A Phase 1 Clinical Trial to Evaluate the Safety and Immunogenicity of Polyvalent Env (A,B,C,A/E) / Gag (C) DNA and gp120 (A,B,C,A/E) Protein/GLA-SE HIV-1 Vaccines (PDPHV-201401) as a Prime-boost Regimen or Co-administered in Repeated Doses, in Healthy, HIV-1-Uninfected Adult Participants
Phase: PHASE1
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
PROTOCOL 
HVTN 124 
A phase 1 clinical trial to evaluate the safety and 
immunogenicity of polyvalent env (A,B,C,A/E) / gag (C) 
DNA and gp120 (A,B,C,A/E) protein/GLA-SE HIV-1 
vaccines (PDPHV-201401) as a prime-boost regimen or 
co-administered in repeated doses, in healthy, HIV-1–
uninfected adult participants 
DAIDS DOCUMENT ID 38302 
BB IND [IND # OR DELETE] 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 PRODUCT(S) PROVIDED BY 
University of Massachusetts Medical School (UMMS) 
Worcester, Massachusetts, USA 
Infectious Disease Research Institute (IDRI) 
Seattle, Washington, USA 
September 28, 2017 
Final 
HVTN 124 
Version 1.0 

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Contents 
1 Ethical considerations ....................................................................................................5 
2 IRB/EC review considerations .......................................................................................7 
2.1 
Minimized risks to participants ......................................................................7 
2.2 
Reasonable risk/benefit balance .....................................................................7 
2.3 
Equitable participant selection .......................................................................8 
2.4 
Appropriate informed consent ........................................................................8 
2.5 
Adequate safety monitoring ...........................................................................8 
2.6 
Protect privacy/confidentiality .......................................................................8 
3 Overview ......................................................................................................................10 
3.1 
Protocol Team ..............................................................................................13 
4 Background ..................................................................................................................14 
4.1 
Rationale for trial concept ............................................................................14 
4.2 
Env (A, B, C, A/E) / Gag (C) DNA plasmids ..............................................19 
4.3 
Recombinant gp120 (A,B,C,A/E) protein with GLA-SE adjuvant ..............20 
4.4 
Trial design rationale ....................................................................................21 
4.5 
Plans for future product development and testing ........................................22 
4.6 
Preclinical safety studies ..............................................................................23 
4.7 
Preclinical immunogenicity studies .............................................................25 
4.8 
Clinical studies .............................................................................................31 
4.9 
Potential risks of study products and administration ...................................36 
5 Objectives and endpoints .............................................................................................37 
5.1 
Primary objectives and endpoints ................................................................37 
5.2 
Secondary objectives and endpoints ............................................................37 
5.3 
Exploratory objectives ..................................................................................38 
6 Statistical considerations ..............................................................................................40 
6.1 
Accrual and sample size calculations ...........................................................40 
6.2 
Randomization .............................................................................................44 
6.3 
Blinding ........................................................................................................44 
6.4 
Statistical analyses ........................................................................................45 
7 Selection and withdrawal of participants .....................................................................54 
7.1 
Inclusion criteria ...........................................................................................54 
7.2 
Exclusion criteria ..........................................................................................57 
7.3 
Participant departure from vaccination schedule or withdrawal ..................60 
8 Study product preparation and administration .............................................................63 
8.1 
Vaccine regimen ...........................................................................................63 
8.2 
Study product formulation ...........................................................................65 
8.3 
Preparation of study products .......................................................................65 
8.4 
Administration ..............................................................................................67 
8.5 
Acquisition of study products ......................................................................68 
8.6 
Pharmacy records .........................................................................................68 
8.7 
Final disposition of study products ..............................................................68 
9 Clinical procedures ......................................................................................................69 
9.1 
Informed consent ..........................................................................................69 

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9.2 
Pre-enrollment procedures ...........................................................................71 
9.3 
Enrollment and vaccination visits ................................................................73 
9.4 
Follow-up visits ............................................................................................74 
9.5 
Mucosal fluid sampling ................................................................................76 
9.6 
Stool sampling ..............................................................................................78 
9.7 
Health contact at 12 months after last vaccination visit ...............................78 
9.8 
HIV counseling and testing ..........................................................................79 
9.9 
Contraception status .....................................................................................81 
9.10 Urinalysis .....................................................................................................81 
9.11 Assessments of reactogenicity .....................................................................81 
9.12 Evaluation of possible DTH or vasculitic reactions to vaccine ...................83 
9.13 Visit windows and missed visits ..................................................................84 
9.14 Early termination visit ..................................................................................84 
9.15 Pregnancy .....................................................................................................84 
10 Laboratory ....................................................................................................................85 
10.1 HVTN CRS laboratory procedures ..............................................................85 
10.2 Total blood volume ......................................................................................85 
10.3 Primary immunogenicity timepoint .............................................................85 
10.4 Endpoint assays: cellular ..............................................................................85 
10.5 Endpoint assays: humoral .............................................................................86 
10.6 Genotyping ...................................................................................................86 
10.7 Lab assay algorithm .....................................................................................87 
10.8 Exploratory studies .......................................................................................87 
10.9 Specimen storage and other use of specimens .............................................88 
10.10 Biohazard containment .................................................................................89 
11 Safety monitoring and safety review ...........................................................................90 
11.1 Safety monitoring and oversight ..................................................................90 
11.2 Safety reporting ............................................................................................91 
11.3 Safety reviews ..............................................................................................93 
11.4 Safety pause and prompt PSRT AE review..................................................94 
11.5 Review of cumulative safety data ................................................................96 
11.6 Study termination .........................................................................................96 
12 Protocol conduct ..........................................................................................................97 
12.1 Social impacts ..............................................................................................98 
12.2 Compliance with NIH guidelines for research involving products containing 
recombinant DNA ........................................................................................98 
12.3 Emergency communication with study participants ....................................99 
13 Version history ...........................................................................................................100 
14 Document references (other than literature citations) ................................................101 
15 Acronyms and abbreviations......................................................................................103 
16 Literature cited ...........................................................................................................106 
Appendix A Sample informed consent form for Part A .................................................113 
Appendix B Sample informed consent form for Part B .................................................131 
Appendix C Approved birth control methods (for sample informed consent form) ......154 

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Appendix D Sample consent form for use of samples and information in other studies 155 
Appendix E Injection schedule for Part A and B sample informed consent forms ........159 
Appendix F Table of procedures for Part A (for sample informed consent form) .........160 
Appendix G Table of procedures for Part B (for sample informed consent form) .........161 
Appendix H Laboratory procedures – Part A (1 of 2) ....................................................162 
Appendix I Laboratory procedures – Part B (1 of 2) ....................................................164 
Appendix J Procedures at HVTN CRS - Part A (1 of 2) ...............................................166 
Appendix K Procedures at HVTN CRS - Part B (1 of 2) ...............................................168 
Appendix L Adverse events of special interest ..............................................................170 
Appendix M Protocol Signature Page .............................................................................171 
 

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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.  
 HVTN clinical trial staff counsel study participants routinely on how to 
reduce HIV risk. Participants who become HIV-infected during the trial are 
provided counseling on notifying their partners and about HIV infection 
according to local guidelines. Staff members will also counsel them about 
reducing their risk of transmitting HIV to others. 
 Participants who become HIV-infected during the trial are referred to medical 
practitioners to manage their HIV infection and to identify potential clinical 
trials they may want to join. If a program for antiretroviral therapy (ART) 
provision is not available at a site and ART is needed, a privately established 
fund will be used to pay for access to treatment to the fullest extent possible. 
 The HVTN provides training so that all participating sites similarly ensure fair 
participant selection, protect the privacy of research participants, and obtain 
meaningful informed consent. During the study, participants will have their 
wellbeing monitored, and to the fullest extent possible, their privacy 
protected. Participants may withdraw from the study at any time. 
 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 values the role of in-country Institutional Review Boards (IRBs), 
Ethics Committees (ECs), and other Regulatory Entities (REs) as custodians 
responsible for ensuring the ethical conduct of research in each setting. 

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2 
IRB/EC review considerations 
US Food and Drug Administration (FDA) and other US federal regulations 
require IRBs/ECs/REs 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/RE questions or concerns regarding these research 
requirements. 
2.1 
Minimized risks to participants 
45 CFR 46.111 (a) 1 and 21 CFR 56.111 (a) 1: Risks to subjects are 
minimized. 
This protocol minimizes risks to participants by (a) correctly and promptly 
informing participants about risks so that they can join in partnership with the 
researcher in recognizing and reporting harms; (b) respecting local/national blood 
draw limits; (c) performing direct observation of participants postvaccination and 
collecting information regarding side effects for several days postvaccination; (d) 
having staff properly trained in administering study procedures that may cause 
physical harm or psychological distress, such as blood draws, vaccinations, HIV 
testing and counseling and HIV risk reduction counseling; (e) providing HIV risk 
reduction counseling and checking on contraception use (for persons assigned 
female at birth); and (f) providing safety monitoring. 
2.2 
Reasonable risk/benefit balance 
45 CFR 46.111(a) 2 and 21 CFR 56.111(a) 2: Risks to subjects are 
reasonable in relation to anticipated benefits, if any, to subjects, and 
the importance of the knowledge that may reasonably be expected to 
result. 
In all public health research, the risk-benefit ratio may be difficult to assess 
because the benefits to a healthy participant are not as apparent as they would be 
in treatment protocols, where a study participant may be ill and may have 
exhausted all conventional treatment options. However, this protocol is designed 
to minimize the risks to participants while maximizing the potential value of the 
knowledge it is designed to generate.  

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2.3 
Equitable participant selection  
45 CFR 46.111 (a) 3 and 21 CFR 56.111 (a) 3: Subject selection is 
equitable 
This protocol has specific inclusion and exclusion criteria for investigators to 
follow in admitting participants into the protocol. Participants are selected 
because of these criteria and not because of positions of vulnerability or privilege. 
Investigators are required to maintain screening and enrollment logs to document 
volunteers who screened into and out of the protocol and for what reasons. 
2.4 
Appropriate informed consent 
45 CFR 46.111 (a) 4 and 5 and 21 CFR 56.111 (a) 4 and 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 124 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 

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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 and Appendix B). The privacy of participants is protected by 
assigning unique identifiers in place of the participant’s name on study data and 
specimens. In the United States, research participants in HVTN protocols are 
protected by a Certificate of Confidentiality from the US NIH, which can prevent 
disclosure of study participation even when that information is requested by 
subpoena. Participants are told of the use and limits of the certificate in the study 
consent form. In addition, each staff member at each study site in this protocol 
signs an Agreement on Confidentiality and Use of Data and Specimens 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 clinical trial to evaluate the safety and immunogenicity of polyvalent 
env (A,B,C,A/E) / gag (C) DNA and gp120 (A,B,C,A/E) protein/GLA-SE HIV-1 
vaccines (PDPHV-201401) as a prime-boost regimen or co-administered in 
repeated doses, in healthy, HIV-1–uninfected adult participants 
Primary objective 
To evaluate the safety and tolerability of Env (A, B, C, A/E) / Gag (C)-expressing 
DNA plasmids and recombinant gp120 (A, B, C, A/E) protein/GLA-SE adjuvant, 
given individually, in combination, or as a prime-boost series in healthy HIV-1 
uninfected adults 
Study products, doses, and routes of administration 
 DNA vaccine: Env (A, B, C, A/E) / Gag (C) DNA plasmids. A total dose of 2 
mg of the 5 DNA plasmids (0.4 mg each) will be given as a 0.8 ml injection 
IM into the deltoid.  
 Protein vaccine: Recombinant gp120 (A, B, C, A/E) proteins/GLA-SE 
adjuvant. GLA-SE is a stable oil-in-water emulsion (SE) containing 
glucopyranosyl Lipid A (GLA), a synthetic analog of monophosphoryl Lipid 
A (MPL®). A total dose of 400 microgram (mcg) of the 4 recombinant 
proteins (100 mcg each) and 5 mcg of GLA-SE will be given as a 1 ml 
injection IM into the deltoid. 
 Placebo for DNA vaccine: Sodium Chloride for Injection, USP 0.9% given as 
a 0.8 ml injection IM into the deltoid.  
 Placebo for protein vaccine: Sodium Chloride for Injection, USP 0.9% given 
as a 1 ml injection IM into the deltoid.  

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Table 3-1 Schema 
Part 
A 
Group 
N 
Month 0 
(Day 0) 
Month 2 
(Day 56) 
 
 
 
 
1 
10 
Protein/ 
GLA-SE 
Protein/ 
GLA-SE 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
Placebo 
Placebo 
 
 
 
 
 
12 
 
 
 
 
 
Part 
B 
Group 
N 
Month 0 
(Day 0) 
Month 1 
(Day 28) 
Month 3 
(Day 84) 
Month 6 
(Day 168) 
Month 8 
(Day 224) 
 
2 
21 
DNA + 
Placebo 
DNA + 
Placebo 
DNA + 
Placebo 
Protein/ 
GLA-SE  
+ Placebo 
Protein/ 
GLA-SE 
+ Placebo 
 
 
 
 
 
 
 
 
 
 
3 
Placebo + 
Placebo 
Placebo + 
Placebo 
Placebo+ 
Placebo 
Placebo+ 
Placebo 
Placebo+ 
Placebo 
 
3 
21 
DNA+ 
Protein/ 
GLA-SE 
DNA+ 
Protein/ 
GLA-SE 
DNA+ 
Protein/ 
GLA-SE 
DNA+ 
Protein/ 
GLA-SE 
DNA+ 
Protein/ 
GLA-SE 
 
 
 
 
 
 
 
 
 
 
3 
Placebo+ 
Placebo 
Placebo+ 
Placebo 
Placebo+ 
Placebo 
Placebo+ 
Placebo 
Placebo+ 
Placebo 
 
 
48 
 
 
 
 
 
 
Total 
60 
(52/8) 
 
 
 
 
 
Notes 
DNA/placebo and protein/GLA-SE and placebo study products will be given in separate 
arms, such that participants in Part B will receive 1 injection in each arm at each 
vaccination timepoint (unless medically contraindicated).  
Enrollment will proceed in stages to optimize safety. Groups 2 and 3 will enroll 
simultaneously. See Section 11.3 for details. 
Participants 
60 healthy, HIV-1–uninfected volunteers aged 18 to 50 years; 52 vaccinees, 8 
placebo recipients 
Design 
Multicenter, randomized, placebo-controlled, double-blind trial 
Duration per participant 
Part A: 8 months of scheduled clinic visits (main study) followed by a health 
contact 12 months after the last vaccination 
Part B: 14 months of scheduled clinic visits (main study) followed by a health 
contact 12 months after the last vaccination 

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Estimated total study duration 
32 months (includes enrollment, planned safety holds, follow-up, and health 
contact) 
Investigational New Drug (IND) sponsor 
DAIDS, NIAID, NIH, DHHS (Bethesda, Maryland, USA) 
Study product providers 
 Env (A,B,C,A/E) / Gag (C) DNA plasmids: University of Massachusetts 
Medical School (UMMS) (Worcester, Massachusetts, USA) 
 Recombinant gp120 (A,B,C,A/E) protein: University of Massachusetts 
Medical School (UMMS) (Worcester, Massachusetts, USA) 
 GLA-SE adjuvant: Infectious Disease Research Institute (IDRI) (Seattle, 
Washington, USA) 
Core operations 
HVTN Vaccine Leadership Group/Core Operations Center, Fred Hutchinson 
Cancer Research Center (Fred Hutch) (Seattle, Washington, USA) 
Statistical and data management center (SDMC) 
Statistical Center for HIV/AIDS Research and Prevention (SCHARP), Fred Hutch 
(Seattle, Washington, USA) 
HIV diagnostic laboratory 
University of Washington Virology Specialty Laboratory (UW-VSL) (Seattle, 
Washington, USA) 
Endpoint assay laboratories 
 Duke University Medical Center (Durham, North Carolina, USA) 
 Fred Hutch/University of Washington (Seattle, Washington, USA) 
Study sites 
HVTN Clinical Research Sites (HVTN CRSs) to be specified in the Site 
Announcement Memo 
Safety monitoring 
HVTN 124 PSRT; HVTN Safety Monitoring Board (SMB) 

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3.1 
Protocol Team 
Protocol leadership 
Chair 
Ian Frank 
University of Pennsylvania  
215-662-7419 
franki@mail.med.upenn.edu 
Statistician 
Sue Li 
SCHARP, Fred Hutch 
206-667-7066 
sli@scharp.org 
Co-chair 
Turner Overton 
University of Alabama, 
Birmingham  
205-996-2373 
toverton@uabmc.edu 
Medical officer 
Mary Allen 
DAIDS, NIAID 
240-627-3036 
mallen@nih.gov 
Protocol Team 
leader 
Marnie Elizaga 
HVTN Core, Fred Hutch 
650-854-4984 
melizaga@fhcrc.org 
Laboratory 
lead 
David Montefiori 
HVTN Laboratory 
Program 
919-684-5278 
monte@duke.edu 
Other contributors to the original protocol 
Core medical monitor 
Marnie Elizaga 
HVTN Core, Fred Hutch 
Clinical safety 
specialist 
Jill Zeller 
HVTN Core,  
Fred Hutch 
Vaccine developer 
representative 
Shan Lu 
University of 
Massachusetts Medical 
School (UMMS) 
Clinical trials manager 
Marianne Hansen 
HVTN Core,  
Fred Hutch 
 
Zachary Sagawa 
Infectious Disease 
Research Institute 
((IDRI) 
Statistical research 
associate 
Daryl Morris 
SCHARP, Fred Hutch 
 
 
SDMC Associate 
director of  Lab Science 
April Randhawa 
SCHARP, Fred Hutch 
Laboratory protocol 
operations manager 
On Ho 
HVTN Laboratory 
Program, Fred Hutch 
Clinical data manager 
Ingrid Durenberger 
SCHARP, Fred Hutch 
Laboratory program 
representative 
Nicole Frahm 
HVTN Laboratory 
Program, Fred Hutch 
Senior clinical data 
manager 
Gina Escamilla 
SCHARP, Fred Hutch 
Regulatory affairs 
associate 
Denelle Reilly 
HVTN Core, FHCRC 
DAIDS Project Officer 
Vijay Mehra 
DAIDS, NIAID 
Clinic coordinator 
Pamela Cunningham 
University of Alabama 
Birmingham  
Protocol development 
manager 
Ramey Fair 
HVTN Core,  
Fred Hutch 
Community Advisory 
Board (CAB) members 
Dennis Hodtwalker 
Univ of Alabama 
Birmingham CAB 
Technical editor 
Erik Schwab 
HVTN Core, Fred 
Hutch 
 
Ja’Nae Tyler 
Univ of Pennsylvania 
CAB 
Community 
engagement unit 
representative 
Gail Broder  
HVTN Core,  
Fred Hutch 
DAIDS protocol 
pharmacist 
Oladapo Alli 
DAIDS, NIAID 
240-627-3593 
Community 
educator/recruiter 
Annet Davis 
Univ of Pennsylvania  

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4 
Background 
4.1 
Rationale for trial concept 
A successful HIV vaccine may require generation of broad immune responses 
against viruses with highly diverse sequences. Thus, it is critical to develop new 
candidate HIV vaccines that can achieve balanced immune responses including 
both antibody and T cell immune responses and, in particular, induce broadly 
cross reactive, high titer and high quality antibody responses. 
The Polyvalent DNA-Protein HIV-1 Vaccine-201401 (PDPHV-201401) regimen 
has the potential to achieve this goal. The DNA prime-protein boost approach has 
been shown to reliably generate both high level humoral and cellular immune 
responses in animals and humans (4). In addition, this strategy has been 
successful at eliciting low titers of neutralizing antibodies (nAb) against Tier 1B 
or Tier 2-like HIV-1 isolates across multiple subtypes in a previous phase 1 
clinical trial (DP6-001; see Section 4.8.1) (5). 
Other investigators are pursuing the development of other strategies to elicit 
broadly neutralizing antibodies (bnAbs) to prevent HIV-1 infection. One strategy 
aims to guide B cells along an accelerated path of B cell selection and antibody 
maturation, similar to that which occurs over years in HIV-infected people (6, 7). 
‘Minimal’ Env immunogens are focused on eliciting antibodies against one of the 
5 sites on the HIV Env that are targets for bnAbs (8, 9). Another strategy uses 
stable soluble cleaved gp140 trimers (SOSIP gp140 trimers) mimicking the Env 
protein spike, to present multiple bnAb epitopes (10, 11). Bivalent gp120s have 
been evaluated for immunogenicity and efficacy as protein only (Vax003, 
Vax004) (12, 13) and as viral vector prime - protein boost protocols (RV144) 
(14). Only sporadic, low titers of Tier 2 virus nAbs were seen in Vax004 (15, 16), 
which were not protective (15). 
Other vaccine strategies, such as various combinations of DNA-HIV-PT123, 
ALVAC-HIV (vCP2438), and a bivalent subtype C gp120 with adjuvant, are 
attempting to improve upon the RV144 trial regimen and the non-neutralizing 
antibody functions identified as correlates of risk in that study, including IgG 
binding antibody to scaffolded gp70 V1V2 envelope protein, which correlated 
inversely with risk (17-19), whereas Env-specific binding IgA correlated directly 
with risk (17). Results of subsequent investigations suggest that FcR-mediated 
antibody effector functions may have contributed to modest efficacy in RV144 
(20-23). 
The PDPHV-201401 protocol differs from the above approaches by using gp120 
from 4 different major subtypes of HIV-1, to expand the breadth of the immune 
responses. A DNA prime is used instead of a viral vector prime, to avoid vector-
specific immune responses and focus immune responses against the Env 
immunogen inserts.  

