being tested in an early phase clinical trial. 
HVTN 096/EV04 is being conducted exclusively in Lausanne, Switzerland. The HVTN 
096/EV04 study design is shown in Table 4-9. 
Table 4-9 Study design of HVTN 096/EV04 
Group 
N 
Month 0 
Month 1 
Month 3 
Month 6 
1 
20 
NYVAC1 
NYVAC 
NYVAC+ AIDSVAX 
B/E3 
NYVAC+ 
AIDSVAX B/E 
4 
Placebo4 
Placebo 
Placebo 
Placebo 
2 
20 
NYVAC+ 
AIDSVAX B/E 
NYVAC+ 
AIDSVAX B/E 
NYVAC+ AIDSVAX 
B/E 
NYVAC+ 
AIDSVAX B/E 
4 
Placebo 
Placebo 
Placebo4 
Placebo 
3 
20 
DNA2 
DNA 
NYVAC+ AIDSVAX 
B/E 
NYVAC+ 
AIDSVAX B/E 
4 
Placebo 
Placebo 
Placebo4 
Placebo 
4 
20 
DNA+ AIDSVAX 
B/E 
DNA+ AIDSVAX 
B/E 
NYVAC+ AIDSVAX 
B/E 
NYVAC+ 
AIDSVAX B/E 
4 
Placebo 
Placebo 
Placebo4 
Placebo 
Total 
80/16 
 
 
 
 
1NYVAC: NYVAC-HIV-PT1 and NYVAC-HIV-PT4 containing clade C ZM96 gp140 and ZM96 gag- CN54 pol-nef 
respectively, each delivered at a dose of ≥ 5x106 plaque-forming units (PFU), administered IM. 
2DNA: DNA-HIV-PT123 containing clade C ZM96 gag and gp140, CN54 pol-nef, delivered at a dose of 4 mg, 
administered IM. 
3AIDSVAX B/E: 300mcg of subtype B (MN) HIV gp120 glycoprotein and 300mcg of subtype E (A244) HIV gp120 
glycoprotein absorbed onto 600mcg of aluminum hydroxide gel adjuvant, administered IM. 
4Placebo: Sodium Chloride for injection, 0.9% administered IM. 
HVTN096/EV04 completed accrual of 96 participants in April, 2013. As of October 31st, 
2014 there have been no SAEs reported that were deemed related to the study products. 
There was 1 death by cranial trauma in a motorcycle accident. In studies where these 
vaccines and other similar vaccines were given, the most common complaints have been 
injection site pain/itching, myalgia/arthralgia, headache, and malaise/fatigue. Most of 
these reactions have been mild to moderate. By October, 2013, all participants had 
completed the vaccine regimens in HVTN 096/EV04, and the most common complaints 
have been mild or moderate malaise/fatigue, myalgia, headache and injection site pain. 
The most common AE deemed by the site investigator to be related to study product was 
lymphadenopathy (n=9, 9.4%). 
Interim immunogenicity data analysis has shown that the DNA prime/NYVAC-
AIDSVAX boost regimen induces higher number of responders and greater magnitude of 
both CD4 and CD8 T-cell responses. In particular, CD4+ T cell response rates and 

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magnitudes for any potential T-cell epitopes are greater in the DNA primed compared to 
NYVAC primed groups, with or without protein co-administration during the prime.  
Co-administration of protein with DNA or NYVAC from the first injection leads to early 
(after 2nd immunization) induction of both binding and neutralizing antibody responses 
in group 2 and 4. Of note there is a trend to more durable antibody responses at the month 
12 timepoint in group 4 (DNA / protein prime with NYVAC / protein boost). 
Additionally, co-administration of protein with DNA or NYVAC from priming 
substantially reduces the generation of IgA binding Ab responses to gp140 and gp120. 
HVTN 092 (BB-IND 15315): DNA-HIV-PT123 in combination with bivalent NYVAC 
(NYVAC-HIV-PT1 and NYVAC-HIV-PT4) vaccines will provide additional safety and 
possibly immunogenicity data. The study opened in April, 2013 and is being conducted 
in the US and Lausanne, Switzerland. As of November 2013, 143 participants had been 
enrolled. The DNA-HIV-PT123 vaccine has been well-tolerated. The most common 
complaints have been mild or moderate injection site pain/tenderness, myalgia, headache, 
and malaise/fatigue. There have been no SAEs related to the DNA-HIV-PT123 vaccine. 
There was 1 SAE, a case of myocarditis, deemed related to NYVAC vaccination that 
prompted a hold on vaccinations. 
HVTN 105 (BB-IND 15997): assesses several vaccine regimens of DNA-HIV-PT123 in 
combination with AIDSVAX B/E. The study opened in July, 2014 and is being 
conducted at multiple sites in the US. The study is fully enrolled and as of April 6, 2015, 
no SAEs have been reported. No AEs graded severe or higher have been reported, and all 
AEs deemed related to the study product have been assessed as mild. The DNA-HIV-
PT123 vaccine has been well-tolerated. The most common complaints have been mild or 
moderate injection site pain/tenderness, headache, and malaise/fatigue. 
4.8.2 
Clinical studies with Novartis Vaccines HIV-1 subunit protein vaccines with MF59 
Although Novartis Bivalent Subtype C gp120 proteins have not yet been administered to 
humans, other closely related recombinant monomeric (gp120) subunit vaccine 
formulations 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 [64]. MF59 safety has been established in clinical studies as 
well as in commercial products. A seasonal influenza vaccine adjuvanted with MF59 
(Fluad®) is licensed in the EU and other countries for use in the elderly. MF59 is also 
used in a pre-pandemic H5N1 influenza vaccine (Aflunov®) licensed in the EU for use in 
adults, and in 2 pandemic H1N1 influenza vaccines (Focetria® and Celtura®), licensed in 
the EU and other countries for use in adults and children. More than 100 million doses of 
MF59-adjuvanted influenza vaccines have been distributed in licensed products. 
Recombinant monomeric (gp120) vaccine candidates studied include Chiron’s early 
gp120-based candidates from subtypes B and E, most of which were CHO-based and 
administered with MF59. More than 1200 subjects participated in the evaluation of the 
Chiron HIV SF2 gp120/MF59 vaccine and the Chiron HIV CM235 Thai E gp120/MF59 
vaccine [62,65-69]. Two clinical trials were conducted using Novartis CHO-based 
subtype B gp140 recombinant Env protein with MF59. There are 3 ongoing phase 1 
studies with Novartis CHO-based subtype C gp140/MF59, 2 of them are being conducted 
by the NIH-sponsored HVTN in the US and the RSA. Additionally, several HVTN phase 

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1/2a studies testing the protein/MF59 combination from HVTN 108 are scheduled to start 
as early as Q1 2015. Table 4-10 summarizes clinical trial experience with Novartis gp120 
and gp140 recombinant vaccine candidates. 
Table 4-10 Novartis recombinant gp120 and gp140 vaccines in human clinical trials* [67] 
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 
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 
140 
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)/MF59 and SAAVI DNA-C2 
and SAAVI MVA-C 
24 
HVTN073E 
Completed 
Subtype C (TV1) gp140 (CHO) & ISS TAT 
11 
ISS P-002 
Terminated* 
Subtype C (TV1) gp140 (CHO)/MF59 
36 
HVTN 088 
Completed 
Subtype C (TV1) gp140 (CHO)/MF59 and SAAVI DNA-C2 
and SAAVI MVA-C 
110 
HVTN 086 
Completed 
Bivalent Subtype C gp120/MF59 and ALVAC-HIV 
(vCP2438) 
210 
HVTN 100 
Planned 
* Due to slow enrollment and expiration of the study product stability program. 
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 [4,62,65-71]. 
4.8.2.1 
Summary of safety, reactogenicity, and tolerability from recent human experience 
There were 2 clinical trials conducted recently using Novartis CHO-based subtype B 
gp140 with MF59. In addition there have been 4 recent clinical trials using Novartis 
CHO-based subtype C gp140.  
A phase 1 single-center trial (C86P1) was conducted using Novartis CHO-based subtype 
B gp140 recombinant Env protein in Great Britain by the Mucosal Vaccines for Poverty 
Related Diseases (MUVAPRED) Consortium to assess safety, tolerability, and 
immunogenicity of IN administration of subtype B gp140 with and without the mucosal 
adjuvant LTK63 (detoxified mutant heat labile protein) followed by IM boosting with 
subtype B gp140/MF59. This study enrolled 30 healthy volunteers aged 18-45, with 20 to 

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receive gp140. The protocol was amended to halt further IN administration of LTK63 
following a report of an AE (ie, facial nerve paralysis) with a possible association with 
the LTK63 adjuvant in another study [72]. During the study, there was 1 SAE reported of 
Bell’s Palsy (facial nerve paralysis) considered possibly related to the study vaccine 
LTK63 in a subject who never received any subtype B gp140 protein or any protein with 
MF59 adjuvant. IN vaccination was reactogenic resulting in upper respiratory tract 
symptoms including nasal congestion, nasal discomfort, pharyngo-laryngeal pain and 
rhinorrhea. The subtype B gp140 MF59 was well tolerated following IM boost.  
Another completed study with Novartis subtype B gp140 MF59 was a multicenter, 
placebo-controlled trial (HVTN 049) conducted by the HVTN in the United States [21]. 
Subjects received 1 of 3 doses of a DNA/PLG vaccine (subtype B gag DNA/PLG and 
subtype B env DNA/PLG microparticles, at doses of 250/250, 500/500, or 
1000/1000mcg) 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 4 events reported as SAEs that were not 
considered related to the study vaccine. A death attributed to cocaine overdose occurred 
in 1 subject, 10 days after receipt of the second dose of the placebo. One subject had a 
Grade 3 increase in creatine phosphokinase (CPK) to 2311 U/L, 14 days after the first 
DNA prime vaccination, which resolved within a week. Another subject had a Grade 4 
increase in CPK to 4806 U/L 15 days after the first DNA prime vaccination, which 
resolved within 2 weeks. Both subjects reported to have initiated new exercise programs 
(one weight lifting and the other aerobics and weight lifting). One subject experienced 
severe fatigue 20 days after the fourth immunization (including 1 dose of subtype B 
gp140/MF59), attributed to working 2 jobs and long hours. Overall, the regimens were 
well tolerated.  
A third study, HVTN 073E, was conducted in the US and RSA as an extension to the 
previous HVTN 073/SAAVI 102 study. This extension study examined the safety and 
immunogenicity of 2 boosting doses of Novartis subtype C gp140/MF59 or placebo in 
subjects who previously received 3 vaccinations of SAAVI DNA-C2 and 2 vaccinations 
of SAAVI MVA-C. This study enrolled 27 subjects. There was 1 report of endometrial 
intra-epithelial neoplasia resulting in hospitalization for hysterectomy, which was 
reported as an SAE and assessed as unrelated to study agents. 
Two other recent phase 1 studies with Novartis subtype C gp140/MF59 have been 
conducted by the HVTN in the US and the RSA. In addition, 1 phase 1 trial was 
conducted by the Istituto Superiore di Sanità (ISS) in Italy. One of these trials, HVTN 
088, was conducted in the 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 enrolled 16 previously vaccinated subjects and 20 naive 
controls. Individuals were identified who had received a clade B Env protein with MF59 
4-17 years earlier, most in combination with a DNA or ALVAC prime. These individuals 
were enrolled in HVTN088 to receive a clade C protein boost in an open label phase 1 
trial. There have been 3 SAEs reported in this trial, 1 involving traumatic injury, 1 
instance of gastroenteritis, and 1 of appendicitis. All of these were assessed as unrelated 
to study agents.  

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The second HVTN study, HVTN 086, was conducted in the RSA. It evaluated the safety 
and immunogenicity of various combinations of SAAVI DNA-C2, SAAVI MVA-C, and 
Novartis subtype C gp140/MF59. All scheduled clinic visits have been completed, 
though study participants remain subject to annual contacts to assess their health status. 
This study enrolled 184 subjects. To date, 6 SAEs have been reported in this study, 1 case 
of acute tonsillitis that required hospitalization, 1 of schizophrenia requiring 
hospitalization (later determined to be a pre-existing condition), 1 of pelvic inflammatory 
disease, 1 soft-tissue injury, 1 instance of anemia, and 1 instance of alcohol-related 
cardiomyopathy. All were assessed as not related to the study products. 
The ISS study (ISS P-002) conducted in Italy examined the safety and immunogenicity of 
subtype C gp140 co-administered with ISS TAT compared to subtype C gp140 alone or 
TAT alone. The study includes intradermal and IM injections (100 mcg for subtype C 
gp140 and 7.5 mcg for ISS TAT). This study did not include MF59. This study was 
stopped early due to slow enrollment and subsequent expiration for the study product 
stability program. No SAEs were reported in this study. 
4.8.2.2 
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 IFN-γ ELISpot and 
ICS responses. Immunogenicity was assessed 14 days after each vaccination. Env-
specific IFN-γ ELISpot response rates did not increase substantially after the 3 1000-mcg 
DNA/PLG prime vaccinations (6/27) compared to baseline, but did rise after the first 
protein/MF59 boost (14/25). nAb titers against the homologous SF162 isolate were 
undetectable after the third 1000 mcg DNA/PLG priming vaccination. Neutralization was 
boosted to high titers in all subjects following the second protein boost. Similarly in the 
group of subjects who received subtype B gp140/MF59 without a DNA/PLG prime, a 
nearly complete response to the SF162 isolate was observed at the second vaccination (all 
but 1 subject) which lasted through the third vaccination. Binding Ab titers against Env, 
measured by enzyme-linked immunosorbent assay (ELISA), were detected following the 
first subtype B gp140/MF59 boost and were very high following the second boost 
administration [21].  
The C86P2 MUVAPRED IN study, demonstrated immunogenicity with considerable IgG 
and IgA Ab responses to subtype B gp140 in serum, cervical, and vaginal secretions of 
subjects following IN administration of subtype B gp140 with the adjuvant LTK63 and 
an IM boost with subtype B gp140 and M59 adjuvant. nAb responses against the 
homologous SF162 were also detected in all groups following IM boost with subtype B 
gp140 and MF59 adjuvant. 
Available data from HVTN 073E show that boosting with protein improves binding and 
neutralizing antibody responses for DNA/MVA primed subjects. All participants who 
received the protein boost had binding antibody responses to TV1.21 gp140 2 weeks after 
the last protein boost and these responses persisted in all participants 6 months later. 
After the last protein boost, neutralizing antibody responses to MW965.26 were seen in 
all participants and persisted in 75% of participants for at least 6 months. Notably, 
neutralizing antibody responses, which were not detected in the main HVTN 073/SAAVI 
102 dataset, were detected after a single protein boost in the study extension. In the 
absence of priming, several protein administrations are typically required to elicit 
neutralizing antibody responses. That these responses were detected after a single dose 

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indicates efficient priming by the DNA/MVA regimen and points to protein boosts as an 
effective way to boost such responses. 
In addition, in the subtype C gp140/MF59 HVTN 088 long-interval boost study 16 
previously primed volunteers and 20 naïve volunteers each received 2 doses of the 
subtype C gp140/MF59 given 6 months apart. HIV-1–specific CD4+ and CD8+ T-cell 
responses were measured by an ICS assay. Ab responses were measured with a Luminex 
binding Ab assay and a nAb assay in TZM-bl cells. Despite the long interval (4-17 years 
from prior protein/MF59 administration), 5 of 16 (31%) of primed participants 
demonstrated CD4+ T-cell responses to Env at baseline, which increased to 12 of 16 
(75%) after a single protein boost. IgG and IgA responses to Con S gp140were present in 
64% (IgG) and 7% (IgA) of primed participants at baseline, and rose to 93% and 85%, 
respectively, after 1 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 vaccine-matched oligomeric TV1 Env in 88% and 50%, respectively. nAb 
developed to MN in 38% and to MW965.26 in 88% of the unprimed participants.  
Three of the 4 vaccine regimens in HVTN 086 contained Novartis subtype C 
gp140/MF59, either as a boost following pox-vector (MVA) primes, administered 
concurrently with a pox-vector (MVA) vaccine, or in a concurrent pox-vector/protein 
boost and second protein boost following DNA plasmid primes. Ab responses were 
measured with a Luminex binding Ab assay and a nAb assay in TZM-bl cells. All three 
vaccine regimens containing subtype C gp140/MF59 elicited high rates (82–100%) and 
magnitudes of IgG binding Ab against a range of gp120 and gp140 antigens. All vaccine 
regimens had evidence of nAb to (Tier 1) HIV strains MN.3, MW965.26, and SF162.LS, 
with the MVA- and DNA-primed regimens showing the highest titers to MW965.26, a 
clade C strain. HIV-1 specific CD4+ and CD8+ T-cell responses to global potential T-
cell epitopes (PTEg) were measured by an ICS assay. The MVA- and DNA-primed 
vaccine regimens elicited the highest rates of CD4+ T cells producing IFN-γ and/or IL-2 
(77% and 45%, respectively), while the regimen with concurrent MVA/protein 
administration elicited the lowest rate (13%). 
4.8.3 
Clinical studies with GSK HIV-1 subunit protein vaccines with AS01B 
Immunogenicity data for studies HVTN 041, PRO HIV-005, ECR-004 and PRO HIV-
002 are presented in Section 4.5.3 and 4.5.4.  
The safety, reactogenicity and tolerability profiles of the vaccine regimens investigated in 
these studies were considered acceptable and are presented below. 
HVTN 041 evaluated a combination vaccine (NefTat and gp120W61D) formulated with 
AS02A (which is an oil-in-water emulsion of a combination of MPL and QS-21, while 
AS01 is a liposomal formulation of the same components) administered at 0, 1 and 3 
months with varying doses (5, 20 and 100 mcg) of the gp120 vaccine component (the 
NefTat antigen dose was constant at 20mcg).  
The vaccinations were well tolerated and none were discontinued because of vaccine-
associated reactogenicity. The most common local symptoms were pain and tenderness. 
Systemic symptoms were generally mild with the exception of moderate myalgia and 
headache occurring in 20 and 25%, respectively. Both symptoms were evenly distributed 
in the 3 NefTat and gp120W61D groups (20% in each group for myalgia and from 10 

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[2/20 subjects] to 40% [8/20 subjects] per group for headache). Severe pain was observed 
in 2/20 subjects of 2 NefTat and gp120W61D groups (5 mcg and 100 mcg of gp120). 
Severe tenderness was observed in 2/20 subjects of 1 NefTat and gp120W61D group (5 
mcg of gp120). Severe malaise was observed in 2/20 subjects of 1 NefTat and 
gp120W61D group (20 mcg of gp120). All vaccine-related reactogenicities were 
transient and had either improved or resolved within 48 h of onset. Grade 4 laboratory 
abnormalities were observed in 1 single participant who was administered the AS02A-
adjuvanted NefTat 20 mcg / gp120W61D 5 mcg vaccine. This participant had an elevated 
CPK value which may have been due to creatine supplements taken prior to exercise and 
likely not vaccine related. There were 6 serious adverse events during the trial that 
occurred within 24 hours postvaccination and were felt to be probably or definitely due to 
the immunizations. These included 2 severe local site reactions in group NefTat 20 mcg 
and gp120W61D 5 mcg (associated to limitation of limb movement in 1 case), 2 
occurrences of severe malaise in 2 subjects of group NefTat 20 mcg / gp120W61D 20 
mcg, a febrile illness (103.2 ◦F) in 1 subject of group NefTat 20 mcg / gp120W61D 20 
mcg, and an episode of generalized urticaria in 1 subject from group NefTat 20 mcg / 
gp120W61D 100 mcg. All of these serious adverse events significantly improved within 
24 h of onset. It is important to note that none of these SAEs would be regarded as such 
in accordance with the current ICH E2A definitions. Grade 3 and Grade 4 related 
Adverse Events were considered SAEs per the “SAE reporting manual” active at the time 
of the study. 
PRO HIV-002 evaluated the gp120W61D 20 mcg / NefTat 20 mcg candidate HIV 
vaccine formulated with 1 of 3 different Adjuvant Systems (AS02A, AS02V and 
AS01B), each in 60 healthy HIV-seronegative adults. The vaccine candidates were 
administered at Month 0, Month 1, Month 3 and Month 6.  
During the 7-day follow-up period after vaccination, almost all doses (90.4% to 98.8%) 
were followed by at least 1 solicited or unsolicited symptom considered to be related to 
vaccination with no difference between groups. The reactogenicity profiles obtained in 
the present study were expected and confirmed the previous results obtained with these 
adjuvants. During the course of the study, a total of 14 SAEs were reported in 12 
subjects, none of them was causally related to vaccination.  
Local and general solicited symptoms could be divided into 4 groups given their 
frequency per dose given into brackets (by decreasing order): 
 
Pain (between 86.3% and 96.3%) with few grade 3 symptoms (≤ 3.4%). 
 
Fatigue (between 33.8% and 46.6%), feverishness (between 22.9% and 53.4%), 
headache (between 35.0% and 48.3%) and myalgia (between 25.8% and 43.3%). 
Few cases of grade 3 myalgia and fatigue were reported (≤ 4.2%). For 
feverishness the frequency of grade 3 symptoms was 10.1% and for headache 
was 5.9% in the gp120/ NefTat/ AS01B group. 
 