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The vaccine regimens to be tested are multigenic, polyvalent, and heterologous – 
three important characteristics to use in HIV vaccine strategy. As it is unlikely 
that antigens from any one gene would be sufficient for an effective HIV regimen, 
the vaccine regimens include both Env and Gag for their respective abilities to 
elicit antibody and T cell responses. For a frequently mutating virus with multiple 
subtypes such as HIV-1, it is important to have multiple variants of a protective 
immunogen (envelope protein, Env) to produce a polyvalent formulation. This 
vaccine regimen includes four Env antigens from subtypes A, B, C, and A/E. 
Notably, IgG to subtype A, B, C and CRF01_AE V1V2-scaffold antigens were 
also identified as inverse correlates of risk in the RV144 trial. Additional 
correlates were IgG to V3 CRF01_AE and plasma levels of antibody-dependent 
cell-mediated cytotoxicity (ADCC) activity against Env V2, in the setting of low 
Env-specific binding IgA (19, 21, 24). This polyvalent vaccine regimen has the 
potential to elicit those responses. It has been demonstrated in a previous phase 1 
trial (DP6-001) (25) that the sequential administration of two types of vaccines 
(DNA and protein) delivering the same subunit gp120 antigens was more 
effective than either type of vaccine alone . Therefore, HVTN 124 will compare 
the relative immunogenicity between sequential administration and co-
administration of the DNA vaccine and the matching recombinant gp120 (A, B, 
C, A/E) proteins in GLA-SE adjuvant. The potential advantages of co-
administration are earlier induction of antibody, which if effective, would lead to 
earlier protection, and higher cumulative doses of both DNA and protein vaccine 
products, in comparison with the sequential DNA–protein immunization 
approach. An important objective is to determine which approach will achieve the 
highest response rate, magnitude, and durability of antibody responses, and to 
characterize any qualitative differences in immune responses to the two regimens. 
A first-generation version of the DNA prime-protein boost regimen developed by 
the University of Massachusetts Medical School (UMMS) team generated 
significant Env-specific antibodies, low titer but cross-clade neutralizing 
antibodies, and cell-mediated immune (CMI) responses (both CD4 and CD8 T 
cells) in participants in the DP6-001 study (5, 26) (see Section 4.8.1). In HVTN 
124, CD4+ and CD8+ T cell responses will also be analyzed. 
To improve upon the immunogenicity and safety profile observed in the DP6-
001study, several modifications have been made to the vaccine formulations for 
HVTN 124. One change is to further enhance the immunogenicity of Env 
antigens by carefully selecting optimal gene inserts from four different HIV-1 
subtypes. Also, the adjuvant to be administered with the protein vaccine, GLA-
SE, differs from the QS-21 adjuvant that was used in the DP6-001 study. QS-21 
has been associated with an increased risk of adverse events of the skin in other 
clinical studies (27). To further minimize risk, this study will enroll participants in 
stages, to monitor for any adverse reactions (Section 11.3). 
In summary, the primary goal of this study is to evaluate the safety and 
immunogenicity of the polyvalent DNA - protein HIV-1 vaccine regimen with 
newly optimized inserts for Envs from subtypes A, B, C, and A/E, and for subtype 
C Gag (DNA only), building on results from the DP6-001 study which 

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demonstrated balanced humoral and cellular immune responses, including cross-
clade neutralization of pseudoviruses expressing Env antigens.  
4.1.1 
Preclinical monovalent DNA prime-protein boost HIV vaccine studies 
The DNA prime-protein boost approach is not a novel concept but it is 
understudied in human trials. Reports of this approach have been published since 
the mid-1990s (28, 29). Testing a wide range of primary HIV-1 Env antigens for 
their immunogenicity in mice, rabbits and non-human primates has demonstrated 
that there is a qualitative difference between antibodies induced by the gp120-
based DNA plus protein approach versus the gp120 protein alone approach (30). 
After DNA prime-protein boost, increased antibody titers, antibody persistence 
and neutralizing activities against a wide range of HIV-1 isolates were 
significantly improved over DNA or protein immunization alone. The quality of 
antibody responses, as measured by antibody avidity, was also improved by the 
DNA prime-protein boost approach compared to the protein alone approach (29, 
31). 
Studies conducted with JR-FL env DNA vaccine in rabbits indicated that DNA 
prime followed by protein boost was more effective than either DNA or protein 
alone in eliciting high level anti-Env IgG responses with no difference between 
the gp120 or gp140 DNA primes (32). The endpoint titers for anti-gp120 IgG in 
DNA prime-protein boosted rabbits reached above 1:500,000, while the protein 
alone approach was only able to elicit titers of ~1:50,000. Only the DNA prime-
protein boost approach elicited consistent JR-FL-specific neutralizing activities. 
At least two subsequent studies from other research groups confirmed the value of 
this DNA prime-protein boost approach (33, 34). 
4.1.2 
Preclinical polyvalent DNA prime-protein boost HIV vaccine studies 
Recent studies from the UMMS team have shown that a polyvalent DNA prime, 
protein boost series was more effective than the polyvalent gp120 recombinant 
protein vaccines alone in eliciting germinal center (GC) B cell responses in mice 
as well as anti-gp120 titers and avidity of gp120-specific antibodies [35]. In 
addition, more recent data from UMMS further demonstrated that DNA 
immunization can activate innate immunity signaling pathways involving absent 
in melanoma 2 (AIM2) and stimulator of interferon genes (STING), for better 
antigen-specific antibody responses [36,37]. 
Studies performed in rabbits demonstrated that the DNA prime-protein boost 
approach was able to elicit nAb responses against primary viral isolates across 
several subtypes, and that the polyvalent Env formulation was more effective than 
the monovalent formulation in generating broader nAbs (35). Analyses on the 
breadth of neutralizing activities revealed a clear advantage of the polyvalent Env 
formulations: polyvalent sera were able to neutralize 68.9% of viruses included in 
the assay while the monovalent group only neutralized 38.4% of the viruses (p < 
.001). Among non-subtype B viruses only, the polyvalent sera were able to 
neutralize 56.3% of the 8 viruses from subtypes A, C, D and A/E as compared to 

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the monovalent group that only neutralized 14.1% of the same set of non-B 
viruses (35). 
The polyvalent DNA prime-protein boost approach was also tested in non-human 
primate studies (36, 37). After protein boosting, regardless of whether DNA had 
initially been delivered via gene gun, intra-muscular (IM), or intra-dermal (ID) 
injection, there was a significant increase of antibody titers among groups 
receiving different routes of DNA priming immunization without significant 
differences for peak level anti-gp120 IgG responses, indicating a DNA prime can 
be efficiently administered via different delivery approaches. 
Macaques immunized with a polyvalent DNA prime-protein boost immunization 
regimen were then rectally challenged with a homologous SHIV expressing an R5 
Env (BaL). Four out of the six immunized macaques had sterilizing immunity 
with an undetectable viral load. The remaining 2 had reduced peak levels of viral 
load, and the seven immunization-naïve macaques showed high levels of viremia 
(36). 
4.1.3 
Optimizing inserts and the choice of adjuvant for PDPHV-201401 
A large study has been conducted by UMMS to differentiate the potential of 
individual HIV-1 Env antigens to elicit nAbs that could neutralize a diverse panel 
of viruses. A total of 62 primary gp120 antigens have been screened through this 
process. Sera from rabbits that received a gp120-expressing DNA vaccine three 
times, and were then boosted twice with a fixed number of five gp120 proteins, 
were analyzed at Monogram Biosciences, using its high throughput assay against 
a panel of 16 pseudotyped viruses. These included three TCLA or sensitive Env 
antigens and 13 primary Env antigens from subtypes A, B, C, D, and A/E. Among 
this group of 62 gp120 antigens, 10 (16%) elicited nAb against more than 50% of 
this panel of viruses and another 11 (18%) elicited nAb against 26-50% of 
viruses. The remaining 41 gp120 antigens (66%) elicited nAb which neutralized 
between 6-25% of viruses in this panel (unpublished data). The immunogens 
selected for PDPHV-201401 were those that were able to elicit nAbs against the 
largest percentage of the pseudotyped viruses for their respective subtypes. 
A bioinformatics study was done using the four gp120 sequences from the 
PDPHV-201401 formulation to determine levels of coverage against worldwide 
HIV-1 Env viral sequences that can be achieved by increasing the valency, ie, the 
number of Env immunogens represented in the vaccine (monovalent, bivalent, 
trivalent, or quadrivalent). 
As shown in Figure 4-1, showing the study results using a heat map approach 
(colder colors mean less of a match and warmer colors mean a better match), it is 
clear that with increasing valency, the coverage of high-match 
subtypes/circulating recombinant forms was gradually increased, across 
subtypes/circulating recombinant forms. With the quadrivalent formulation, no 
subtype is matched less than 90% for 11 major subtypes (Figure 4-1). 

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While this is purely a modeling analysis, it shows the power of polyvalency – a 
key principle in modern vaccinology. 
 
Figure 4-1. Bioinformatics analysis on the potential coverage of HIV-1 viruses by 1-, 2-, 3-, or 
4- valent gp120 vaccines (A, B, C, and A/E). The heat map shows the percent of coverage: 
cold/blue (low match) to hot/red (high match) colors representing the levels of coverage. 
Gag-mediated CMI responses, more than any other HIV-1 antigen-specific CMI 
responses, have been shown to play an important role in the control and 
containment of virus replication in HIV-1 infected patients. While previous small 
animal and non-human primate model studies have validated the immunogenicity 
of gag DNA vaccines included in this multiple-gene HIV vaccine design, the 
UMMS team conducted an additional mouse study as part of the IPCAVD 
program to confirm the relative immunogenicity of various gag DNA vaccine 
designs. 
Balb/C mice (10 mice/group) were immunized with wild type gag-C8 (gag-
C8.wt) or codon optimized gag-C8 (gag-C8.opt) DNA vaccine. At 1 week after 
the 4th DNA immunization, mouse splenocytes were collected to detect Gag 
peptide-specific T cell responses by IFN-γ ELISpot. The gag-C8.opt DNA 
vaccine induced significantly higher levels of IFN-γ T cell responses that were 
specific to the Gag peptides (38). Based on these analyses, the codon optimized 
gag-C8.opt DNA vaccine is included as a component in the PDPHV-201401 
DNA vaccine. 

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After consultation with NIAID, a clinical adjuvant formulation GLA-SE 
(Infectious Disease Research Institute [IDRI], Seattle, Washington, USA) was 
selected as the adjuvant for the protein vaccine. GLA-SE is a stable oil-in-water 
emulsion (SE) containing glucopyranosyl lipid A (GLA), a synthetic analog of 
MPL. GLA is a potent TLR4 agonist and improves the immunogenicity of a wide 
variety of antigens by increasing the magnitude of the immune response and 
tailoring the response to the Th1-type cell-mediated paradigm. 
IDRI and collaborators have tested GLA adjuvant formulations with antigens for 
several candidate infectious disease vaccines including leishmaniasis, 
schistosomiasis, tuberculosis, malaria, influenza, leprosy, and hookworm (39-44). 
It has been generally well tolerated in studies to date, without any significant 
safety concerns. 
4.2 
Env (A, B, C, A/E) / Gag (C) DNA plasmids 
The polyvalent DNA vaccine contains equal amounts of 5 individual DNA 
plasmid components utilizing the same vector pSW3891 (45): 4 plasmids each 
containing a codon optimized gp120 gene sequence from 3 primary HIV-1 
subtype A, B, C envelope proteins and a CRF01_AE consensus, and a fifth 
plasmid containing a codon optimized gag gene from subtype C (Table 4-1). 
DNA vaccines 
The 4 gp120-expressing (Env-A, B, C and A/E) and one Gag expressing (Gag-C) 
plasmids were constructed with the vector pSW3891 backbone. This backbone 
contains the following elements: 1) human cytomegalovirus (CMV) immediate-
early promoter/Intron A enhancer for high-level gene expression in a wide range 
of mammalian cells; 2) the bovine growth hormone (BGH) polyadenylation signal 
for proper termination and processing of the recombinant transcript; 3) the tissue 
plasminogen activator (tPA) signal peptide sequence to lead the secretion of 
encoded proteins; 4) pUC origin for high copy replication and maintenance of the 
plasmid in E. coli; and 5) Kanamycin (Kan) resistance gene for selection in E. 
coli. The gp120 and gag cDNA that were cloned into the pSW3891 vector are 
described in Table 4-1. The codon optimized gp120 and gag cDNA genes were 
chemically synthesized at Geneart (Germany). Each codon optimized gp120 gene 
was individually cloned into NheI and BamHI sites in frame with tPA leader 
sequence of the pSW3891 vector. The gag-C gene was cloned into HindIII and 
BamHI sites of the pSW3891 vector. 
 
 

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Table 4-1 Five plasmids each encoding a codon optimized pg120 or gag gene sequence 
DNA Vaccine 
Name 
Vector 
Backbone 
gp120 or gag 
Gene Insert 
HIV-1 Isolate 
GenBank 
Accession No. of 
original viral gene 
Size 
(bp) 
PDPHV-ENV-A 
pSW3891 
gp120-A2-opt 
92UG037.1 
U09127 
6163 
PDPHV-ENV-B 
pSW3891 
gp120-JR-FL-
opt 
JR-FL 
U63632 
6181 
PDPHV-ENV-C 
pSW3891 
gp120-C2-opt 
93MW965.26 
U08455 
6151 
PDPHV-ENV-E 
pSW3891 
gp120-AE-
Cons-opt 
Subtype A/E 
consensus 
N/A 
6163 
PDPHV-GAG-C 
pSW3891 
gag-C8-opt 
96BW15C02 
Af110974 
6166 
The DNA vaccines were manufactured at Waisman Biomanufacturing (Madison, 
WI) under GMP-compliant conditions. 
No adjuvant will be used for the DNA vaccines in HVTN 124. Previous HIV-1 
gp120 and gag DNA vaccines using the same plasmid vector pSW3891 were 
evaluated in the DP6-001 phase 1 clinical trial and effectively primed the immune 
system (5, 26, 46). The final Drug Product for the polyvalent DNA vaccine 
mixture in saline has the 5 plasmids vialed together by the manufacturer. 
4.3 
Recombinant gp120 (A,B,C,A/E) protein with GLA-SE adjuvant 
4.3.1 
Recombinant gp120 protein vaccine 
The recombinant gp120 (A,B,C,A/E) protein vaccine contains equal amounts of 4 
gp120 proteins matching the Env genes used in the DNA vaccine, produced in 
stable CHO cell lines by Waisman Biomanufacturing (Madison, WI) under GMP 
compliant conditions. The gp120 proteins are highly glycosylated and consist of 5 
relatively conserved domains (C1-C5) interspersed with 5 hypervariable domains 
(V1-V5). 
Each of the 4 gp120 proteins will be produced and vialed individually. 
4.3.2 
GLA-SE adjuvant 
Glucopyranosyl lipid adjuvant-stable oil-in-water emulsion (GLA-SE) provided 
by Infectious Disease Research Institute (IDRI, Seattle, WA) will be used as the 
adjuvant for recombinant gp120 protein vaccines. GLA-SE contains 
glucopyranosyl lipid A, a synthetic and non-toxic form of bacterial 
lipopolysaccharide. The GLA-SE (6% oil) will be vialed separately at a volume of 
0.4 mL at a concentration of 15 mcg/mL GLA in a 2.0 mL vial. The excipients in 
the GLA-SE formulation are: Glycerin (isotonicity adjustment), D,L-α-tocopherol 
(Vitamin E) (anti-oxidant), 1,2-dimyristoyl-sn-glycero-3-phosphocholine 
(DMPC) (emulsifier/stabilizer), Poloxamer 188 (emulsifier/stabilizer), 
Ammonium phosphate, monobasic (NH4H2PO4) (buffer), and Ammonium 
phosphate, dibasic ([NH4]2HPO4) (buffer). All clinical lots were manufactured by 

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IDRI under cGMP guidelines. Bulk GLA was manufactured for IDRI by Avanti 
Polar Lipids (Alabaster, Alabama, USA). 
4.3.3 
Recombinant gp120 protein/GLA-SE formulation 
The final mixture of the four proteins plus GLA-SE adjuvant formulation will be 
prepared onsite at the local CRS pharmacy. 
4.4 
Trial design rationale 
The main objective of the HIV vaccine formulation PDPHV-201401 is to safely 
induce high quality antibody responses able to protect against HIV infection. 
Based upon evidence from the RV144 trial that antibody responses are associated 
with protection from HIV acquisition (14-24), in this trial serum binding 
antibodies to gp120 and serum neutralizing antibodies will be the major 
immunogenicity outcomes. The secondary objectives are key immunogenicity 
parameters that will characterize and rank the vaccination regimens in terms of 
response rates, magnitudes and durability of HIV-1 Env antibody and CD4+ T 
cell responses, and determine whether the current HIV vaccine formulations will 
move to more advanced phases of clinical studies.  
4.4.1 
Safety 
In order to carefully evaluate the safety of each component of the vaccine 
strategy, HVTN 124 will be conducted in two parts. Part A will evaluate the 
safety and immunogenicity of the protein vaccine with adjuvant, independent of 
the DNA prime. In Part B, the prime-boost regimen of 3 DNA primes (months 0, 
1, 3) followed by 2 protein/adjuvant boosts (months 6, 8) will be compared to a 
study arm consisting of the DNA and protein/adjuvant vaccines co-administered 
at the same timepoints (months 0, 1, 3, 6, 8). Therefore Part B will evaluate the 
safety of the DNA prime individually or in combination regimens. 
The protocol will enroll each part of the study in stages, with frequent safety 
reviews (see Section 11.3). The group sizes in Part B will allow for reasonable 
precision in the characterizations of the safety endpoints, as well as reasonable 
power for comparisons between the groups with respect to immunogenicity 
endpoints, particularly with assays that might have less frequent responses, such 
as Tier 2 neutralizing antibodies (see Sections 6.1.1 and 6.1.2). 
4.4.2 
Dose (amount and number) 
Multiple studies in the HVTN have used plasmid DNA vaccines at doses between 
0.3 mg and 8 mg. All doses have been well tolerated, and even the lowest dose 
demonstrated priming (47). DNA doses given in the DP6-001 study were 1.2 or 
7.2 mg. In that study, there did appear to be a dose-dependent effect, with the 
higher dose producing higher response rates and magnitudes of immune responses 
after administration of the DNA vaccine. However, there were no differences in 
immunogenicity between the low and high dose DNA arms after the protein 

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boost. Therefore, the 2 mg IM dose (0.4 mg/each DNA plasmid) has been selected 
for HVTN 124. 
The dose of protein vaccine in HVTN 124 will be 400 mcg (100 mcg of each 
gp120 protein), which is similar to the 375 mcg total dose given in the DP6-001 
study. Protein doses in HVTN studies have recently ranged from 100 mcg to 600 
mcg of gp120. Gp120 has been well tolerated with alum or MF59, and other 
adjuvants currently under investigation at these doses. The dose of GLA-SE 
adjuvant in HVTN 124 will be 5 mcg with 2% oil. The GLA-SE dose has been 
determined based on immunogenicity and tolerability results obtained from 
previous clinical studies including influenza vaccine and cancer vaccine clinical 
studies by IDRI. 
4.4.3 
Schedule 
The prime-boost schedule of vaccinations at 0, 1, 3, 6 and 8 months has been 
chosen to give a minimum of a 2-month rest period between the protein boost 
vaccinations in Groups 1 and 2. Other HVTN trials evaluating DNA prime 
followed by a protein or vectored vaccine boost strategies follow a schedule of 
two or three DNA prime immunizations followed by two boosts (eg, HVTN 092, 
HVTN 105, HVTN 106, HVTN 108, HVTN 111, HVTN 112, and HVTN 115). A 
similar schedule of vaccinations, including DNA immunizations at months 0, 1, 3 
and protein immunizations at months 6 and 8, was selected for this study. This 
will allow for some informal comparisons across studies. 
4.4.4 
DNA + protein vaccination regimen 
In addition to the polyvalent DNA prime-protein boost arm, HVTN 124 includes 
an arm to test the DNA vaccine given simultaneously with the adjuvanted protein 
vaccine for comparison. Assessments starting after the third vaccination in this 
group will evaluate when recipients have achieved peak immune responses to the 
combination. 
An important objective is to determine which of the two regimens will achieve the 
highest response rate, magnitude, and durability of antibody responses, and to 
characterize any qualitative differences in immune responses to the two regimens. 
4.4.5 
Choice of placebo control 
Sodium Chloride for Injection, USP 0.9% is nonreactogenic and well tolerated. It 
will be used for placebo groups and as a control to blind between groups in Part 
B. 
4.5 
Plans for future product development and testing 
Once HVTN 124 is initiated, the UMMS team will work on the optimization of 
the manufacturing process to allow vaccine production on a much larger scale, 
and being able to provide the protein vaccine components premixed in one vial, to 

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prepare for a possible phase 2 study. Clinical safety and immunogenicity data 
from HVTN 124 will provide key information to drive the further advancement of 
this unique polyvalent DNA-protein HIV vaccine regimen to more advanced 
studies. 
4.6 
Preclinical safety studies 
A multiple dose toxicology study was conducted by Wuxi AppTec Inc. at its 
toxicology test facility located in St Paul, Minnesota (study protocol number: 
C13474-1). 
Table 4-2 Summary of preclinical safety studies 
Study 
number 
Product 
Type of 
study 
Animal 
N 
Dose 
groups 
Route 
Schedule 
(days) 
C13474-1 
PBS 
Toxicology 
Rabbit 
(Group 1) 
10m, 10f 
 
N/A 
IM 
1, 21, 42, 
63, 84, 
105 
 
GLA-SE 
Toxicology 
Rabbit 
(Group 2) 
10m, 10f 
 
0.005mg 
 
IM 
Same 
 
DNA+ 
Protein+ 
GLA-SE 
Toxicology 
Rabbit 
(Group 3) 
10m, 10f 
 
2mg DNA 
0.4mg Protein 
0.005mg GLA-
SE 
IM 
Same 
4.6.1 
General toxicology study of proposed product combination in New 
Zealand White rabbits (Study #C13474-1)  
Administration of Test and Control Articles 
Route: Intramuscular Injection 
Frequency: Days 1, 21, 42, 63, 84 and 105 
Vaccinations were administered as detailed in Table 4-2. The dose consisted of 
bilateral single intramuscular injections of constant volume regardless of body 
weight. For each dose, the adjuvant (Group 2), or adjuvant/protein (Group 3) 
injections were administered on the right thigh and the DNA injections (Group 3) 
were administered on the left thigh. Each injection was administered at a 
shaved/marked site.  
Group 1 
For each rabbit of Group 1, 0.8 mL of PBS was drawn into a syringe for 
intramuscular injection into the left thigh; then, 1.0 mL of PBS was drawn into a 
syringe for intramuscular injection into the right thigh. 
Group 2 
For each rabbit of Group 2, 0.8 mL of PBS by intramuscular injection was 
administered to the left thigh; then, 1.0 mL of PBS + GLA-SE adjuvant mixture 
was administered by intramuscular injection to the right thigh. 

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Group 3 
For each rabbit of Group 3, 0.8 mL of DNA vaccine from one vial was 
administered by intramuscular injection to the left thigh; then 1.0 mL of the 4 
protein vaccines + GLA-SE adjuvant mixture (0.2 mL of each gp120 protein (0.6 
mg/mL) with 0.4 mL of GLA-SE (15 mcg/mL) was administered by 
intramuscular injection to the right thigh. 
Observations 
The study monitored body temperatures, daily mortality/moribundity checks, feed 
consumption, general health observations, clinical health observations, Draize 
scoring, and body weight. Blood was sampled for serological testing, C-reactive 
protein (CRP) and serum protein electrophoresis (SPEP) at Day 1 (pre-dose 
baseline) and at Days 2, 8, 21 (pre-dose 2), 43, 49, and 63 (pre-dose 4). Samples 
were also drawn for potential evaluation of antigen-specific IgG antibodies, 
hematology, coagulation studies, chemistry. Final observations included gross 
necropsy, organ weights, and histopathology. 
Conclusion for General Toxicology Study 
It was concluded that under the conditions of this study, C13474-1 Multiple Dose 
Toxicology Study for a Modified Polyvalent HIV Vaccines Delivered 
Intramuscularly, when taking all the toxicology, Draize scoring, body 
temperature, serum protein, and pathology data into account, there was no 
evidence of systemic toxicity or adverse findings specifically attributed to the test 
article. Please see the IB for additional information.  
In addition, an immunogenicity analysis was conduct to measure gp120-specific 
IgG responses in rabbits included in the toxicology study. High titer antibody 
responses were clearly detected in Group 3 at the end of study while there were 
no detectable gp120-specific IgG responses in Groups 1 and 2. 

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4.7 
Preclinical immunogenicity studies 
Table 4-3 Summary of preclinical immunogenicity studies 
Study 
number 
 Product 
Anima
l 
N 
Dose 
groups 
Route 
Schedule 
(weeks) 
Assay 
LNAV-
01 
JR-FL protein 
NZW 
rabbits 
3f 
P 50 mcg 
/ A 300 
l 
IM 
0, 2, 4, 8 10 
Breadth of nAb 
(Fig. 4-2) 
 
JR-FL DNA 
Same 
3f 
D 36 
mcg 
GG 
0, 2, 4, 8, 10 
 
 
JR-FL DNA 
>> JR-FL 
protein/IFA 
Same 
3f 
D 36 
mcg >> 
P 60 mcg 
/ A 300 
l 
GG>> 
IM 
D 0, 2, 4 >> P 8, 
10 
 
 
JF-FL DNA 
>> polyvalent 
proteins /IFA 
Same 
3f 
D 36 
mcg >> 
P 60 mcg 
/ A 300 
l 
GG>> 
IM 
D 0, 2, 4 >> P 8, 
10 
 
 
 
 
 
 
 
 
 
LNAV-
02 
DP6-001 
DNAs >> 
DP6-001 
proteins /QS-
21 
NZW 
rabbits 
5f 
D 400 
mcg >> 
P 100 
mcg / A 
50 mcg 
IM 
D 0, 2, 4 >> P 10 
14 
Titers and 
breadth of nAb 
 
New 
polyvalent 
DNAs >> 
proteins/IFA 
Same 
5f 
D 400 
mcg >> 
P 100 
mcg / A 
300 l 
IM 
D 0, 2, 4 >> P 10 
14 
(Figs. 4-4 and 4-
5) 
 
 
 
 
 
 
 
 
LNAV-
03 
4-valent 
gp120 
(ABCE) 
proteins + 
GLA-SE 
NZW 
rabbits 
5f 
P 100 
mcg + A 
25 mcg 
IM 
0, 4, 8 
ELISA (Fig. 4-6) 
 
4-valent 
gp120 
(ABCE) 
proteins + 
GLA-SE 
Same 
5f 
P 400 
mcg + A 
25 mcg 
IM 
0, 4, 8 
 
 
4-valent 
gp120 
(ABCE) 
Same 
5f 
P 400 
mcg 
IM 
0, 4, 8 
 
 
 
 
 
 
 
 
 
LNAV-
04 
Empty Vector 
>> DP6-001 
proteins 
NZW 
rabbits 
2f 
D 36 
mcg >> 
100 mcg 
/ A 300 
l 
GG>> 
IM 
D 0, 4, 12 >> P 
20, 28 
ELISA (Fig. 4-7) 
 
DP6-001 
DNAs >> 
DP6-001 
proteins/IFA 
Same 
4f 
D 36 
mcg >> 
100 mcg 
/ A 300 
l 
GG>> 
IM 
D 0, 4, 12 >> P 
20, 28 
 

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4.7.1 
Immunogenicity of JR-FL gp120 protein alone, JR-FL DNA alone, 
DNA prime + JR-FL protein boost (monovalent), and JR-FL DNA 
prime + 5-gp120 proteins boost (polyvalent proteins), with IFA 
included as part of protein boosts (LNAV study #1) 
In order to provide a full description of the quality of antibody elicited by the 
DNA prime-protein boost approach, different prime-boost vaccination regimens 
(ie, DNA only, protein only, DNA plus protein and Incomplete Freund’s Adjuvant 
[IFA]) in rabbits were tested using the gp120 antigen from HIV-1 JR-FL as a 
model antigen. Results demonstrated that incorporating DNA immunization as a 
prime in a heterologous prime-boost regimen was able to elicit a more diverse and 
conformational epitope profile, higher antibody avidity, and improved 
neutralizing activity than immunization with protein alone. In addition, polyvalent 
Env protein boost was more effective than monovalent protein boost in rabbits 
receiving the same JR-FL gp120 DNA prime immunization to elicit broader 
neutralizing activities against more resistant Tier-2 viruses (32). See Figure 4-2. 
 
Figure 4-2. Breadth of neutralizing antibody responses induced by JR-FL gp120 protein 
alone (5 immunizations), DNA alone (5 immunizations), DNA prime (3 immunizations) + 
protein boost (2 immunizations with one gp120 protein and IFA), and DNA prime (3 
immunizations) + protein boost (2 immunizations with five gp120 proteins and IFA). The 
neutralization was performed against the standard panel of 12 subtype B Tier 2 viruses in TZM-bl 
cells. 
Additional studies using a mouse model have demonstrated that DNA prime-
protein boost immunization was more effective than DNA or protein alone 
approaches in establishing gp120-specific B cell responses in both spleen and 
bone marrow when measured by B cell ELISpot analysis. This finding suggests 
that the DNA prime-protein boost strategy is effective in eliciting both circulating 
antibody secreting cell (ASC) and memory B cell responses (Shan Lu, 
unpublished data). 
4.7.2 
Immunogenicity of new polyvalent Env formulation (5-valent) vaccine 
versus DP6-001 (LNAV study #2) 
The new gp120 immunogens were selected based on results of a comprehensive 
study in rabbits, which screened more than 60 primary Env immunogens. Only 
about 15% of primary gp120 immunogens were effective in eliciting broad 
0%
5%
10%
15%
20%
25%
30%
Protein alone
DNA alone
DNA+Protein(1)
DNA+Protein(5)
% viruses neutralized

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neutralizing antibody responses (Shan Lu, unpublished data). Five top candidate 
gp120 immunogens with the ability to prime broad nAb responses, each 
representing one of the five subtypes (A, B, C, D and A/E), were selected as 
candidates to form a new polyvalent formulation to compare with the 
immunogenicity of DP6-001 (which also contained five gp120 immunogens). 
A limited antigenicity analysis was conducted to see if these gp120 immunogens 
could be recognized by several well-known broadly neutralizing mAbs, including 
recently discovered ones. As shown in Figure 4-3, different mAbs (VRC01, b12, 
2G12, PGT128 and PG9) may recognize different subsets of the five gp120 
immunogens included in the tested polyvalent formulation. (The final PDPHV-
201401 formulation to be used as the clinical trial materials is quadrivalent, 
without gp120 from subtype D). Several gp120 immunogens can be recognized 
by more than one mAb. These would provide a good diversity of immunogen 
conformations and they may supplement each other in a polyvalent formulation. 
One interesting finding is that mAb PG9 showed very high and specific binding to 
the A/E consensus gp120 immunogen. The data suggested that the gp120 
immunogens produced for this new vaccine have well preserved critical 
conformations, which are important for the induction of high quality antibody 
responses. 
 
Figure 4-3. ELISA assay showing the recognition of five selected gp120 proteins (A2, JR-FL, 
C2, D and A/E) in by neutralizing mAb VRC01, b12, 2G12, PGT128 and PG9. 
In a rabbit immunogenicity study, antibody responses with the new pentavalent 
DNA prime-protein boost regimen PDPHV-2011 were compared to sera elicited 
by the DP6-001 formulation and were found to produce improved nAb responses 
in rabbits compared to the first generation vaccine regimen DP6-001, as measured 
by both potency (Figure 4-4) and breadth (Figure 4-5). 
The assay done at Monogram Biosciences used a standard panel, and a second 
assay used a panel of 26 pseudotyped viruses spanning Tier 1 to 3 viruses. Figure 
4-4 shows that the nAb titers done at Dr. Montefiori’s lab were similar against 
SF162 (p = 0.062) but significantly improved in pentavalent PDPHV-2011 
0 .0 1
0 .1
1
1 0
0 .0
0 .5
1 .0
1 .5
m A b  C o n c . (u g /m L )
O D 4 5 0  n m
A 2
J R -F L
C 2
D
A E  C o n
0 .0 0 1
0 .0 1
0 .1
1
1 0
1 0 0
0 .0
0 .5
1 .0
1 .5
m A b  C o n c . (u g /m L )
O D 4 5 0  n m
A 2
JR -F L
C 2
D
A E  C o n
0.001
0.01
0.1
1
10
100
0.0
0.5
1.0
1.5
A2
JRFL
C2
D
AE
antibody conc (ug/ml)
OD450 nm
0.001
0.01
0.1
1
10
100
0.0
0.5
1.0
1.5
A2
JRFL
C2
D
AE
antibody conc (ug/ml)
OD450 nm
0.001
0.01
0.1
1
10
100
0.0
0.5
1.0
1.5
A2
JRFL
C2
D
AE
antibody conc (ug/ml)
OD450 nm
PG9
2G12
b12
PGT128
VRC01

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compared to DP6-001 in testing against two Tier 1B viruses, SS1196.1 (p = 
0.022) and 6535.3 (p = 0.041). The new regimen elicited higher nAb titers than 
the DP6-001 regimen. Figure 4-5 shows the neutralization assays conducted 
against an expanded panel of viruses, including many Tier 2 subtypes B and C 
viruses. Results from these analyses demonstrated that a higher percentage of 
viruses in the panel was neutralized by the PDPHV-2011 rabbit sera than the 
DP6-001 rabbit sera. 
 
Figure 4-4. nAb titers against HIV-1 subtype B Tier 1 (SF162) and Tier 1b (1196 and 6535) 
pseudotyped viruses in rabbit sera immunized with DP6-001 or (5-valent) PDPHV-2011 
gp120 DNA prime – protein boost. 
 
Figure 4-5. Frequency of pseudotyped viruses neutralized by rabbit sera immunized with 
either DP6-001 or the new 5-valent formulation (5 rabbits in each group).  Rabbits were 
immunized with 3 DNA prime immunizations and 2 protein boost immunizations.  Rabbit 
sera were collected at 2 weeks after the second protein boost.  A: Rabbit sera that can 
neutralize any pseudotyped viruses in this assay (Tiers 1, 2 and 3) are highlighted in yellow 
R729
R730
R731
R732
R733
R754
R755
R756
R757
R758
Tier
Clade
Virus ID
1A
B
SF162
945
1537
27
78
1405
5266
7720
677
>21870
4718
B
SS1196
28
133
54
92
83
259
92
309
270
C
ZM197.PB7
16
14
38
21
C
ZM109F.PB4
15
15
25
20
AC10.0.29
10
QH0692.42
23
20
SC422661.8
10
20
REJO4541.67
24
6535.3
22
47
21
26
190
74
P6LN40
10
CAAN5342.A2
21
11
TRO.11
20
RHPA4259.7
26
12
WITO4160.3
22
10
ZM249.PL1
24
22
>>90
13
41
19
DU156.12#1
11
38
132
86
22
12
22
17
44
19
DU172.17#3
14
34
19
11
28
17
ZM135M.PL10a
53
12
19
31
19
CAP45.200.E8
12
20
Du422.1
13
ZM53M.PB12
ZM214.pB7
29
ZM233M.PB6
15
21
19
22
CAP210.2.00.E8
21
11
27
PVO.4
TRJO4551.58
20
MLV
Neg-control virus
A.
IC50 NAb titers against HIV-1 pseudoviruses
Vaccine (DNA prime - Protein boost)
DP6-001 gp120 
new 5 valnet gp120 
Rabbit#
1B
B
3
2
B
C

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with neutralizing antibody titers (IC50) shown.  The blank cells indicate that there was no 
detectable neutralizing activity (cut off at titer =/<10).  B: Frequency of HIV-1 pseudotyped 
viruses neutralized by either DP6-001 (23%) or new 5-valent formulation (43.1%) based on  
data shown in panel.  
4.7.3 
Preclinical studies of GLA-SE adjuvant conducted at IDRI and UMMS 
(LNAV Study #3) 
GLA-SE, an adjuvant developed by IDRI, has been tested in several toxicity 
studies in rabbits and rats conducted under GLP guidelines. Parameters evaluated 
included the following: morbidity/mortality; clinical signs; injection site 
reactogenicity; body weights; body temperatures; food consumption; 
ophthalmologic evaluations; clinical chemistry; hematology; coagulation; gross 
necropsy observations; organ weights; histopathology; and immunogenicity. In 
these studies, GLA-SE was found to be safe, well-tolerated, and 
immunostimulatory. No treatment-related adverse effects were observed in the 
parameters evaluated except for reversible injection site reactions (erythema, 
edema, inflammation) and a mild, transient acute inflammatory response (changes 
in hematologic values, increased fibrinogen levels) in some animals receiving 
GLA adjuvant formulations. 
In addition, many preclinical and nonclinical studies in mice, guinea pigs, rats, 
rabbits, and non-human primates have demonstrated the immunostimulatory 
properties of GLA-SE with no significant safety signals. Thousands of mice have 
been immunized with candidate antigens for infectious disease vaccines (eg, 
leishmaniasis, tuberculosis, leprosy, malaria, influenza) formulated in GLA-SE. 
No safety issues have been observed. In addition, the potential for auto-antibody 
generation following GLA administration was evaluated through extensive 
immunohistochemistry assays for immune complexes and/or autoimmune 
pathology, and no signs of detrimental autoimmune effects were found. Studies 
have also assayed for anti-nuclear antibody and have not found abnormal levels in 
GLA-immunized mice. 
More than 300 guinea pigs have been immunized with candidate tuberculosis 
vaccine antigens formulated with GLA. No safety issues have been observed. In 
addition, a safety study was conducted in guinea pigs in which various GLA 
adjuvant formulations (oil emulsions, aqueous suspensions, liposomes) were 
administered without antigen by three different injection routes (subcutaneous 
[SC], intramuscular [IM], and intradermal [ID]). Administration of GLA-SE by 
all three routes appeared to be safe and well-tolerated. 
In several nonhuman primate studies using the adjuvant in male and female 
rhesus, male cynomolgus, and male aotus monkeys, the adjuvant was safe, well-
tolerated, and increased the immune response to the co-administered antigen. No 
treatment-related adverse effects were observed in the safety parameters evaluated 
except for mild injection site reactions and a mild, transient acute phase 
inflammatory response characterized by increases in C-reactive protein (CRP), 
fibrinogen, and neutrophils.  

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Once GLA-SE was selected jointly by UMMS scientists and NIAID program 
officers in consultation with our Scientific Advisory Board members, one rabbit 
immunization study was conducted to confirm the ability of GLA-SE adjuvant in 
enhancing the gp120-specific antibody responses elicited by recombinant gp120 
protein immunization. 
The rabbits received the same quadrivalent gp120 protein immunization (A, B, C 
and A/E) as PDPHV-201401 at Weeks 0, 4 and 8 by intramuscular injection at 
two dosing levels (100 mcg or 400 mcg total protein at each immunization). The 
sera were collected to evaluate the gp120-antibody responses by ELISA (using 
plates coated with the 4-gp120 protein mix). The results demonstrated that GLA-
SE could significantly enhance the gp120-specific antibody responses in rabbits 
(Figure 4-6). 
 
Figure 4-6. The gp120-specific serum antibody responses in rabbits immunized by the 4-
valent gp120 proteins (gp120-ABCE) with or without GLA-SE adjuvant. A: the temporal 
antibody responses with sera at 1:3,000 dilutions. The arrows indicate the times of immunizations. 
B: The gp120-specific antibody titers at 2 weeks after the 3rd protein immunization. 
4.7.4 
Epitope mapping analysis (LNAV Study #4) 
An epitope mapping study was performed that revealed that the DP6-001 DNA-
primed, protein-boosted sera generated significant levels of conformation-
dependent antibodies specific for the CD4 binding site (CD4bs) while animals 
immunized with protein alone were not efficient in generating such antibodies. 
Figure 4-7 shows that three mapped epitope areas (p30, p61-p64 and p113-117) 
overlapped with CD4bs as shown by their positions at the gp120 crystal structure. 
The importance of anti-CD4bs antibody in neutralizing HIV-1 has been described 
by studies with monoclonal antibody (mAb) b12, long term non-progressor HIV 
patients’ sera reported from John Mascola’s group, and the new mAb VRC01 (48, 
49). 
Group A – gp120-ABCE (100 ug) + GLA-SE
Group B – gp120-ABCE (400 ug) + GLA-SE
Group C – gp120-ABCE (100 ug) no adjuvant
0       2      4        6       8     10      12
Weeks
A                 B                C                D
gp120-specific Ab titers
Rabbit groups
Group A – gp120-ABCE (100 ug) + GLA-SE
Group B – gp120-ABCE (400 ug) + GLA-SE
Group C – gp120-ABCE (100 ug) no adjuvant
Group D - PBS
A.
B.

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Figure 4-7. Identification of three clusters of targeted epitopes (in blue color, p30, p61-64 
and p113-117) elicited by DP6-001 DNA prime-protein boost vaccine, overlapping either with 
known CD4bs (in purple color, upper row) or with the binding site for CD4bs mAb b12 (in 
red color, lower row). 
4.8 
Clinical studies 
No previous clinical studies of the PDPHV-201401 vaccines have been 
performed. However, similar vaccines have been tested in an earlier study. 
4.8.1 
Phase 1 clinical study H11163 of the first generation regimen, DP6-
001 
Based on the results of the rabbit and non-human primate studies described above, 
a clinical formulation, DP6-001, was developed that included six DNA vaccine 
plasmids as the prime: one codon optimized gag gene from subtype C (96ZM651) 
plus 5 primary env genes representing 5 randomly selected Env antigens from 
four major subtypes, subtypes A (92UG037.8), B (92US715.6 [B] and Bal), C 
(96ZM651), and E (93TH976.17), followed by a boost using 5 matching 
recombinant gp120 proteins produced in CHO cells. This first generation regimen 
was tested in a phase 1 clinical trial (H11163) in healthy adults. The study was a 
randomized, 3-arm trial. The groups received 1.2 mg DNA ID (Group A), 1.2 mg 
DNA IM (Group B), or 7.2 mg DNA IM (Group C) without any adjuvant at 
weeks 0, 4, and 12, followed by one standard dose of protein (0.375mg) 
administered IM with the adjuvant QS-21 at weeks 20 and 28, except for the high 
dose DNA group who received the adjuvanted protein IM injection only at week 
20, due to all study vaccinations being discontinued early. 
In this study, a high level of local and systemic reactogenicity was observed, 
including injection site pain and erythema, fevers, myalgia, fatigue, headache, and 
arthralgias. Fevers were common within the first week after vaccination in Groups 
A and B, occurring in 2/3 of participants at one or more timepoints. All fevers 
were Grade 1 (38.0°C-39.0°C, 100.4-102.2°F) except for 1 Grade 2 fever 
(39.1°C-40°C, 102.3-104.0°F) in a Group B participant after the second DNA 
vaccination. Other adverse events included bilateral eye pain, sensitivity to light, 

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blurry vision, changes in sleep or appetite, increased liver function tests, 
decreased CD4+ T cell counts and 2 events of vasculitis (described below). 
Three clinically distinct types of skin reactions were encountered. The most 
frequent skin reaction, in 39% who received at least two vaccine doses, was 
localized skin erythema. These reactions typically appeared 36–72 h after 
injection of either the DNA (8 reactions) or the protein vaccine (12 reactions), at 
the sites of prior ID or IM DNA inoculation (“recall reactions”). Several were 
biopsied and consistent with Delayed Type Hypersensitivity (DTH) reactions. 
DTH reactions were common in both the low dose DNA ID (66.7%) and high 
dose DNA IM groups (44.4%). 
The second type of skin reaction was probably related to QS-21 based on prior 
reports of similar reactions to Env proteins formulated with QS-21. This pattern 
of localized skin erythema typically developed <24 h after vaccination with the 
protein vaccine, and was associated with greater induration, distinguishing it from 
the DTH reactions. However, a hypersensitivity reaction to the HIV antigens 
cannot be definitively excluded as a cause. 
The third type of skin reaction occurred in two subjects, both developing 
vasculitis within days following inoculation of the protein vaccine. One low dose 
DNA IM participant received one dose of protein vaccine and experienced 
reactivation of Henoch-Schonlein Purpura (HSP), a past medical history that was 
not reported prior to enrollment. A participant in the high dose DNA IM group 
received one dose of protein vaccine and developed leukocytoclastic vasculitis 
(LCV). Following the LCV event, vaccinations were halted for the study (46).  
LCV and HSP are categorized as immune-complex-mediated diseases. Several 
factors may have contributed to these vasculitis events: DNA priming 
immunization, HIV envelope antigens, and/or the use of QS-21 as an adjuvant 
and/or the protein/adjuvant combination. In any case, no significant skin or 
systemic reactions were observed in the DP6-001 rabbit toxicology study prior to 
the phase 1 clinical trial or in the additional toxicology study conducted in rabbits 
following the cases of vasculitis and DTH reactions. 
The causes of the DTH reactions and the vasculitis events, and their relationship 
to each other, if any, are not clear. It is notable that several DTH events occurred 
prior to protein vaccination, and therefore cannot be attributed to boost effect or 
combination of protein vaccine and QS-21. In regard to the vasculitis events, the 
temporal relationship to vaccination (following protein boost after DNA prime) 
suggests various possible mechanisms, including: strong cytokine production, 
enhanced reactions to the multiplicity of Env antigens in the DNA and protein 
vaccine regimen, or due to the protein vaccine formulation with QS-21 adjuvant, 
and/or an amplified reaction to the protein-adjuvant combination after DNA 
priming. The potential relationship to HIV Env warrants consideration in the 
design and analysis of this and other vaccine trials (46). Future clinical trials will 
include study designs that would help clarify etiologies of potential adverse 
reactions. 