Redness, swelling, nausea and fever: the frequency of those symptoms did not 
exceed 30.3%. Few grade 3 nausea and fever were reported (≤ 2.1%). The 
frequency of grade 3 redness and swelling was 20.2% and 13.9% respectively in 
the gp120/ NefTat/ AS01B group.  
 
Diarrhea and vomiting: the frequency of these symptoms was less than or equal 
to 7.5%. No grade 3 diarrhea was observed, and only 0.4% of the doses were 
followed by grade 3 vomiting. 

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Almost all general symptoms (fatigue, feverishness, headache, myalgia, nausea and fever, 
vomiting) were considered as related to the vaccination, except for diarrhea.  
The duration of general symptoms was less than or equal to 2 days in most cases whereas 
the duration of local symptoms was often more than 2 days. In the gp120/ NefTat/AS01B 
group the overall frequency of the general symptoms tended to be higher after the 2nd, 
3rd, or 4th dose of vaccine compared to the first dose (but not for all symptoms and all 
groups). 
The incidence of unsolicited AEs ranged from 78.3% to 83.3%. The most frequently 
reported symptoms were upper respiratory tract infections and headache, followed by 
injection site induration, injection site pruritus and pharyngeal pain. Less than half 
unsolicited symptoms were causally related to vaccination (incidence between 31.7% and 
36.7%). The most frequent symptoms causally related to vaccination were administration 
site reactions (injection site induration, pruritus or warmth) and asthenia. Few grade 3 or 
grade 3 related symptoms occurred: 18 subjects (incidence between 6.7% and 13.3%. 
according to group) experienced grade 3 unsolicited symptoms, among which a majority 
were non-related infectious conditions (cystitis, gastroenteritis, otitis, pyelonephritis, 
tonsillitis, tooth abscess, upper respiratory tract infection and vaginal candidiasis). 6 of 
them had symptoms considered to be causally related to vaccination (lymphadenopathy, 
palpitations, application site hyperesthesia, asthenia, muscle rigidity, headache, and 
tremor).  
No significant changes in laboratory parameters (hematology, biochemistry, urinalysis) 
and vital signs were observed throughout the study. 
PRO HIV-005 evaluated an HIV vaccine candidate consisting of a recombinant fusion 
protein (F4) containing 4 HIV-1 clade B antigens (Gag p24, Pol-RT, Nef, and Gag p17) 
adjuvanted with AS01B in 3 different doses: 10, 30, and 90mcg. Each dose of the 
AS01B-adjuvanted vaccine candidate was administered twice in a group of 50 subjects, 
following a Month 0 and Month 1 schedule. Three control groups of 10 subjects received 
a dose of 10, 30 or 90 mcg F4 in water for injection (WFI).  
Reactogenicity was higher during the 7-day period after each vaccine dose in the 
F4/AS01 groups than in the F4 in WFI groups. The incidence of local and general 
symptoms tended to be higher in the F4/AS01 groups after the second vaccine dose. Pain 
was the most common solicited local symptom, reported after 96.0%–98.0% of doses in 
the F4/AS01 groups and after 10.0%–30.0% of doses in the F4 in WFI groups (grade 3 
severity after 5.0%-10.1% of doses in the F4/AS01 groups). Fatigue was the most 
common solicited general symptom, reported after 66.0%-77.8% and 30.0%-45.0% of 
doses in the F4/AS01 and F4 in WFI groups, respectively (grade 3 severity after 7.0%-
12.1% of doses in the F4/AS01 groups). Fever of more than 39°C was reported in 3.0%, 
2.0% and 1.0% of the doses in the respective 10, 30 and 100 mcg F4/AS01 groups). No 
solicited local or general grade 3 symptoms were reported in the F4 in WFI groups. No 
differences in reactogenicity were observed between the antigen dose levels in the 
F4/AS01 groups. During the 30-day postvaccination period, 60.0%–84.0% of subjects in 
the F4/AS01 groups reported unsolicited symptoms, compared with 50.0%–70.0% in the 
F4 in WFI groups. In the F4/AS01 groups, unsolicited symptoms (mainly chills and 
injection site reactions) were considered causally related to vaccination in 30.0%–44.0% 
of subjects and were of grade 3 severity in <10.0%. All related symptoms were transient 
and resolved without sequelae, generally within 2–3 days. Six serious adverse events 
were reported in the F4/AS01 groups, all considered unrelated to vaccination No subjects 
died during the study period, and no subject withdrew because of adverse events. 

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ECR 004, a subset of volunteers primed 3 years before with 2 doses F4 10 mcg / AS01B 
(PRO HIV-005) received a (third) single booster dose of F4 10 mcg / AS01B.  
93.3% (ie, 14 out of 15 subjects) of the subjects reported at least 1 AE and 40% (ie, 6 out 
of 15 subjects) of the subjects in the group F4 reported at least 1 grade 3 symptom 
considered by the investigator to be related to vaccination. Pain was the most frequent 
solicited local AE. Grade 3 pain (13.3% or in 2 out of 15 subjects), redness (in 6.7% or in 
1 out of 15 subjects) or swelling (in 13.3% or in 2 out of 13 subjects) were reported for a 
maximum duration of 2 days. Fatigue and headache were the 2 most frequently reported 
solicited general AEs. Fever was recorded in 6 out of 15 subjects (40%) within the 2 days 
after vaccination. Grade 3 fatigue (in 20% or in 3 out of 15 subjects) or fever (in 1 out of 
15 subjects) was reported with a maximum duration of 1 day. Grade 3 unsolicited AEs 
were reported by 13.3% (ie, 2 out of 15 subjects). Out of these cases, 2 cases were 
considered by the investigator to be causally related to vaccination: 1 case of chills and 1 
case of insomnia. All of the grade 3 unsolicited AEs were resolved without sequelae. No 
subjects died, experienced an SAE, or withdrew due to an AE. 
4.9 
Potential risks of study products and administration 
Table 4-11 summarizes the potential risks associated with administration of the study 
products.  

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Table 4-11 Summary of potential risks of study products and administration 
Common 
 Mild to moderate injection site pain, tenderness, erythema, or 
swelling/induration/edema 
 Fever, malaise/fatigue/weakness, chills, myalgia, nausea, or 
headache in the first few days following injection 
 A vaccine-induced positive HIV Ab test result 
Less common 
 Severe injection site pain or tenderness 
 Flu-like syndrome, arthralgia, rash, or dizziness in the first few 
days following injection  
 Vasovagal reaction/lightheadedness/dizziness related to the 
injection procedure 
 Diarrhea, vomiting 
 Lymphadenopathy 
 Transient changes in clinical laboratory values 
 Injection site hematoma, bruising/ecchymosis, other transient 
lesions, warmth, itching, or bleeding related to the injection 
procedure 
Uncommon or rare 
 Severe localized injection site reaction, such as sterile abscess or 
secondary bacterial infection 
 Abdominal pain  
 Allergic reaction, including rash, urticaria, angioedema, 
bronchospasm, or anaphylaxis 
 Muscle damage at the injection site 
Theoretical risks 
 Autoimmune disease  
 Neuromuscular system disorders: Neuralgia, paresthesias, neuritis, 
convulsions, encephalomyelitis, muscle weakness, and Guillain-
Barré syndrome 
 Thrombocytopenia 
 Effects on a participant’s response to an approved HIV vaccine 
administered in the future 
 Effects on susceptibility to HIV, if the participant is exposed to 
HIV  
 Effects on the course of HIV infection/disease, if the participant is 
infected with HIV 
 Effects on the fetus and on pregnancy 

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5 
Objectives and endpoints 
5.1 
Primary objectives and endpoints 
Primary objective 1 
 
To evaluate the safety and tolerability of DNA and/or different doses of clade C 
bivalent gp120 protein with either MF59 or AS01B adjuvant in various regimens in 
HIV uninfected healthy adults. 
Primary endpoints 1 
 
Severe local and systemic reactogenicity signs and symptoms (pain, tenderness, 
erythema, induration, fever, malaise/fatigue, myalgia, headache, nausea, vomiting, 
chills, arthralgia) up to 7 days after each vaccine dose 
 
AEs by body system, Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term, severity, and assessed relationship to study products up to 30 days 
after each vaccine dose 
 
SAEs, AESIs, and new chronic conditions (requiring medical intervention for ≥ 30 
days) throughout the study 
 
Laboratory measures: white blood cells (WBC), neutrophils, lymphocytes, 
hemoglobin, platelets, alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alkaline phosphate (ALP), and creatinine at baseline and following 
vaccinations 
 
AEs leading to early participant withdrawal or early discontinuation of study 
products administration throughout the study. 
Primary objective 2 
 
To evaluate the systemic immune responses at the Month 6.5 timepoint (2 weeks 
after the 4th vaccination) of clade C DNA, bivalent gp120 protein/MF59, and/or 
bivalent gp120 protein/AS01B in each vaccine regimen 
Primary endpoints 2 
 
HIV-specific total IgG binding antibody response breadth and magnitude as assessed 
by multiplex assay. 
 
Anti –V1/V2 scaffold IgG binding antibody responses as assessed by multiplex 
assay. 
 
Neutralizing antibody responses against HIV-1 isolates. 
 
HIV-specific CD4+ and CD8+ T-cell responses as assessed by flow cytometry. 

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5.2 
Secondary objectives and endpoints 
Secondary objective 1 
 
To further evaluate the systemic immune responses of each vaccine regimen at the 
Month 6.5 timepoint (2 weeks after the 4th vaccination)  
Secondary endpoint 1  
 
Contingent upon results from the primary immunogenicity objective described above 
(primary objective 2), additional immunogenicity assays may be performed on blood 
samples based on the HVTN Laboratory Assay Algorithm. 
5.3 
Exploratory objectives 
Exploratory objective 1 
 
To evaluate the durability of immunogenicity of each vaccine regimen measured at 
Month 12 (6 months after the 4th vaccination) 
Exploratory objective 2 
 
To further evaluate immunogenicity of each vaccine regimen, additional 
immunogenicity assays may be performed on blood and mucosal samples, including 
samples from other timepoints, based on the HVTN Laboratory Assay Algorithm  
Exploratory objective 3 
 
To assess whether the diversity of gut microbiome correlates with vaccine responses 
using optionally provided stool specimens. 
Exploratory objective 4 
 
To conduct analyses related to furthering the understanding of HIV, immunology, 
vaccines, and clinical trial conduct 

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6 
Statistical considerations 
6.1 
Accrual and sample size calculations 
Recruitment will target enrolling 334 healthy, HIV-uninfected adult participants ages 18-
40 in Southern Africa and the United States. Participants will be randomized to 8 
treatment groups (7 vaccine groups and 1 placebo group). Vaccine groups 1-3 share the 
same DNA prime and test 3 different boosts consisting of DNA coadministered with a 
protein/adjuvant combination (gp120 proteins at 100 mcg with MF59 adjuvant, gp120 
proteins at 100 mcg with AS01B, or gp120 proteins at 20 mcg with AS01B) at 2 
timepoints. In groups 4-6 the DNA is coadministered with 1 of the protein/adjuvant 
combinations at 3 timepoints. An additional vaccine group (group 7) will test the proteins 
alone at the 20 mcg dose adjuvanted with AS01B administered at 3 timepoints. Groups 2, 
3 and 5-7 will enroll 50 participants per group. Groups 1 and 4 evaluating the proteins 
adjuvanted with MF59 will enroll 30 participants per group as these two vaccine 
regimens are also being evaluated in HVTN 111 at sites in Southern Africa (HVTN 111 , 
n=30 per group). Evaluation of these 2 regimens will pool data from HVTN 108 and 
HVTN 111 for a total of 60 participants per group. The primary purpose of the placebo 
group (Group 8 n=24) is to ensure blinding. To ensure that both men and women will be 
adequately represented in the trial, the trial will enroll at least approximately 40% of each 
sex overall. Hence, when approximately 200 participants of 1 sex are enrolled, 
recruitment of persons born of that sex will stop. 
Since enrollment is concurrent with receiving the first study vaccination, all participants 
will provide some safety data. However, for immunogenicity analyses, it is possible that 
data may be missing for various reasons, such as participants terminating from the study 
early, problems in shipping specimens, low cell viability of processed peripheral blood 
mononuclear cells (PBMCs) or high background. Immunogenicity data from 17 phase 1 
and 2 phase 2a HVTN vaccine trials, which began enrolling after June 2005 (data as of 
September 2014), indicate that 15% is a reasonable estimate for the rate of missing data 
at Month 6.5. For this reason, the sample size calculations in Section 6.1.2 for n=50 
account for 7 enrolled participants on each group having missing data for the primary 
immunogenicity endpoint.   
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. Various statistical considerations for safety assessment are 
addressed below based on groups with n=50. The statistical properties for the combined 
safety data from the MF59 regimens in 108 and 111 (n=60 for each) will be slightly 
better than the properties for n=50 discussed below.  
The ability of the study to detect serious adverse events (SAEs) (See Section 11.2) can be 
expressed by the true event rate above which at least 1 SAE would likely be observed and 
the true event rate below which no events would likely be observed. Specifically, for each 
group of the study (n =50), there is a 90% chance of observing at least 1 event if the true 
rate of such an event is 4.5% or more; and there is a 90% chance of observing no events 
if the true rate is 0.2% or less. As a reference, in HVTN vaccine trials from December 
2000 through April 2014, about 4% of participants who received placebos experienced an 
SAE.  

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Probabilities of observing 0, 1 or more, and 2 or more events among groups of size 50 are 
presented in Table 6-1 for a range of possible true adverse event rates. These calculations 
provide a more complete picture of the sensitivity of this study design to identify 
potential safety problems with a vaccine regimen. 
Table 6-1 Probability of observing no events, 1 or more events, and 2 or more events, 
among groups of size 50, for different true event rates 
True event rate (%) 
Pr(0/50) 
Pr(1+/50) 
Pr(2+/50) 
1 
0.61 
0.39 
0.09 
4 
0.13 
0.87 
0.60 
10 
0.005 
0.99 
0.97 
20 
<0.001 
>0.99 
>0.99 
30 
<0.001 
>0.99 
>0.99 
An alternative way of describing the statistical properties of the study design is in terms 
of the 95% confidence interval for the true rate of an adverse event based on the observed 
data. Table 6-2 shows the 2-sided 95% confidence intervals for the probability of an 
event based on a particular observed rate. Calculations are done using the score test 
method [73]. If none of the 50 participants receiving a vaccine regimen experience a 
safety event, the 95% 2-sided upper confidence bound for the true rate for such an event 
is 7.1%. 
Table 6-2 Two-sided 95% confidence intervals based on observing a particular rate of safety 
endpoints for groups of size 50 
Observed event rate 
Confidence interval (%) 
0/50 = 0.0% 
(0.0, 7.1) 
1/50 = 2.0% 
(0.4, 10.5) 
2/50= 4.0% 
(1.1, 13.5) 
5/50 = 10.0% 
(4.3, 21.4) 
10/50 = 20.0% 
(11.2, 33.0) 
20/50 = 40.0% 
(27.6, 53.8) 
6.1.2 
Sample size calculations for immunogenicity 
The primary immunogenicity evaluation of each vaccine regimen will be an assessment 
of whether the regimen meets the ‘adequate take/potency’ (ATP) conditions, which are 
based on the assessment of the primary immunogenicity endpoints (section 5.1). For 
purposes of power and type 1 error calculations we use ATP conditions as defined in 
Table 6-3 based upon 11 endpoints from 4 immunogenicity assays. The assessment of the 
group 1 and 4 vaccine regimens, which use the MF59 adjuvant, will be based on the 
pooled HVTN 108 and HVTN 111 data. Since our knowledge of the importance of 
immunologic endpoints is evolving with time, changes may be made to the ATP 
definition prior to ATP assessment. The final criteria used to assess the ATP condition, 
once the trial is complete, and before analysis has commenced, will be defined in the 
HVTN 108 Statistical Analysis Plan (SAP). 

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Table 6-3 Adequate take/potency definition for power and type 1 error calculations (as of 
January 2015), ATP is established as meeting criterion (1) and at least 2 of criteria (2) - (4).  
Immunogenicity endpoints 
Criteria 
(1) 1-3 endpoints: IgG binding antibodies 
to 3 vaccine-matched gp120 proteins  
1. For ≥ 2 gp120s the LL of the 95% CI for 
vaccine response rate > 65%  
(2) 4-6 endpoints: IgG binding to a panel of 
3 scaffolded-V1V2 proteins 
2. For ≥ 1 V1V2 variable the LL of the 95% 
CI for vaccine response rate > 30%  
(3) 7-9 endpoints: Neutralizing antibodies 
to 3 vaccine-matched gp120 pseudoviruses 
3. For ≥ 1 gp120 pseudoviruses the LL of the 
95% CI for vaccine response rate > 30%  
(4) 10-11 endpoints: CD4+ and CD8+ T-
cell response to at least 1 peptide pool  
4. The LL of the 95% CI for either CD4+ or 
CD8+ response rate to at least 1 peptide pool 
> 30%  
Criteria for ‘adequate take/potency’ for each category of endpoints are presented in the 
right column of Table 6-3 based on comparing the lower limits (LL) of the 95% CIs for 
the crude positive response rates with the thresholds for the category. These criteria have 
largely been chosen to reflect the findings of the correlates analysis performed in the 
wake of the RV 144 trial (see Section 4.1.2). Future phase 2b efficacy testing will target 
vaccine efficacy (VE) of at least 40%; therefore, we would like to screen out regimens 
that have an immunogenicity profile that is unlikely to provide this level of efficacy. In 
particular: 
1. The first category includes 3 variables measuring IgG binding antibodies to each of 
the 3 vaccine-matched gp120s. The criterion will be satisfied for this category if for 
≥2 gp120s the LL of the 95% CI for vaccine response rate is greater than 65%. The 
rationale for choosing this 65% threshold is the belief that high rates of homologous 
IgG binding antibodies are likely to be necessary for a vaccine to prevent HIV 
infection with VE of at least 40%. 
2. The second category includes IgG binding antibodies to a panel of scaffolded-V1V2 
proteins. IgG binding antibodies to V1V2 proteins have been identified as an immune 
correlate of risk in RV144 with a response rate of 64% (LL 58%). The criterion will 
be satisfied for this category if for ≥1 V1V2 endpoint the LL of the 95% CI for 
vaccine response rate is greater than 30%. The rationale for choosing this 30% 
threshold is to screen out regimens that have very low chance of achieving 40%VE; 
note that a perfect binary correlate of protection would require a 40% response rate to 
achieve 40% VE.  
3. The third category includes neutralizing antibody (Nab) to vaccine-matched gp120s. 
Nab are generally believed to be important for preventing infectious diseases. The 
criterion will be satisfied for this category if for ≥1 gp120s pseudoviruses the LL of 
the 95% CI for vaccine response rate is greater than 30%. The rationale for choosing 
this 30% % threshold is to screen out regimens that have very low chance of 
achieving 40%VE. 
4. The fourth category includes CD4+ and CD8+ T-cell responses to vaccine-matched 
peptide pools. Adequate T-cell responses may be necessary for an efficacious 
vaccine. The estimated CD4+ T-cell response rate was 74% (LL 68%) in RV144.The 
criterion will be satisfied for this category if the LL of the 95% CI for either CD4+ or 
CD8+ T-cell response rates to at least 1 peptide pool is greater than 30%. The 
rationale for choosing this 30% threshold is to screen out regimens that have very 
low chance of achieving 40%VE.  

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A vaccine group satisfies the ATP condition if it meets the criteria for the first category 
IgG binding antibodies to vaccine-matched gp120s and satisfies the criteria for at least 2 
out of categories 2-4.  
Figure 6-1 addresses the power and type 1 error for passing ATP for a regimen of size 43, 
which allows for missing assay data from 15% of participants in a group with 50 
participants enrolled. Among all possible configurations of the 11 endpoints in Table 6-3 
(based on the endpoint either passing or failing it’s individual pre-specified lower 
confidence limit threshold criteria), the minimum probability that a vaccine regimen 
passes the ATP condition given that it truly meets the condition and the maximum 
probability that a vaccine regimen passes the ATP condition given that it does not truly 
meet the condition are shown in Figure 6-1 for varying values of δ, where δ is the 
difference between the true response rate of an endpoint that passes the individual criteria 
and the lower confidence limit threshold. These calculations assume each individual 
endpoint either has positive response rate = lower confidence limit threshold (fails 
threshold criteria) or has positive response rate = threshold + δ (passes threshold criteria). 
The threshold value is used to define failure of the endpoint so that calculations provide 
the minimum power [P(Pass ATP|ATP)] and maximum Type 1 error [P(Pass ATP|Not 
ATP)]. With 43 participants, the probability of correctly identifying ATP for a regimen is 
at least 80% when δ=24%; and the probability of incorrectly identifying ATP for a 
vaccine regimen is at most 18% for δ ≤ 30% (Figure 6-1) (note that a vaccine does not 
satisfy the adequate take/potency condition if ≥ 2 endpoints in the first category fail or all 
endpoints in 2 or more of categories 2-4 fail). The group 1 and 4 regimens (HVTN 108 
and 111 pooled data) will have slightly better properties with anticipated sample size of 
51 participants evaluable for ATP. These simulations are based on 10,000 simulated 
datasets and use an exchangeable correlation structure between responses with pairwise 
correlations of 0.3 (a modest correlation based on RV144 data). 
 