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Clinical immunogenicity data from Protocol H11163 evaluating DP6-001 
High titer HIV-1 Env-specific antibody responses were generated with the DP6-
001 DNA prime-protein boost formulation. In the groups receiving low doses of 
DNA, most volunteers did not have detectable levels of Env-specific antibody 
responses after three DNA immunizations. However, the antibody titers rose 
quickly after just one protein boost. The anti-gp120 IgG titers reached levels 
comparable to those observed in chronically infected HIV patients (ie, 1:105 or 
higher) after only 1 or 2 protein boosts. By the end of the trial at week 52, 11 of 
11 participants who had received low-dose DNA IM primes maintained 
significant levels of serum anti-gp120 IgG titers (median, 8000, range 200-
104,000). In the high-dose DNA group, four out of six volunteers showed 
detectable Env-specific IgG responses even before the protein boost. Furthermore, 
Western blot analysis revealed that antibodies elicited by the polyvalent Env 
formulation DP6-001 were broadly reactive against a wide range of 11 
heterologous primary HIV-1 gp120 antigens from subtypes A to G (5). 
Three different laboratory studies were organized to assess the nAb activities in 
DP6-001 sera. The first study by David Montefiori found positive neutralizing 
antibody activities against a Tier 1 TCLA HIV-1 virus and different homologous 
pseudotyped viruses in immunized sera, whereas none of the 7 control samples 
had positive nAb against the above viruses (5). 
The second neutralization study was conducted at Monogram Biosciences and 
used a high-throughput, pseudotyped virus assay system to test sera from 
volunteers who received low-dose DNA, collected two weeks after the second 
protein boost, against a panel of 11 heterologous primary viruses from subtypes A 
to E, as well as three sensitive viruses. High-titer nAb responses were identified in 
all human immune sera against the three sensitive viruses. The geometric mean 
nAb titers were 1:771 (range: 348~1184) against SF162, 1:696 (range: 418~2147) 
and 1:196 (range: 49~426) in the low dose DNA IM group. A majority of 
volunteers had positive nAb activities (nAb titer of 1:20 as cutoff) against at least 
half of the pseudotyped viruses expressing primary Env antigens included in the 
study (5). The levels of nAb were higher than what was reported in previous 
literature with different HIV vaccine designs that include a DNA component (47). 
The geometric mean nAb titers against HIV-1 primary pseudotyped viruses were 
1:30 (20~90) in the low dose DNA IM vaccinees. 
The third neutralization study was also conducted by David Montefiori and tested 
the ability of the DP6-001 vaccinee sera to neutralize standardized panels of Tier 
2 viruses. Although positive neutralizing activity was higher than the negative 
control sera, most volunteer sera displayed viral inhibition of less than 50% at a 
serum dilution of 1:10. 
Positive CMI responses were also observed with the DP6-001 formulation, 
supporting the effectiveness of DNA prime-protein boost approach to elicit a 
balanced antibody and CMI response. Overall, 83-100% of volunteers had 
positive Env-specific IFN-γ responses observed in this study, and these responses 

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were mediated predominantly by polyfunctional CD4+ T cells (5, 26). HIV-1 
specific CD8+ T cell responses were also detected in the high dose group, but at a 
lower frequency (67% of subjects responded (26). CMI responses to Gag peptides 
increased in the high dose DNA group compared with the low dose DNA groups, 
in direct correlation with amounts of gag DNA in each arm. 
Further comparisons were done on the specificities of antibody responses in sera 
from DP6-001 volunteers and volunteers enrolled in two other HIV vaccine trials 
that used different immunization regimens: HVTN 041, recombinant proteins 
with AS02A adjuvant; and HVTN 203, a canarypox viral vector prime-protein 
boost (alum adjuvanted). Analysis included testing sera from each regimen’s 
volunteers for HIV-1 Env-specific binding antibody, nAb, antibody-dependent 
cell-mediated cytotoxicity (ADCC), and profiles of antibody specificity. While 
HVTN 041 had the highest binding antibody responses and nAb activities against 
the sensitive virus, DP6-001 sera showed the highest frequency of positive nAb 
activities against more resistant viral isolates with a significantly higher CD4 
binding site antibody response compared to both HVTN 041 and HVTN 203. No 
differences were found in CD4-induced antibody responses, ADCC activity, or 
complement activation by Env-specific antibody among these sera (4). This study 
further supported the rabbit study finding that the DNA prime-protein boost 
approach is highly effective in eliciting antibodies targeting conformationally 
sensitive and functionally conserved epitopes (35). 
4.8.2 
Clinical studies of GLA-SE adjuvant 
GLA-SE adjuvant has been used in a number of protein vaccines for phase 1 
human clinical studies (Table 4-4). 

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Table 4-4 Summary of selected clinical studies of GLA-SE adjuvant 
Study  
number 
[Reference] 
Products 
Type of 
study 
Subjects 
N 
Dose groups 
Route 
Schedule 
IDC 2008-001 
Fluzone® + 
GLA-SE 
Phase 1 
randomiz
ed 
Healthy 
adults (18 to 
45) and 
healthy 
elderly (65+) 
32 
adults, 
56 
elderly 
All groups received  
Fluzone + 
A: 0.5 mcg GLA-SE  
B: 1.0 mcg 
GLA-SE  
C: 2.5 mcg GLA-SE  
D: Fluzone alone  
E: SE 
IM 
Single dose 
PSC-22; 
NCT01147068 
(50) 
PanBlok® 
pandemic 
influenza 
vaccine, rHA 
A/Indonesia/
05/2005 
[H5N1] + 
GLA-SE 
Phase 1 
randomiz
ed 
placebo 
controlled 
Healthy 
adults 
392 
1: placebo  
2: PanBlok (135 mcg)  
3: PanBlok (45 mcg)  
4: PanBlok (45 mcg) +  
1.0 mcg GLA-SE 
5: PanBlok (15 mcg) +  
1.0 mcg GLA-SE  
6: PanBlok (7.5 mcg)+ 
1.0 mcg GLA-SE  
7: PanBlok (3.8 mcg)+ 
1.0 mcg GLA-SE  
IM 
Day 0, 21 
IDRI-LVVPX-
111 
Recombinant 
fusion 
antigen 
LEISH-F3 + 
GLA-SE 
Phase 1 
randomiz
ed 
Healthy 
adults 
18 
1: 20 mcg LEISH-F3+ 
2 mcg GLA-SE  
2: 20 mcg LEISH-F3+ 
5mcg GLA-SE  
3: 20 mcg LEISH-F3 
alone 
IM 
Day 0, 28, 56 
DMID 11-0031 
LEISH-F3 + 
GLA-SE or 
MPL-SE or 
SE 
Phase 1 
randomiz
ed open 
label 
Healthy 
adults 
48 
1: 20 mcg LEISH-F3+ 
5 mcg GLA-SE  
2: 20 mcg LEISH-F3+ 
10mcg MPL-SE  
3: 20 mcg LEISH-F3 + 
SE 
IM 
Day 0, 28, 
168 
NCT01154049 
(43) 
Schistosoma 
mansoni 
antigen 
Sm14 + 
GLA-SE 
Phase 1 
open label 
Healthy men 
20 
50 mcg LEISH-F3+ 
10mcg GLA-SE 
IM 
Day 0, 30, 60 
NCT01540474 
Recombinant  
malaria 
antigen 
FMP012 +  
GLA-SE 
Phase 1 
randomize
d 
Healthy adults 
30 
1: 10 mcg FMP012 +  
2 mcg GLA-SE 
2: 10 mcg FMP012 +  
5 mcg GLA-SE 
3: 50 mcg FMP012 +  
5 mcg GLA-SE 
IM 
1: Week 0, 
 4, 16  
2: Week 2, 
 6, 16 
3: Week 8, 
 12, 16 
NCT02115815 
(51) 
Soluble RSV 
fusion 
protein 
(sF) +  
GLA-SE 
Phase 1 
randomiz
ed 
Healthy 
adults 
> 60 
144 
1: 20 mcg RSV sF  
2: 50 mcg RSV sF 
3: 80 mcg RSV sF 
4: 20 mcg RSV sF +  
2.5 mcg GLA-SE 
5: 50 mcg RSV sF +  
2.5 mcg GLA-SE 
6: 80 mcg RSV sF+  
2.5 mcg GLA-SE 
7: placebo 
IM 
Single dose 
The GLA/SE formulated with either recombinant influenza H5 hemagglutinin 
(HA) or the influenza split-virus vaccines containing A/Solomon Islands/3/2006 
(HIN1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 were well 

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tolerated, safe, and immunogenic in healthy adults, and GLA-SE substantially 
improved the serum antibody responses (41, 50). In the study of GLA-SE with 
soluble RSV fusion protein (sF), immune responses were RSV sF dose-dependent 
and increased in the presence of adjuvant (51). 
In IDC 2008-001, GLA-SE at 5 mcg was associated with fever and chills and 
subsequent doses were reduced. GLA-SE significantly increased influenza-
specific antibody responses to Fluzone® and PanBlok® antigens, and had a dose-
sparing effect. Please refer to the IB for additional information including 
numerous clinical studies. Overall, the study injections have been generally well 
tolerated with an acceptable safety profile, at the proposed dose of 5 mcg. There 
have been no serious adverse events related to study injection. Injection site 
reactions are common and may include pain, tenderness, erythema, and 
induration. Systemic reactions may include headache, fatigue, anorexia, fever, 
chills, myalgia, and arthralgia. Transient elevations in CRP levels were noted in 
one study. Hematologic changes may occur (including decreases in hemoglobin, 
WBC, and neutrophils). These reactions varied from study to study, were 
generally mild, resolved quickly, and are typical of vaccinations by the IM route. 
4.9 
Potential risks of study products and administration 
Table 4-5 Summary of potential risks of study products and administration 
Common 
 
Mild to moderate injection site pain, tenderness, erythema, or 
swelling/induration/edema 
 
Malaise/fatigue, myalgia, or headache in the first few days following 
injection 
 
Localized skin erythema 
 
“Recall reactions” (Type IV Delayed-type hypersensitivity) at sites of 
previous vaccine administration 
 
A vaccine-induced positive HIV antibody test result 
Less common 
 
Severe injection site pain or tenderness 
 
Fever, chills, flu-like syndrome, arthralgia, rash, nausea, or dizziness in the 
first few days following injection  
 
Vasovagal reaction/lightheadedness/dizziness related to the injection 
procedure 
 
Decreased appetite (anorexia) 
 
Transient changes in clinical laboratory values 
 
Injection site hematoma, bruising/ecchymosis, other transient lesions, 
itching, or bleeding related to the injection procedure 
Uncommon or rare 
 
Severe localized injection site reaction, such as sterile abscess or secondary 
bacterial infection  
 
Allergic reaction, including rash, urticaria, angioedema, bronchospasm, or 
anaphylaxis 
 
Muscle damage at the injection site 
Unknown frequency 
 
Autoimmune disease, vasculitis 
Theoretical risks 
 
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 Env (A,B,C,A/E)/Gag (C)-expressing 
DNA plasmids and recombinant gp120 (A,B,C,A/E) protein/GLA-SE adjuvant, 
given individually, in combination, or as a prime-boost series in healthy HIV-1 
uninfected adults 
Primary endpoints 1: 
 Frequency and severity of local injection site (including DTH) and systemic 
reactogenicity signs and symptoms, Adverse Events (AE) categorized by 
MedDRA system organ class, MedDRA preferred term, severity, and assessed 
relationship to study products; detailed description of all AEs meeting DAIDS 
criteria for expedited reporting by treatment arm throughout the trial 
 The distribution of values of safety laboratory measures: white blood cells, 
neutrophils, lymphocytes, hemoglobin, alkaline phosphatase, platelets, ALT, 
AST, and creatinine at baseline and at follow-up visits post vaccination 
 Number of participants with early discontinuation of vaccinations and reason 
for discontinuation 
5.2 
Secondary objectives and endpoints 
Secondary objective 1: 
To evaluate the serum IgG binding antibody responses to Env proteins elicited by 
each vaccination regimen 
Secondary endpoint 1: 
Magnitude and breadth of serum HIV-1 Env-specific IgG responses assessed by 
Binding Antibody Multiplex Assay two weeks after the last vaccination  
Secondary objective 2: 
To evaluate the serum neutralizing antibody responses elicited by each 
vaccination regimen in Part B 
 
 

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Secondary endpoint 2: 
Serum neutralizing antibody responses against Tier 1A, Tier 1B, and selected Tier 
2 viruses, assessed by TZM-bl assay, two weeks after the last vaccination in Part 
B 
Secondary objective 3: 
To evaluate each vaccination regimen with specific antibody assays to measure 
correlates of risk identified in the RV144 trial 
Secondary endpoint 3: 
Breadth of gp70-V1V2 IgG and gp120 IgA, assessed by Binding Antibody 
Multiplex Assay, and ADCC activities against HIV-1 subtypes A, B, C and A/E 
two weeks after the last vaccination in Part B 
Secondary objective 4: 
To evaluate HIV-specific T-cell responses elicited by each vaccination regimen 
Secondary endpoint 4: 
Frequency, magnitudes and quality of HIV-1 specific CD4+ and CD8+ T-cell 
responses as measured by ICS two weeks after the last vaccination  
5.3 
Exploratory objectives 
Exploratory objective 1: 
To evaluate serum IgG3 binding antibody responses to Env proteins 2 weeks after 
the third, fourth and fifth vaccinations and six months after the fifth vaccination in 
Part B 
Exploratory objective 2: 
To evaluate HIV-1 Env-specific B-cell responses elicited after the last vaccination 
in Part B 
Exploratory objective 3: 
To determine the frequency of circulating Tfh and plasmablasts in response to 
each vaccination regimen 
Exploratory objective 4: 
To assess the elicitation of mucosal immune responses in saliva, semen (men), 
cervicovaginal fluid (women), and rectal fluid 

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Exploratory objective 5: 
To assess whether the diversity of gut microbiome correlates with vaccine 
responses using optionally provided stool specimens 
Exploratory objective 6: 
To assess the effects of BMI on the safety and immunogenicity of the vaccine 
regimens 
Exploratory objective 7: 
To further evaluate immunogenicity of each vaccine regimen, additional 
immunogenicity assays may be performed, including on samples from other 
timepoints, based on the HVTN Laboratory Assay Algorithm 

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6 
Statistical considerations 
6.1 
Accrual and sample size calculations 
Recruitment will target enrolling 60 healthy, HIV-uninfected adult participants. 
The protocol is composed of two parts, Part A and Part B. Part A will assess the 
safety of recombinant gp120 (A, B, C, A/E) protein/GLA-SE adjuvant. Part B will 
evaluate the safety and immunogenicity of DNA prime and protein/adjuvant boost 
or DNA and protein/adjuvant co-administered. Part A will proceed prior to Part B. 
In Part A, 12 participants will be enrolled and randomized to receive either the 
protein or a placebo with a 5:1 ratio. In Part B, 48 participants will be enrolled 
into Group 2 and Group 3 with a 1:1 ratio. Within each group, the participants 
will be randomized to receive either the vaccine (DNA prime and 
protein/adjuvant boost in Group 2 and DNA+protein/adjuvant co-administered in 
Group 3) or a placebo with a vaccine:placebo ratio of 7:1. Therefore, in Group 2, 
21 participants will receive the DNA prime and protein/adjuvant boost and 3 will 
receive the placebo; in Group 3, 21 participants will receive the DNA and 
protein/adjuvant co-administered and 3 participants will receive the placebo. 
To ensure that both men and women will be adequately represented in the trial, 
the trial will attempt to enroll approximately 40% to 60% of each sex assigned at 
birth overall in each Part. Hence, at least 5 participants in Part A and 19 
participants in Part B of each sex will be enrolled. 
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, or 
low cell viability of processed peripheral blood mononuclear cells (PBMCs). 
Immunogenicity data from nine phase 1 and one phase 2a HVTN vaccine trials, 
which began enrolling after June 2005 (data as of September 2014), indicate that 
10% is a reasonable estimate for the rate of missing data at early timepoints (≤6 
months) and 15% for later timepoints (>6 months). For this reason, the sample 
size calculations in Section 6.1.1 account for 15% enrolled participants 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. The ability of the study to detect serious 
adverse events (SAEs) (see Section 11) can be expressed by the true event rate 
above which at least 1 SAE would likely be observed and the true event rate 
below which no events would likely be observed. Specifically, for the vaccine 
arm (n =10) in Part A, there is a 90% chance of observing at least 1 event if the 
true rate of such an event is 20.6% or more; and there is a 90% chance of 
observing no events if the true rate is 1% or less. For each vaccine arm (n =21) in 

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Part B, there is a 90% chance of observing at least 1 event if the true rate of such 
an event is 10.4% or more; and there is a 90% chance of observing no events if 
the true rate is 0.5% or less. For the vaccine arms combined from Part B (n=42), 
there is a 90% chance of observing at least 1 event if the true rate of such an event 
is 5.4% 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. 
Binomial probabilities of observing 0, 1 or more, and 2 or more events for the arm 
of size 10 in Part A, an arm of size 21 in Part B, and for the combined vaccine 
arms in Part B of size 42 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 the 
vaccine. 
Table 6-1 Probability of observing 0, 1 or more, and 2 or more events, for an arm (or 
combined arms) of size n=10, 21, and 42, for a range of possible adverse event rates 
True event 
rate (%) Pr(0/10) Pr(1+/10) Pr(2+/10) Pr(0/21) Pr(1+/21) Pr(2+/21) Pr(0/42) Pr(1+/42) Pr(2+/42) 
1 
90.4 
9.6 
0.4 
81 
19 
1.9 
65.6 
34.4 
6.6 
4 
66.5 
33.5 
5.8 
42.4 
57.6 
20.4 
18 
82 
50.5 
10 
34.9 
65.1 
26.4 
10.9 
89.1 
63.5 
1.2 
98.8 
93.2 
20 
10.7 
89.3 
62.4 
0.9 
99.1 
94.2 
<0.001 
>99.9 
99.9 
30 
2.8 
97.2 
85.1 
0.1 
99.9 
99.4 
<0.001 
>99.9 
>99.9 
40 
0.6 
99.4 
95.4 
<0.001 
>99.9 
>99.9 
<0.001 
>99.9 
>99.9 
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 (52). If none of the 42 participants receiving a 
vaccine regimen in Part B experience a safety event, 95% 2-sided upper 
confidence bound for the true rate of such events in the total vaccinated 
population is 8.4%. For each individual vaccine arm in Part B (n=21), the 2-sided 
95% upper confidence bound for this rate is 15.5%. For the protein only arm in 
Part A (n=10), the 2-sided upper confidence bound for this rate is 27.8%. 
Table 6-2 Two-sided 95% confidence intervals based on observing a particular rate of safety 
endpoints for arms of size 10, 21, and 42 
Observed event 
rate 
Confidence interval (
%) 
0/10 
[0, 27.8] 
1/10 
[1.8, 40.4] 
2/10 
[5.7, 51] 
 
 
0/21 
[0, 15.5] 
1/21 
[0.8, 22.7] 

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2/21 
[2.7, 28.9] 
 
 
0/42 
[0, 8.4] 
1/42 
[0.4, 12.3] 
2/42 
[1.3, 15.8] 
6.1.2 
Sample size calculations for immunogenicity 
The main goal of this trial regarding immunogenicity outcomes involves studying 
frequency, magnitude and breadth of IgG and IgA binding antibodies (measured 
by BAMA) and neutralizing antibodies (nAb) to various Env antigens, as well as 
studying frequency, magnitude, and quality of CD4 and CD8 T cell responses 
measured by intracellular cytokine staining. We consider statistical power and 
precision for studying the first aspect of this goal− immune response rate 
frequency to a given Env antigen or peptide pool in vaccinees in each Group in 
Part B. No adjustment for multiple comparisons will be made for the use of 
multiple assays. The precision with which the true response rate can be estimated 
from the observed data depends on the true underlying response rate and the 
sample size. Two-sided 95% confidence intervals for the response rate based on 
observing a particular rate of responses in the vaccinees is shown in Table 6-3. 
Calculations are done using the score test method (52). The n = 18 in each arm in 
Part B assumes a 15% of missing immunogenicity data. 
Table 6-3 Two-sided 95% confidence intervals for the true response rate based on observing 
a particular rate of responses in the vaccinees in each vaccine arm (n =18) 
No. of responses 
Observed response rate (%) 
95% Confidence interval 
9/18 
50 
[29, 71] 
11/18 
61.1 
[38.6, 79.7] 
13/18 
72.2 
[49.1, 87.5] 
14/18 
77.8 
[54.8, 91] 
16/18 
88.9 
[67.2, 96.9] 
As shown in Table 6-4, there is a limited power for a formal comparison of 
immunogenicity response rates between vaccine arms of size n = 18. For either 
80% or 90% power, the sizes of differences that the trial is powered to detect are 
fairly large. These calculations use a Fisher’s exact 2-sided test with a Type I 
error rate of 0.05. 

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Table 6-4 Power for comparison of response rates between 2 vaccine arms of size 18 in 
each arm (n1=18, n2=18) 
 
 
Minimum true response rate in Arm 2 (%) 
in order to detect the difference with 
True response rate in Arm 1 (%) 
 
80% power 
 
90% power 
10 
 
58 
 
65 
20 
 
71 
 
77 
30 
 
81 
 
87 
40 
 
89 
 
94 
50 
 
95 
 
99 
An alternative to formal superiority comparisons of arms is to rank the arms by 
their response rates. For arms of size 18 with assuming 15% missing 
immunogenicity data, we can assess the reliability of this study to select the best 
arm with respect to the magnitude of response rates. For a single assay, Table 6-5, 
shows for arms of size 18 various true response rates for which this study will 
correctly select the arm with the highest response rate with 0.8 or 0.9 
probabilities. Each line in the table shows the results based on 40,000 simulated 
datasets of response rates for 2 arms of size 18 generated using 2 different 
binomial probabilities, with the best response probability used to generate data for 
one arm and the second best response probability used to generate data for the 
remaining 1 arm (53). If the difference in response between the best and second 
best arms is smaller than the assumed difference, the chance of correctly selecting 
the arm with the true highest response rate will be less than 80% (90%). 
Table 6-5 True immunogenicity response rates for which the regimen with the highest 
response probability will be correctly selected with 0.8 (0.9 probability) among the 2 vaccine 
arms of size (n1=18, n2=18) 
Second best response 
probability 
Best response probability 
Difference 
10% 
21% (26%) 
11% (16%) 
20% 
32% (39%) 
12% (19%) 
30% 
44% (52%) 
14% (22%) 
40% 
54% (62%) 
14% (22%) 
50% 
64% (71%) 
14% (21%) 
60% 
73% (80%) 
13% (20%) 
70% 
83% (88%) 
13% (18%) 
80% 
91% (94%) 
11% (14%) 
90% 
98% (100%) 
8% (10%) 
 
 
 
Response magnitudes between arms will be compared among the positive 
responders when the response rates between the two arms are similar. Table 6-6 
shows the minimum detectable difference in mean (or geometric mean for the 
log10-transformed) response magnitudes between the two arms of size 18 for 80% 
and 90% power based on an exact Wilcoxon test with a Type 1 error rate of 0.05, 
given each common true response rate. The calculations assume that the 
immunogenicity magnitudes (or after log10 transformation) are normally 
distributed with a common standard deviation in both groups. 

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Table 6-6 Minimum detectable difference in mean (or geometric mean for log10 -transformed) 
response magnitudes between two arms of size 18 (n1=18, n2=18), when response rates are 
similar 
 
Minimum detectable difference in mean 
(or geometric mean in log10) response 
magnitude relative to standard deviation 
 
Common true response rate 
(%) 
Power=80% 
Power=90% 
50 
1.6 
1.8 
60 
1.5 
1.8 
70 
1.4 
1.6 
80 
1.3 
1.4 
90 
1.2 
1.3 
100 
1.1 
1.3 
6.2 
Randomization 
A participant’s randomization assignment will be computer generated and 
provided to the HVTN CRS pharmacist through a Web-based randomization 
system. The randomization will be done in blocks to ensure balance across arms 
in Part A and in each Group in Part B. The randomization will be stratified by 
gender. At each institution, the pharmacist with primary responsibility for 
dispensing study products is charged with maintaining security of the treatment 
assignments (except in emergency situations as specified in the HVTN MOP). 
6.3 
Blinding 
Participants and site staff (except for site pharmacists) will be blinded as to 
participant treatment arm assignments (eg, vaccine or placebo). Study product 
assignments are accessible to those HVTN CRS pharmacists, DAIDS protocol 
pharmacists and contract monitors, and SDMC staff who are required to know 
this information in order to ensure proper trial conduct. Any discussion of study 
product assignment between pharmacy staff and any other HVTN CRS staff is 
prohibited. The HVTN SMB members also are unblinded to treatment assignment 
in order to conduct review of trial safety.  
Part A will be unblinded independently of Part B. Unblinding need not await 
completion of health contacts, which are not considered part of the “main study.” 
When a participant leaves the trial prior to study completion, the participant will 
be told he or she must wait until all participants in that part of the study (A or B) 
are unblinded to learn his or her treatment assignment.  
Emergency unblinding decisions will be made by the site investigator. If time 
permits, the HVTN 124 PSRT should be consulted before emergency unblinding 
occurs. 

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6.4 
Statistical analyses 
This section describes the final study analyses, unblinded as to treatment arm 
assignment. All data from enrolled participants will be analyzed according to the 
initial randomization assignment regardless of how many vaccinations they 
received. 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 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, as discussed below, when the assay endpoint is viewed as a collection of 
hypotheses (eg, testing multiple peptide pools to determine a positive response). 
6.4.1 
Analysis variables 
The analysis variables consist of baseline participant characteristics, safety, and 
immunogenicity for primary- and secondary-objective analyses. 
6.4.2 
Baseline comparability 
Treatment arms will be compared for baseline participant characteristics using 
descriptive statistics. 
6.4.3 
Safety/tolerability analysis 
Since enrollment is concurrent with receiving the first vaccination, all participants 
will have received at least 1 vaccination and therefore will provide some safety 
data. 
6.4.3.1 
Reactogenicity 
The number and percentage of participants experiencing each type of 
reactogenicity sign or symptom will be tabulated by severity and treatment arm 
and the percentages displayed graphically by arm. For a given sign or symptom, 
each participant’s reactogenicity will be counted once under the maximum 
severity for all injection visits. In addition, to the individual types of events, the 
maximum severity of local pain or tenderness, induration or erythema, and of 
systemic symptoms will be calculated. Wilcoxon rank sum tests will be used to 
test for differences in severity between arms. 

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6.4.3.2 
AEs and SAEs 
AEs will be summarized using MedDRA System Organ Class and preferred 
terms. Tables will show by treatment arm 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 arms 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 autoimmune 
disorders; a sample list of AESI is provided in Appendix L. 
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 arm 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 arm and timepoint, as well as changes from baseline for postenrollment 
values. In addition, the number (percentage) of participants with local laboratory 
values recorded as meeting Grade 1 AE criteria or above as specified in the 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (see section 9.11) will be tabulated by treatment arm for each 
postvaccination timepoint. Reportable clinical laboratory abnormalities without an 
associated clinical diagnosis will also be included in the tabulation of AEs 
described above. 
6.4.3.4 
Reasons for vaccination discontinuation and early study termination 
The number and percentage of participants who discontinue vaccination and who 
terminate the study early will be tabulated by reason and treatment arm. 
6.4.4 
Immunogenicity analysis 
6.4.4.1 
General approach 
For the statistical analysis of immunogenicity endpoints, data from enrolled 
participants will be used according to the initial randomization assignment 
regardless of how many injections they received. Additional analyses may be 
performed, limited to participants who received all scheduled injections per 

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protocol. Assay results that are unreliable, from specimens collected outside of 
the visit window, or from HIV-infected participants post infection are excluded. 
Since the exact date of HIV infection is unknown, any assay data from blood 
draws 4 weeks prior to an infected participant’s last seronegative sample and 
thereafter may be excluded. If an HIV-infected participant does not have a 
seronegative sample post enrollment, then all data from that participant may be 
excluded from the analysis. 
Discrete categorical assay endpoints (eg, response rates) will be analyzed by 
tabulating the frequency of positive response for each assay by antigen and 
treatment arm at each timepoint for which an assessment is performed. Crude 
response rates will be presented with their corresponding 95% confidence interval 
estimates calculated using the score test method (52). Because of the small 
numbers of control participants in each group, no adjustment will be made to the 
vaccine arm estimates for the false positive rates in the control arms. Barnard or 
Fisher’s exact tests, as specified in the SAP, will be used to compare the response 
rates of any 2 vaccine arms, with a significant difference declared if the 2-sided p-
value is ≤ 0.05. In general Barnard’s is preferred since under most circumstances 
it is more powerful than Fisher’s (54).  
In addition to response rate estimates for each timepoint, the probability of 
observing at least 1 positive response by a given timepoint and the probability of 
observing more than 1 positive response by a given timepoint will be estimated, 
with corresponding confidence intervals, for each vaccine arm using maximum 
likelihood-based methods (55). 
For quantitative assay data (eg, IgG binding Ab response from BAMA or 
percentage of positive cells from the ICS assay), graphical and tabular summaries 
of the distributions by antigen, treatment arm, and timepoint will be made. For all 
primary and secondary immunogenicity endpoints, box plots and plots of 
estimated reverse cumulative distribution curves will be used for graphical display 
of all of the study arms. Typically the results will be shown for each vaccine arm 
and for the set of placebo arms pooled into one group.  
The difference between arms at a specific timepoint will be tested 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. 
Some immunologic assays have underlying continuous or count-type readout that 
are dichotomized into responder/nonresponder categories (eg, ICS). If treatment 
arm differences for these assays are best summarized by a mixture model, then 
either Lachenbruch’s test statistic (56) or an alternative two-part test (57) (as 
defined in the SAP) will be used to evaluate the composite null hypothesis of 
equal response rates in the 2 arms and equal response distributions. 
Lachenbruch’s 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, 

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differences in response rates between arms will be estimated using the methods 
described above, and in the subgroup of positive responders, differences in 
location parameters between arms will be estimated using the methods described 
above.  
More sophisticated analyses employing repeated measures methodology (for 
example, linear mixed models or marginal mean models fit by generalized 
estimating equations) may be utilized to incorporate immune responses over 
several timepoints and to test for differences over time. However, inference from 
such analyses would be limited by the small sample size of this study. All 
statistical tests will be 2-sided and will be considered statistically significant if 
p  0.05. 
Based upon previous HVTN trials, missing 10-15% 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 
peripheral blood mononuclear cells (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 and hypothesis tests.  
If a substantial amount of immunogenicity data are missing for an endpoint (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 (58) will be used, 
because they accommodate the censoring. In addition, secondary analyses of 
repeated immunogenicity measurements may be done using weighted GEE (59) 
methods, which are valid under MAR. All of the models described above in this 
paragraph will include as covariates all available baseline predictors of the 
missing outcomes.  

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6.4.4.2 
Multivariate display of immunogenicity endpoints 
Data visualization techniques may be used to explore the relationship among 
immunogenicity readouts. The set of readouts may be based on one of the primary 
endpoints (eg, ICS), on the set of primary endpoints, or on immunogenicity 
endpoints that also include secondary or exploratory endpoints. To understand the 
relationship between pairs of readouts, scatter plots may be used when the number 
of readouts is small or for a larger number of readouts, a heat map showing the 
degree of correlation between any two pairs. Principal component analysis (PCA) 
and associated ‘biplots’ of the scores and loadings are particularly useful to 
understand associations between readouts, especially when readouts are correlated 
(60). PCA is a method to reduce the dimensionality of the number of readouts to a 
smaller set of values (principal components) that are normalized linear 
combinations of the readouts in such a way that the first principal component 
accounts for the most variability in the data and subsequent components, while 
maximizing variability, are uncorrelated with each other. A ‘biplot’ displays the 
first and second principal component scores and principal component loadings. 
The x-axis is the value from the first principal component and the y-axis is the 
second principal component, where each axis label includes the percentage of 
variation in the total set of readouts captured by the principal component. The top 
axis is the first principal component loadings and the right axis is the second 
principal component loadings. An arrow is drawn for each immunogenicity 
readout (eg, Env-specific CD4+ T cell polyfunctionality score, Env-specific 
CD8+ T cell total magnitude) from the origin to the point defined by its first two 
principal component loadings. The length of the arrow represents the amount of 
total variation of the set of readouts captured by the given readout. The direction 
of an arrow conveys the extent to which the variation of a readout is in the 
direction of the first or second principal component. The angle between two 
arrows conveys information about the correlation of the two readouts, with a zero 
degree angle denoting perfect correlation and a 90 degree angle denoting no 
correlation. Each arrow on the biplot is labeled by the immunogenicity readout it 
represents. A biplot is annotated with key meta-information such as the treatment 
arm (most common application) or a demographic category. Depending on the 
application, K-means clustering and hierarchical clustering may also be applied 
for multivariate graphical display of immunogenicity readouts. 
6.4.4.3 
Primary analyses of neutralization magnitude-breadth curves 
Separate analyses of magnitude-breadth of neutralization will be conducted for 
the Tier 1B isolate panel and for the Tier 2 isolate panel, for all analyses whether 
primary, secondary, or exploratory. 
For each panel, individual magnitude-breadth curves will be plotted by vaccine 
arm and pooled placebo, with average magnitude-breadth curves overlaid on the 
plots. For each panel, the area-under-the-magnitude-breadth curve (AUC-MB) 
(61) will be computed for each participant, as described in (62). Dunnett’s 
procedure will be applied with 2-sided alpha = 0.05 to determine which of the two 
vaccine arms have a significantly higher mean AUC-MB than that of the pooled 

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placebo groups, as described in (63) (see their formula (1.1)). This procedure will 
be applied to construct 95% CIs about the 2 differences in mean AUC-MB for 
each vaccine regimen versus the pooled placebos (vaccine – placebo), which 
simultaneously have at least 95% coverage probability.  
The vaccine regimens will be ranked by the estimated mean of the AUC-MB 
curves. The vaccine regimen with the highest estimated mean will be selected as 
the best regimen. 
6.4.4.4 
Secondary analyses of neutralization magnitude-breadth curves 
Superiority comparisons of vaccine regimens 
Simultaneous 95% CIs about the mean-differences in AUC-MBs for each vaccine 
regimen versus pooled placebo will be reported. These CIs are computed as the 
estimated mean-difference plus or minus tN-2,025 multiplied by the square-root of 
S2 (1/n1 + 1/n2), where tN-2,025 is the 97.5th percentile of a t-distribution with N – 2 
degrees of freedom, where N is the total number of vaccine recipients evaluated 
(summing over the two vaccine regimens). In addition, S2 is an estimate of the 
common sample variance of the AUC-MB, whereas n1 and n2 are the sample sizes 
of evaluable participants for vaccine regimens 1 and 2 being compared. If the 
95% CI comparing the two vaccine arms excludes zero then the two vaccine arms 
have a significant difference bounding the false positive rate at 5%. Nominal 
(unadjusted) 95% CIs comparing the vaccine arms will also be reported. 
Omnibus comparison of magnitude-breadth distributions 
The analyses of magnitude-breadth described above are based on the endpoint 
area-under-the-curve, which is interpreted as the average log10 IC50 to the set of 
isolates in the test panel. Use of this endpoint is maximally statistically powerful 
if 1 vaccine arm has greater magnitude and breadth than the comparator vaccine 
arm, but may miss an effect wherein 1 vaccine arm has greater magnitude and the 
comparator vaccine arm has greater breadth. Therefore, a secondary analysis may 
compare the distribution of magnitude-breadth curves among vaccine arms using 
the test statistic max|BdG| from Huang, et al (62) (see page 85), which is designed 
to detect general differences in magnitude-breadth curve distributions.  
Selecting the best vaccine regimen 
The best vaccine regimen will be deemed as that with the greatest value of the 
max|BdG| test statistic comparing its distribution of magnitude-breadth curves 
versus the pooled placebo group.  
Superiority comparisons of vaccine regimens 
Similarly, the max|BdG| test statistic will be used to compare the distribution of 
magnitude-breadth curves between the two vaccine regimens. Nominal 
(unadjusted) 95% CIs comparing the two vaccine arms will also be reported. 

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6.4.4.5 
Analyses of IgG binding antibody magnitude and breadth 
Secondary objectives 1 and 3 include the analysis of magnitude and breadth of 
IgG to panels of Env antigens. For each panel of Envs, the same statistical 
methods described above for assessing magnitude and breadth of neutralization 
responses will be used. 
6.4.4.6 
Analysis of CD4+ and CD8+ T-cell response as measured by the ICS 
assay  
The analysis of CD4+ and CD8+ T-cell response rates as measured by the ICS 
assay will be evaluated and compared as described under the general approach. 
For each T-cell subset, the positivity call for each peptide pool will include a 
multiple comparison adjustment for the number of peptide pools used in the 
assay. In general, the Mixture Models for Single-cell Assays (MIMOSA) 
statistical framework (64) and/or the Fisher’s exact test-based positivity criteria 
will be used. Details of the positivity criteria will be discussed in the SAP. The 
magnitude of marginal response will be analyzed as described for quantitative 
data in the general approach section. For each T-cell subset, graphs will be used to 
display the background-subtracted magnitudes for each participant by protein, 
treatment arm and timepoint. When 3 or more cytokines are being measured by 
the ICS assay, the polyfunctionality of ICS responses may also be analyzed as an 
exploratory endpoint. Besides descriptive plots of the magnitude of polyfunctional 
responses, the COMPASS (Combinatorial Polyfunctionality analysis of Antigen-
Specific T-cell Subsets) statistical framework (65) may also be used to perform 
joint modelling of multiple T-cell subsets of different cytokine combinations. For 
example, the functionality score (FS) and the polyfunctionality score (PFS) may 
be used to summarize the multi-parameter ICS responses.  
6.4.4.7 
Analysis of epitope mapping data 
The minimal set of optimal length epitopes that can explain the observed T cells 
responses to a set of individually tested overlapping 15mer peptides may be 
obtained to assess the breadth and depth of the T cell responses based on the 
epitope mapping data. When HLA data are also available, computational 
HLA:peptide binding predictors (eg, NetMHCpan) may be used to more 
accurately identify each participant’s T-cell epitopes. 
Once estimates of breadth (number of epitopes) are determined for each 
participant by the above method or other methods, the distribution of participants 
with different numbers of total or antigen-specific reactive epitopes may be used 
to summarize the epitope mapping-based breadth data for each vaccine regimen. 
Poisson regression models with robust covariance (“sandwich”) estimators or 
other count data analysis methods may be used to compare epitope breadth 
between vaccine regimens. Zero-inflated models may also be considered if there 
is interest in differentiating true zero breadth (ie, zero epitope recognized) and 
excess zeros (ie, no epitope mapping data due to negative T-cell response) in the 
data.  

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The set of epitopes may also be used to assess “coverage” of a representative set 
of circulating viruses by each participant’s set of T-cell responses. The coverage 
provided by each epitope is defined by the fraction of viruses that match the 
sequence of the mapped epitope. The coverage provided by a participant’s set of 
epitopes is defined by the fraction of viruses covered by at least one of the 
participant’s epitopes.  
6.4.4.8 
Analysis of multiplexed immunoassay data 
When a small panel of analytes (eg, ≤5) is being assessed in a multiplexed 
immunoassay, the analysis of response rates and response magnitudes will be 
evaluated and compared as described under the general approach. Details for 
calculating a positive response and response magnitude will be provided in the 
SAP. When a larger panel is being assessed, two approaches may be considered to 
evaluate the magnitude and breadth of these responses. First, Magnitude–Breadth 
(M-B) curves maybe employed to display individual- and group-level response 
breadth as a function of magnitude. Two choices are to compare the M-B curves 
among vaccine arms, as follows: a non-parametric Wilcoxon rank sum test on the 
subject-specific area-under-the M-B curve (AUC M-B) or a Kolmogorov-
Smirnov type test on the 2 group-average M-B curves. Simulations can be used to 
obtain 2-sided p-values for the latter test. Second, a weighted-average score-like 
variable may be constructed to account for the correlations between analytes as an 
integrate magnitude of responses to multiple analytes. Similar group comparison 
methods described in the first approach may be adopted. Details of either 
approach will be described in the SAP.  
6.4.5 
Exploratory analyses of binding IgG antibodies including the Month 
3.5 and Month 14 timepoints 
To assess Exploratory objective 1, for each participant with IgG binding antibody 
data measured at the Month 3.5, 8.5, and 14 timepoints, the Scaled area-under-the 
(time) curve will be calculated based on linear segments between Month 0 and 
3.5, 3.5 and 8.5, and 8.5 and 14, divided by 14 months. The individual participant 
IgG curves over time will be plotted stratified by vaccine arm and for the pooled 
placebo group, together with estimates of the mean at each of the three timepoints 
with a 95% confidence interval (based on sample averages and a t-statistic based 
confidence interval). Moreover, a two-sample t-test with unequal variances will 
be used to test whether the mean Scaled AUC differs between the two vaccine 
regimens, and correspondingly a t-statistic based 95% confidence interval about 
the mean vaccine arm difference in Scaled AUC will be reported. 
6.4.6 
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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6.4.6.1 
Safety 
During the course of the trial, unblinded analyses of safety data will be prepared 
approximately every 4 months during the main study, as defined in Section 3, for 
review by the SMB. Ad hoc safety reports may also be prepared for SMB review 
at the request of the HVTN 124 PSRT. The HVTN leadership must approve any 
other requests for unblinded safety data prior to the end of the scheduled follow-
up visits. 
6.4.6.2 
Immunogenicity 
An unblinded statistical analysis by treatment assignment of a primary 
immunogenicity endpoint may be performed when all participants have 
completed the corresponding primary immunogenicity visit and data are available 
for analysis from at least 80% of these participants. Similarly, an unblinded 
statistical analysis by treatment assignment of a secondary or exploratory 
immunogenicity endpoint may be performed when all participants have 
completed the corresponding immunogenicity visit and data are available for 
analysis from at least 80% of these participants. However, such analyses for a 
secondary or exploratory immunogenicity endpoint will only take place after at 
least one of the primary immunogenicity endpoints of the same class (humoral, 
cell-mediated, innate or mucosal) or, if no primary endpoint of the same class, at 
least one of the primary immunogenicity endpoints reaches the aforementioned 
threshold. 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. 
In the phase 1 clinical trial that tested the polyvalent DNA prime-protein boost 
DP6-001 HIV vaccine regimen, a high level of reactogenicity was observed, 
including injection site pain and erythema, fevers, myalgia, fatigue, headache, and 
arthralgias. There were also AEs of delayed type hypersensitivity (DTH) 
reactions, and one person each developed Henoch-Schonlein purpura and 
leukocytoclastic vasculitis. The causes of the DTH reactions and the vasculitis 
events, and their relationship to each other, if any, are not clear. The next 
generation regimen has undergone significant changes to further enhance the 
breadth of nAb responses by carefully selecting optimal gene inserts. 
Additionally, the adjuvant to be administered with the protein vaccine differs 
from that in the phase 1 trial of DP6-001. However, as a precaution, the exclusion 
for autoimmune diseases also excludes people with connective tissue disease, or a 
history of vasculitis, and urinalysis will be performed as part of the safety 
evaluation after each vaccination. 
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 50 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 

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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. Willing to be contacted 12 months after the last vaccination 
6. Agrees not to enroll in another study of an investigational research agent 
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.  
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. Low risk guidelines are found on 
the protocol web page under Study Materials on the HVTN Members' site 
(https://members.hvtn.org/protocols/hvtn124) 
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/mm3 to 450,000/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). 

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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 total hysterectomy or bilateral oophorectomy (verified 
by medical records), are not required to undergo pregnancy testing. 
22. Reproductive status: A volunteer who was born female must: 
 Agree to consistently use effective contraception (see Appendix A and 
Appendix B) for sexual activity that could lead to pregnancy from at least 21 
days prior to enrollment until after the last required protocol clinic visit. 
Effective contraception is defined as using the following methods: 
 Condoms (male or female) with or without a spermicide, 
 Diaphragm or cervical cap with spermicide, 
 Intrauterine device (IUD), 
 Hormonal contraception, or 
 Any other contraceptive method approved by the HVTN 124 PSRT 
 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 not be of reproductive potential, such as having reached menopause (no 
menses for 1 year) or having undergone hysterectomy, bilateral 
oophorectomy, or tubal ligation; 

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 Or be sexually abstinent. 
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 
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: age 
> 45, 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 124 study  
5. Pregnant or breastfeeding 
6.  Active duty and reserve US military personnel 
Vaccines and other Injections 
7. HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have 
received control/placebo in an HIV vaccine trial, the HVTN 124 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 by the HVTN 124 PSRT for vaccines that 
have subsequently undergone licensure by the FDA. For volunteers who have 
received control/placebo in an experimental vaccine trial, the HVTN 124 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 124 PSRT on a case-by-case basis. 
9. Live attenuated vaccines 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. 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) 

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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 prednisone or equivalent at doses < 60 
mg/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, connective tissue disease, or history of vasculitis, , eg, 
leukocytoclastic vasculitis, Henoch-Schonlein purpura 
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, 
 Any contraindication to repeated injections or blood draws, 
 A condition that requires active medical intervention or monitoring to avert 
grave danger to the volunteer’s health or well-being during the study period, 
 A condition or process for which signs or symptoms could be confused with 
reactions to vaccine, or 
 Any condition specifically listed among the exclusion criteria below. 

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19. Any medical, psychiatric, occupational, or other condition that, in the 
judgment of the investigator, would interfere with, or serve as a contraindication 
to, protocol adherence, assessment of safety or reactogenicity, or a volunteer’s 
ability to give informed consent 
20. Psychiatric condition that precludes compliance with the protocol. 
Specifically excluded are persons with psychoses within the past 3 years, ongoing 
risk for suicide, or history of suicide attempt or gesture within the past 3 years. 
21. Current anti-tuberculosis (TB) prophylaxis or therapy 
22. Asthma exclusion criteria: 
Asthma other than mild, well-controlled asthma. (Symptoms of asthma severity 
as defined in the most recent National Asthma Education and Prevention Program 
(NAEPP) Expert Panel report).  
 