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Figure 6-1 Power and type-I error for passing the individual regimen (n=43) adequate 
take/potency condition based on comparing positive response rates with prespecified 
thresholds (65% for IgG binding antibodies to vaccine-matched gp120s and 30% for other 
endpoints). The calculations assume an endpoint that passes its threshold criteria has 
positive response rate = δ% + threshold and an endpoint that fails its threshold criteria has 
positive response rate equal to the prespecified threshold. 
The correspondence between response rate point estimates and CIs are shown in Table 
6-4 for a range of observed response rates. Calculations are done using the score test 
method [73]. For example with an n of 43, a lower limit > 30% for the response rate 
corresponds to a point estimate ≥ 44.2%, and a lower limit > 65% for the response rate 
corresponds to a point estimate ≥ 81.4%.  
Table 6-4 Two-sided 95% confidence intervals for the true response rate based on observing 
a particular rate of responses and calculated by the score method (n=43). Highlighted are 
the minimum number of responses necessary to achieve the 30% and 65% lower confidence 
limit thresholds. 
No. of 
responses 
Observed response rate 
(%) 
 95% Confidence interval (%) 
5 
11.6 
(5.1, 24.5) 
9 
20.9 
(11.4, 35.2) 
13 
30.2 
(18.6, 45.1) 
18 
41.9 
(28.4, 56.7) 
19 
44.2 
(30.4, 58.9) 
22 
51.2 
(36.8, 65.4) 
26 
60.5 
(45.6, 73.6) 
31 
72.1 
(57.3, 83.3) 
35 
81.4 
(67.4, 90.3) 
39 
90.7 
(78.4, 96.3) 
6.2 
Randomization  
The randomization sequence will be obtained by computer-generated random numbers 
and provided to each HVTN CRS through a Web-based randomization system. The 
randomization will be done in blocks to ensure balance across groups. At each institution, 
the pharmacist with primary responsibility for dispensing study products is charged with 

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maintaining security of the treatment assignments (except in emergency situations as 
specified in the HVTN MOP). Randomization will be stratified by geographical region 
(Southern Africa and US).  
6.3 
Blinding 
Participants and site staff (except for site pharmacists) will be blinded as to participant 
treatment group assignments. Study product assignments are accessible to those HVTN 
CRS pharmacists, DAIDS protocol pharmacists and contract monitors, and SDMC staff 
who are required to know this information in order to ensure proper trial conduct. Any 
discussion of study product assignment between pharmacy staff and any other HVTN 
CRS staff is prohibited. The HVTN SMB members also are unblinded to treatment 
assignment in order to conduct review of trial safety.  
When a participant leaves the trial prior to study completion, the participant will be told 
he or she must wait until all participants are unblinded to learn his or her treatment 
assignment.  
Emergency unblinding decisions will be made by the site investigator. If time permits, 
the HVTN 108 Protocol Safety Review Team (PSRT) should be consulted before 
emergency unblinding occurs. 
6.4 
Statistical analyses 
This section describes the final study analyses, unblinded as to treatment group 
assignment. Data from enrolled participants will be analyzed according to the initial 
randomization assignment regardless of how many vaccinations they received. In the rare 
instance that a participant receives the wrong treatment at a specific vaccination time, the 
Statistical Analysis Plan (SAP) will address how to analyze the participant’s safety data. 
Analyses are modified intent-to-treat analysis in that individuals who are randomized but 
not enrolled do not contribute data and hence are excluded. Because of blinding and the 
brief length of time between randomization and enrollment—typically no more than 4 
working days—very few such individuals are expected. 
Analyses for primary endpoints will be performed using SAS and R. All other descriptive 
and inferential statistical analyses will be performed using SAS, StatXact, or R statistical 
software. 
No formal multiple comparison adjustments will be employed for multiple safety 
endpoints, multiple primary immunogenicity endpoints, or secondary endpoints. 
However, multiplicity adjustments will be made for certain immunogenicity assays 
specified in the SAP, when the assay is viewed as a collection of hypotheses (eg, testing 
multiple peptide pools to determine a positive response). 
Data from HVTN 108 and 111 will be combined to assess the safety and immunogenicity 
of the MF59 regimens. Data from these studies may be evaluated with data from other 
phase 1/2a studies within the P5 partnership HIV vaccine program. Comparable 
eligibility criteria and validated assays for primary immunogenicity endpoints will be 
used to mitigate the potential bias introduced by combining data across studies conducted 
over an extended period of time.  

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6.4.1 
Analysis variables 
The analysis variables consist of baseline participant characteristics, safety, and 
immunogenicity for primary- and secondary-objective analyses. 
6.4.2 
Baseline comparability 
Treatment groups will be compared for baseline participant characteristics using 
descriptive statistics. 
6.4.3 
Safety/tolerability analysis 
Since enrollment is concurrent with receiving the first vaccination, all participants will 
have received at least 1 vaccination and therefore will provide some safety data. 
6.4.3.1 
Reactogenicity 
The number and percentage of participants experiencing each type of reactogenicity sign 
or symptom will be tabulated by severity and treatment group and the percentages 
displayed graphically by group. For a given sign or symptom, each participant’s 
reactogenicity will be counted once under the maximum severity for all injection visits. 
In addition, to the individual types of events, the maximum severity of local pain or 
tenderness, induration or erythema, and of systemic symptoms will be calculated. 
Kruskal-Wallis tests will be used to test for differences in severity between groups. 
6.4.3.2 
AEs and SAEs 
AEs will be summarized using MedDRA System Organ Class and preferred terms. 
Tables will show by treatment group the number and percentage of participants 
experiencing an AE within a System Organ Class or within preferred term category by 
severity or by relationship to study product. For the calculations in these tables, a 
participant with multiple AEs within a category will be counted once under the maximum 
severity or the strongest recorded causal relationship to study product. Formal statistical 
testing comparing groups is not planned since interpretation of differences must rely 
heavily upon clinical judgment. 
A listing of SAEs reported to the DAIDS Regulatory Support Center (RSC) Safety Office 
will provide details of the events including severity, relationship to study product, time 
between onset and last vaccination, and number of vaccinations received. A separate 
listing will do the same for AEs of special interest (AESI). AESI for this protocol include 
but are not limited to potential immune-mediated disorders; a sample list of AESI is 
provided in Appendix J. These listings will be submitted to the FDA in all annual reports 
and clinical trial reports. 
6.4.3.3 
Local laboratory values  
Box plots of local laboratory values will be generated for baseline values and for values 
measured during the course of the study by treatment group and visit. Each box plot will 
show the first quartile, the median, and the third quartile. Outliers (values outside the box 
plot) will also be plotted. If appropriate, horizontal lines representing boundaries for 
abnormal values will be plotted. 
For each local laboratory measure, summary statistics will be presented by treatment 
group and timepoint, as well as changes from baseline for postenrollment values. In 
addition, the numbers (percentages) of participants with local laboratory values recorded 

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as meeting Grade 1 AE criteria or above as specified in the DAIDS AE Grading Table 
(see Section 11.2) will be tabulated by treatment group for each postvaccination 
timepoint. Reportable clinical laboratory abnormalities without an associated clinical 
diagnosis will also be included in the tabulation of AEs described above. 
6.4.3.4 
Reasons for vaccination discontinuation and early study termination 
The number and percentage of participants who discontinue vaccination and who 
terminate the study early will be tabulated by reason and treatment group. 
6.4.4 
Immunogenicity analysis 
6.4.4.1 
General approach 
For the statistical analysis of immunogenicity endpoints, data from enrolled participants 
will be used according to the initial randomization assignment regardless of how many 
injections they received. Additional analyses may be 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.  
For each of the 11 primary endpoints listed in Table 6-3, response rates will be analyzed 
by tabulating the frequency of positive response for each endpoint and treatment group at 
each timepoint for which an assessment is performed. For CD4+ and CD8+ T-cell 
response, response rates to the individual peptide pools will also be calculated. Crude 
response rates will be presented with their corresponding 95% confidence interval 
estimate calculated using the score test method [73]. For secondary and exploratory assay 
endpoints, response rates and 95% confidence intervals will be calculated if appropriate 
for the endpoint. Criteria for a positive response for an assay will be described in the 
SAP. 
All of the primary assays, and likely some of the secondary assays, will have quantitative 
assay data, including IgG binding antibody magnitude, neutralizing antibody titers, area 
under the magnitude-breadth curve [AUC-MB] for the neutralizing antibody assay, and 
percentage of positive cells from the ICS assay. Quantitative data will be displayed as 
graphical and tabular summaries of the distributions by antigen, treatment group, and 
timepoint. For all primary and secondary immunogenicity endpoints, box plots and plots 
of estimated reverse cumulative distribution curves will be presented by group. 
Formal statistical comparisons between individual arms is not the primary objective of 
the trial, although these are likely to be made to better understand the effect of adjuvants 
on immune response and the effect of dose for arms adjuvanted with AS01B. For 
comparisons in which the response rate for 1 of the groups is low (eg, ≤ 20% for the 
class), statistical testing will use Fisher’s exact test comparing the 2 response rates as 
most of the continuous data readouts would be left censored at the lower limit of 
detection. For comparisons in which the response rates for both groups are high (eg, ≥ 
75%), the difference between groups will be tested using the continuous readouts with a 
nonparametric Wilcoxon rank sum test if the data are not normally distributed and with a 
2-sample t-test if the data appear to be normally distributed.  

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Some immunologic assays have underlying continuous or count-type readout that are 
dichotomized into responder/nonresponder categories (eg, CD4+ T cell response). If 
treatment group differences for these assays are best summarized by a mixture model of 
response rates and magnitudes, then Lachenbruch’s test statistic [74] will be used to 
evaluate the composite null hypothesis of equal response rates in the 2 groups and equal 
response distributions among responders in the 2 such groups. This test statistic equals 
the square of a binomial Z-statistic for comparing the response rates plus the square of a 
Wilcoxon statistic for comparing the response distributions in the subgroup of 
responders. A permutation procedure is used to obtain a 2-sided p-value. For estimation, 
differences in response rates between groups will be estimated using the methods 
described above, and in the subgroup of positive responders, differences in location 
parameters between groups will be estimated using the methods described above. 
Based upon previous HVTN trials, missing 15% of immunogenicity results for a specific 
assay is common due to study participants terminating from the study early, problems in 
shipping specimens, or low cell viability of processed PBMCs. To achieve unbiased 
statistical estimation and inferences with standard methods applied in a complete-case 
manner (only including participants with observed data in the analysis), missing data 
need to be missing completely at random (MCAR). Following the most commonly used 
definition, MCAR assumes that the probability of an observation being missing does not 
depend on any participant characteristics (observed or unobserved). When missing data 
are minimal (specifically, if no more than 20% of participants are missing any values), 
then standard complete-case methods will be used, because violations of the MCAR 
assumption will have little impact on the estimates.  
If a substantial amount of immunogenicity data are missing (at least 1 value missing from 
more than 20% of participants), then using the methods that require the MCAR 
assumption may give misleading results. In this situation, analyses of the immunogenicity 
endpoints at a specific timepoint will be performed using parametric generalized linear 
models fit by maximum likelihood. These methods provide unbiased estimation and 
inferences under the parametric modeling assumptions and the assumption that the 
missing data are missing at random (MAR). MAR assumes that the probability of an 
observation being missing may depend upon the observed responses and upon observed 
covariates, but not upon any unobserved factors. Generalized linear models for response 
rates will use a binomial error distribution and for quantitative endpoints, a normal error 
distribution. For assessing repeated immunogenicity measurement, linear mixed effects 
models will be used. If the immunological outcomes are left- and/or right- censored, then 
the linear mixed effects models of Hughes [75] will be used, because they accommodate 
the censoring. In addition, secondary analyses of repeated immunogenicity measurements 
may be done using weighted GEE [76] 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 
approximately every 4 months, as defined in Section 11.1.2, for review by the SMB. Ad 
hoc safety reports may also be prepared for SMB review at the request of the HVTN 108 
PSRT. The HVTN leadership must approve any other requests for unblinded safety data 
prior to the end of the scheduled follow-up visits. 
6.4.5.2 
Immunogenicity 
An unblinded statistical analysis by treatment assignment of a primary immunogenicity 
endpoint may be performed when all participants have completed the 6.5 month primary 
immunogenicity visit and data are available for analysis from at least 80% of these 
participants. Analysis of secondary endpoints (ie, additional immunogenicity assays) will 
occur after the unblinded primary immunogenicity analysis since selection of secondary 
assays is dependent upon the primary analysis. Analysis of exploratory objectives 
(including the month 12 timepoint) will take place after the primary analysis. 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. The Laboratory Program will review the analysis report prior to 
distribution to the protocol chairs, DAIDS, vaccine developer, and other key HVTN 
members and investigators. Distribution of reports will be limited to those with a need to 
know for the purpose of informing 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 
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 before the last 
required protocol clinic visit 
6. Willing to be contacted by phone, text message, or e-mail 6 months after completion of 
the scheduled clinic visits  
7. Good general health as shown by medical history, physical exam, and screening 
laboratory tests 
HIV-Related Criteria: 
8. Willingness to receive HIV test results 
9. Willingness to discuss HIV infection risks and amenable to HIV risk reduction 
counseling.  

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10. Assessed by the clinic staff as being at “low risk” for HIV infection and committed to 
maintaining behavior consistent with low risk of HIV exposure through the last required 
protocol clinic visit. 
Laboratory Inclusion Values 
Hemogram/CBC 
11. Hemoglobin ≥ 11.0 g/dL for volunteers who were born female, ≥ 13.0 g/dL for 
volunteers who were born male 
12. White blood cell count = 3,300 to 12,000 cells/mm3 
13. Total lymphocyte count ≥ 800 cells/mm3 
14. Remaining differential either within institutional normal range or with site physician 
approval 
15. Platelets = 125,000 to 550,000/mm3 
Chemistry 
16. Chemistry panel: ALT, AST, and alkaline phosphatase < 1.25 times the institutional 
upper limit of normal; creatinine ≤ institutional upper limit of normal. 
Virology 
17. Negative HIV-1 and -2 blood test: US volunteers must have a negative FDA-approved 
enzyme immunoassay (EIA). Non-US sites may use locally available assays that have 
been approved by HVTN Laboratory Operations. 
18. Negative Hepatitis B surface antigen (HBsAg)  
19. Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV polymerase 
chain reaction (PCR) if the anti-HCV is positive 
Urine 
20. 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 
21. Volunteers who were born female: negative serum or urine beta human chorionic 
gonadotropin (β-HCG) pregnancy test performed prior to vaccination on the day of initial 
vaccination. Persons who are NOT of reproductive potential due to having undergone 

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total hysterectomy or bilateral oophorectomy (verified by medical records), are not 
required to undergo pregnancy testing. 
22. Reproductive status:  
United States 
A volunteer who was born female must: 
 
Agree to consistently use effective contraception (see Appendix B) for sexual activity 
that could lead to pregnancy from at least 21 days prior to enrollment through the last 
required protocol clinic visit. Effective contraception for participants in the United 
States is defined as using any 1 or more of the following methods: 
 
Condoms (male or female) with or without a spermicide, 
 
Diaphragm or cervical cap with spermicide, 
 
IUD, 
 
Hormonal contraception, or 
 
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 108 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. 
Southern Africa 
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 Southern 
Africa is defined as using 2 methods of birth control. These include 1 of the 
following methods: 
 
Condoms (male or female) 
 
Diaphragm or cervical cap 
PLUS 1 of the following methods: 
 
Intrauterine device (IUD), 
 
Hormonal contraception (in accordance with applicable national contraception 
guidelines), or 
 
Successful vasectomy in the male partner (considered successful if a volunteer 
reports that a male partner has [1] documentation of azoospermia by microscopy, 

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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 108 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. 
23. 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 
Other 
24. Volunteers 21 years of age and older who were born female consenting to provide 
cervical samples: 
 
Pap smear within: 
 
the 3 years prior to enrollment with the latest result reported as normal or 
ASCUS (atypical squamous cells of undetermined significance), OR  
 
the 5 years prior to enrollment, with the latest result reported as normal, or 
ASCUS with no evidence of high risk HPV. 
 
If no pap smear was done within the last 3 years (or within the last 5 years, if high 
risk HPV testing was performed), the volunteer must be willing to undergo a pap 
smear with the result reported as normal or ASCUS prior to sample collection. 
7.2 
Exclusion criteria 
General 
1. Blood products received within 120 days before first vaccination  
2. Investigational research agents received within 30 days before first vaccination 
3. Body mass index (BMI) ≥ 40; or BMI ≥ 35 with 2 or more of the following: systolic 
blood pressure > 140 mm Hg, diastolic blood pressure > 90 mm Hg, current smoker, 
known hyperlipidemia  
4. Intent to participate in another study of an investigational research agent or any other 
study that requires non-HVTN HIV antibody testing during the planned duration of the 
HVTN 108 study  
5. Pregnant or breastfeeding 
6. Active duty and reserve US military personnel 
Vaccines and other Injections 

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7. HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received 
control/placebo in an HIV vaccine trial, the HVTN 108 PSRT will determine eligibility 
on a case-by-case basis. 
8. Non-HIV experimental vaccine(s) received within the last 5 years in a prior vaccine 
trial. Exceptions may be made for vaccines that have subsequently undergone licensure. 
For volunteers who have received control/placebo in an experimental vaccine trial, the 
HVTN 108 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 108 PSRT on a case-by-case basis. 
9. 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) 
10. 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) 
11. Allergy treatment with antigen injections within 30 days before first vaccination or 
that are scheduled within 14 days after first vaccination  
Immune System  
12. Immunosuppressive medications received within 168 days before first vaccination. 
(Not exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical 
corticosteroids for mild, uncomplicated dermatitis; or [4] a single course of 
oral/parenteral corticosteroids at doses < 2 mg/kg/day and length of therapy < 11 days 
with completion at least 30 days prior to enrollment.) 
13. Serious adverse reactions to vaccines or to vaccine components 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.)  
14. Immunoglobulin received within 60 days before first vaccination 
15. Autoimmune disease  
16. Immunodeficiency 
Clinically significant medical conditions  
17. Untreated or incompletely treated syphilis infection 
18. Clinically significant medical condition, physical examination findings, clinically 
significant abnormal laboratory results, or past medical history with clinically significant 
implications for current health. A clinically significant condition or process includes but 
is not limited to: 
 
A process that would affect the immune response, 
 
A process that would require medication that affects the immune response, 

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 
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. 
19. Any medical, psychiatric, occupational, or other condition that, in the judgment of the 
investigator, would interfere with, or serve as a contraindication to, protocol adherence, 
assessment of safety or reactogenicity, or a volunteer’s ability to give informed consent 
20. Psychiatric condition that precludes compliance with the protocol. Specifically 
excluded are persons with psychoses within the past 3 years, ongoing risk for suicide, or 
history of suicide attempt or gesture within the past 3 years. 
21. Current anti-tuberculosis (TB) prophylaxis or therapy 
22. Asthma other than mild, well-controlled asthma. (Symptoms of asthma severity as 
defined in the most recent US National Asthma Education and Prevention Program 
(NAEPP) Expert Panel report).  
 
Exclude a volunteer who: 
 
Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or 
 
Uses moderate/high dose inhaled corticosteroids, or 
 
In the past year has either of the following: 
 
Greater than 1 exacerbation of symptoms treated with oral/parenteral 
corticosteroids; 
 
Needed emergency care, urgent care, hospitalization, or intubation for asthma. 
23. Diabetes mellitus type 1 or type 2, including cases controlled with diet alone. (Not 
excluded: history of isolated gestational diabetes.) 
24. Thyroidectomy, or thyroid disease requiring medication during the last 12 months 
25. Hypertension: 
 
If a person has been found to have elevated blood pressure or hypertension during 
screening or previously, exclude for blood pressure that is not well controlled. Well-
controlled blood pressure is defined as consistently ≤ 140 mm Hg systolic and ≤ 90 
mm Hg diastolic, with or without medication, with only isolated, brief instances of 
higher readings, which must be ≤ 150 mm Hg systolic and ≤ 100 mm Hg diastolic. 
For these volunteers, blood pressure must be ≤ 140 mm Hg systolic and ≤ 90 mm Hg 
diastolic at enrollment. 

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 
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. 
26. Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or platelet 
disorder requiring special precautions) 
27. Malignancy (Not excluded from participation: Volunteer who has had malignancy 
excised surgically and who, in the investigator’s estimation, has a reasonable assurance of 
sustained cure. or who is unlikely to experience recurrence of malignancy during the 
period of the study) 
28. Seizure disorder: History of seizure(s) within past 3 years. Also exclude if volunteer has 
used medications in order to prevent or treat seizure(s) at any time within the past 3 
years. 
29. Asplenia: any condition resulting in the absence of a functional spleen 
30. History of hereditary angioedema, acquired angioedema, or idiopathic angioedema. 
7.3 
Participant departure from vaccination schedule or withdrawal 
This section concerns an individual participant’s departure from the vaccination schedule. 
Pause rules for the trial as a whole are described in Section 11.3. 
7.3.1 
Delaying vaccinations for a participant 
Under certain circumstances, a participant’s scheduled vaccination will be delayed. The 
factors to be considered in such a decision include but are not limited to the following: 
 
Within 45 days prior to any study injection  
 
Receipt of blood products or immunoglobulin 
 
Within 30 days prior to any study injection 
 
Receipt of live attenuated vaccines 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)  
 
Pre-vaccination abnormal vital signs or clinical symptoms that may mask assessment 
of vaccine reaction. 
 