Exclude a volunteer who: 
 Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or 
 Uses 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. 
 If a person has NOT been found to have elevated blood pressure or 
hypertension during screening or previously, exclude for systolic blood 

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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 three years. Also exclude if 
volunteer has used medications in order to prevent or treat seizure(s) at any time 
within the past 3 years. 
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 11.4. 
7.3.1 
Delaying vaccinations for a participant 
Under certain circumstances, a participant’s scheduled vaccination will be 
delayed. The factors to be considered in such a decision include but are not 
limited to the following: 
 Within 45 days prior to any study injection  
 Receipt of blood products or immunoglobulin 
 Within 30 days prior to any study injection 
 Receipt of live attenuated vaccines 
 Receipt of allergy treatment with antigen injections 
 Within 14 days prior to any study injection 
 Receipt of any vaccines that are not live attenuated vaccines (eg, 
pneumococcal)  
 Pre-vaccination abnormal vital signs or clinical symptoms that may mask 
assessment of vaccine reaction. 

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Vaccinations should not be administered outside the visit window period specified 
in the HVTN 124 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 2-week 
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 124 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 (regardless of outcome) 
 Any grade 4 local or systemic reactogenicity symptom, lab abnormality, or 
AE that is subsequently considered to be related to vaccination 
 Vasculitis, regardless of grade or relatedness 
 Any grade 3 lab abnormality or other clinical AE (exception: fever or 
vomiting and subjective local and systemic symptoms) that is 
subsequently considered to be related to vaccination; upon review, the 
PSRT may allow continuation of vaccination if the event is grade 3 
erythema and/or induration 
 Clinically significant type 1 hypersensitivity reaction associated with 
study vaccination. Consultation with the HVTN 124 PSRT is required 

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prior to subsequent vaccinations following any type 1 hypersensitivity 
reaction associated with study vaccination 
 DTH reaction at previous study agent injection sites 
 Investigator determination in consultation with Protocol Team leadership (eg, 
for repeated nonadherence to study staff instructions). 
 Participant misses more than 2 vaccinations(s) (see Section 7.3.2). 
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). 
 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 
Part A: 
Group 1 
Treatment 1 (T1):  
400 mcg Recombinant gp120 (A,B,C,A/E) admixed with GLA-SE, to be 
administered as a 1 mL (IM) injection in the deltoid of the non-dominant arm 
(unless medically contraindicated) at months 0 and 2. 
OR 
Control 1 (C1):  
Placebo for Recombinant gp120 (A,B,C,A/E) (labeled as Sodium Chloride for 
Injection, 0.9% USP) to be administered as a 1 mL (IM) injection in the deltoid of 
the non-dominant arm (unless medically contraindicated) at months 0 and 2. 
Part B: 
Group 2 
Treatment 2 (T2):  
2 mg Env (A,B,C,A/E) / Gag (C) DNA plasmids (labeled as PDPHV-201401 
Plasmid) to be administered as a 0.8 mL (IM) injection in the deltoid of the LEFT 
arm (unless medically contraindicated) at months 0, 1 and 3  
AND 
Placebo for Recombinant gp120 (A,B,C,A/E) (labeled as Sodium Chloride for 
Injection, 0.9% USP) to be administered as a 1 mL (IM) injection in the deltoid of 
the RIGHT arm (unless medically contraindicated) at months 0, 1 and 3. 
THEN 
Placebo for Env (A,B,C,A/E) / Gag (C) DNA plasmids (labeled as Sodium 
Chloride for Injection, 0.9% USP) to be administered as a 0.8 mL (IM) injection 

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in the deltoid of the LEFT arm (unless medically contraindicated) at months 6 and 
8 
AND  
400 mcg Recombinant gp120 (A,B,C,A/E) admixed with GLA-SE, to be 
administered as a 1 mL (IM) injection in the deltoid of the RIGHT arm (unless 
medically contraindicated) at months 6 and 8. 
OR 
Control 2 (C2):  
Placebo for Env (A,B,C,A/E) / Gag (C) DNA plasmids (labeled as Sodium 
Chloride for Injection, 0.9% USP) to be administered as a 0.8 mL (IM) injection 
in the deltoid of the LEFT arm (unless medically contraindicated) at months 0, 1, 
3, 6 and 8. 
AND  
Placebo for Recombinant gp120 (A,B,C,A/E) (labeled as Sodium Chloride for 
Injection, 0.9% USP) to be administered as a 1 mL (IM) injection in the deltoid of 
the RIGHT arm (unless medically contraindicated) at months 0, 1, 3, 6 and 8. 
Group 3 
Treatment 3 (T3):  
2 mg Env (A,B,C,A/E) / Gag (C) DNA plasmids (labeled as PDPHV-201401 
Plasmid) to be administered as a 0.8 mL (IM) injection in the deltoid of the LEFT 
arm (unless medically contraindicated) at months 0, 1, 3, 6 and 8. 
AND 
400 mcg Recombinant gp120 (A,B,C,A/E) admixed with GLA-SE, to be 
administered as a 1 mL (IM) injection in the deltoid of the RIGHT arm (unless 
medically contraindicated) at months 0, 1, 3, 6 and 8. 
OR 
Control 2 (C2):  
Placebo for Env (A,B,C,A/E) / Gag (C) DNA plasmids (labeled as Sodium 
Chloride for Injection, 0.9% USP) to be administered as a 0.8 mL (IM) injection 
in the deltoid of the LEFT arm (unless medically contraindicated) at months 0, 1, 
3, 6 and 8. 
AND  

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Placebo for Recombinant gp120 (A,B,C,A/E) (labeled as Sodium Chloride for 
Injection, 0.9% USP) to be administered as a 1 mL (IM) injection in the deltoid of 
the RIGHT arm (unless medically contraindicated) at months 0, 1, 3, 6 and 8. 
8.2 
Study product formulation 
8.2.1 
GLA-SE (glucopyranosyl lipid adjuvant-stable emulsion, labeled as 
AP 10-205) 
The GLA-SE (labeled as AP 10-205) adjuvant will be provided in 2 mL vials 
containing 6 mcg GLA in a 6% oil-in-water emulsion. Each sterile, single use vial 
contains 0.4 mL of product at a concentration of 15 mcg/mL. The product appears 
as a milky-white liquid. GLA-SE must be stored at 2-8°C and must not be frozen. 
The study product is described in further detail within the GLA-SE IB. 
8.2.2 
Env (A,B,C,A/E) / Gag (C) DNA plasmids 
The Polyvalent DNA (PDPHV-201401 Plasmid) vaccine will be supplied in 2 mL 
vials containing 1 mL polyvalent DNA vaccine at a concentration of 2.5 mg/mL. 
The product must be stored at ≤ -60°C. (See study product IB for detailed vaccine 
components.) 
8.2.3 
Recombinant gp120 proteins (A, B, C & A/E) 
Each gp120 protein (PDPHV-201401 Recombinant Proteins gp120A, gp120B, 
gp120C, gp120AE) will be supplied as individual vials each containing 0.3 mg 
gp120 protein in a total fill volume of 0.5 mL.  
The final concentration per each vial of protein is 0.6 mg/mL. The product must 
be stored at ≤ -60°C. (See study product IB for detailed vaccine components.) 
8.2.4 
Placebo for Recombinant gp120 proteins (A, B, C & A/E) and Env 
(A,B,C,A/E) / Gag (C) DNA plasmids 
Sodium Chloride for injection, 0.9% USP will be used as the placebo. It must be 
stored as recommended by the manufacturer. 
8.3 
Preparation of study products 
8.3.1 
Env (A,B,C,A/E) / Gag (C) DNA plasmids 
One vial of polyvalent DNA (PDPHV-201401 Plasmid) vaccine 2.5 mg/mL will 
be required to prepare the study dose. 
Prior to the preparation of the study dose, the pharmacist will remove one vial of 
polyvalent DNA vaccine from the freezer and allow to thaw completely at 
ambient room temperature. Preparation of the vaccine for injection can be 

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performed at the ambient temperature of the pharmacy, but the vaccine dose 
should be prepared and used within 2 hours of removing from storage at ≤ -60°C. 
Gently swirl and invert the vial for at least 10 inversions (do not shake 
vigorously). 
Using aseptic technique, withdraw 0.8 mL of polyvalent DNA vaccine into a 1 
mL syringe, remove the needle and cap syringe. 
The final syringe for administration must be covered with an overlay and then 
labeled as “Polyvalent DNA vaccine or Placebo”. The syringe must also be 
labeled for IM administration into the LEFT deltoid, with an expiration date and 
time of 2 hours. 
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. 
8.3.2 
Recombinant gp120 proteins (A, B, C & A/E) admixed with GLA-SE 
One vial of each gp120 protein (0.3 mg/0.5 mL) (4 vials total) and one vial of 
GLA-SE (6 mcg/0.4 mL) will be needed to prepare the study dose. 
Prior to the preparation of the study dose, the pharmacist will remove one vial 
each of the recombinant gp120 proteins (gp120A, gp120B, gp120C, gp120AE) 
from the freezer and allow to thaw completely at ambient room temperature. 
Preparation of the vaccine for injection can be performed at the ambient 
temperature of the pharmacy, but the vaccine dose should be prepared and used 
within 2 hours of removing from storage at ≤ -60°C. Gently swirl and invert each 
vial for at least 10 inversions (do not shake vigorously). The pharmacist will also 
remove one vial of GLA-SE from the refrigerator.  
Using aseptic technique, the pharmacist will withdraw 0.2 ml from each vial of 
gp120A, gp120B, gp120C, and gp120AE using a separate 1 mL syringe for each 
and inject them directly into the vial containing 0.4 mL GLA-SE. The pharmacist 
will then mix the vial containing the 1.2 mL mixture of gp120A, gp120B, 
gp120C, gp120AE, and GLA-SE. Gently swirl and invert the vial for at least 10 
inversions (do not shake vigorously).  
The pharmacist using aseptic technique will withdraw 1 mL of the polyvalent 
gp120 protein vaccine into a 3 mL syringe, remove the needle and cap the 
syringe. 
The final syringe for administration must be covered with an overlay and then 
labeled as “Polyvalent protein vaccine or Placebo”. For Group 1, the syringe must 
be labeled for IM administration into the deltoid of the non-dominant arm. For 
Groups 2 and 3, the syringe must be labeled for IM administration into the 
RIGHT deltoid. The syringe must also be labeled with an expiration date and time 
of 2 hours. 

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Any unused portion of vials or expired prefilled syringes should be disposed of in 
accordance with institutional or pharmacy policy. 
8.3.3 
Placebo for Env (A,B,C,A/E) / Gag (C) DNA plasmids 
The pharmacist using aseptic technique will withdraw 0.8 mL of Sodium Chloride 
for Injection, 0.9% USP into a 1 mL syringe, remove the needle and cap the 
syringe. 
The final syringe for administration must be covered with an overlay and then 
labeled as “Polyvalent DNA vaccine or Placebo”. The syringe must also be 
labeled for IM administration into the LEFT deltoid, with an expiration date and 
time of 2 hours following. 
Any unused portion of vials or expired prefilled syringes should be disposed of in 
accordance with institutional or pharmacy policy. 
8.3.4 
Placebo for Recombinant gp120 proteins (A, B, C & A/E) 
The pharmacist using aseptic technique will withdraw 1 mL of Sodium Chloride 
for Injection, 0.9% USP into a 3 mL syringe, remove the needle and cap the 
syringe. 
The final syringe for administration must be covered with an overlay and then 
labeled as “Polyvalent protein vaccine or Placebo”. For Group 1, the syringe must 
be labeled for IM administration into the deltoid of the non-dominant arm. For 
Groups 2 and 3, the syringe must be labeled for IM administration into the 
RIGHT deltoid. The syringe must also be labeled with an expiration date and time 
of 2 hours following. 
Any unused portion of vials or expired prefilled syringes should be disposed of in 
accordance with institutional or pharmacy policy. 
8.4 
Administration 
Administration of vaccine or placebo for Group 1 consists of 1 injection at each 
vaccination timepoint. Administration of vaccine or placebo for Groups 2 and 3 
consists of 2 vaccinations at each timepoint.  
All injections will be given by needle and syringe. Group 1 injections are given in 
the non-dominant deltoid, unless medically contraindicated. For Groups 2 and 3, 
Polyvalent DNA vaccine or placebo injection will be given in the LEFT deltoid, 
and Polyvalent protein vaccine or placebo will be given in the RIGHT deltoid, 
unless medically contraindicated. 
If an injection is administered in the contralateral deltoid due to a medical 
contraindication, the appropriate study staff should document this clearly. Under 
this circumstance, this is NOT a protocol violation. 

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Any administrator of study product will be blinded to the individual participant’s 
treatment assignment. 
When preparing a dose in a syringe and administering the dose, consideration 
should be given to the volume of solution in the needle before and after the dose 
is administered. Particularly, if the needle used to withdraw the product is 
replaced prior to vaccine administration, consideration should be given to 
conserving the full dose of product. The pharmacy and clinic staff members are 
encouraged to work together to administer the dose specified in the protocol. 
8.5 
Acquisition of study products 
PDPHV-201401 Plasmid (the Env (A,B,C,A/E) / Gag (C) DNA plasmids) and 
PDPHV-201401 Recombinant Proteins gp120A, gp120B, gp120C, gp120AE (the 
Recombinant gp120 (A,B,C,A/E) vaccines) will be provided by the University of 
Massachusetts Medical School.  
The GLA-SE (AP 10-205) adjuvant will be provided by Infectious Disease 
Research Institute (IDRI).  
The placebo (Sodium Chloride for Injection, USP 0.9%) will not be provided 
through the protocol but must be purchased by the site. 
The syringes and needles used for the preparation and delivery of the study 
products will not be provided through the protocol and must be purchased by the 
site. 
Once an HVTN CRS is protocol registered, the pharmacist can obtain study 
products from the NIAID Clinical Research Products Management Center 
(CRPMC) by following the ordering procedures given in Pharmacy Guidelines 
and Instructions for DAIDS Clinical Trials Networks. 
8.6 
Pharmacy records 
The HVTN CRS pharmacist is required to maintain complete records of all study 
products. The pharmacist of record is responsible for maintaining randomization 
codes and randomization confirmation notices for each participant in a secure 
manner. 
8.7 
Final disposition of study products 
All unused study products must be returned to the CRPMC after the study is 
completed or terminated unless otherwise instructed by the CRPMC. The 
procedures and relevant form are included in the Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks.  

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9 
Clinical procedures 
The schedule of clinical procedures is shown in Appendix J and Appendix K. 
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 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 

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enrollment consent. Sites conducting general screening or prescreening approved 
by their IRB/EC and any applicable RE may use the results from this screening to 
determine eligibility for this protocol, provided the tests are conducted within the 
time periods specified in the eligibility criteria.  
9.1.2 
Protocol-specific consent forms 
The protocol-specific consent forms describe the study products to be used and all 
aspects of protocol participation, including screening and enrollment procedures. 
The sample protocol-specific consent forms for the study are is located in 
Appendix A and Appendix B. 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, Appendix B, and Appendix D. The consent form(s) must be 
developed in accordance with requirements of the following: 
 CRS’s IRB/EC and any applicable REs, 
 CRS’s institution, and 
 Elements of informed consent as described in Title 45, CFR Part 46 and 
Title 21 CFR, Part 50, and in 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.  

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An Assessment of Understanding is used to document the participant’s 
understanding of key concepts in this HIV vaccine trial. The participant must 
complete the Assessment of Understanding before enrollment. Staff may provide 
assistance in reading and understanding the questions and responses, if necessary. 
Participants must verbalize understanding of all questions answered incorrectly. 
This process and the participant’s understanding of the key concepts should be 
recorded in source documentation at the site. 
IRB/EC and any applicable RE may require that a participant has signed either a 
screening or protocol-specific consent document prior to administering the 
Assessment of Understanding. The consent process (including the use of the 
Assessment of Understanding) should be explained thoroughly to the IRB/EC and 
any applicable RE, whose recommendations should be followed. 
9.2 
Pre-enrollment procedures 
Screening may occur over the course of several contacts/visits, up to and 
including before vaccination on day 0. All inclusion and exclusion criteria must 
be assessed within 56 days before enrollment, unless otherwise specified in the 
eligibility criteria (or below in this section). 
After the appropriate informed consent has been obtained and before enrollment, 
the following procedures are performed: 
 Medical history, documented in the case history record; 
 Assessment of Understanding (see Section 9.1.3) 
 Assessment of whether the volunteer is at low risk for HIV infection; 
 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, 
 HBsAg, 
 Anti-HCV antibodies, 
 Syphilis test, 
 CBC with differential and platelets, 

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 Chemistry panel (ALT, AST, alkaline phosphatase, and creatinine), 
 Urine dipstick (as described in Section 9.10), and 
 Urine or serum pregnancy test (participants who were born female) 
 Pap smear (only for volunteers who were born female and are age 21 or older) 
Pap smear is not required: 
 if volunteer disagrees to provide cervicovaginal fluid samples, 
 if volunteer has reported having had a Pap smear within previous 5 years 
with most recent result normal or ASCUS [atypical squamous cells of 
undetermined significance] with no evidence of high-risk HPV), or 
 if high-risk HPV testing was not conducted, and volunteer has reported 
having had a Pap smear within the 3 years prior to enrollment, with the 
latest result normal or ASCUS. 
 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 
 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). 

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9.3 
Enrollment and vaccination visits 
Enrollment is simultaneous with first vaccination. The HVTN CRS requests the 
randomization assignment via a Web-based randomization system. In general, the 
time interval between randomization and enrollment should not exceed 4 working 
days. However, circumstances may require a participant’s enrollment visit to be 
changed. This may exceed the 4-day randomization time limit. 
At all vaccination visits, the following procedures are performed before 
vaccination: 
 Abbreviated physical examination, including weight, vital signs, and a 
symptom-directed evaluation by history and/or appropriate physical exam 
based on participant self-reported symptoms or complaints; 
 Assessment of baseline reactogenicity parameters; 
 Assessment of concomitant medications (as described in Section 9.2); 
 Assessment of any new or unresolved AEs/intercurrent illnesses; and 
 Urine or serum pregnancy test (for participants who were 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 is given the postvaccination memory tool and is instructed 
on how to complete it. The site will make arrangements to be in contact with the 
participant during the reactogenicity period (as described in Section 9.11). 
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 Section 
9.9); and 

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 Assessment of new or unresolved social impacts (site staff will ask participant 
about the status of any unresolved social impacts and if s/he has experienced 
any new social impacts as a result of the trial participation). 
Additional procedures will be performed at scheduled visits as specified in 
Appendix H and Appendix K:  
 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;  
 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, mucosal, and/or stool) should be completed prior 
to vaccination); 
 Clinical laboratory tests for study participants who agree to provide semen, 
rectal, or cervicovaginal fluid samples, including: 
 Syphilis; 
 Gonorrhea and chlamydia; 
 Trichomonas vaginalis (for participants providing cervicovaginal 
samples); 
 Bacterial vaginosis (for participants providing cervicovaginal samples); 
and 
 Yeast (for participants providing cervicovaginal samples, if clinically 
indicated). 
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);  

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 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 J, Appendix H and Appendix K: 
 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, 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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 Clinical laboratory tests for study participants who agree to provide (semen, 
rectal, or cervicovaginal) mucosal fluid samples, including: 
 Syphilis 
 Gonorrhea and chlamydia 
 Trichomonas vaginalis (for participants providing cervicovaginal 
samples), 
 Bacterial vaginosis (for participants providing cervicovaginal samples), 
 Yeast (for participants providing cervicovaginal samples, if clinically 
indicated) 
 Urine or serum pregnancy test (for participants who were born female). 
Persons who are NOT of reproductive potential due to having undergone total 
hysterectomy or bilateral oophorectomy (verified by medical records), are not 
required to undergo pregnancy testing 
9.5 
Mucosal fluid sampling 
Mucosal samples will be collected at the timepoints indicated in Appendix I from 
the study participants who agree to these procedures. 
Participants who consent to provide cervicovaginal, rectal, or semen samples will 
be tested for the following infections at the mucosal sampling visits: gonorrhea, 
chlamydia, and syphilis. Participants who consent to provide cervicovaginal fluid 
samples will be tested for trichomoniasis and for bacterial vaginosis and (if 
clinically indicated) for hyphae/budding yeast. Test results will be provided to 
participants and all participants who test positive for 1 or more of these infections 
will receive counseling as well as treatment (or referral for treatment) as 
appropriate. Sample collection may not be performed or may be deferred to a later 
date within the visit window if a contraindication to sampling (eg, active GTI) is 
present (as indicated below). 
Salivary fluid sampling (optional, both sexes): Participants willing to provide 
salivary samples should abstain from smoking, eating, or drinking anything other 
than water, brushing their teeth, using mouthwash, chewing gum or tobacco, or 
engaging in intimate oral activity for one hour prior to sample collection. 
Rectal fluid sampling (optional, both sexes): For participants born female, a 
pregnancy test must be performed and be negative prior to any rectal mucosal 
sampling. Persons who are NOT of reproductive potential due to having 
undergone total hysterectomy or bilateral oophorectomy (verified by medical 
records), are not required to undergo pregnancy testing. Rectal fluid sampling 
should be deferred if a participant is menstruating, but should be performed as 
soon as possible, if still within the visit window. 

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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 fluid sampling, 
such as an active infection or inflammation of the colorectal area [such as a herpes 
simplex virus (HSV)-2 outbreak or inflamed hemorrhoids or colitis/diarrhea] or if 
the participant has any active genital tract infection (GTI). 
For 48 hours prior to sample collection, participants should abstain from: 
 Receptive anal sex,  
 Insertion of any foreign object or substance into the anus (including but not 
limited to cleaning products [creams, gels, lotions, pads, etc.], lubricant, 
enemas, and douching even with water), and  
 Using perianal or intra-anal steroid or other anti-inflammatory cream in or 
around the anus.  
Cervicovaginal fluid sampling (optional, 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 (see Section 7.1). A pregnancy test must be performed on 
the day of cervicovaginal sampling. The pregnancy test can be performed after 
collection has taken place. Persons who are NOT of reproductive potential due to 
having undergone total hysterectomy or bilateral oophorectomy (verified by 
medical records), are not required to undergo pregnancy testing. Cervicovaginal 
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, 
cervicovaginal sampling will not be performed (or may be deferred to a later date 
if still within the visit window) if a participant is known to have an active 
ulcerative genital lesion or an active GTI at the scheduled timepoint. Participants 
providing cervicovaginal fluid 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 (optional, only for participants who were born male): For at 
least 48 hours prior to specimen collection, participants providing semen samples 
are asked: 
 not to have sex, including insertive oral sex 
 not to ejaculate 

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 not to use anything with lubricants 
 not to put saliva on the penis 
In addition, semen sampling will not be performed (or may be deferred to a later 
date if still within the visit window) if a participant is known or believes to have 
an active GTI at the scheduled timepoint. 
9.6 
Stool sampling 
Two stool samples will be collected at the timepoints indicated in Appendix I 
from the study participants who agree to this procedure. These samples will be 
collected using swabs, either via rectal swabs or by taking swabs from stool. 
Information will be collected from these participants about dietary habits, 
antibiotic use, and gastrointestinal symptoms. 
9.7 
Health contact at 12 months after last vaccination visit 
CRS staff will contact study participants at 12 months after the last vaccination to 
collect the information listed below. This contact may be accomplished by phone, 
text message, or email. Clinic visits will only be required if HIV confirmatory 
testing is necessary (see Section 9.8.1); however, a clinic visit may be arranged 
for other reasons. 
 Confirmation of vital status; if deceased, attempt to learn cause and date of 
death; 
 If participant is alive, report any of the following events: 
 New or updated AEs related to study product(s), including: 
o Life-threatening adverse experiences; 
o Persistent or significant disability/incapacity;  
o Hospitalizations and reasons; 
o Other important medical events that may jeopardize the participant or 
may require intervention to prevent 1 of the other outcomes listed 
above;  
o New chronic conditions requiring more than 30 days of medical 
intervention or medication; 
 AESI (Section 11.2.2). A sample list of AESI is provided in Appendix L. 
AESI are reported regardless of relationship to study product(s). 
 New diagnosis of HIV infection; and 
 Pregnancies and outcomes, including congenital anomalies/birth defects. 

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All such events will be recorded, and adverse events will be assessed for 
relationship to study product(s).  
9.7.1 
Interim contacts 
CRSs may report safety information obtained at a contact other than the annual 
contact. These contacts are reported as interim visits. 
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. 

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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 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 J 
and Appendix K. 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 J and Appendix K). The Laboratory Program (or approved 
diagnostic laboratory) will follow the HVTN HIV testing algorithm (see Study 
Specific Procedures [SSP]), which is able to distinguish vaccine-induced 
antibody responses from actual HIV infections.  
 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 antibody 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. 

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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 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 followed until resolution and graded according to the Division of AIDS Table 
for Grading the Severity of Adult and Pediatric Adverse Events, Corrected 
Version 2.1, July 2017, except as noted in Section 11.2.2. 
The reactogenicity assessment period is 7 full days following each vaccination per 
the assessment schedule shown in Table 9-1. Participants are instructed to record 
symptoms using a postvaccination memory tool. Contacts between the participant 
and the site staff should take place daily between 1-3 days postvaccination for the 

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collection of reactogenicity data, and 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. Clinic staff will follow new or unresolved reactogenicity 
symptoms present at day 7 to resolution. 
Reactogenicity events are reported using CRFs that correspond to the time of 
assessment in Table 9-1. Reactogenicity assessments include assessments of 
systemic and local symptoms, vaccine-related lesions, 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 events 
requiring expedited reporting to DAIDS criteria, 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 
1-7 b 
Between 12:00am and 11:59pm on the 
respective day  
HVTN CRS staff or 
participant 
a Day of vaccination 
b New or unresolved reactogenicity symptoms present on day 7 are followed 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 tenderness at the injection site. The daily maximum severity 
reached for each symptom during the assessment period is reported.  
Body temperature is measured by oral or infrared thermometry 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/redness and induration/swelling. The 
maximum horizontal and maximum vertical measurements for all injection site 
reactions are recorded. 
All injection site reactions are monitored until resolution. Areas greater than 25 
cm2 are followed daily; otherwise, the frequency of follow-up is based on 
clinician judgment. 

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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 
Evaluation of possible DTH or vasculitic reactions to vaccine 
As described in Section 4.8.1, delayed-type hypersensitivity reactions were 
observed in recipients of DNA and protein vaccinations in the study of the DP6-
001 vaccines. They were not seen in the preclinical safety studies of the DP6-001 
products prior to the clinical trial, and there is no known predictive model for 
whether the PDPHV-201401 vaccines might also elicit DTH reactions. There 
were also two participants who developed vasculitis in the study of DP6-001. The 
safety of trial participants is the major priority of the HVTN and protocol team, 
and monitoring for DTH reactions or vasculitis that may be related to vaccination 
is an important part of this protocol.  
The DTH reactions and vasculitis events in the study of the DP6-001 vaccines 
arose within a few days of vaccination. The DTH reactions typically occurred 
after the second or subsequent immunizations. If similar reactions were to occur 
in HVTN 124, they would likely appear within the 7-day reactogenicity period. 
DTH reactions may be difficult to distinguish from common vaccine 
reactogenicity such as injection site erythema, swelling, and pruritus. Vasculitis 
syndromes are systemic illnesses with variable presentations. In the case of DP6-
001, both affected participants had a purpuric rash. The study includes urine 
dipstick assessments after each vaccination to look for protein or blood, which 
may be renal manifestations of vasculitis. 
Any participant who develops a possible DTH reaction should be promptly 
recalled to clinic for assessment and evaluation of the injection sites and affected 
areas. Photography of skin lesions is optional for the participant, but encouraged. 
The participant may be asked to provide additional photographs of skin lesions if 
they continue during the days that follow the initial evaluation. Referral to a 
dermatologist to obtain a skin biopsy is encouraged.  
For participants who have developed a possible vasculitis, the assessment should 
include a symptom-directed physical exam including inspection of injection sites 
and affected areas, CBC with differential, serum chemistries, urine dipstick (with 
urine microscopy, if indicated), ESR, CRP, and photography of injection sites and 
affected areas (optional for the participant, but strongly encouraged). HLA-typing 
may be requested from stored PBMC. The participant may be referred for 

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additional evaluation (eg, by a dermatologist and/or rheumatologist), and a skin 
biopsy may be obtained, with separate participant consent. Records of these 
contacts will be requested to complete the study record. 
DTH reactions and vasculitis events that are related to vaccination must be 
promptly reported according to the AE notification and safety pause/AE review 
rules (Table 11-1) and, if applicable, the requirements for expedited reporting of 
AEs to DAIDS (see Section 11.2.3). 
9.13 
Visit windows and missed visits 
Visit windows are defined in HVTN 124 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. 
9.14 
Early termination visit 
In the event of early participant termination, site staff should consider if the 
following assessments are appropriate: a final physical examination, clinical 
laboratory tests (including urine dipstick, CBC with differential, and chemistry 
panel), pregnancy testing, social impact assessment, and HIV test. 
9.15 
Pregnancy 
If a participant becomes pregnant during the course of the study, no more 
injections of study product will be given, but remaining visits and study 
procedures should be completed unless medically contraindicated or applicable 
regulations require termination from the study. If the participant terminates from 
the study prior to the pregnancy outcome, the site should make every effort to 
keep in touch with the participant in order to ascertain the pregnancy outcome. 
Pregnancies and pregnancy outcomes will be reported. 

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10 
Laboratory 
10.1 
HVTN CRS laboratory procedures 
The HVTN 124 Site Lab Instructions and SSP provide further guidelines for 
operational issues concerning the clinical and processing laboratories. These 
documents include guidelines for general specimen collection, special 
considerations for phlebotomy, specimen labeling, whole blood processing, HIV 
screening/diagnostic testing, and general screening and safety testing. 
Tube types for blood collection are specified in Appendix H and Appendix I. For 
tests performed locally, the local lab may assign appropriate tube types. 
10.2 
Total blood volume 
Required blood volumes per visit are shown in Appendix H and Appendix I. 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 timepoints in this study occur 2 weeks after the last 
vaccination for Parts A and B. Endpoint assays for humoral and cellular responses 
are performed on specimens collected from participants at the primary 
immunogenicity timepoints and may be performed on samples collected at 
baseline. Depending on the initial results, assays for humoral and cellular 
responses may be performed on samples collected from participants at other 
timepoints; the schedule is shown in Appendix H and Appendix I. 
10.4 
Endpoint assays: cellular 
10.4.1 
Flow cytometry (Parts A and B) 
Flow cytometry will be used to examine vaccine-specific CD4+ and CD8+ T-cell 
responses following stimulation of PBMCs with synthetic HIV peptides that span 
the proteins encoded by the vaccine. ICS parameters will include cytokines such 
as IFN-γ, interleukin (IL)-2, and tumor necrosis factor (TNF)-α, and may include 
other cytokines (such as cytokines relevant to Th2 and Th17 responses) to identify 
T cells of specific functionality . Markers of cytotoxic potential (eg, granzyme B 
and that identify circulating T follicular helper (Tfh) cells (e.g., CXCR5 and PD-
1) may also be included. Data will be reported as percentages of CD4+ or CD8+ 

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T cells responding to a specific peptide pool. Additional cell surface markers, 
cytokines, or functional markers may also be analyzed. 
10.5 
Endpoint assays: humoral 
10.5.1 
Binding antibody multiplex assay (Parts A and B) 
HIV-1-specific total gp120 and gp70 V1V2 binding IgG antibodies will be 
assessed on serum samples from study participants taken at the primary 
immunogenicity timepoints and baseline. In addition, HIV-1-specific total binding 
IgA antibodies and binding to IgG subclasses (IgG1, IgG2, IgG3, and IgG4) may 
also be assessed. Specimens from other timepoints may also be assayed based on 
the results of the initial assay. 
10.5.2 
Neutralizing antibody assay (Part B) 
HIV-1–specific nAb assays will be performed on serum samples from study 
participants taken at the primary immunogenicity timepoint(s). Specimens from 
the baseline and other timepoints may also be analyzed at the discretion of the 
HVTN Laboratory Program, which may be contingent on the results of the 
primary immunogenicity timepoints. The TZM-bl assay will test neutralization of 
the vaccine strains and at least one highly neutralization-sensitive tier 1A virus. 
The global panel and/or clade-specific panels may be used to assess tier 2 virus 
neutralization (61, 66). Additional TZM-bl assays may be performed to test 
neutralization of Tier 1B strains. 
10.5.3 
Antibody-Dependent Cellular Cytotoxicity assay (ADCC) (Part B) 
ADCC activity may be assessed using serum samples from study participants 
taken at the primary immunogenicity timepoints. Specimens from the baseline 
and other timepoints may also be analyzed at the discretion of the HVTN 
Laboratory Program, which may be contingent on the results of the primary 
immunogenicity timepoints. For the Granzyme B flow-based cytotoxicity assay, 
participant sera are incubated with effector cells and gp120-coated target cells. 
ADCC is quantified as net percent granzyme B activity which is the percent of 
target cells positive for GranToxiLux (GTL), an indicator of granzyme B uptake, 
minus the percent of target cells positive for GTL when incubated with effector 
cells but without sera. For the Luciferase-based cytotoxicity assay, participant 
sera are incubated with infectious molecular clone (IMC)-infected cells and 
percent killing is measured through the use of Viviren luminescence. 
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 

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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-1disease progression may also be assessed.  
10.7 
Lab assay algorithm 
The Lab Assay Algorithm lists assays to characterize cellular, humoral, and innate 
immune responses as well as host genetics that may be conducted to determine 
endpoints in HVTN vaccine trials. The type of assay(s) employed will be 
dependent on the response obtained by the primary immunogenicity assays at 
relevant timepoints. Please note that the Lab Assay Algorithm will be updated 
periodically to include new assays. 
10.8 
Exploratory studies 
Samples may be used for other testing and research related to furthering the 
understanding of HIV immunology or vaccines. In addition, cryopreserved 
samples may be used to perform additional assays to support standardization and 
validation of existing or newly developed methods.  
10.8.1 
B-cell ELISpot (Part B) 
B-cell ELISpot assays may be conducted on PBMCs to enumerate B cells that 
secrete HIV-specific antibodies. The total number of B cells secreting IgG and/or 
IgA will be compared to the number of B cells secreting HIV-specific antibodies 
using Env proteins as antigens. Responses will be reported as the percentage of 
antigen-specific B cells among total antibody-secreting cells. 
10.8.2 
B-cell Phenotyping (Part B) 
Antigen-specific B cells induced by vaccination will be identified and 
characterized using fluorescently-labeled recombinant proteins in combination 
with a flow cytometry phenotyping panel. In particular, HIV Env-reactive B cells 
will be enumerated and may be further characterized for expression of memory, 
activation, inhibitory or other markers by protein and/or gene expression. 
Antigen-specific B cells may also be sorted for further analysis by B cell receptor 
sequencing or gene expression analysis. Lastly, functional properties may be 
confirmed by cloning of the B cell receptor (VH and VL) genes into an IgG 
expression vector in order to express the antibody for functional characterization 
using binding, neutralization or other assay. 
10.8.3 
Tfh phenotyping  
Flow cytometry may be used to identify peripheral blood follicular helper 
T (pTfh) cells. Phenotyping of pTfh cells will be based on expression of CXCR5 
and PD-1 on CD4+ T cells, and may include additional markers. For example, if 
flow cytometry panels are successfully developed to assess CD69, OX40, IL-21 

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and CD154 expression as a functional read-out, vaccine-specific Tfh cells may be 
assessed and isolated for further analysis.  
10.8.4 
B cell plasmablasts  
Flow cytometry may be used to identify the early precursors for antibody-
secreting B cells, called B cell plasmablasts, in the peripheral blood. Plasmablasts 
will be mainly characterized by CD19+ CD20- and high expression of CD27 and 
CD38. The flow cytometry panels might also include additional markers and 
assessment of antigen specificity. 
10.8.5 
Mucosal studies (Part B) 
Saliva, cervicovaginal fluid, rectal fluid, and semen samples will be collected at 
timepoints indicated in Appendix I, then processed and assessed for HIV-specific 
IgA and IgG antibodies. Additional exploratory analyses may be performed on 
these samples. 
10.8.6 
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 sequencing approaches or other methods.  
10.9 
Specimen storage and other use of specimens 
The HVTN stores specimens from all study participants indefinitely, unless a 
participant requests that specimens be destroyed or if required by IRB/EC, or RE. 
Other use of specimens is defined as studies not covered by the protocol or the 
informed consent forms for the study (see Appendix A and Appendix B). 
This research may relate to HIV, vaccines, the immune system, and other 
diseases. This could include genetic testing and, potentially, genome-wide studies. 
This research is done only to the extent authorized in each study site’s informed 
consent form, or as otherwise authorized under applicable law. Other research on 
specimens (‘other use’) will occur only after review and approval by the HVTN, 
the IRB/EC of the researcher requesting the specimens, and the CRS’s 
IRBs/ECs/REs if required. 
As part of consenting for the study, participants document their initial decision to 
allow or not allow their specimens to be used in other research, and they may 
change their decision at any time. The participant’s initial decision about other 
use of their specimens, and any later change to that decision, is recorded by their 
CRS in a Web-based tool that documents their current decisions for other use of 
their specimens. The HVTN will only allow other research to be done on 
specimens from participants who allow such use. 

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CRSs must notify HVTN Regulatory Affairs if institutional or local governmental 
requirements pose a conflict with or impose restrictions on specimen storage or 
other use of specimens. 
10.10 
Biohazard containment 
As the transmission of HIV and other blood-borne pathogens can occur through 
contact with contaminated needles, blood, and blood products, appropriate 
precautions will be employed by all personnel in the drawing of blood and 
shipping and handling of all specimens for this study, as currently recommended 
by the CDC and the NIH or other applicable agencies. 
All dangerous goods materials, including Biological Substances, Category A or 
Category B, must be transported according to instructions detailed in the 
International Air Transport Association Dangerous Goods Regulations. 

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11 
Safety monitoring and safety review 
11.1 
Safety monitoring and oversight 
11.1.1 
HVTN 124 PSRT 
The HVTN 124 PSRT is composed of the following members: 
 DAIDS medical officer representative, 
 Protocol chair and cochair, 
 Protocol Team leader, 
 Core medical monitor, and 
 Clinical safety specialist. 
The clinician members of HVTN 124 PSRT are responsible for decisions related 
to participant safety. 
The Protocol Team clinic coordinator, clinical data manager, vaccine developer 
representative, clinical trial manager, and others may also be included in HVTN 
124 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 evaluation of cumulative reactogenicity 
events, AE, laboratory safety data, and individual reports of adverse events 
requiring expedited reporting to DAIDS. The SMB conducts additional special 
reviews at the request of the HVTN 124 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: 
 Maintaining a central database management system for HVTN clinical data; 

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 Providing reports of clinical data to appropriate groups such as the HVTN 124 
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 124 PSRT AE review criteria (see Section 11.4); 
 Notifying HVTN CRSs and other groups when safety pauses or planned holds 
are instituted and lifted (see Section 11.4); 
 Querying HVTN CRSs for additional information regarding reported clinical 
data; and 
 Providing support to the HVTN 124 PSRT. 
11.2 
Safety reporting 
11.2.1 
Submission of safety forms to SDMC 
Sites must submit all safety forms (eg, reactogenicity, adverse experience, 
urinalysis, local lab results, and concomitant medications) before the end of the 
next business day 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 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected Version 2.1, July 2017, available on the RSC website at http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids-grading-tables, except: 
 Unintentional weight loss is required to be reported as an AE only if it is 
considered to be potentially deleterious to the participant’s health (see HVTN 
124 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: 

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 Grade 1 is: 2.5 to < 5 cm in diameter OR 6.25 to < 25 cm2 surface area; 
 Grade 2 is: ≥ 5 to < 10 cm in diameter OR ≥ 25 to < 100 cm2 surface area; 
 Grade 3 is: ≥ 10 cm in diameter OR ≥ 100 cm2 surface area OR Ulceration 
OR Secondary infection OR Phlebitis OR Sterile abscess OR Drainage; 
 Grade 4 is: Potentially life-threatening consequences (eg, abscess, 
exfoliative dermatitis, necrosis involving dermis or deeper tissue). 
All AEs are reported to the SDMC on the appropriate CRF. Clinic staff should 
evaluate every AE to determine if (1) the AE meets the requirements for 
expedited reporting to DAIDS (see Section 11.2.3), and (2) if the AE meets the 
criteria for a safety pause/prompt AE review (see Section 11.4), and (3) if the AE 
is an AESI. A sample list of AESI is provided as Appendix L. 
Sites are expected to notify HVTN clinical safety staff of any serious safety 
concern requiring their attention (see Table 11-1). Telephone numbers and email 
addresses are found on the protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/hvtn124). Concerns requiring immediate 
attention should be communicated by calling the clinical safety phone. 
In the case of email notification, the CSS will reply during working hours (local 
time) to confirm that the email has been received and reviewed. If email service is 
not available, the CRS should notify clinical safety staff of the event by 
telephone, then submit CRFs. 
In addition, site investigators are required to submit AE information in accordance 
with IRB/EC and any applicable RE requirements. 
11.2.3 
Expedited reporting of 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/clinical-research-sites/safety-reporting/manual. 
The SAE Reporting Category will be used for this study.  
The internet-based DAIDS Adverse Experience Reporting System (DAERS) must 
be used for expedited AE (EAE) reporting to DAIDS. In the event of system 
outages or technical difficulties, expedited AE reports may be submitted via the 
DAIDS EAE Form. This form is available on the DAIDS RSC website at 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids/paper-eae-
reporting. 
For questions about DAERS, please contact CRMSsupport@niaid.nih.gov or 
from within the DAERS application itself.  
For questions about expedited AE reporting, please contact the DAIDS RSC 
Safety Office at (DAIDSRSCSafetyOffice@tech-res.com). 

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The study products for which expedited reporting are required are 
 Env (A, B, C, A/E) / Gag (C) DNA plasmids or placebo 
 Recombinant gp120 (A, B, C, A/E) proteins/GLA-SE adjuvant or placebo 
In addition to the expedited Reporting Category identified above, any AE of 
vasculitis related to study product(s) must also be reported in an expedited 
manner. 
While the participant is in the study reporting period (Section 3, Duration per 
participant), the SAE Reporting Category will be used.  
After the protocol-defined AE reporting period for the study, unless otherwise 
noted, only Suspected, Unexpected Serious Adverse Reactions as defined in 
Version 2.0 of the DAIDS EAE Manual must be reported to DAIDS, if the study 
staff become aware of the events.  
The NIAID/DAIDS will report all unexpected SAEs related to the study products 
observed in this clinical trial to the FDA in accordance with 21 CFR 312.32 (IND 
Safety Reports). However, because safety is a primary study endpoint, the 
Sponsor Medical Officer will not routinely be unblinded to study treatment 
assignment when there is an assessment of relatedness of the SAE with the study 
product(s); and the safety report will be sent to the FDA based on the blinded 
attribution assessment. 
If the PSRT believes unblinding is appropriate (eg, if unblinding of the site PI to 
treatment assignment will assist with the clinical management of the SAE), the 
PSRT will consult the independent HVTN SMB for a recommendation. In the 
event the HVTN SMB determines that unblinding is indicated, the SMB will 
inform the individual (eg, site physician) of the participant’s treatment assignment 
in such a manner as to maintain the study blind of the PSRT and study team. For 
additional impact and management of SAEs on the study, see Section 11.4. 
11.3 
Safety reviews 
11.3.1 
Initial safety evaluation 
Enrollment across all participating HVTN CRSs will be restricted to a maximum 
of 1 participant per day until 6 participants have been enrolled in Group 1. The 
HVTN 124 PSRT will review the cumulative safety data including at minimum 
local and systemic reactogenicity data reported for the first 72 hours 
postvaccination on each of these 6 participants, and will determine whether it is 
safe to proceed with full enrollment in Group 1. The PSRT may consult with the 
HVTN SMB on an ad hoc basis for this evaluation. 

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11.3.2 
Safety evaluation for moving from Part A to Part B 
In addition to monitoring participant safety throughout the study period, the 
HVTN 124 PSRT will review all cumulative safety data available from Group 1, 
when data is available for the first 6 participants, up to and including the 2-week 
visit after the second vaccination, and from the second 6 participants, up to and 
including the 2-week visit after the first vaccination. Based on the assessment of 
this safety data, the PSRT will make a decision regarding the appropriateness of 
moving to Part B. The PSRT may consult with the HVTN SMB on an ad hoc 
basis for this evaluation. 
11.3.3 
Interim safety evaluation for Part B 
Part B will first open to enrollment to 10 participants, randomized between Group 
2 and Group 3. The PSRT will review all cumulative safety data available from 
the first 10 participants in Part B, up to and including the 2-week visit after the 
second vaccination, to make a decision regarding the appropriateness of 
proceeding with full enrollment in Part B. Based on the assessment of this safety 
data, the PSRT will make a decision regarding the appropriateness of proceeding 
with full enrollment in Part B. The PSRT may consult with the HVTN SMB on an 
ad hoc basis for this evaluation. 
11.4 
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 124 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 124 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 124 PSRT 
notification 
SAE, related 
Grade 3 
Email and submit forms 
immediately 
Immediate HVTN 124 PSRT 
notification and prompt HVTN 124 
PSRT AE review to consider pause 
AEb, related 
Grade 4 or 
3 
Email and submit forms 
immediately 
Immediate HVTN 124 PSRT 
notification and prompt HVTN 124 
PSRT AE review to consider pause 
Vasculitis, related  
Any grade 
Phone immediately, email 
and submit forms 
immediately 
Immediate pause 
DTH responses, 
related  
Any grade 
Email and submit forms 
immediately 
Prompt HVTN 124 PSRT notification 
and 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/hvtn124). 
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 124 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 124 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 124 PSRT assessment, DAIDS RAB 
notifies the FDA as needed. 
If an immediate HVTN 124 PSRT notification or prompt HVTN 124 PSRT AE 
review is triggered, HVTN Core notifies the HVTN 124 PSRT as soon as possible 
during working hours (local time)—or, if the information was received during off 
hours, by the morning of the next workday. If a prompt HVTN 124 PSRT AE 
review cannot be completed within 72 hours of notification (excluding weekends 
and US federal holidays), an automatic safety pause occurs. 
The HVTN requires that each CRS submit to its IRB/EC and any applicable RE 
protocol-related safety information (such as IND safety reports, notification of 
vaccine holds due to the pause rules, and notification of other unplanned safety 
pauses). CRSs must also follow all applicable RE reporting requirements. 