Pregnancy: for participants who become pregnant, no study vaccinations will be 
given; except for participants who may have been pregnant during the study but are 
no longer pregnant as shown by 2 negative urine pregnancy tests taken from 2 
different urine samples that may be collected on the same day; in this circumstance, 
the HVTN 108 PSRT should be consulted to determine if the participant may resume 
vaccinations.  

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Vaccinations should not be administered outside the visit window period specified in the 
HVTN 108 Study Specific Procedures. 
In order to avoid vaccination delays and missed vaccinations, participants who plan to 
receive licensed vaccines or allergy treatments should be counseled to schedule receipt of 
these substances, when possible, outside the intervals indicated above. The effects of 
these substances on safety and immunogenicity assessments and their interactions with 
study vaccines are unknown. Therefore, if circumstances allow, these substances should 
also be avoided in the interval between a study vaccination and completion of the 2 week 
postvaccination follow-up visit. 
7.3.2 
Participant departure from vaccination schedule 
Every effort should be made to follow the vaccination schedule per the protocol. If a 
participant misses a vaccination and the visit window period for the vaccination has 
passed, that vaccination cannot be given. The participant should be asked to continue 
study visits. The participant should resume the vaccination schedule with the next 
vaccination unless there are circumstances that require further delay or permanent 
discontinuation of vaccination (see Sections 7.3.1 and 7.3.3).  
7.3.3 
Discontinuing vaccination for a participant 
Under certain circumstances, an individual participant’s vaccinations will be permanently 
discontinued. Specific events that will result in stopping a participant’s vaccination 
schedule include: 
 
Co-enrollment in a study with an investigational research agent (rare exceptions 
allowing for the continuation of vaccinations may be granted with the unanimous 
consent of the HVTN 108 PSRT). 
 
Clinically significant condition (ie, a condition that affects the immune system or for 
which continued vaccinations and/or blood draws may pose additional risk), 
including but not limited to the following: 
 
Pregnancy (vaccinations will be stopped while a participant is pregnant. If the 
participant is no longer pregnant and can be vaccinated within an appropriate 
visit window, vaccinations may resume, see Section 7.3.1); 
 
Any grade 4 local or systemic reactogenicity symptom, or AE that is 
subsequently considered to be related to vaccination; 
 
Any grade 3 clinical AE (exception: fever or vomiting and subjective local and 
systemic symptoms) that is subsequently considered to be related to vaccination;  
 
Any grade 3 or 4 lab abnormality confirmed by a repeated value that is 
subsequently considered to be related to vaccination. Upon PSRT review the 
participant may be allowed to continue study vaccinations. 
 
Clinically significant type 1 hypersensitivity reaction associated with study 
vaccination. Consultation with the HVTN 108 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). 

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 
A study participant who misses a study injection is permitted to continue with 
subsequent study injections that can still be scheduled within the time interval 
specified in the HVTN 108 Study Specific Procedures (SSP) unless there is a 
protocol-mandated reason for discontinuation. 
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 7.3.4 and 9.8.1). 
7.3.4 
Participant termination from the study 
Under certain circumstances, an individual participant may be terminated from 
participation in this study. Specific events that will result in early termination include: 
 
Participant refuses further participation, 
 
Participant relocates and remote follow-up or transfer to another HVTN CRS is not 
possible, 
 
HVTN CRS determines that the participant is lost to follow-up,  
 
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), or 
 
Any condition where termination from the study is required by applicable 
regulations. 

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8 
Study product preparation and administration 
CRS pharmacists should consult the Pharmacy Guidelines and Instructions for DAIDS 
Clinical Trials Networks for standard pharmacy operations. The protocol schema is 
shown in Table 3-1. See the Investigator’s Brochures for further information about study 
products. 
8.1 
Vaccine regimen 
The schedule of vaccination is shown in Section 3 and additional information is given 
below.  
Group 1 
Treatment 1 (T1): DNA-HIV-PT123 (4 mg/mL) 4 mg to be administered as 1 mL IM in 
the LEFT deltoid (unless medically contraindicated) at Months 0 and 1 
AND 
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.5 mL IM in the RIGHT deltoid (unless medically contraindicated) at 
Months 0 and 1  
AND 
Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.75 mL IM in the RIGHT deltoid (unless medically contraindicated) 
at Months 0 and 1; 
THEN 
DNA-HIV-PT123 (4 mg/mL) 4 mg to be administered as 1 mL IM in the LEFT deltoid 
(unless medically contraindicated) at Months 3 and 6 
AND 
Bivalent Subtype C gp120 / MF59 (an admixture of 100 mcg of TV1.C gp120, 100 mcg 
of 1086.C gp120, and MF59C.1) to be administered as 0.5 mL IM in the RIGHT deltoid 
(unless medically contraindicated) at Months 3 and 6  
AND 
Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.75 mL IM in the RIGHT deltoid (unless medically contraindicated) 
at Months 3 and 6. 
Group 2 
Treatment 2 (T2): DNA-HIV-PT123 (4 mg/mL) 4 mg to be administered as 1 mL IM in 
the LEFT deltoid (unless medically contraindicated) at Months 0 and 1 

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AND 
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.5 mL IM in the RIGHT deltoid (unless medically contraindicated) at 
Months 0 and 1 
AND 
Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.75 mL IM in the RIGHT deltoid (unless medically contraindicated) 
at Months 0 and 1; 
THEN 
DNA-HIV-PT123 (4 mg/mL) 4 mg to be administered as 1 mL IM in the LEFT deltoid 
(unless medically contraindicated) at Months 3 and 6 
AND  
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.5 mL IM in the RIGHT deltoid (unless medically contraindicated) at 
Months 3 and 6 
AND 
Bivalent Subtype C gp120 / AS01B (an admixture of 100 mcg of TV1.C gp120, 100 mcg 
of 1086.C gp120, and AS01B) to be administered as 0.75 mL IM in the RIGHT deltoid 
(unless medically contraindicated) at Months 3 and 6. 
Group 3 
Treatment 3 (T3): DNA-HIV-PT123 (4 mg/mL) 4 mg to be administered as 1 mL IM in 
the LEFT deltoid (unless medically contraindicated) at Months 0 and 1 
AND 
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.5 mL IM in the RIGHT deltoid (unless medically contraindicated) at 
Months 0 and 1 
AND 
Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.75 mL IM in the RIGHT deltoid (unless medically contraindicated) 
at Months 0 and 1; 
THEN 
DNA-HIV-PT123 (4 mg/mL) 4 mg to be administered as 1 mL IM in the LEFT deltoid 
(unless medically contraindicated) at Months 3 and 6 
AND 

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Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.5 mL IM in the RIGHT deltoid (unless medically contraindicated) at 
Months 3 and 6 
AND 
Bivalent Subtype C gp120 / AS01B (an admixture of 20 mcg of TV1.C gp120, 20 mcg of 
1086.C gp120, and AS01B) to be administered as 0.75 mL IM in the RIGHT deltoid 
(unless medically contraindicated) at Months 3 and 6. 
Group 4 
Treatment 4 (T4): DNA-HIV-PT123 (4 mg/mL) 4 mg to be administered as 1 mL IM in 
the LEFT deltoid (unless medically contraindicated) at Months 0, 1 and 6 
AND 
Bivalent Subtype C gp120 / MF59 (an admixture of 100 mcg of TV1.C gp120, 100 mcg 
of 1086.C gp120, and MF59C.1) to be administered as 0.5 mL IM in the RIGHT deltoid 
(unless medically contraindicated) at Months 0, 1 and 6  
AND 
Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.75 mL IM in the RIGHT deltoid (unless medically contraindicated) 
at Months 0, 1 and 6; 
AND 
Placebo for DNA (Sodium Chloride for Injection, 0.9%) to be administered as 1 mL IM 
in the LEFT deltoid (unless medically contraindicated) at Month 3 
AND 
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.5 mL IM in the RIGHT deltoid (unless medically contraindicated) at 
Month 3 
AND 
Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.75 mL IM in the RIGHT deltoid (unless medically contraindicated) 
at Month 3. 
Group 5 
Treatment 5 (T5): DNA-HIV-PT123 (4 mg/mL) 4 mg to be administered as 1 mL IM in 
the LEFT deltoid (unless medically contraindicated) at Months 0, 1 and 6  
AND 
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.5 mL IM in the RIGHT deltoid (unless medically contraindicated) at 
Months 0, 1 and 6 

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AND 
Bivalent Subtype C gp120 / AS01B (an admixture of 100 mcg of TV1.C gp120, 100 mcg 
of 1086.C gp120, and AS01B) to be administered as 0.75 mL IM in the RIGHT deltoid 
(unless medically contraindicated) at Months 0, 1 and 6; 
AND 
Placebo for DNA (Sodium Chloride for Injection, 0.9%) to be administered as 1 mL IM 
in the LEFT deltoid (unless medically contraindicated) at Month 3 
AND 
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.5 mL IM in the RIGHT deltoid (unless medically contraindicated) at 
Month 3 
AND 
Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.75 mL IM in the RIGHT deltoid (unless medically contraindicated) 
at Month 3. 
Group 6 
Treatment 6 (T6): DNA-HIV-PT123 (4 mg/mL) 4 mg to be administered as 1 mL IM in 
the LEFT deltoid (unless medically contraindicated) at Months 0, 1 and 6 
AND 
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.5 mL IM in the RIGHT deltoid (unless medically contraindicated) at 
Months 0, 1 and 6 
AND 
Bivalent Subtype C gp120 / AS01B (an admixture of 20 mcg of TV1.C gp120, 20 mcg of 
1086.C gp120, and AS01B) to be administered as 0.75 mL IM in the RIGHT deltoid 
(unless medically contraindicated) at Months 0, 1 and 6; 
AND 
Placebo for DNA (Sodium Chloride for Injection, 0.9%) to be administered as 1 mL IM 
in the LEFT deltoid (unless medically contraindicated) at Month 3 
AND 
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.5 mL IM in the RIGHT deltoid (unless medically contraindicated) at 
Month 3 
AND 

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Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.75 mL IM in the RIGHT deltoid (unless medically contraindicated) 
at Month 3. 
Group 7 
Treatment 7 (T7): Placebo for DNA (Sodium Chloride for Injection, 0.9%) to be 
administered as 1 mL IM in the LEFT deltoid (unless medically contraindicated) at 
Months 0, 1 and 6 
AND 
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.5 mL IM in the RIGHT deltoid (unless medically contraindicated) at 
Months 0, 1 and 6 
AND 
Bivalent Subtype C gp120 / AS01B (an admixture of 20 mcg of TV1.C gp120, 20 mcg of 
1086.C gp120, and AS01B) to be administered as 0.75 mL IM in the RIGHT deltoid 
(unless medically contraindicated) at Months 0, 1 and 6; 
AND 
Placebo for DNA (Sodium Chloride for Injection, 0.9%) to be administered as 1 mL IM 
in the LEFT deltoid (unless medically contraindicated) at Month 3 
AND 
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.5 mL IM in the RIGHT deltoid (unless medically contraindicated) at 
Month 3 
AND 
Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.75 mL IM in the RIGHT deltoid (unless medically contraindicated) 
at Month 3. 
Group 8 
Placebo 1 (P1): Placebo for DNA (Sodium Chloride for Injection, 0.9%) to be 
administered as 1 mL IM in the LEFT deltoid (unless medically contraindicated) at 
Months 0, 1, 3 and 6 
AND 
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.5 mL IM in the RIGHT deltoid (unless medically contraindicated) at 
Months 0, 1, 3 and 6 
AND 

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Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 0.9%) to 
be administered as 0.75 mL IM in the RIGHT deltoid (unless medically contraindicated) 
at Months 0, 1, 3 and 6. 
8.2 
Study product formulation  
DNA-HIV-PT123 (labeled as DNA-HIV-PT123 [4 mg/mL]) is supplied as a 4 mg/mL 
DNA solution in a 2 mL sterile glass vial containing a volume to deliver 1 mL of a clear, 
colorless solution. The product must be stored at -200C +/-50C.  
The study product is described in further detail in the Investigator’s Brochure (IB). 
Placebo for DNA-HIV-PT123 (Sodium Chloride for Injection, 0.9%) 
Sodium Chloride for Injection, 0.9%, will be used as the placebo for DNA-HIV-PT123. 
Product must be stored as directed by the manufacturer. 
Bivalent Subtype C 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 (800 mcg/mL) 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. Once thawed, the study product 
should be used immediately or stored in refrigerator at 2 to 8°C, for no longer 
than 24 hours. Unused vials should be quarantined after this time. 
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 (800 mcg/mL) 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. Once thawed, the study product 
should be used immediately or stored in refrigerator at 2 to 8°C, for no longer 
than 24 hours. Unused vials should be quarantined after this time. 
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 Investigator’s Brochure (IB). 
AS01B is produced as a liposomal formulation containing MPL and QS-21. It is 
provided as an opalescent colorless to yellowish liquid in pre-filled vials.  Each 
vial contains a volume to deliver 0.5 mL. The product must be stored refrigerated 
at 2 to 8° C.  
The study product is described in further detail in the IB. 
Placebo for Bivalent Subtype C gp120 / MF59 (Sodium Chloride for Injection, 0.9%) 

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Sodium Chloride for Injection, 0.9%, will be used as the placebo for Bivalent Subtype C 
gp120 / MF59. Product must be stored as directed by the manufacturer. 
Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 0.9%) 
Sodium Chloride for Injection, 0.9%, will be used as the placebo for Bivalent Subtype C 
gp120 / AS01B. Product must be stored as directed by the manufacturer. 
8.3 
Preparation of study products 
Pharmacists should refer to USP 38 General Chapter Physical Tests / <797> 
Pharmaceutical Compounding - Sterile, and should follow the requirements of their 
country, their institution, and their pharmacy regulatory authority regarding these 
procedures. At a minimum, study products must be prepared in a biological safety 
cabinet/isolator by appropriately trained/qualified pharmacy personnel using aseptic 
technique. 
8.3.1 
DNA-HIV-PT123 
One vial of DNA-HIV-PT123 (labeled as DNA-HIV-PT123 [4 mg/mL]) will be needed 
to prepare the dose. Prior to dispensing, the pharmacist will remove the study product 
from the freezer and allow it to thaw at room temperature. 
Once thawed, the pharmacist, using aseptic technique, will gently swirl the vial and then 
withdraw 1 mL into a syringe. The syringe should be no smaller than 1.5 mL syringe and 
no larger than a 5 mL syringe. 
The syringe should be labeled as “DNA 4 mg or Placebo 1 mL” and have an overlay to 
maintain blinding. The syringe must also be labeled for administration in the LEFT 
deltoid. The study product should be administered as soon as possible after preparation.  
Any partial vials or expired filled syringes should be autoclaved immediately prior to 
disposal and disposed of in accordance with institutional or pharmacy policy. 
8.3.2 
Placebo for DNA 
Using aseptic technique, the pharmacist will withdraw 1 mL of Sodium Chloride for 
Injection, 0.9% into a syringe. The syringe should be no smaller than 1.5 mL syringe and 
no larger than a 5 mL syringe. 
The syringe should be labeled as “DNA 4 mg or Placebo 1 mL” and have an overlay to 
maintain blinding. The syringe must also be labeled for administration in LEFT deltoid. 
The 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.  
8.3.3 
Bivalent Subtype C gp120 / MF59 (an admixture of 100 mcg of TV1.C gp120, 100 
mcg of 1086.C gp120, and MF59C.1) 
One vial of TV1.C gp120 protein, 1 vial of 1086.C gp120 protein, and 1 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 allowed to thaw at room 

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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 3 mL syringe or smaller.  
The needle should be removed and the syringe capped. 
The syringe should be labeled as “Bivalent Subtype C gp120 / MF59 or Placebo 0.5 mL” 
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 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. 
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 S1 product.  
8.3.4 
Placebo for Bivalent Subtype C gp120 / MF59  
Using aseptic technique, the pharmacist will withdraw 0.5 mL of Sodium Chloride for 
Injection, 0.9% into a 3 mL or smaller syringe. The needle should be removed and the 
syringe capped. 
The syringe should be labeled as “Bivalent Subtype C gp120 / MF59 or Placebo 0.5 mL” 
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 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. 
Any unused portion of entered vials or expired prefilled syringes should be disposed of in 
accordance with institutional or pharmacy policy.  
8.3.5 
Bivalent Subtype C gp120 / AS01B (an admixture of 100 mcg of TV1.C gp120, 100 
mcg of 1086.C gp120, and AS01B)  
One vial of TV1.C gp120 protein, one vial of 1086.C gp120 protein, two vials of AS01B, 
and one empty sterilized vial (for admixing) will be needed to prepare the dose. Prior to 
dispensing, the pharmacist will remove the TV1.C gp120 and 1086.C gp120 vials from 
the freezer and allow them to thaw at room temperature. The pharmacist will also remove 
the AS01B vials from the refrigerator. 

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Using aseptic technique, the pharmacist will withdraw 0.5 mL into a 1 mL syringe from 
the first vial of AS01B. This volume will be transferred into the empty sterilized vial 
(“preparation vial”). The pharmacist will then repeat this process using the second vial of 
AS01B. The preparation vial now contains 1 mL of AS01B. 
Using aseptic technique, the pharmacist will gently swirl the contents of the vial 
containing TV1.C gp120 and then withdraw 0.25 mL of TV1.C gp120 from the correct 
vial and inject it into the preparation vial containing AS01B. The pharmacist will then 
gently swirl the vial containing 1086.C gp120 after which, using aseptic technique, the 
pharmacist will withdraw 0.25 mL of 1086.C gp120 from the correct vial and inject it 
into the preparation vial (which contains TV1.C gp120 and AS01B). After gentle swirling 
and inversion (do not shake vigorously) the pharmacist, using aseptic technique, will 
withdraw 0.75 mL of the mixed preparation (100 mcg of each protein mixed with AS01B 
Adjuvant System) for dosing into a 3 mL syringe or smaller. The needle should be 
removed and the syringe capped. 
The syringe should be labeled as “Bivalent Subtype C gp120 / AS01B or Placebo 
0.75 mL” and have an overlay to maintain blinding. The syringe must also be labeled for 
administration in the deltoid of the right arm. The syringe containing study product 
should be bagged for transport to the clinic where it will be administered. This study 
product should be administered immediately, defined as within 30 minutes as per IAC 
recommendations.  If this is not possible, the 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. 
Any unused portion of vials, preparation vials, or expired prefilled syringes should be 
disposed of in compliance with local health, safety and environmental requirements. 
8.3.6 
Bivalent Subtype C gp120 / AS01B (an admixture of 20 mcg of TV1.C gp120, 20 mcg 
of 1086.C gp120, and AS01B)  
One vial of TV1.C gp120 protein, one vial of 1086.C gp120 protein, two vials of AS01B, 
one vial/IV bag/ampule of Sodium Chloride for Injection, 0.9% , and one empty sterilized 
vial (for admixing) will be needed to prepare the dose. Prior to dispensing, the pharmacist 
will remove the TV1.C gp120 and 1086.C gp120 from the freezer and allow them to thaw 
at room temperature. The pharmacist will also remove the AS01B vial from the 
refrigerator. 
Using aseptic technique, the pharmacist will withdraw 0.5 mL into a 1 mL syringe from 
the first vial of AS01B. This volume will be transferred into the empty sterilized vial 
(“preparation vial”). The pharmacist will then repeat this process using the second vial of 
AS01B. The preparation vial now contains 1 mL of AS01B. 
Using aseptic technique, the pharmacist will gently swirl the contents of the vial 
containing TV1.C gp120 and then withdraw 0.05 mL of TV1.C gp120 from the correct 
vial and inject it into the preparation vial containing AS01B. The pharmacist will then 
gently swirl the vial containing 1086.C gp120 after which, using aseptic technique, the 
pharmacist will withdraw 0.05 mL of 1086.C gp120 from the correct vial and inject it 
into the preparation vial (which contains TV1.C gp120 and AS01B). Using a new syringe, 
the pharmacist will then withdraw 0.4 mL of Sodium Chloride for Injection, 0.9% and 
transfer it into the preparation vial (containing TV1.C gp120, 1086.C gp120 and AS01B). 
After gentle swirling and inversion (do not shake vigorously) the pharmacist, using 
aseptic technique, will withdraw 0.75 mL of the mixed preparation (20 mcg of each 

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protein mixed with AS01B and 0.9% NaCl) for dosing into a 3 mL syringe or smaller.  
The needle should be removed and the syringe capped. 
The syringe should be labeled as “Bivalent Subtype C gp120 / AS01B or Placebo 
0.75 mL” and have an overlay to maintain blinding. The syringe must also be labeled for 
administration in the deltoid of the right arm. The syringe containing study product 
should be bagged for transport to the clinic where it will be administered. This study 
product should be administered immediately, defined as within 30 minutes as per IAC 
recommendations.  If this is not possible, the 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. 
Any unused portion of reconstituted vials or expired prefilled syringes is disposed of in 
compliance with local health, safety and environmental requirements. 
8.3.7 
Placebo for Bivalent Subtype C gp120 / AS01B (Sodium Chloride for Injection, 0.9%) 
Using aseptic technique, the pharmacist will withdraw 0.75 mL of Sodium Chloride for 
Injection, 0.9% into a 3 mL syringe or smaller. The needle should be removed and the 
syringe capped. 
The syringe should be labeled as “Bivalent Subtype C gp120 / AS01B or Placebo 
0.75 mL” 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. The 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 vaccine 
should be stored at 2°C - 8°C until administration and if not used within 2 hours, it 
should be discarded. 
Any unused portion of entered vials or expired prefilled syringes should be disposed of in 
accordance with institutional or pharmacy policy. 
8.3.8 
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. 
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.  

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All injections are to be given using standard IM injection technique. 
For all syringes containing Bivalent Subtype C gp120/MF59 or placebo or Bivalent 
Subtype C gp120/AS01B or placebo, the person administering the injection should gently 
roll the syringe prior to administration of the study product. 
If an injection(s) needs to be administered in an alternate body site (eg, thigh) due to a 
medical contraindication, the injection(s) should not be administered in the same deltoid 
as the other injection(s). The appropriate study staff should document this clearly. Under 
this circumstance, this is NOT a protocol violation. 
8.5 
Acquisition of study products 
DNA-HIV-PT123 will be provided by IPPOX Foundation.  
Bivalent Subtype C gp120 (TV1.C gp120 and 1086.C gp120) and the MF59 adjuvant will 
be provided by Novartis Vaccines. 
AS01B will be provided by GlaxoSmithKline Biologics. 
Placebo for all study products (Sodium Chloride for Injection, 0.9%) will not be provided 
through the protocol and must be obtained by the site. 
Once an HVTN CRS is protocol registered and all importation requirements have been 
met, 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 schedule of clinical procedures is shown in Appendix H. 
9.1 
Informed consent 
Informed consent is the process of working with participants so that they fully understand 
what will and may happen to them while participating in a research study. The HVTN 
informed consent form documents that a participant (1) has been informed about the 
potential risks, benefits, and alternatives to participation, and (2) is willing to participate 
in an HVTN study. Informed consent encompasses all written or verbal study information 
HVTN CRS staff provide to the participant, before and during the trial. HVTN CRS staff 
will obtain informed consent of participants according to HVTN policies and procedures. 
The informed consent process continues throughout the study. Key study concepts should 
be reviewed periodically with the participant and the review should be documented. At 
each study visit, HVTN CRS staff should consider reviewing the procedures and 
requirements for that visit and for the remaining visits. Additionally, if any new 
information is learned that might affect the participants’ decisions to stay in the trial, this 
information will be shared with trial participants. If necessary, participants will be asked 
to sign revised informed consent forms. 
An HVTN CRS may employ recruitment efforts prior to the participant consenting. For 
example, some HVTN CRSs use a telephone script to prescreen people before they come 
to the clinic for a full screening visit. Participants must sign a screening or protocol-
specific consent before any procedures are performed to determine eligibility. HVTN 
CRSs must submit recruitment and prescreening materials to their IRB/EC and any 
applicable Regulatory Entity (RE) for human subjects protection review and approval. 
Note: As defined in the DAIDS Protocol Registration Manual, an RE is “Any group other 
than the local IRB/EC responsible for reviewing and/or approving a clinical research 
protocol and site-specific ICFs [informed consent forms] prior to implementation at a 
site.” CRSs are responsible for knowing the requirements of their applicable REs. 
9.1.1 
Screening consent form 
Without a general screening consent, screening for a specific study cannot take place 
until the site receives protocol registration from the DAIDS RSC Protocol Registration 
Office. 
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 separate sample consent form for other uses of specimens is located in Appendix D. 
Each HVTN CRS is responsible for developing a protocol-specific consent form(s) for 
local use, based on the sample protocol-specific consent forms in Appendix A and 
Appendix D. The consent form(s) must be developed in accordance with the 
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, 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. 
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. 

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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 9.10), 
 
HBsAg,  
 
Anti-HCV Ab, 
 
Syphilis test, 
 
Urine or serum pregnancy test (volunteers who were born female); 
 
Pap smear (only for volunteers 21 years or older who were born female and who 
agree to provide cervical samples; for specific requirements see Section 7.1, 
Bullet 24); 
 
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 9.8; 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). 
9.3 
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 
randomizes the participant via the Web-based randomization system as described in the 
HVTN 108 Study Specific Procedures. 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 or 
bilateral oophorectomy (verified by medical records), are not required to undergo 
pregnancy testing. 
Following completion of all procedures in the preceding list, and if results indicate that 
vaccination may proceed, vaccination is prepared and administered (see Sections 8.3 and 
8.4). 
Administration of all injections during a vaccination visit must be accomplished within 1 
calendar day. 
Immediately following vaccination, the participant remains in the clinic for observation. 
An initial reactogenicity assessment is made at a target of 30 minutes after injection, with 
an acceptable range of 25-60 minutes. Before leaving the clinic, the participant will be 

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given the 7 day postvaccination symptom log and is instructed on how to complete it. 
Contacts between the participant and the site staff should take place daily during the first 
3 days of the assessment period. Site staff will review the rest of the postvaccination 
symptom log at the first follow up visit (as described in Section 9.11). 
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 9.8);  
 
Pregnancy prevention assessment (as described in Section 9.2 and 9.9); 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:  
 
HIV infection assessment including pretest counseling. A subsequent follow-up 
contact is conducted to provide post-test counseling and to report results to 
participant; 
 
Confirm that participants received HIV test results from previous visit. If not, provide 
test results and post-test counseling as appropriate; and 
 
Administration of the social impact assessment questionnaire (types of impacts 
assessed involve personal relationships, health insurance, life insurance, educational 
or employment opportunities, housing, immigration, or travel); 
 
Administration of behavioral risk assessment questionnaire; 
 
Administration of a questionnaire that asks the participant about any HIV testing he 
or she may have received outside of the study. Participants will also be asked whether 
they believe they received the active vaccine or the control; 
 
Specimen collection (blood and/or mucosal and/or stool) should be completed prior 
to vaccination; 
 
For participants who agree to mucosal sampling collection (see Appendix H and 
Section 9.6): 
 
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. 

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9.4 
Follow-up visits 
The following procedures are performed at all scheduled follow-up visits: 
 
Risk reduction counseling (as described in Section 9.8);  
 
Pregnancy prevention assessment (as described in Section 9.2 and 9.9); 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:  
 
Administration of the social impact assessment questionnaire (types of impacts 
assessed involve personal relationships, health insurance, life insurance, educational 
or employment opportunities, housing, immigration, or travel); 
 
Administration of a questionnaire that asks the participant about any HIV testing he 
or she may have received outside of the study. Participants will also be asked whether 
they believe they received the active vaccine or the control; 
 
Administration of behavioral risk assessment questionnaire; 
 
HIV infection assessment including pre-test counseling. A subsequent follow-up 
contact is conducted to provide post-test counseling and to report results to 
participant; 
 
Confirm that participants received HIV test results from previous visit. If not, provide 
test results and post-test counseling as appropriate; 
 
Abbreviated physical examination including weight, vital signs, and a symptom-
directed evaluation by history and/or appropriate physical exam based on participant 
self-reported symptoms or complaints; 
 
Complete physical examination, including weight, vital signs, and clinical 
assessments of head, ears, eyes, nose, and throat; neck; lymph nodes; heart; chest; 
abdomen; extremities; neurological function; and skin; 
 
Specimen collection (blood and/or mucosal and/or stool); 
 
Clinical laboratory tests including: 
 
CBC with differential and platelet count, 
 
Chemistry panel (see Section 9.2), and 
 
Urine dipstick (urinalysis if appropriate; see Section 9.10); and 

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 
Urine or serum pregnancy test (for participants who were born female). Persons who 
are NOT of reproductive potential due to having undergone total hysterectomy or 
bilateral oophorectomy (verified by medical records), are not required to undergo 
pregnancy testing 
 
For participants who agree to mucosal sampling collection (see Section 9.6): 
 
Urine test or swab for gonorrhea and chlamydia; 
 
Vaginal swab for Trichomonas and bacterial vaginosis (for participants providing 
cervical samples); 
 
Vaginal swab (if indicated) for hyphae/budding yeast (for participants providing 
cervical samples); 
 
Syphilis serology; 
 
Pregnancy test (see Section 9.6 and 9.14); and 
 
Mucosal specimen collection. 
9.5 
AESI contact 
Participants will be contacted 6 months after the last scheduled visit (see Appendix I). 
This contact may be accomplished by phone, text message, or email. At this contact, CRS 
staff will collect information about their health, specifically related to potential AESIs. If 
indicated, the participant may be asked to come in for a clinical assessment which may 
also include referrals for AESI assessment. AESIs are described further in Appendix J. 
9.6 
Mucosal sampling 
Mucosal samples will be collected at the timepoints indicated in Appendix H from the 
study participants who agree to these procedures. 
Participants who consent to provide cervical, rectal, or semen samples will be tested for 
the following infections at the mucosal sampling visits: gonorrhea, chlamydia, and 
syphilis. Participants who were born female who consent to provide cervical fluid 
samples will be tested for trichomoniasis and for bacterial vaginosis and (if clinically 
indicated) for hyphae/budding yeast. Test results will be provided to participants and all 
participants who test positive for 1 or more of these infections will receive counseling as 
well as treatment (or referral for treatment) as appropriate. 
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 with 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 an herpes simplex virus (HSV)-2 
outbreak or inflamed hemorrhoids or colitis/diarrhea] or if the participant has any active 
genital tract infection (GTI). 

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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 3-5 
years prior to enrollment, with the latest result reported as normal or ASCUS. A 
pregnancy test must be performed and must be negative prior to cervical sampling with a 
sponge. For sampling with Softcup, the pregnancy test can be performed after collection 
has taken place, but should be performed on the same day as the collection. 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. Cervical sampling should be deferred if a participant is menstruating, 
but should be performed as soon as possible, if still within the visit window. In addition, 
cervical sampling will not be performed (or may be deferred to a later date if still within 
the visit window) if a participant has an active ulcerative genital lesion or is known to 
have 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 to have an 
active GTI at the scheduled timepoint. 
9.7 
Stool sampling 
Two stool samples will be collected from the study participants who agree to this 
procedure: 1 prior to enrollment (before the injection of the vaccine) and 1 at the Month 
6.5 timepoint. These samples will be collected using swabs, either via rectal swabs or by 
taking swabs from stool. 

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9.8 
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 antibody positive due to the 
vaccine. They will also be counseled on the risks of HIV antibody testing outside of the 
HVTN CRSs and will be discouraged from doing so during study participation and/or 
during any period of vaccine-induced positive serology. 
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 
medical treatment, counseling, and management of the HIV infection. These individuals 
may also be referred to appropriate ongoing clinical trials or observational studies. 
9.8.1 
Distinguishing intercurrent HIV infection from vaccine-induced positive serology 
The study product may elicit an antibody response to HIV proteins. Therefore, vaccine-
induced positive serology (VISP) 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. 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 H). The Laboratory Program (or approved diagnostic laboratory) will 
follow the HVTN HIV testing algorithm (as described in the Laboratory Manual of 
Operations), which is able to distinguish vaccine-induced antibody responses from 
actual HIV infections.  

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 
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 
antibody screening tests) at or after the study is unblinded will be offered poststudy 
HIV-1 diagnostic testing (per the HVTN poststudy HIV-1 testing algorithm) 
periodically and free of charge as medically/socially indicated (approximately every 
6 months) unless or until HIV Ab testing is no longer the standard test in clinical 
settings.  
9.8.2 
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). 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.  
9.9 
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 
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. 
9.10 
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 

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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. 
9.11 
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 2.0, November 2014, 
except as noted in Section 11.2.2. 
The reactogenicity assessment period is 7 full days following each vaccination per the 
assessment schedule shown in Table 9-1. Participants will be given a tool on which to 
record reactogenicity symptoms. Contacts between the participant and the site staff 
should take place daily during the first 3 days of the assessment period. Participants are 
instructed to record the resolution date of new or unresolved reactogenicity symptoms 
present at day 7 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 7 full days 
after), or those meeting SAE/adverse event criteria requiring expedited reporting to 
DAIDS, are recorded on an adverse experience log form.  
Table 9-1 Schedule of reactogenicity assessments 
Day 
Time 
Performed by 
0a 
Baseline: before vaccination 
HVTN CRS 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 
3 
Between 12:00am and 11:59pm day 3 
HVTN CRS staff or participant 
4 
Between 12:00am and 11:59pm day 4 
HVTN CRS staff or participant 
5 
Between 12:00am and 11:59pm day 5 
HVTN CRS staff or participant 
6 
Between 12:00am and 11:59pm day 6 
HVTN CRS staff or participant 
7 b 
Between 12:00am and 11:59pm day 7 
HVTN CRS staff or participant 
a Day of vaccination 
b New or unresolved reactogenicity symptoms present on day 7 are recorded until resolution 
9.11.1 
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 

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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. 
9.11.2 
Assessment of injection site 
Typical injection site reactions are erythema or redness and induration or swelling. The 
maximum horizontal and maximum vertical measurements for all injection site reactions 
are recorded. 
All injection site reactions are monitored until resolution. Areas greater than 25 cm2 are 
followed daily; otherwise, the frequency of follow-up is based on clinician judgment. 
9.11.3 
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). 
9.12 
Visit windows and missed visits 
Visit windows are defined in HVTN 108 Study Specific Procedures. For a visit not 
performed within the window period, a Missed Visit form is completed. If the missed 
visit is one that required safety assessments or local safety labs, HVTN CRS staff should 
attempt to bring the participant in for an interim visit as soon as possible. 
Procedures performed at an interim visit are usually toxicity/safety assessments 
(including local safety labs) and HIV testing. With the exception of HIV testing, these 
procedures are performed only if they were required at the missed visit or if clinically 
indicated. HIV testing may be performed as deemed appropriate by the study staff. Blood 
samples for immunogenicity assays are not typically collected at interim visits. 
If a missed visit required vaccination, please refer to Section 7.3.2 and Section 7.3.3 for 
resolution. 
9.13 
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. 

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9.14 
Pregnancy 
If a participant becomes pregnant during the course of the study, no more injections of 
study product will be given during the pregnancy, but remaining visits and study 
procedures should be completed unless medically contraindicated. For participants who 
are no longer pregnant, see Section 7.3.1. In case of required termination from the study, 
enrollment in an observational study should be offered to the participant. If 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 Reference Manual provides further guidelines for operational issues 
concerning the clinical and processing laboratories. The manual includes guidelines for 
general specimen collection, special considerations for phlebotomy, specimen labeling, 
whole blood processing, HIV screening/diagnostic testing, and general screening and 
safety testing. 
Tube types for blood collection are specified in Appendix 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 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 in this study is at visit 10 (day 182) (ie, 2 weeks 
after the 4th 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, assays for 
humoral and cellular responses may be performed on participants at other timepoints; the 
schedule is shown in Appendix G. 
10.4 
Endpoint assays: humoral 
10.4.1 
HIV-1 multiplex antibody assay 
Total binding IgG antibodies to HIV-1 Env proteins (including V2 regions of interest) 
will be assessed on serum and mucosal secretion samples from study participants taken at 
the primary immunogenicity timepoints and baseline. Specimens from other timepoints 
as well as other HIV antigens and Ab isotypes may also be assayed based on the results 
of the initial assay. 
10.4.2 
Neutralizing antibody (nAb) assay  
HIV-1–specific nAb assays will be performed on serum samples from study participants 
taken at the primary immunogenicity timepoint. Specimens from the baseline and other 

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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 the vaccine strains (96ZM651, TV1.C, 1086.C) and 
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 [77,78]. 
10.5 
Endpoint assays: cellular 
10.5.1 
Flow cytometry 
Flow cytometry will be used to examine vaccine-specific CD4+ and CD8+ T-cell 
responses following stimulation of PBMCs with synthetic HIV peptides that span the 
proteins encoded by the vaccine construct. ICS parameters will include cytokines such as 
IFN-γ, interleukin (IL)-2, and tumor necrosis factor (TNF)-α, and may include other 
cytokines (such as cytokines relevant to Th2 and Th17 responses) to identify T cells of 
specific functionality. Markers of cytotoxic potential (Granzyme B, perforin, and CD57) 
may also be included. Data will be reported as percentages of CD4+ or CD8+ T cells 
responding to a specific peptide pool. Additional cell surface markers, cytokines, or 
functional markers may also be analyzed. 
10.6 
Genotyping 
Molecular human leukocyte antigen (HLA) typing may be performed on enrolled 
participants using cryopreserved PBMC collected at baseline, initially on specimens from 
participants who demonstrate vaccine-induced T-cell responses at postvaccination 
timepoints. Other participants (including control recipients) may be HLA-typed to 
support future studies of immunological interest at the discretion of the HVTN 
Laboratory Program. Other 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. 
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.  

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10.8.1 
Microbiome analysis 
Swabs of stool will be shipped to a central laboratory. Specimens are processed to enable 
nucleic acid sequencing. 16s rRNA sequences will then be determined using pyro-
sequencing approaches or other 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 108 PSRT 
The HVTN 108 PSRT is composed of the following members: 
 
DAIDS medical officer representative, 
 
Protocol chair and cochair, 
 
Protocol Team leader, 
 
Core medical monitor,  
 
Clinical safety specialist (CSS) 
 
Regional medical liaison (RML), and  
 
A medical officer from an organization in Southern Africa designated by the study 
sponsor will also participate in the PSRT. 
The clinician members of HVTN 108 PSRT are responsible for decisions related to 
participant safety. 
The Protocol Team clinic coordinator, project manager, vaccine developer representative, 
clinical trial manager, and others may also be included in HVTN 108 PSRT meetings. 
11.1.2 
HVTN SMB 
The SMB is a multidisciplinary group consisting of biostatisticians, clinicians, and 
experts in HIV vaccine research that, collectively, has experience in the conduct and 
monitoring of vaccine trials. Members of the SMB are not directly affiliated with the 
protocols under review.  
The SMB reviews safety data, unblinded as to treatment arm, approximately every 4 
months. The reviews consist of evaluations of cumulative reactogenicity events, AEs, 
laboratory safety data, and individual reports of adverse events requiring expedited 
reporting to DAIDS. To increase the sensitivity for detecting potential safety problems, 
the SMB will review safety data aggregated across multiple protocols that use the same 
or similar vaccine candidates. The SMB conducts additional special reviews at the 
request of the HVTN 108 PSRT.  
Study sites will receive SMB summary minutes and are responsible for forwarding them 
to their IRB/EC and any applicable RE. 
11.1.3 
SDMC roles and responsibilities in safety monitoring  
The roles and responsibilities of the SDMC in relation to safety monitoring include: 

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 
Maintaining a central database management system for HVTN clinical data; 
 
Providing reports of clinical data to appropriate groups such as the HVTN 108 PSRT 
and HVTN SMB (see Section 11.1.2); 
11.1.4 
HVTN Core roles and responsibilities in safety monitoring 
 
Daily monitoring of clinical data for events that meet the safety pause and HVTN 
108 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 108 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 resubmitted 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 2.0, November 2014, available on the RSC 
website at http://rsc.tech-res.com/safetyandpharmacovigilance/, except: 
 
Weight loss is required to be reported as an AE only if it is considered to be 
deleterious to the participant’s health (see HVTN 108 Study Specific Procedures); 
 
Injection Site Erythema or Redness and Injection Site Induration or Swelling will not 
consider interference with usual social and functional activities such that: 
 
Grade 1 is: 2.5 to < 5 cm in diameter OR 6.25 to < 25 cm2 surface area; 
 
Grade 2 is: ≥ 5 to < 10 cm in diameter OR ≥ 25 to < 100 cm2 surface area; 
 
Grade 3 is: ≥ 10 cm in diameter OR ≥ 100 cm2 surface area OR Ulceration OR 
Secondary infection OR Phlebitis OR Sterile abscess OR Drainage; 

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 
Grade 4 is: Potentially life-threatening consequences (e.g., abscess, exfoliative 
dermatitis, necrosis involving dermis or deeper tissue); 
 
The grading of Insomnia events will consider the criteria within the Insomnia 
parameter as well as the general AE functional table such that: 
 
Grade 1 Insomnia is defined as: Mild difficulty falling asleep, staying asleep, or 
waking up early causing no or minimal interference with usual social and 
functional activities with intervention not indicated; 
 
Grade 2 Insomnia is defined as: Moderate difficulty falling asleep, staying 
asleep, or waking up early, causing greater than minimal interference with usual 
social and functional activities with intervention indicated; 
 
Grade 3 Insomnia is defined as: Severe difficulty falling asleep, staying asleep, or 
waking up early, causing inability to perform usual social & functional activities 
with intervention or hospitalization indicated. 
If a definition of insomnia falls between 2 grades, the final grading will be selected 
based on the degree of interference with usual social and functional activities caused 
by the symptoms. 
Unsolicited AEs will be collected over a period of 30 days after each vaccination visit. 
All collected AEs are reported to the SDMC on the appropriate CRF. Clinic staff should 
evaluate every AE to determine if (1) the AE meets the requirements for expedited 
reporting (Section 11.2.3), (2) if the AE meets the criteria for a safety pause/prompt AE 
review (Section 11.3), and (3) if the AE is a potential immune-mediated disease that may 
be listed as an AE of special interest (AESI). A sample list of AESI is provided in 
Appendix J. 
Certain AEs will be collected and reported throughout the entire study:  
 
SAEs/EAEs,  
 
AESIs, 
 
New chronic conditions requiring medical intervention for ≥ 30 days, 
 
Newly diagnosed or treated STIs, 
 
AEs leading to early participant withdrawal or early discontinuation of study 
product(s) administration. 
CRSs are expected to notify the CSS or RML of any serious safety concern requiring 
their attention (see Table 11-1). Telephone numbers and email addresses are found on the 
Protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/hvtn108). Concerns requiring immediate attention 
should be communicated by calling the clinical safety phone. 
In the case of email notification the CSS or RML 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 or RML of the event by 
telephone, then submit CRFs. 

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In addition, site Investigators of Record (IoRs) or their designees are required to submit 
AE information in accordance with IRB/EC and any applicable RE requirements. 
11.2.3 
Expedited reporting of adverse events to DAIDS 
Requirements, definitions and methods for expedited reporting of AEs are outlined in 
Version 2.0 (January 2010) of the Manual for Expedited Reporting of Adverse Events to 
DAIDS (DAIDS EAE Manual), which is available on the RSC website at http://rsc.tech-
res.com/safetyandpharmacovigilance/. The SAE Reporting Category will be used for the 
main study period.  
The internet-based DAIDS Adverse Event Reporting System (DAERS) must be used for 
expedited AE reporting to DAIDS. In the event of system outages or technical 
difficulties, expedited AE reports may be submitted via the DAIDS EAE Form. For 
questions about DAERS, please contact DAIDS-ESSupport@niaid.nih.gov or from 
within the DAERS application itself.  
Sites where DAERS has not been implemented will submit expedited AE reports by 
documenting the information on the current DAIDS EAE Form. This form is available on 
the RSC website: http://rsc.tech-res.com/safetyandpharmacovigilance/. For questions 
about expedited AE reporting, please contact the RSC (DAIDSRSCSafetyOffice@tech-
res.com).  
Under ICH E2A (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting), an SAE is defined as any untoward medical occurrence that at any 
dose: 
 
results in death, 
 
is life-threatening (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the patient was at risk of death at the time of the event; it 
does not refer to an event, which hypothetically might have caused death, if it were 
more severe), 
 
requires patient hospitalization or prolongation of existing hospitalization,  
 
results in persistent or significant disability/incapacity,  
 
is a congenital anomaly/birth defect, or 
 
is a medically important event or reaction* 
*Medical and scientific judgment should be exercised when deciding if other situations are 
serious. Such instances could include medical events that may not be immediately life-
threatening or result in death or hospitalization, but which may jeopardize the patient or may 
require intervention to prevent 1 of the outcomes listed in the definition above. Examples of 
such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions not resulting in hospitalization, or 
development of drug dependency or drug abuse. 
While the participant is in the main study reporting period (see Section 3), the SAE 
Reporting Category will be used.  
If the participant has completed the main study and has not yet completed the AESI 
contact (Section 9.5) the SUSAR reporting category will be used.  

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After the participant has completed the AESI contact and is off study, sites must report 
SUSARs if the study site staff become aware of the events on a passive basis (eg, from 
publicly available information). 
The study products that must be considered in determining relationships of AEs requiring 
expedited reporting to DAIDS and pertinent national regulatory authorities are: 
 
DNA-HIV-PT123/ placebo 
 
Bivalent Subtype C gp120/MF59/placebo 
 
Bivalent Subtype C gp120/AS01B/placebo  
The NIAID/DAIDS will report all unexpected SAEs related to the study products 
observed in this clinical trial to the FDA in accordance with 21 CFR 312.32 (IND Safety 
Reports). All AESIs will be considered “unexpected”, and, if deemed related to the study 
products, will be reported to FDA as SUSARs, if applicable. However, because safety is 
a primary study endpoint, the Sponsor Medical Officer will not be unblinded to study 
treatment assignment when there is an assessment of relatedness of the SAE with the 
study product(s); and the safety report will be sent to the FDA based on the blinded 
attribution assessment. 
11.2.4 
Expedited reporting of AEs to pertinent national regulatory authorities  
The study sponsor or designee(s) prepares and files expedited reports to appropriate 
regulatory authorities within the timelines required by pertinent national regulatory 
authorities.  
 
Site IoRs/designees will submit AE information and any other relevant safety 
information to their ECs/IRBs in accordance with EC/IRB requirements. 
11.3 
Safety pause and prompt PSRT AE review 
When a trial is placed on safety pause, all enrollment and vaccination with the product 
related to the event that triggered the pause will be held until further notice. The AEs that 
will lead to a safety pause or prompt HVTN 108 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 108 
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 actiona 
HVTN Core action 
SAE, related 
Grade 5 or 
Grade 4 
Phone immediately, email 
and submit forms 
immediately 
Immediate pause 
SAE, not related 
Grade 5 
Phone immediately, email 
and submit forms 
immediately 
Immediate HVTN 108 PSRT 
notification 
SAE, related 
Grade 3 
Email and submit forms 
immediately 
Prompt HVTN 108 PSRT AE 
review to consider pause 
AEb, related 
Grade 4 or 3 
Email and submit forms 
immediately 
Prompt HVTN 108 PSRT AE 
review to consider pause 
a Phone numbers and email addresses are found on the Protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/hvtn108). 
b Does not include subjective reactogenicity symptoms (injection site pain, tenderness, fatigue/malaise, myalgia, arthralgia, chills, headache, 
nausea). 
For all safety pauses, HVTN Core notifies the HVTN 108 PSRT, HVTN Regulatory 
Affairs, DAIDS Pharmaceutical Affairs Branch (PAB), DAIDS Regulatory Affairs 
Branch (RAB), DAIDS Safety and Pharmacovigilance Team (SPT), and participating 
HVTN CRSs. When an immediate safety pause is triggered, HVTN Core notifies the 
SMB.  
Once a trial is paused, the HVTN 108 PSRT reviews safety data and decides whether the 
pause can be lifted or permanent discontinuation of vaccination is appropriate, consulting 
the SMB if necessary. HVTN Core notifies the participating HVTN CRSs, HVTN 
Regulatory Affairs, DAIDS PAB, DAIDS RAB, and DAIDS SPT of the decision 
regarding resumption or discontinuation of study vaccinations. Based on the HVTN 108 
PSRT assessment, the trial sponsor or designee(s) notifies pertinent national regulatory 
authorities as needed. 
If an immediate HVTN 108 PSRT notification or prompt HVTN 108 PSRT AE review is 
triggered, HVTN Core notifies the HVTN 108 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 108 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 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 108 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 HVTN Core for events requiring 
expedited reporting to DAIDS, and events that meet safety pause criteria or prompt 
HVTN 108 PSRT AE review criteria. 
11.4.2 
Weekly review 
During the injection phase of the trial, the HVTN 108 PSRT reviews clinical safety 
reports on a weekly basis and conducts calls to review the data as appropriate. After the 
injections and the final 2-week safety visits are completed, less frequent reporting and 
safety reviews may be conducted at the discretion of the HVTN 108 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. 
11.4.3 
AESI contact 
After the main study period, a monitoring team reviews safety reports after the AESI 
contact. This monitoring team comprises at least a DAIDS Medical Officer, Core medical 
monitor, and a CSS. 
11.5 
Study termination 
This study may be terminated early by the determination of the HVTN 108 PSRT, FDA, 
a pertinent national regulatory authority, 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 108 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 

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negative social impacts associated with the vaccine trial. If HVTN CRS staff have 
questions regarding ways to assist a participant dealing with a social impact, a designated 
NIAID or HVTN Core representative can be contacted.  
Social harms are tabulated by the SDMC and are subjected to descriptive analysis. The 
goal is to reduce their incidence and enhance the ability of study staff to mitigate them 
when possible. 
Summary tables of social impact events will be generated weekly, and made available for 
review by the protocol chairs, protocol team leader, and the designated NIAID 
representative. 
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 or 
Synthetic Nucleic Acid Molecules. Information about the study must be submitted to site 
Institutional Biosafety Committees (IBC) and must be approved before participants are 
enrolled at the site. Investigators at each site are responsible for obtaining IBC approval 
per NIH guideline section IV-B07-a-(1). IBC review and approval must be documented 
by the investigator and submitted as part of initial protocol registration for this trial. If 
this protocol is amended, investigators should follow the requirements of their IBC. 
12.3 
Specific regulatory considerations for Republic of South Africa and 
other Southern African countries 
The Republic of South Africa has laws regarding the use, manufacture, importation, and 
experimentation of products which are genetically modified. These are contained in the 
Genetically Modified Organism (GMO) Act 15 of 1997, administered by the South 
African National Department of Agriculture, Pretoria. If required, the Registrar of GMO 
shall be consulted on all formal developments relating to this protocol and clinical trial, 
and a formal application will be made to the Registrar of GMO to review the HVTN 108 
clinical trial, to obtain approval for the proposed clinical trial, and for the importation of 
the study products.  
Any regulations specific to other countries containing CRSs at which HVTN 108 will be 
implemented will also be observed. 
12.4 
Emergency communication with study participants 
As in all clinical research, this study may generate a need to reach participants quickly to 
avoid imminent harm, or to report study findings that may otherwise concern their health 
or welfare.  
When such communication is needed, the CRS will request that its IRB/EC and any 
applicable RE expedite review of the message. If this review cannot be completed in a 
timeframe consistent with the urgency of the required communication, the site 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 108 are described below. 
Protocol history and modifications 
Date: August 8, 2016 
Protocol version: Version 2.0 
Protocol modification: Full Protocol Amendment 1 
Item 1 
Added to cover page: BB IND number 
Item 2 
Updated in Section 3.1, Protocol Team: Protocol leadership 
Item 3 
Revised in Section 5.1, Primary objectives and endpoints, Section 9.3, 
Enrollment and vaccination visits, Section 9.11, Assessments of 
reactogenicity, Appendix A, SICF, Item 12, and in Appendix H, 
Procedures at HVTN CRS: Reactogenicity assessment period extended 
from 3 days to 7 days 
Item 4 
Revised in Section 6.4.3.2, AEs and SAEs, Section 11.2.3, Expedited 
reporting of adverse events to DAIDS, and Appendix J, Adverse events of 
special interest: AESI reporting requirements 
Item 5 
Updated Section 8.3, Preparation of study products: instructions for 
preparing and handling of study products. 
Item 6 
Revised Section 9.2, Pre-enrollment procedures: Coding of concomitant 
medications 
Item 7 
Revised Section 9.6, Mucosal sampling and Appendix A, SICF, Item 14: 
Cervicovaginal secretion collection 
Item 8 
Clarified in Appendix A, SICF, Item 14: Rectal fluid collection 
Item 9 
Revised in Appendix A, SICF: Item 16 regarding sample testing 
Item 10 Revised in Appendix A, SICF, Item 26: Study-related injury language 
Item 11 Added to Appendix A, SICF, Item 28: MCC contact information for South 
African sites 
Item 12 Corrected in Appendix A, SICF, Item 29 and Item 30: Placement of prompt 
to delete check-boxes 
Item 13 Clarified in footnotes in Appendix G, Laboratory procedures and 
Appendix H, Procedures at HVTN CRS: Pregnancy testing and baseline 
specimen collection prior to initial vaccination 
Item 14 Updated: Section 13, Version history 
 

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Date: May 8, 2015 
Protocol version: 1.0 
Protocol modification: Original protocol 
 
 

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14 
Document references (other than literature 
citations) 
Other documents referred to in this protocol, and containing information relevant to the 
conduct of this study, include: 
 
Assessment of Understanding. Accessible through the HVTN protocol-specific 
website. 
 
Current CDC Guidelines. Revised Recommendations for HIV Testing of Adults, 
Adolescents, and Pregnant Women in Health-Care Settings. Available at 
http://www.cdc.gov/mmwr/PDF/rr/rr5514.pdf.  
 
Division of AIDS (DAIDS) Clinical Research Policies and Standard Procedures 
Documents. Available at 
http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/ 
 
Division of AIDS Protocol Registration Manual. Available at 
http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Document
s/prmanual.pdf 
 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events. Version 2.0, November 2014. Available at http://rsc.tech-
res.com/safetyandpharmacovigilance/gradingtables.aspx  
 
The Manual for Expedited Reporting of Adverse Events to DAIDS. Version 2.0, 
January 2010. Available at http://rsc.tech-
res.com/safetyandpharmacovigilance/manualforexpeditedreporting.aspx 
 
HVTN Certificate of Confidentiality. Accessible through the HVTN website. 
 
HVTN 108 Special Instructions. Accessible through the HVTN protocol-specific 
website. 
 
HVTN 108 Study Specific Procedures. Accessible through the HVTN protocol-
specific website. 
 
HVTN Laboratory Manual of Operations. Accessible through the HVTN 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/ps/publications/dgr/Pages/index.aspx. 
 
Lab assay algorithm. Accessible through the HVTN website. 
 
HVTN algorithm for diagnosis of HIV infections. Part of the HVTN Site Lab 
Reference Manual (see above). 

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 
International Conference on Harmonisation (ICH) E6 (R1), Guideline for Good 
Clinical Practice. Available at 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/good-clinical-
practice.html 
 
International Conference on Harmonisation (ICH) E2A, Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting. Available at 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
2A/Step4/E2A_Guideline.pdf 
 
Participants’ Bill of Rights and Responsibilities. Accessible through the HVTN 
website. 
 
NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid 
Molecules. Available at http://osp.od.nih.gov/office-biotechnology-
activities/biosafety/nih-guidelines 
 
NIH Policy on Reporting Race and Ethnicity Data: Subjects in Clinical Research. 
Available at http://grants1.nih.gov/grants/guide/notice-files/NOT-OD-01-053.html. 
 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks, July 
2008. 
 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials. Available at 
https://phacs.nichdclinicalstudies.org/publicDocs/DAIDS_SourceDocPolicy.pdf 
 
Title 21, Code of Federal Regulations, Part 50. Available at 
http://ecfr.gpoaccess.gov/cgi/t/text/text-
idx?c=ecfr&sid=2e2429c70115b7df5635f222901ae8f7&rgn=div5&view=text&node
=21:1.0.1.1.19&idno=21 
 
Title 45, Code of Federal Regulations, Part 46. Available at 
http://ecfr.gpoaccess.gov/cgi/t/text/text-
idx?c=ecfr&sid=2e2429c70115b7df5635f222901ae8f7&rgn=div5&view=text&node
=45:1.0.1.1.25&idno=45 
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 
Ad 
adenovirus 
AE 
adverse event  
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
ART 
antiretroviral therapy 
AS 
adjuvant system 
AST 
aspartate aminotransferase  
ATP 
adequate take/potency 
AVEG 
AIDS Vaccine Evaluation Group 
β-HCG 
beta human chorionic gonadotropin 
BMI 
body mass index 
CAB 
Community Advisory Board 
CBC 
complete blood count 
CDC 
US Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CI 
confidence intervals 
CoR 
correlate of risk 
CRF 
case report form 
CRPMC 
NIAID Clinical Research Products Management Center 
CRS* 
clinical research site 
CTL 
cytotoxic T lymphocyte 
DAERS 
DAIDS Adverse Event Reporting System 
DAIDS 
Division of AIDS (US NIH) 
DHHS 
US Department of Health and Human Services 
EAE 
adverse events requiring expedited reporting to DAIDS 
EC 
Ethics Committee 
EIA 
enzyme immunoassay 
ELISA 
enzyme-linked immunosorbent assay 
ELISpot 
enzyme-linked immunospot 
FDA 
US Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equation 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HVTN 
HIV Vaccine Trials Network 
IB 
Investigator’s Brochure 

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IBC 
Institutional Biosafety Committee 
ICH 
International Conference on Harmonisation 
ICS 
intracellular cytokine staining 
IFN-γ 
interferon gamma 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
MAR 
missing at random 
MCAR 
missing completely at random 
MMR 
measles, mumps, and rubella 
nAb 
neutralizing antibody 
NHP 
nonhuman primate 
NIAID 
National Institute of Allergy and Infectious Diseases (US NIH) 
NICD 
National Institute for Communicable Diseases (Johannesburg, South Africa) 
NIH 
US National Institutes of Health 
OHRP 
US Office for Human Research Protections 
OPV 
oral polio vaccine 
PAB 
DAIDS Pharmaceutical Affairs Branch 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PI 
Principal Investigator 
PSRT 
Protocol Safety Review Team 
RAB 
DAIDS Regulatory Affairs Branch 
RE 
regulatory entity 
RSC 
DAIDS Regulatory Support Center 
SAE 
serious adverse event 
SCHARP Statistical Center for HIV/AIDS Research and Prevention 
SDMC 
statistical and data management center 
SIV 
simian immunodeficiency virus 
SMB 
Safety Monitoring Board 
SPT 
DAIDS Safety and Pharmacovigilance Team 
TB 
tuberculosis 
UW-VSL University of Washington Virology Specialty Laboratory 
VISP 
Vaccine induced seropositivity 
VRC 
Vaccine Research Center (NIAID) 
* 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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   64.   O'Hagan DT, Ott GS, De GE, Seubert A. The mechanism of action of MF50-An 
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Hu D, Tappero JW, Choopanya K. Randomized, Double-Blind, Placebo-Controlled 
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controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-
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2001;20:1215-34. 
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Appendix A 
Sample informed consent form 
Title: A phase 1/2a clinical trial to evaluate the safety and immunogenicity of HIV clade 
C DNA, and of MF59®- or AS01B-adjuvanted clade C Env protein, in various 
combinations, in healthy, HIV-uninfected adult participants 
HVTN protocol number: HVTN 108 
Site: [Insert site name] 
Thank you for your interest in our research study. Please read this consent form or ask 
someone to read it to you. If you decide to join the study, we will ask you to sign or make 
your mark on this form. We will offer you a copy to keep. We will ask you questions to 
see if we have explained everything clearly. You can also ask us questions about the 
study.  
Research is not the same as treatment or medical care. The purpose of a research study is 
to answer scientific questions. 
About the study 
The HIV Vaccine Trials Network (HVTN) and [Insert site name]  are doing a study to 
test HIV vaccines. HIV is the virus that causes AIDS. 
About 334 people will take part in this study at multiple sites in Southern Africa and the 
US. At least 40 percent will be men and at least 40 percent will be women. The 
researcher in charge of this study at this clinic is [Insert name of site PI]. The United 
States National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation are 
paying for the study.  
1. We are doing this study to answer several questions. 
 
Are the study vaccines safe to give to people? 
 
Are people able to take the study vaccines without becoming too uncomfortable? 
 
How do people’s immune systems respond to different combinations and doses of the 
study vaccines? (Your immune system protects you from disease.) 
2. The study vaccines cannot give you HIV. 
The study vaccines are not made from actual HIV. It is impossible for the study vaccines 
to give you HIV. Also, they cannot cause you to give HIV to someone else. 
3. We do not know if the study vaccines will decrease, increase, or not change your 
risk of becoming infected with HIV if you are exposed to the virus. 
Sites: Any change to the language in this section requires approval from HVTN 
Regulatory Affairs. 
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 

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got the vaccine seemed to have a lower risk of getting HIV than people who did not get 
the vaccine. In studies with a different vaccine, some people who got the vaccine had a 
higher risk of getting HIV than people who did not get the vaccine.  
This study differs from the studies in which people who got the vaccine had a higher or 
lower risk of getting HIV. The 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. These study vaccines are experimental. 
There are 3 study vaccines being tested in this study. They are all experimental vaccines. 
That means we do not know whether the vaccines will be safe to use in people, or 
whether they will work to prevent HIV infection. These vaccines are used only in 
research studies. The study vaccines are called DNA-HIV-PT123, Bivalent Subtype C 
gp120/MF59, and Bivalent Subtype C gp120/AS01B. From here on, we will call them the 
DNA vaccine, the Protein/MF59 vaccine, and the Protein/AS01B vaccine, or the study 
vaccines.  
The DNA vaccine: 
The DNA vaccine was developed by the IPPOX Foundation (Lausanne, Switzerland).  
The DNA vaccine is being tested in people in 2 other studies in the US and in 
Switzerland. These studies are giving the DNA vaccine in combination with other 
vaccines. As of June 2014, over 180 people received the DNA vaccine. So far, it has not 
made them too uncomfortable or caused them serious health problems. However, studies 
with a small number of people do not tell us everything about the safety of the study 
vaccines. 
The Protein/MF59 vaccine: 
The Protein/MF59 vaccine was developed by Novartis Vaccines (Cambridge, MA, USA). 
The Protein/MF59 vaccine has man-made pieces of a protein found on the outside of 
HIV. These proteins will be mixed with an adjuvant. An adjuvant is a substance added to 
the vaccine to help the immune system respond better. In this study vaccine the adjuvant 
is called MF59. MF59 is commonly used in licensed flu vaccines in many European 
countries. It has also been used in other vaccines that have been given to over 50,000 
people in research studies without causing any serious health problems. 
The Protein/MF59 vaccine has not been given to people before. It has been tested in 
mice, rabbits, and monkeys and it did not cause any health concerns. Animal testing may 
not always tell us what will happen with humans. Similar vaccines have been given to 
more than 10,000 people in research studies. In these studies, the protein vaccines did not 
cause serious health problems.  
The Protein/AS01B vaccine: 
The Protein/AS01B vaccine was developed by GlaxoSmithKline Biologicals (Rixensart, 
Belgium). 

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The Protein /AS01B vaccine has the same proteins used in the Protein/MF59 vaccine. 
However, these protein pieces are mixed with a different adjuvant called AS01B. The 
Protein/AS01B has not been given to people before either. Similar vaccines have been 
given to over 1400 people in past studies. In these studies, the vaccines did not cause 
serious health problems. 
General risks of vaccines: 
All vaccines can cause fever, chills, rash, aches and pains, nausea, headache, dizziness, 
and feeling tired. Vaccines can also cause pain, redness, swelling, or itching at the 
injection site. 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. 
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. 
Rarely, people who have received vaccines with adjuvants have developed illnesses 
called autoimmune diseases. Autoimmune diseases have also occurred in people who 
have not been vaccinated. These diseases develop when immune cells that normally 
protect you from illness attack your organs instead. Autoimmune diseases can be serious 
and can also be lifelong. They can involve, for example, your liver, kidneys, skin, joints, 
eyes, brain, as well as other parts of the body. Since no one knows for sure if vaccines 
with adjuvants might cause autoimmune diseases, we continue to monitor this situation 
closely. 
Risks of the study vaccines: 
This section lists the side effects we know about. There may be others that we don’t yet 
know about, even serious ones. We will tell you if we learn about any new side effects. 
The DNA vaccine: 
In studies with this and similar DNA vaccines, the most common complaints were mild 
to moderate pain or itching in the area where they got the injection, headache, and feeling 
tired. Some people felt flu-like symptoms, nausea, and rash. These problems usually 
happened within a couple of days after injection(s) and usually went away on their own 
within a few days. 
The Protein/MF59 vaccine: 
This study vaccine has not been tested in people before. In studies with similar products, 
some people had redness, swelling, pain, tenderness, or itching in the area where they got 
the injection. Some people had headaches. A small number of people had joint pain, flu-
like symptoms, nausea, rash, vomiting, diarrhea, or swollen lymph nodes after getting an 
injection. A very small number of people had a stomach ache. Most people who had 
symptoms only had some of these symptoms, not all of them. 
The Protein/AS01B vaccine: 
This study vaccine has not been tested in people before. In studies with similar products 
some people had redness, swelling, pain, tenderness, warmth, or itching in the area where 
they got the injection. Some people had headache, fever, tiredness or weakness. A small 

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

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 
For the care that we cannot give, we will explain how we will help you get care 
elsewhere.  
We will not be able to pay for care for health problems that are unrelated to this study. 
8. If you were born female and could become pregnant, you must agree to use birth 
control to join this study. 
Site: List approved birth control methods for your country here if you do not want to 
hand out the separate Approved Birth Control Methods sheet (Appendix B or Appendix 
C). 
You should not become pregnant during the study because we do not know how the study 
vaccines could affect the developing baby. You must agree to use effective birth control 
from 3 weeks before your first injection until 6 months after your last study injection. We 
will talk to you about effective birth control methods. They are listed on a handout that we 
will give to you. Site: Delete the preceding sentence if you include the approved birth 
control methods for your country from Appendix B or Appendix C 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: 
9. You will come to the clinic for scheduled visits about [#] times over 12 months. 
Site: Insert number of visits and range of visit lengths. (There is site-specific variation in 
screening protocols and in the number of possible follow-up visits between protocol-
mandated visits.) 
Visits can last from [#] to [#] hours. 
You may have to come for more visits if you have a lab or health issue. 
We may contact you after the main study ends (for example, to tell you about the study 
results). 
10. We will give you [Site: Insert compensation] for each study visit you complete. 
This amount is to cover the costs of [Site: Insert text] 
Site: Insert any costs to participants (eg, birth control costs for female participants who 
could become pregnant). 
US sites only: 
Payments you receive for being in the study may be taxable. This happens if we pay you 
more than $600 between January 1 and December 31 of the same year. The clinic staff 
may need to ask you for your Social Security number for tax reasons. 
You do not have to pay anything to be in this study. 

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11. Not everyone in this study will get the study vaccines.  
Some people will get the study vaccines and the placebo. Some people will get only the 
placebo. A placebo is a substance that does not contain vaccine. The placebo in this study 
is saline solution. We do not expect the placebo to cause any health problems in people. 
Site: Modify the randomization metaphor in the next sentence as appropriate to your 
local culture. Whether you get the study vaccines or the placebo is completely random, 
like flipping a coin. 
You have about a 1 out of 14 chance of getting only the placebo. You have about an 13 
out of 14 chance of getting some combination of study vaccines and placebo. We will 
compare the results from people who got only the placebo with results from people who 
got different combinations of the study vaccines and placebo. 
The clinic staff will not know which study products you are getting, and neither will you. 
Only the pharmacist at your site will have this information while the study is going on.  
You will have to wait until everyone completes their final study visits to find out what 
study products you got. This could be 2-5 years. But, if you have a serious medical 
problem and need to know what you got before the end of the study, we can tell you. 
12. We will give you the study products on a schedule. 
There are 8 groups in this study. Each group will get a different combination of study 
products. Also, different groups will get different doses (high or low) of the protein used 
in the protein vaccines. Each group will get 12 injections during the study. You will get 
the injections into your upper arms. You will get 3 injections at every injection visit.  
The DNA vaccine will go into the left arm. The Protein/MF59 vaccine and the 
Protein/AS01B vaccine will go into the right arm. The placebo can be given in both arms. 
Site: A picture version of the injection schedule has been provided in Appendix E. You 
may insert it below in place of (or in addition to) the text version or give it as a separate 
document to your participants. You are not required to do either. 

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Time after first injection visit 
Group 
Number 
of people 
Protein 
dose 
Arm 
First injection 
visit 
1 month 
3 months 
6 months 
1 
30 
High dose 
Left 
DNA 
DNA 
DNA 
DNA 
Right 
Placebo + Placebo 
Placebo + Placebo 
Protein/MF59 + 
Placebo 
Protein/MF59 + 
Placebo 
2 
50 
High dose 
Left 
DNA 
DNA 
DNA 
DNA 
Right 
Placebo + Placebo 
Placebo + Placebo 
Protein/AS01B + 
Placebo 
Protein/AS01B + 
Placebo 
3 
50 
Low dose 
Left 
DNA 
DNA 
DNA 
DNA 
Right 
Placebo + Placebo 
Placebo + Placebo 
Protein/AS01B + 
Placebo 
Protein/AS01B + 
Placebo 
4 
30 
High dose 
Left 
DNA 
DNA 
Placebo 
DNA 
Right 
Protein/MF59 + 
Placebo 
Protein/MF59 + 
Placebo 
Placebo + Placebo 
Protein/MF59 + 
Placebo 
5 
50 
High dose 
Left 
DNA 
DNA 
Placebo 
DNA 
Right 
Protein/AS01B + 
Placebo 
Protein/AS01B + 
Placebo 
Placebo + Placebo 
Protein/AS01B + 
Placebo 
6 
50 
Low dose 
Left 
DNA 
DNA 
Placebo 
DNA 
Right 
Protein/AS01B + 
Placebo 
Protein/AS01B + 
Placebo 
Placebo + Placebo 
Protein/AS01B + 
Placebo 
7 
50 
Low dose 
Left 
Placebo 
Placebo 
Placebo 
Placebo 
Right 
Protein/AS01B + 
Placebo 
Protein/AS01B + 
Placebo 
Placebo + Placebo 
Protein/AS01B + 
Placebo 
8 
24 
N/A 
Left 
Placebo 
Placebo 
Placebo 
Placebo 
Right 
Placebo + Placebo 
Placebo + Placebo 
Placebo + Placebo 
Placebo + Placebo 
At each injection visit, you will have to wait in the clinic for about a half hour after 
getting the injections to see if there are any problems. You will need to record how you 
feel each day for a total of 7 days after each injection visit. To help you do this, we will 
give you tools and show you how to use them. For 3-4 days after each injection visit, you 
will need to tell the clinic staff how you have been feeling. We will ask you the ways we 
can contact you. If you do not contact us, we will contact you. For the rest of the 7 days, 
you only need to contact us if you have any symptoms that prevent you from doing your 
usual activities. You should also contact us if you have any questions. 
Also, please contact 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. 
13. In addition to giving you the study products, we will:  
 
Do regular HIV testing, as well as counseling on your results and on how to avoid 
getting HIV; 
 
Perform physical exams; 
 
Do pregnancy tests if you were born female; 
 
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.  
 
Take urine and blood samples. 

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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 (2 teaspoons to a little more 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: Insert Appendix F, Table of procedures (for informed consent form) in this section 
or distribute it as a separate sheet if it is helpful to your study participants. You are not 
required to do either. 
We will be looking for side effects. We will review the results of these procedures and 
tests with you at your next visit, or sooner if necessary. If any of the results are important 
to your health, we will tell you.  
14. If you agree, we will also collect stool, rectal fluid and cervical fluid or semen.  
At the end of this form we will ask if you allow us to collect stool, rectal fluid and 
cervical fluid (if you were born female) or semen (if you were born male). You can 
decide not to give any of these samples and still be in the study.  
Stool  
We would like to collect a small sample of your stool to look at the bacteria living in your 
stomach. We want to learn if your immune response to the study vaccines is influenced 
by these bacteria. We will do this twice during this study. If you agree to give the rectal 
fluid sample described below, we can collect the stool sample at the same time, or you 
may provide a stool sample at home or at the clinic. The clinic must receive the stool 
sample within 24 hours after it is collected. 
Rectal fluid, cervical fluid, or semen 
We want to see how the study vaccines affect the parts of the body where people may be 
exposed to HIV: their rectum, vagina, and penis.  
We would like to collect these samples at 3 visits. When we collect the samples, we will 
test you for gonorrhea, chlamydia and syphilis. If you were 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. 
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 
in 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.  

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For the 2 days before we collect your rectal fluid, we will ask you not to do these things:  
 
have receptive anal intercourse  
 
put anything into your anus, including cleaning products (creams, gels, lotions, pads, 
etc.), lubricant, or enemas  
 
douche (even with water), 
 
use any anti-inflammatory creams in or around your anus.  
We will not collect rectal fluid if you are menstruating, pregnant or if we think you may 
have an infection. You should tell us if your rectal area is sore. 
Cervical fluid 
If you are 21 years or older you must have had a Pap smear within the last 3-5 years with 
the most recent result being normal. If you haven’t had a Pap smear within the last 3-5 
years and would like to get one, we will help you get one at no cost to you. 
We will collect cervical fluids by using either a soft sponge inserted into the opening of 
your cervix, or by using something called a Softcup inserted into your vagina. If we use a 
soft sponge to collect cervical fluids, we will insert a speculum (a device that holds your 
vagina open) into your vagina and place the sponge in the opening of the cervix. This is 
similar to getting a pap smear. If we use the Softcup, we will explain how to use it.  
For the 2 days before we collect your cervical fluid, we will ask you to not do these 
things:  
 
use any spermicide, lubricants, douche (even with water), or medication in or around 
your vagina;  
 
have vaginal intercourse or insert anything into your vagina.  
We will not start the collection of cervical fluid if we learn that you are menstruating or 
pregnant or if we think you may have a cervical or vaginal infection. 
Semen 
You may provide the semen at home or at the clinic. We will ask you to ejaculate into a 
plastic cup, which we will give to you. The clinic must receive the semen sample within 2 
hours or less after it is collected. We will ask you not to ejaculate for 2 days before 
providing the semen. You should tell us if you think you have an infection on your penis. 
If you have an infection we may not use your sample.  
15. 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.  

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 
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. 
16. We will test your samples for this study. 
We will send your samples (without your name) to labs approved by the HVTN for this 
study, which are located in the United States and South Africa. Researchers at these labs 
will test your samples to see how your immune system responds to the study products. In 
rare cases, some of your samples may be sent to labs approved by the HVTN in other 
countries for research related to this study. 
Researchers may also do genetic testing related to this study on your samples. Your genes 
are passed to you from your birth parents. They affect how you look and how your body 
works. The differences in people’s genes can help explain why some people get a disease 
while others do not. These types of genetic tests involve some of your genes, not all of 
your genes (your genome). The researchers will study the genes related to the immune 
system and HIV and those that affect how people get HIV.  
If you become HIV infected, the researchers may look at all of the genes of the virus 
found in your samples. If you give cervical, stool, or rectal fluid samples, the researchers 
may look at all of the genes of the bacteria found in your samples. In both cases, the 
researchers will use this information to learn more about HIV and the study products. The 
researchers may put this information about the virus and/or bacteria into a protected 
database so that other researchers can access it. They would not be able to link the 
information from your samples to you.  
In some cases, researchers may take cells from your samples and grow more of them over 
time, so that they can continue to contribute to this study.  
Tests done on your samples are for research purposes only. The labs will not give the 
results to you or this clinic, and the results will not become part of your study record. 
When your samples are no longer needed for this study, the HVTN will continue to store 
them. 
Site: Delete next section if using Appendix D, the separate consent for use of samples and 
information in other studies 
17. 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 by HVTN or other researchers. 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.  

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Where are the samples stored? Extra samples are stored in a secure place called a 
repository. [Site: choose one of the following two sentences. African sites should choose 
the sentence referencing the repository in South Africa. All other sites should choose the 
sentence referencing the repository in the United States.] Your samples will be stored in 
the HVTN repository in South Africa. Your samples will be stored in the HVTN 
repository in the United States.  
How long will the samples be stored? There is no limit on how long your extra samples 
will be stored. [Site: 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. 
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. If the research plan is 
approved, the HVTN will send your samples to the researcher’s location.  
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 

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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  
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. 
18. We will do our best to protect your private information. 
US sites: Check HIPAA authorization for conflicts with this section. 
Your study records and samples will be kept in a secure location. We will label all of 
your samples and most of your records with a code number, not your name or other 
personal information. However, it is possible to identify you, if necessary. We will not 
share your name with the lab that does the tests on your samples, or with anyone else who 
does not need to know your name. 
Sites: Any change to the following highlighted text requires approval from HVTN 
Regulatory Affairs 
 
We do need to share your name with the HVTN in case you need proof in the future that 
you participated in an HIV vaccine study. The HVTN will keep your name in a secure 
file with these items:  
 The name of your study  
 Your age or date of birth  
 Your study ID number  
 What study product(s) you received  
There are no HIV test results kept in this file. The HVTN will not share any information 
that could identify you without your agreement. The HVTN will remove your name from 
the file if you do not want it there. 
Clinic staff will have access to your study records. Your records may also be reviewed by 
groups who watch over this study to see that we are protecting your rights, keeping you 
safe, and following the study plan. These groups include: 

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 The US NIH, its study monitors, and its chosen Southern African representatives, 
 The US Food and Drug Administration, 
 [Insert name of local IBC], 
 [Insert name of local IRB/EC] , 
 [Insert name of local and/or national regulatory authority as appropriate], 
 The South African Medicines Control Council, 
 IPPOX Foundation, Novartis Vaccines, and GlaxoSmithKline and people who work 
for them, 
 The HVTN and people who work for them,  
 The HVTN Safety Monitoring Board, and 
 The US Office for Human Research Protections. 
All reviewers will take steps to keep your records private. 
We cannot guarantee absolute privacy. At this clinic, we have to report the following 
information:  
Site: Include any public health or legal reporting requirements. Bulleted examples should 
include all appropriate cases (reportable communicable disease, risk of harm to self or 
others, etc.). 
 [Item 1] 
 [Item 2] 
 [Item 3] 
US sites: Include the following boxed text. You can remove the box. 
We have a Certificate of Confidentiality from the US government, to help protect your 
privacy. With the certificate, we do not have to release information about you to someone 
who is not connected to the study, such as the courts or police. Sometimes we can’t use 
the certificate. Since the US government funds this research, we cannot withhold 
information from it. Also, you can still release information about yourself and your study 
participation to others. 
The results of this study may be published. No publication will use your name or identify 
you personally. 
We may share information from the study with other researchers. We will not share your 
name or information that can identify you. 
Sites: The text below may not be deleted or changed, per FDA requirement. It’s OK to 
remove the box around it. 

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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This website will not include information that can identify you. At 
most, the website will include a summary of the results. You can search this website at 
any time. 
19. We may stop your injections or take you out of the study at any time. We may do 
this even if you want to stay in the study and even if you were scheduled for 
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. 
20. 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. 
21. 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 
care, and about other studies you may want to join. Site: Modify the following sentence as 
appropriate. We will not provide or pay for any of your HIV care directly.  
Other Risks 
22. There are other risks to being in this study. 
This section describes the other risks and restrictions we know about. There may also be 
unknown risks, even serious ones. We will tell you if we learn anything new that may 
affect your willingness to stay in the study. 
Risks of routine medical procedures:  
In this study, we will do some routine medical procedures. These are taking blood and 
giving injections. These procedures can cause bruising, pain, fainting, soreness, redness, 
swelling, itching, a sore, bleeding, and (rarely) muscle damage or infection at the 

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injection site. Taking blood can cause a low blood cell count (anemia), making you feel 
tired. 
Risks of collecting rectal and cervical fluids: 
You may have some discomfort and minor bleeding during these procedures. This does 
not usually last very long. 
Personal problems/discrimination/testing HIV antibody positive: 
About 10 to 20% of people who join HVTN studies report personal problems or 
discrimination because of joining an HIV vaccine study. Family or friends may worry, 
get upset or angry, or assume that you are infected with HIV or at high risk and treat you 
unfairly as a result. Rarely, a person has lost a job because the study took too much time 
away from work, or because their employer thought they had HIV.  
The body makes antibodies to fight or prevent infection. Most vaccines cause the body to 
make antibodies as a way of preventing infection. Your body may make antibodies to 
HIV because you received 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.  
Site: Modify the following paragraph if applicable. If someone believes you are infected 
with HIV even if you are not, you could face discrimination and other problems. For 
example, you could be denied medical or dental care, employment, insurance, a visa, or 
entry into the military (in some countries). If you do have a positive HIV antibody test 
caused by the study vaccines, you will not be able to donate blood or organs. Your family 
and friends may treat you differently. We will give you a brochure that tells you more 
about testing HIV positive because of an HIV vaccine, and how you can avoid some of 
these problems. 
If you become pregnant during or after the study and have VISP, we don't know if the 
antibodies could be passed to your baby. We know that this happens with other vaccines, 
like tetanus vaccine. These antibodies from the mother are not a danger to the baby, and 
they go away over time. 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 

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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.  
U.S. Sites, include the following paragraph In the very unlikely event that your genetic 
information becomes linked to your name, a federal law called the Genetic Information 
Nondiscrimination Act (GINA) helps protect you. GINA keeps health insurance 
companies and employers from seeing results of genetic testing when deciding about 
giving you health insurance or offering you work. GINA does not help or protect you 
against discrimination by companies that sell life, disability or long-term care insurance. 
Unknown risks:  
We do not know if the study vaccines will increase, decrease, or not change your risk of 
becoming infected with HIV if exposed. If you get infected with HIV, we do not know 
how the study vaccines might affect your HIV infection or how long it takes to develop 
AIDS. 
We do not know if getting these study vaccines will affect how you respond to any future 
approved HIV vaccine. It could be that a future HIV vaccine may not work as well for 
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.  

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Benefits 
23. The study may not benefit you. 
We do not know whether getting the study vaccines might benefit you in any way. 
However, being in the study might still help you in some ways. The counseling that you 
get as part of the study may help you avoid getting HIV. The lab tests and physical exams 
that you get while in this study might detect health problems you don’t yet know about.  
This study may help in the search for a vaccine to prevent HIV. However, if the study 
vaccines later become approved and sold, there are no plans to share any money with 
you.  
Your rights and responsibilities 
24. If you join the study, you have rights and responsibilities. 
You have many rights that we will respect. You also have responsibilities. We list these 
in the Participant’s Bill of Rights and Responsibilities. We will give you a copy of it. 
Leaving the study 
25. Tell us if you decide to leave the study.  
You are free to leave the study at any time and for any reason. Your care at this clinic and 
your legal rights will not be affected, but it is important for you to let us know.  
We will ask you to come back to the clinic one last time for a physical exam, and we may 
ask to take some blood and urine samples. We will also ask about any personal problems 
or benefits you have experienced from being in the study. We believe these steps are 
important to protecting your health, but it is up to you whether to complete them. 
Injuries 
Sites: Do not make changes to the following section without obtaining approval from 
HVTN Regulatory Affairs at vtn.core.reg@hvtn.org 
26. If you get sick or injured during the study, contact us immediately. 
Next 4 paragraphs for US sites only  
Your health is important to us. (Sites: adjust the following 2 sentences if applicable to the 
care available at your site) We will tell you about the care that we can give here. For the 
care that we cannot provide, we will explain how we will help you get care elsewhere. 
If you become sick or injured in this study, there is a process to decide if it is related to 
the study products and/or procedures. If it is, we call it a study-related injury. There are 
funds to pay for treatment of study-related injuries if certain conditions are met. The 
HVTN has limited funds to pay medical costs that it determines are reasonable. There 
may be funds from other groups as well. (Sites: insert locale- appropriate medical 
insurance language in the following sentence) If the injury is not study related, then you 
and your health insurance will be responsible for treatment costs.  

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Some injuries are not physical. For example, you might be harmed emotionally by being 
in an HIV vaccine study. Or you might lose wages because you cannot go to work. 
However, there are no funds to pay for these kinds of injuries, even if they are study 
related. 
You may disagree with the decision about whether your injury is study related. If you 
wish, the HVTN will ask independent experts to review the decision. You always have 
the right to use the court system if you are not satisfied. 
Next 6 paragraphs for South African sites only 
Your health is important to us. (Sites: adjust the following 2 sentences if applicable to the 
care available at your site) We will tell you about the care that we can give here. For the 
care that we cannot provide, we will explain how we will help you get care elsewhere. 
If you become sick or injured in this study, there is a process to decide if it is related to 
the study products and/or procedures. If it is, we call it a study-related injury. There are 
funds to pay for treatment of study-related injuries if certain conditions are met. The 
funds may come from different groups, as described below. 
(Sites: adjust the language in this paragraph so it is applicable to your site) In this study, 
our clinic has insurance to cover your medical treatment in the case of a study-related 
injury. The insurance will follow the Association of the British Pharmaceutical Industry 
guidelines for payment of study-related injury. We can give you a copy of these 
guidelines. In rare cases, the insurance funds may not be enough. There may be other 
ways that study-related injuries can be funded. We can give you more information, if you 
would like. 
For study-related injuries that cannot be funded as described above, the HVTN has 
limited funds to pay medical costs that it determines are reasonable. (Sites: insert locale- 
appropriate medical insurance language in the following sentence) If the injury is not 
study related, then you and your health insurance will be responsible for treatment costs.  
Some injuries are not physical. For example, you might be harmed emotionally by being 
in an HIV vaccine study. Or you might lose wages because you cannot go to work. 
However, there are no funds to pay for these kinds of injuries, even if they are study 
related.  
You may disagree with the decision about whether your injury is study related. If you 
wish, the HVTN will ask independent experts to review the decision. You always have 
the right to use the court system if you are not satisfied. 
After-study contact 
27. After your clinic visits end, we will contact you once, 6 months after your last 
scheduled study visit.  
As we explained in Section 4 of this form, people who have received vaccines with 
adjuvants have rarely developed illnesses called autoimmune diseases. Since no one 
knows for sure if vaccines with adjuvants might cause autoimmune diseases, we continue 
to monitor this situation closely. 
We will contact you by phone, email or text message [Site: Modify mode of contact as 
appropriate] once, 6 months after your last scheduled study visit, to ask questions about 

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your health and if you have been diagnosed with an autoimmune disease. If you prefer to 
answer these questions in person, you can come to the clinic to do this. If we have any 
concerns about your health, we may need to have more contact with you. You are also 
welcome to contact us at any time if you have concerns about your health related to being 
in the study.  
Because we will want to contact you, please tell us if your contact information changes, 
or if you are moving away. 
Questions  
28. 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]. 
South African sites: Include the following: 
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 
Medicines Control Council 
Department of Health 
Private Bag X828 
PRETORIA 
0001 
 
Fax: (012) 395 9201 
e-mail: gouwsj@health.gov.za 

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 Your permissions and signature  
29. In section 14 of this form, we told you about collecting stool, rectal fluid and cervical 
fluid or semen. Please write your initials or make your mark in the boxes next to the 
options you choose. 
I agree to provide stool samples. 
I do not agree to provide stool samples. 
 
 
I agree to provide rectal fluid. 
I do not agree to provide rectal fluid. 
 
For people born female: 
I agree to provide cervical fluid. 
I do not agree to provide cervical fluid. 
N/A 
 
For people born male: 
I agree to provide semen. 
I do not agree to provide semen. 
N/A 

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Site: Delete the following section if using a separate consent for use of samples and 
information in other studies 
30. In Section 17 of this form, we told you about possible other uses of your extra 
samples and limited information, outside this study. Please choose only one of the 
options below and write your initials or make your mark in the box next to it. 
 
I allow my extra samples combined with limited information to be used for other 
studies related to HIV, vaccines, 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.  
 

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31. 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 
Approved birth control methods (for sample 
informed consent form) for US sites 
You should not become pregnant during the study because we do not know how the study 
vaccines could affect the developing baby.  
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 
injection until 6 months after your last injection.  
Effective birth control means using any of the following methods every time you have 
sex: 
 
Birth control drugs that prevent pregnancy—given by pills, shots, patches, 
vaginal rings, or inserts under the skin; 
 
Male or female condoms, with or without a cream or gel that kills sperm; 
 
Diaphragm or cervical cap with a cream or gel that kills sperm; or 
 
Intrauterine device (IUD).  
You do not have to use birth control if: 
 
You are only having sex with a partner or partners who have had a vasectomy. 
(We will ask you some questions to confirm that the vasectomy was successful.); 
 
You have reached menopause, with no menstrual periods for one year; 
 
You have had a hysterectomy (your uterus removed); 
 
You have had your ovaries removed; 
 
You have a tubal ligation (your “tubes tied”) or confirmed successful placement 
of a product that blocks the fallopian tubes; 
 
You are having sex only with a female partner or partners; 
 
You only have oral sex; or, 
 
You are sexually abstinent (no sex at all). 
Remember: If you are having sex, you need to use male or female condoms to protect 
yourself from HIV infection. 

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Appendix C 
Approved birth control methods (for sample 
informed consent form) for Southern African sites 
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 
injection until 6 months after your last injection.  
Effective birth control is defined as using 2 methods of birth control. These include 1 of 
the following methods: 
 
Male or female condoms; or, 
 
Diaphragm or cervical cap; 
PLUS 1 of the following methods: 
 
Birth control drugs that prevent pregnancy—given by pills, shots, patches, 
vaginal rings, or inserts under the skin;  
 
Intrauterine device (IUD); or 
 
You are only having sex with a partner who has had a vasectomy. (We will ask 
you some questions to confirm that the vasectomy was successful.).  
You do not have to use birth control if: 
 
You have reached menopause, with no menstrual periods for one year; 
 
You have had a hysterectomy (your uterus removed); 
 
You have had your ovaries removed; 
 
You have a tubal ligation (your “tubes tied”) or confirmed successful placement 
of a product that blocks the fallopian tubes;  
 
You are sexually abstinent (no sex at all) 
Sites may delete the bullets below, if desired. 
 
You are having sex only with a female partner or partners; 
 
You only have oral sex.  
Remember: If you are having sex, you need to use male or female condoms to protect 
yourself from HIV infection. 

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Appendix D 
Sample consent form for use of samples and 
information in other studies 
Title: A phase 1/2a clinical trial to evaluate the safety and immunogenicity of HIV clade 
C DNA, and of MF59®- or AS01B-adjuvanted clade C Env protein, in various 
combinations, in healthy, HIV-uninfected adult participants 
HVTN protocol number: HVTN 108 
Site: [Insert site name] 
When samples are no longer needed for this study, the HVTN wants to keep them for use 
in other studies by HVTN or other researchers. 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 place called a repository. [Site: choose one of the 
following two sentences. African sites should choose the sentence referencing the 
repository in South Africa. All other sites should choose the sentence referencing the 
repository in the United States.] Your samples will be stored in the HVTN repository in 
South Africa. Your samples will be stored in the HVTN repository in the United States.  
3. How long will the samples be stored?  
There is no limit on how long your extra samples will be stored. [Site: 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. 
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 and information, we will not be able to get them back. 

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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. 
If the research plan is approved, the HVTN will send your samples to the researcher’s 
location.  
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 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.  
U.S. Sites, include the following paragraph  
In the very unlikely event that your genetic information becomes linked to your name, a 
federal law called the Genetic Information Nondiscrimination Act (GINA) helps protect 
you. GINA keeps health insurance companies and employers from seeing results of 
genetic testing when deciding about giving you health insurance or offering you work. 
GINA does not help or protect you against discrimination by companies that sell life, 
disability or long-term care insurance.  

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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 Institutional Review Board or Ethics Committee 
 
The people who work with the researcher  
All of these people will do their best to protect your information. The results of any new 
studies that use your extra samples 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 choose only one of the options below and write your initials or make your 
mark in the box next to it.  
 
I allow my extra samples combined with limited information to be used for other 
studies related to HIV, vaccines, 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.  
 
 
 

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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 E 
Injection schedule for sample informed 
consent form 
This table shows the injections you will get while you are in the study. This table does 
not show all of your study visits. 
 

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Appendix F 
Table of procedures (for sample informed consent form) 
Procedure 
Screening 
visit(s) 
First 
injection 
visit 
Time after 1st injection visit 
2 
weeks 
1 
month 
1½ 
months 
3 
months 
3½ 
months 
6 
months 
6 months 
+ 1 week 
6½ 
months 
9 
months 
12 
months 
Injection 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
√ 
 
 
 
 
 
 
 
 
 
 
√ 
Brief physical 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Urine test 
√ 
 
√ 
 
 
 
 
 
 
√ 
 
 
Blood drawn 
√ 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Pregnancy test (participants 
born female)* 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√** 
 
√** 
HIV testing and counseling 
√ 
 
 
 
 
√ 
 
√ 
 
 
√ 
√ 
HIV risk reduction 
counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Interview and/or 
questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Pap smear (if needed) 
√ 
 
 
 
 
 
 
 
 
 
 
 
Rectal fluids/cervical 
fluids/semen samples 
(optional) 
 
√ 
 
 
 
 
 
 
 
√ 
 
√ 
Genital Tract Infection 
testing (urine, blood and 
swab for females) for people 
who agree to provide the 
optional samples 
 
√ 
 
 
 
 
 
 
 
√ 
 
√ 
Stool Sample and/or swab 
(optional)*** 
(√) 
(√) 
 
 
 
 
 
 
 
√ 
 
 
Not shown in this table is a time after all study participants have completed their last scheduled visit when you can find out what products you received.  
Also not shown in this table is the after-study contact 6 months after your last scheduled study visit. 
*People who are NOT of reproductive potential due to having had total hysterectomy or bilateral oophorectomy are not required to have pregnancy tests. 
**Only for those who agree to provide cervical / rectal fluids samples. 
***Stool sample collection at the Screening and First Injection visits indicates that only one stool sample collection will be performed at any point before the enrollment vaccination. 

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Appendix G 
Laboratory procedures 
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
Day:
D0
14
D28
D42
D84
D98
D168
D175
D182
D273
D364
Weeks
W0
W2
W4
W6
W12
W14
W24
W25
W26
W39
W52
Month
M0
M0.5
M1
M1.5
M3
M3.5
M6
M6.25
M6.5
M9
M12
VAC1
VAC2
VAC3
VAC4
DNA + Placebo OR 
DNA + Prot + MF59 OR
DNA + Prot + AS01B OR
Prot + AS01B OR
Placebo
DNA + Placebo OR 
DNA + Prot + MF59 OR
DNA + Prot + AS01B OR
Prot + AS01B OR
Placebo
DNA + Prot + MF59 OR
DNA + Prot + AS01B OR
Placebo
DNA + Prot + MF59 OR 
DNA + Prot + AS01B OR 
Prot + AS01B OR 
Placebo
Procedure
Ship to1, 2
Assay 
location2
Tube 
Type4
Tube size 
(vol. 
capacity)4
Total
BLOOD COLLECTION
Screening/Diagnostic
Screening HIV test
Local lab
Local lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
5
HBsAg/anti-HCV
Local lab
Local lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
5
HIV diagnostics 9
UW-VSL / 
HSML-NICD
UW-VSL / 
HSML-NICD
EDTA
10mL
—
—
—
—
—
10
—
10
—
—
10
20
50
Safety labs
CBC/ Diff/ platelets
Local lab
Local lab
EDTA
5mL
5
—
5
—
5
—
5
—
—
5
—
—
25
Chemistry panel5
Local lab
Local lab
SST
5mL
5
—
5
—
5
—
5
—
—
5
—
—
25
STI Serology
Syphilis
Local lab
Local lab
SST
5mL
5
5 11
—
—
—
—
—
—
—
5 11
—
5 11
20
Immunogenicity & Virologic assays 6
HLA host genetics 7
CSR
FHCRC
ACD
8.5mL
—
17
—
—
—
—
—
—
—
—
—
—
17
Cellular assays
ICS
CSR
FHCRC / 
CHIL
ACD
8.5mL
—
68
—
—
—
—
—
—
—
68
—
68
204
Humoral assays
Binding Ab Assay
CSR
Duke
SST
8.5mL
—
8.5
—
—
—
—
—
—
—
8.5
—
8.5
25.5
Neutralizing Ab Assay
CSR
Duke /
SAIL-NICD
SST
8.5mL
—
8.5
—
—
—
—
—
—
—
8.5
—
8.5
25.5
Ab Avidity
CSR
Duke
SST
8.5mL
—
y
—
—
—
—
—
—
—
y
—
y
0
ADCC
CSR
Duke
SST
8.5mL
—
y
—
—
—
—
—
—
—
y
—
y
0
STORAGE
Serum storage
CSR
—
SST
8.5mL
—
17
—
—
—
—
—
—
8.5
8.5
17
8.5
60
PBMC storage
CSR
—
ACD
8.5mL
—
51
—
—
—
—
—
—
34
17
—
17
119
Visit total
25
175
10
0
10
10
10
10
43
126
27
136
581
56-Day total
 
25
200
210
210
220
20
30
10
53
178
27
136
URINE COLLECTION
Urinalysis
Local lab
Local lab
X
—
X
—
—
—
—
—
—
X
—
—
Pregnancy Test8
Local lab
Local lab
X
X
—
X
—
X
—
X
—
X10
X
X10
Chlamydia/Gonorrhea11
Local lab
Local lab
—
X
—
—
—
—
—
—
—
X
—
X
CERVICAL/VAGINAL SWAB COLLECTION12
Trichomonas vaginalis
Local lab
Local lab
—
X
—
—
—
—
—
—
—
X
—
X
Bacterial vaginosis
Local lab
Local lab
—
X
—
—
—
—
—
—
—
X
—
X
Yeast
Local lab
Local lab
—
X
—
—
—
—
—
—
—
X
—
X
MUCOSAL COLLECTION (OPTIONAL)
Semen
CSR
Duke
—
X13
—
—
—
—
—
—
—
X
—
X
Cervical Secretions
CSR
Duke
—
X13
—
—
—
—
—
—
—
X
—
X
Rectal Secretions
CSR
Duke
—
X13
—
—
—
—
—
—
—
X
—
X
STOOL COLLECTION (OPTIONAL) 
Stool 
CSR
FHCRC
—
X14
—
—
—
—
—
—
—
X
—
—
Screening 
visit3
 
1CSR = central specimen repository 
2HVTN Laboratory Program includes laboratories at UW-VSL, Duke, FHCRC, HSML-NICD and SAIL-NICD, UW-VSL = University of Washington Virology Specialty Laboratory (Seattle, Washington, USA); Duke = Duke University Medical Center 
(Durham, North Carolina, USA); Duke-ADCC = Antibody-Dependent Cellular Cytotoxicity Assay Laboratory, Duke University Medical Center (Durham, NC, USA); FHCRC = Fred Hutchinson Cancer Research Center (Seattle, Washington, USA); CHIL = 
Cape Town HVTN Immunology Laboratory (Cape Town, South Africa); SAIL-NICD = South African Immunology, Laboratory–National Institute for Communicable Diseases (Johannesburg, South Africa); HSML-NICD = HIV Sero-Molecular Laboratory - 
National Institute for Communicable Diseases (Johannesburg, South Africa) 
3Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination. 
4Local labs may assign appropriate alternative tube types for locally performed tests. 
5Chemistry panels are defined in Section 9.2 (pre-enrollment) and Section 9.4 (postenrollment). 
6Immunogenicity 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. 
7Genotyping 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. 
8For 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. 

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9At an early termination visit for a withdrawn or terminated participant (see Section 9.13), blood should be drawn for HIV diagnostic testing, as shown for visit 12 above.  
10Pregnancy testing at the indicated visit is only required of participants who are born female and are providing a cervical and/or rectal secretion sample. 
11Syphilis testing by serology and Chlamydia and gonorrhea testing by urine or swab will only be performed if the participant agrees to provide a mucosal sample. 
12Cervical/vaginal swabs will only be collected from participants who agree to provide a cervical secretion sample and for bacterial vaginosis, trichomonas vaginalis, and (if clinically indicated) yeast. 
13 Optional mucosal specimens must be collected prior to first vaccination once the participant has been found to have met mucosal specimen collection criteria specified in section 9.6.  
14 Optional stool specimens must be collected prior to first vaccination.  
 y = 17mL of SST blood collected for binding and neutralizing Ab assays will also cover specimen needs for Ab avidity and ADCC assays; no separate blood draw is needed. 

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Appendix H 
Procedures at HVTN CRS  
Visit: 
01a  
02n 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
Post 
Day: 
 
D0 
D14 
D28 
D42 
D84 
D98 
D168 
D175 
D182 
D273 
D364 
 
Month: 
 
M0 
M0.5 
M1 
M1.5 
M3 
M3.5 
M6 
M6.25 
M6.5 
M9 
M12 
 
Procedure 
Scr. 
VAC1 
 
VAC2 
 
VAC3 
 
VAC4 
 
 
 
 
 
Study proceduresb 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed screening consent (if used) 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Assessment of understanding 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Signed protocol consent  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Medical history  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Complete physical exam 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
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 
— 
— 
Stool collection - optionalc 
— 
X 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
Risk reduction counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Pregnancy prevention assessmentd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Behavioral risk assessment questionnaire 
X 
— 
— 
— 
— 
X 
— 
X 
— 
— 
X 
X 
— 
Social impact assessment 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Social impact assessment questionnaire 
— 
— 
— 
— 
— 
X 
— 
X 
— 
— 
— 
X 
— 
Outside testing and belief questionnaire 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
X 
— 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Intercurrent illness/adverse experience 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
HIV infection assessmente 
— 
— 
— 
— 
— 
X 
— 
X 
— 
— 
X 
X 
— 
Confirm HIV test results provided to participant 
— 
X 
— 
— 
— 
— 
X 
— 
X 
— 
— 
X 
X 
Local lab assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening HIV test 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Urine dipstick 
X 
— 
X 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
Pregnancy (urine or serum HCG)f 
X 
X 
— 
X 
— 
X 
— 
X 
— 
Xg 
— 
Xg 
— 
CBC, differential, platelet 
X 
— 
X 
— 
X 
— 
X 
— 
— 
X 
— 
— 
— 
Chemistry panel  
X 
— 
X 
— 
X 
— 
X 
— 
— 
X 
— 
— 
— 
Hepatitis B, Hepatitis C 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Syphilis 
X 
Xh 
— 
— 
— 
— 
— 
— 
— 
Xh 
— 
Xh 
— 
Chlamydia/Gonorrheah 
— 
X 
— 
— 
— 
— 
— 
— 
— 
X 
— 
X 
— 
Trichomonas vaginalis(cervical/vaginal swab)i 
— 
X 
— 
— 
— 
— 
— 
— 
— 
X 
— 
X 
— 
 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 G. 
c Optional stool specimens must be collected prior to first vaccination.  
d Pregnancy prevention assessment is required only for participants who were born female and are capable of becoming pregnant. 
e Includes pre-test counseling. A subsequent follow-up contact is conducted to provide post-test counseling and to report results to participant. 
f 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. Pregnancy test to determine 
eligibility may be performed at screening, but must also be done on Day 0 prior to vaccination. Persons who have undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing. 
g 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. 
h Syphilis testing by serology and Chlamydia and gonorrhea testing by urine or swab will only be performed if the participant agrees to provide a mucosal sample. 

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Bacterial vaginosis (cervical/vaginal swab)i 
— 
X 
— 
— 
— 
— 
— 
— 
— 
X 
— 
X 
— 
Yeast, if indicated (cervical/vaginal swab)i 
— 
X 
— 
— 
— 
— 
— 
— 
— 
X 
— 
X 
— 
Pap smearj 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Mucosal secretion collection (optional)k 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cervical, rectal, semen 
— 
X 
— 
— 
— 
— 
— 
— 
— 
X 
— 
X 
— 
Vaccination procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccinationl 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
— 
— 
— 
Reactogenicity assessmentsm 
— 
X 
— 
X 
— 
X 
— 
X 
X 
— 
— 
— 
— 
Poststudy 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblind participant  
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
 i Cervical/vaginal swabs will only be collected from participants who agree to provide a cervical secretion sample; and, testing for Trichomonas vaginalis, bacterial vaginosis, and (if clinically indicated) yeast. 
j Only for volunteers born female who consent to provide cervical secretion samples, per Sections 7.1 and 9.6. If collection of a pap smear is required, this may be done at any time provided the results are available prior to the collection of the 
cervical secretion samples. 
k Optional mucosal specimens must be collected prior to first vaccination once the participant has been found to have met mucosal specimen collection criteria specified in in section 9.6.  
l Blood draws required at vaccination visits must be performed prior to vaccination; however, it is not necessary to have results prior to vaccination, except for results of a urine or serum pregnancy test, if indicated. 
m Reactogenicity assessments performed or recorded in the postvaccination symptom log for at least 7 days postvaccination (see Section 9.11). 
n Specimens collected at the enrollment visit may be obtained within the 14 days prior to vaccination, except for a pregnancy test which must be performed on urine or blood specimens on the day of vaccination with negative results received 
prior to vaccination 
 
 
 

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Appendix I 
AESI contact 
 
Contacta Day 
545 
Month 
18 
Procedures 
 
AESI assessmentb  
X 
 
a Clinic visits are not required unless a participant indicates symptoms that require further assessment. See Section 9.5. 
b See Appendix J. 

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