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In addition, all other AEs are reviewed routinely by the HVTN 124 PSRT (see 
Section 11.5.2). 
11.5 
Review of cumulative safety data 
Routine safety review occurs at the start of enrollment and then throughout the 
study. 
Reviews proceed from a standardized set of protocol-specific safety data reports. 
These reports are produced by the SDMC and include queries to the HVTN CRSs. 
Events are tracked by internal reports until resolution.  
11.5.1 
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 124 PSRT AE review criteria. 
11.5.2 
Weekly review 
During the injection phase of the trial, the HVTN 124 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 124 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. 
11.6 
Study termination 
This study may be terminated early by the determination of the HVTN 124 PSRT, 
a pertinent national regulatory authority, NIH, Office for Human Research 
Protections (OHRP), the Food and Drug Administration (FDA), or vaccine 
developer(s). In addition, the conduct of this study at an individual HVTN CRS 
may be terminated by the determination of the IRB/EC and any applicable RE. 

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12 
Protocol conduct 
This protocol and all actions and activities connected with it will be conducted in 
compliance with the principles of GCP (ICHe6), and according to DAIDS and 
HVTN policies and procedures as specified in the HVTN Manual of Operations, 
DAIDS Clinical Research Policies and Standard Procedures Documents including 
procedures for the following: 
 Protocol registration, activation, and implementation; 
 Informed consent, screening, and enrollment; 
 Study participant reimbursement; 
 Clinical and safety assessments; 
 Safety monitoring and reporting; 
 Data collection, documentation, transfer, and storage; 
 Participant confidentiality; 
 Study follow-up and close-out; 
 Unblinding of staff and participants; 
 Quality control; 
 Protocol monitoring and compliance; 
 Advocacy and assistance to participants regarding negative social impacts 
associated with the vaccine trial; 
 Risk reduction counseling;  
 Specimen collection, processing, and analysis;  
 Exploratory and ancillary studies and sub-studies, and 
 Destruction of specimens. 
Any policies or procedures that vary from DAIDS and HVTN standards or require 
additional instructions (eg, instructions for randomization specific to this study) 
will be described in the HVTN 124 Study Specific Procedures.  

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12.1 
Social impacts 
Participants in this study risk experiencing discrimination or other personal 
problems, resulting from the study participation itself or from the development of 
VISP. The HVTN CRS is obliged to provide advocacy for and assistance to 
participants regarding these negative social impacts associated with the vaccine 
trial. If HVTN CRS staff have questions regarding ways to assist a participant 
dealing with a social impact, a designated NIAID or HVTN Core representative 
can be contacted.  
Social harms are tabulated by the SDMC and are subjected to descriptive analysis. 
The goal is to reduce their incidence and enhance the ability of study staff to 
mitigate them when possible. 
Summary tables of social impact events will be generated weekly, and made 
available for review by the protocol chairs, protocol team leader, and the 
designated NIAID representative. 
12.2 
Compliance with NIH guidelines for research involving products 
containing recombinant DNA 
Because this study is evaluating products containing recombinant or synthetic 
DNA, it must comply with regulations set forth in the NIH Guidelines for 
Research Involving Recombinant or Synthetic Nucleic Acid Molecules (April 
2016). Information about the study must be submitted to site Institutional 
Biosafety Committees (IBCs) and Institutional Review Boards/Ethics Committees 
(IRBs/ECs). IBCs and IRBs/ECs must provide a written assessment of whether 
Recombinant DNA Advisory Committee (RAC) review is warranted. In 
exceptional cases that meet specific criteria outlined in the NIH Guidelines 
Appendix M-I-B, IBCs and IRBs/ECs assessment can include a request for RAC 
review. Regardless of the potential for RAC review, the HVTN and DAIDS will 
register the protocol with the NIH Office of Scientific Policy (OSP). The Protocol 
Team, jointly with the University of Massachusetts and IDRI, will prepare the 
NIH OSP registration documents. 
Investigators at each site are responsible for obtaining IBC approval per NIH 
Guidelines section IV-B7-a-(1). IBC review and approval must be documented by 
the investigator and submitted as part of DAIDS’s initial protocol registration for 
this trial before participants are enrolled at the site. If this protocol is amended, 
investigators should follow the requirements of their IBC. 
The HVTN and DAIDS will ensure that reporting requirements to NIH OSP, as 
outlined in Appendix M-I-C-1.Initiation of the Clinical Investigation, Appendix 
M-I-C-2.Additional Clinical Trial Sites. Appendix M-I-C-3.Annual Reports and 
Appendix M-I-C-4.Safety Reporting are satisfied per the NIH Guidelines. 

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12.3 
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 124 are described below. 
Protocol history and modifications 
Date: September 28, 2017 
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 
https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-
procedures 
 Division of AIDS Protocol Registration Manual. Available at 
https://www.niaid.nih.gov/sites/default/files/prmanual.pdf 
 Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Corrected Version 2.1, July 2017. Available at http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
 The Manual for Expedited Reporting of Adverse Events to DAIDS. Version 
2.0, January 2010. Available at http://rsc.tech-res.com/clinical-research-
sites/safety-reporting/manual 
 HVTN Certificate of Confidentiality. Accessible through the HVTN website. 
 HVTN 124 Special Instructions. Accessible through the HVTN protocol-
specific website. 
 HVTN 124 Study Specific Procedures. Accessible through the HVTN 
protocol-specific website. 
 HVTN 124 Site Lab Instructions. Accessible through the HVTN protocol-
specific website. 
 HVTN Manual of Operations. Accessible through the HVTN website. 
 Dangerous Goods Regulations (updated annually), International Air Transport 
Association. Available for purchase at 
http://www.iata.org/publications/Pages/index.aspx 
 Lab assay algorithm (available upon request) 

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 International Conference on Harmonisation (ICH) E6 (R1), Guideline for 
Good Clinical Practice: Section 4.8, Informed consent of trial subjects. 
Available at http://www.ich.org/products/guidelines/efficacy/article/efficacy-
guidelines.html 
 Participants’ Bill of Rights and Responsibilities. Accessible through the 
HVTN website. 
 NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic 
Acid Molecules. Available at 
http://osp.od.nih.gov/sites/default/files/resources/NIH_Guidelines.pdf. 
 NIH Policy on Reporting Race and Ethnicity Data: Subjects in Clinical 
Research. Available at http://grants1.nih.gov/grants/guide/notice-files/NOT-
OD-01-053.html. 
 Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks, 
July 2008. 
 Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials. Available at 
https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf 
 Title 21, Code of Federal Regulations, Part 50. Available at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFR
Part=50 
 Title 45, Code of Federal Regulations, Part 46. Available at 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html 
See Section 16 for literature cited in the background and statistics sections of this 
protocol. 

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15 
Acronyms and abbreviations 
Ab 
antibody 
Ad 
adenovirus 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANOVA analysis of variance 
ART 
antiretroviral therapy 
AST 
aspartate aminotransferase 
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 
CRF 
case report form 
CRPMC 
NIAID Clinical Research Products Management Center 
CRS* 
clinical research site 
CTL 
cytotoxic T lymphocyte 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS (US NIH) 
DHHS 
US Department of Health and Human Services 
DSMB 
NIAID Data and Safety Monitoring Board 
EAE 
adverse events requiring expedited reporting to DAIDS 
EC 
Ethics Committee 
EIA 
enzyme immunoassay 
ELISA 
enzyme-linked immunosorbent assay 
ELISpot 
enzyme-linked immunospot 
FDA 
US Food and Drug Administration 
FPR 
false positive rate 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equation 
HAART 
highly active antiretroviral therapy 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 

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HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HVTN 
HIV Vaccine Trials Network 
IB 
Investigator’s Brochure 
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 
LTFU 
loss to follow-up 
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 
OBA 
NIH Office of Biotechnology Activities 
OHRP 
US Office for Human Research Protections 
OPV 
oral polio vaccine 
PAB 
DAIDS Pharmaceutical Affairs Branch 
PBMC 
peripheral blood mononuclear cell 
PBS 
phosphate-buffered saline 
PCR 
polymerase chain reaction 
PI 
Principal Investigator 
PSRT 
Protocol Safety Review Team 
PTE 
potential T-cell epitope 
RAB 
DAIDS Regulatory Affairs Branch 
RAC 
NIH Recombinant DNA Advisory Committee 
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 
SFC 
spot-forming cell 
SFU 
spot-forming unit 

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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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16 
Literature cited 
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Cross-subtype antibody and cellular immune responses induced by a 
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7. Haynes BF, Shaw GM, Korber B, Kelsoe G, Sodroski J, Hahn BH, et al. 
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8. Buonaguro L, Tagliamonte M, Tornesello ML, Buonaguro FM. Can HIV p24 
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48. Li Y, Migueles SA, Welcher B, Svehla K, Phogat A, Louder MK, et al. 
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49. Wu X, Yang ZY, Li Y, Hogerkorp CM, Schief WR, Seaman MS, et al. 
Rational design of envelope identifies broadly neutralizing human 
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50. Treanor JJ, Essink B, Hull S, Reed S, Izikson R, Patriarca P, et al. Evaluation 
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al. Global panel of HIV-1 Env reference strains for standardized assessments 
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62. Huang Y, Gilbert P, Montefiori D, Self S. Simultaneous evaluation of the 
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Appendix A 
Sample informed consent form for Part A 
Title: A phase 1 clinical trial to evaluate the safety and immunogenicity of 
polyvalent env (A,B,C,A/E) / gag (C) DNA and gp120 (A,B,C,A/E) protein/GLA-
SE HIV-1 vaccines (PDPHV-201401) as a prime-boost regimen or co-
administered in repeated doses, in healthy, HIV-1–uninfected adult participants 
HVTN protocol number: HVTN 124 
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 60 people will take part in this study at multiple sites. The researcher in 
charge of this study at this clinic is [Insert name of site PI]. The US National 
Institutes of Health (NIH) is paying for the study.  
This study tests 2 vaccines and another study product called an adjuvant, which 
we will explain in a later section. The study is divided into two parts, Part A and 
Part B. About 12 people will take part in Part A of this study. After we see the 
safety results from the first 6 people in Part A, we will decide whether or not to do 
Part B of the study.  
You are being invited to join Part A of the study, which tests one HIV vaccine 
and a study adjuvant. We will call this HIV vaccine and study adjuvant the “study 
vaccine.” They are described below. 
1. We are doing this study to answer several questions. 
 Are the study vaccines safe to give to people? 
 Are people able to take the study vaccines without becoming too 
uncomfortable? 
 How do people’s immune systems respond to the study vaccines? (Your 
immune system protects you from disease.) 

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2. The study vaccines cannot give people HIV. 
The study vaccines are not made from actual HIV. It is impossible for the study 
vaccines to give anyone HIV. Also, the study vaccines cannot cause someone to 
give HIV to someone else. 
3. We do not know if the study vaccine in Part A will decrease, increase, or not 
change your risk of becoming infected with HIV if you are exposed to the 
virus. 
Site: Any change to the following boxed text requires approval from HVTN 
Regulatory Affairs at vtn.core.reg@hvtn.org. 
Several studies have tested whether HIV vaccines can reduce the risk of getting 
HIV from another person. In some studies, people who got the vaccine seemed to 
have the same risk of getting HIV as people who did not get the vaccine. In one 
study, people who got the vaccine seemed to have a lower risk of getting HIV 
than people who did not get the vaccine. In 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. We can tell you about the differences.  
We do not know whether the vaccines in this study will affect your risk of getting 
HIV from another person. The risk could be higher, lower, or unchanged. It’s very 
important to avoid exposure to HIV during and after the study. We will tell you 
how to avoid HIV. 
4. The study vaccine in Part A is experimental. 
Experimental means we do not know if the study vaccine will be safe to use in 
people, or if it will work to prevent HIV infection. These study vaccines are used 
only in research studies.  
Part A tests a protein vaccine. Proteins are natural substances that the body uses to 
build and maintain itself and also to protect itself against disease. The vaccine is 
made of man-made proteins that are similar to proteins from the outer surface of 
the HIV virus. Your body’s immune system may respond to this study vaccine by 
making antibodies that recognize and fight against HIV. Antibodies are special 
proteins made by the body that can recognize and prevent infections.  
The protein vaccine was developed by scientists at the University of 
Massachusetts Medical School (Worcester, Massachusetts) with support from the 
Division of AIDS (DAIDS) at the National Institutes of Health (NIH).  
Sometimes vaccines work better when they are combined with another substance 
that helps to alert the immune system. These substances are called adjuvants. In 

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this study, the protein vaccine is mixed with an adjuvant called GLA-SE. The 
GLA-SE adjuvant was developed by Infectious Disease Research Institute located 
in Seattle, Washington. 
The study vaccine has not been given to people before. It has been tested in mice 
and rabbits and appears safe. Even if something looks like it is safe or works in 
animals, it may not be true for people.  
The GLA-SE adjuvant has been tested in mice, guinea pigs, rats, and rabbits. It 
has also been given to over 900 people in research studies of vaccines for other 
diseases. In those studies, there were no serious safety concerns with the GLA-SE 
adjuvant. This is the first time the GLA-SE adjuvant has been tested with this 
protein vaccine against HIV. 
General risks of vaccines: 
All vaccines can cause fever, chills, rash, aches and pains, nausea, headache, 
dizziness, and feeling tired. Vaccines can also cause pain, redness, swelling, or 
itching where you got the injection. Most people can still do their planned 
activities after getting a vaccine. Rarely, people have side effects that limit their 
normal activities or make them go to the doctor.  
Rarely, a vaccine or adjuvant can cause an allergic reaction, including a rash, 
hives, or trouble breathing. Allergic reactions can be life-threatening. You should 
tell us if you have ever had a bad reaction to any injection or vaccine. 
Very rarely, a vaccine causes an autoimmune disease in a person, or makes an 
autoimmune disease worse. An autoimmune disease happens when your immune 
system attacks your own body, instead of attacking an infection. 
Risks of the study vaccine: 
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. 
Possible risks related to the protein vaccine include muscle damage at the site of 
the injection, the production of antibodies which might react with normal body 
tissues and cause an autoimmune disease, and temporary lab changes such as a 
low white blood cell count.  
The GLA-SE adjuvant may also cause the same risks as shown above for vaccines 
in general. It may also cause lack or loss of appetite. 
In an earlier study, people received two kinds of vaccines; one vaccine was a 
similar protein vaccine to this study but with a different adjuvant. Almost 
everyone had some injection site pain. A wide area of redness around the injection 
site was also common. After either type of vaccine, a couple of days later, some 
people developed redness and swelling at a previous injection site. After either 

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type of vaccine, some people also had injection site swelling, fevers, body aches, 
tiredness, headache, and joint aches. After receiving both types of vaccines, two 
people developed a kind of autoimmune disease called vasculitis that caused a 
rash in one person, and a rash along with kidney and liver injury in another 
person, who had had a similar illness before. These people recovered without any 
problem. We do not know if participants in this study will have similar effects, 
because the study vaccines and study adjuvant are different.  
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 get a study product. Being in more than one study 
may not be safe. 
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 want 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. 

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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.  
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. 
For the care that we cannot give, we will explain how we will help you get care 
elsewhere. For health problems that are unrelated to the study, we will not pay for 
care. 
8. If you were born female and could become pregnant, you must agree to use 
birth control to join this study. 
Site: If you want to include Appendix C, Approved birth control methods (for sample 
informed consent form), in this consent form, paste it below and delete paragraph 
below. 
You should not become pregnant during the study because we do not know how 
the study vaccines could affect the developing baby. You must agree to use 
effective birth control from 21 days before your first injection until after your last 
required protocol clinic visit. We will talk to you about effective birth control 
methods. They are listed on a handout that we will give to you.  
Being in the study 
If you meet the study requirements and want to join, here is what will happen: 
9. You will come to the clinic for scheduled visits about [#] times over 
[Insert period of time]. 
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] 

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Site: Insert any costs to participants (eg, birth control costs for female participants 
who could become pregnant). 
Payments you receive for being in the study may be taxable. We may need to ask 
you for your Social Security number for tax reasons. 
You do not have to pay anything to be in this study. 
11. We will give you either the study vaccine or a placebo.  
Not everyone in Part A will get the study vaccine. Some people will get a 
placebo, a substance that does not contain vaccine or adjuvant. We will compare 
the results from people who got the placebo with results from people who got the 
study vaccine. In this study, the placebo is sterile salt water. 
You have a 5-in-6 chance of getting the study vaccine. Whether you get the study 
vaccine or the placebo is completely random, like flipping a coin.  
We have no say in whether you get the study vaccine or the placebo. We will not 
know which one you are getting, and neither will you. Only the pharmacist at this 
clinic will have this information while the study is going on.  
You will have to wait until everyone in Part A completes their final study visits to 
find out whether you got the study vaccine or the placebo. This could take 1-2 
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 vaccine or the placebo on a schedule. 
You will be in Part A of the study. You will get 1 injection with a needle and 
syringe into your upper arm, at each of 2 separate visits. The injections will be 
given 2 months apart.  
Part A 
Month 0 
(Day 0) 
Month 2 
(Day 56) 
10 people 
Protein vaccine with 
GLA-SE adjuvant 
Protein vaccine with 
GLA-SE adjuvant 
2 people 
Placebo 
Placebo 
You will have to wait in the clinic for about a half hour after each injection to see 
if there are any problems. Then for that night and for 7 more days, you will need 
to keep track of how you are feeling and if you have any symptoms. Within 3 
days of each injection, we will also ask you how you are doing. If you have a 
problem, we will continue to check on you until it goes away. 
Because this is the first study using these products in people, it is important for 
you to call us if you have any symptoms, issues or concerns. We may ask you to 
return to the clinic. In the clinic, we may do some additional lab tests. If you have 
a reaction on your skin, we may take a picture of it. If we think it’s needed, we 
may send you to a specialist outside this clinic. You may be asked for your 

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permission to take a skin biopsy. You will be given another consent form to 
explain this procedure. You would not have to pay for the specialist or for a skin 
biopsy. We will ask for these medical records to be shared with us so that we can 
use the information for this study.  
13. In addition to giving you the study vaccine or placebo, we will: 
 Do regular HIV testing, as well as counseling on your results and on how to 
avoid getting HIV; 
 Do physical exams; 
 Do pregnancy tests if you were 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; and 
 Take urine and blood samples; 
When we take blood, the amount will depend on the lab tests we need to do. It 
will be some amount between 20 mL and 170 mL (1 tablespoon to 3/4 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. We will counsel you on avoiding HIV infection. 
We will ask you personal questions about your HIV risk factors such as sexual 
behavior, alcohol, and drug use. We will talk with you about ways to keep your 
risk of getting HIV low.  

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15. The HVTN will test your samples to see how your immune system responds 
to the study products. 
We will send your samples (without your name) to labs approved by the HVTN 
for this study, which are located in the United States. In rare cases, some of your 
samples may be sent to labs approved by the HVTN in other countries for 
research related to this study. 
Researchers may also do genetic testing related to this study on your samples. 
Your genes are passed to you from your birth parents. They affect how you look 
and how your body works. The differences in people’s genes can help explain 
why some people get a disease while others do not. The genetic testing will only 
involve some of your genes, not all of your genes (your genome). The researchers 
will study only the genes related to the immune system and HIV and those that 
affect how people get HIV.  
If you become HIV infected, the researchers may look at all of the genes of the 
virus found in your samples. The researchers will use this information to learn 
more about HIV and the study product(s).  
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.  
These tests done on your samples are for research purposes, not to check your 
health. The labs will not give the results to you or this clinic, because their tests 
are not approved for use in making health care decisions. These labs are only 
approved to do research tests.  
When your samples are no longer needed for this study, the HVTN will continue 
to store them. 
Site: Delete next section if using separate consent for use of samples and information 
in other studies 
16. When samples are no longer needed for this study, the HVTN wants to use 
them in other studies and share them with other researchers. 
The HVTN calls these samples “extra samples”. The HVTN will only allow your 
extra samples to be used in other studies if you agree to this. You will mark your 
decision at the end of this form. If you have any questions, please ask. 
Do I have to agree? No. You are free to say yes or no, or to change your mind 
after you sign this form. At your request, we will destroy all extra samples that we 
have. Your decision will not affect your being in this study or have any negative 
consequences here.  
Where are the samples stored? Extra samples are stored in a secure central place 
called a repository. Your samples will be stored in the HVTN repository in the 
United States. 

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How long will the samples be stored? There is no limit on how long your extra 
samples will be stored. [Site: Revise the previous sentence to insert limits if your 
regulatory authority imposes them.] 
Will I be paid for the use of my samples? No. Also, a researcher may make a new 
scientific discovery or product based on the use of your samples. If this happens, 
there is no plan to share any money with you. The researcher is not likely to ever 
know who you are. 
Will I benefit from allowing my samples to be used in other studies? Probably not. 
Results from these other studies are not given to you, this clinic, or your doctor. 
They are not part of your medical record. The studies are only being done for 
research purposes. 
Will the HVTN sell my samples and information? No, but the HVTN may share 
your samples with HVTN or other researchers. Once we share your samples and 
information, we may not be able to get them back. 
How do other researchers get my samples and information? When a researcher 
wants to use your samples and information, their research plan must be approved 
by the HVTN. Also, the researcher’s institutional review board (IRB) or ethics 
committee (EC) will review their plan. [Site: If review by your institution’s 
IRB/EC/RE is also required, insert a sentence stating this.] IRBs/ECs protect the 
rights and well-being of people in research. If the research plan is approved, the 
HVTN will send your samples to the researcher’s location.  
What information is shared with HVTN or other researchers? The samples and 
information will be labeled with a code number. Your name will not be part of the 
information. However, some information that we share may be personal, such as 
your race, ethnicity, sex, health information from the study, and HIV status. We 
may share information about the study product you received and how your body 
responded to the study product.  
What kind of studies might be done with my extra samples and information? The 
studies will be related to HIV, vaccines, the immune system and other diseases.  
Researchers may also do genetic testing on your samples.  
In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to contribute to this study.  
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 

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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 extra samples and information for other research 
 Government agencies that fund or monitor the research using your extra 
samples and information 
 The researcher’s Institutional Review Board or Ethics Committee 
 The people who work with the researcher  
All of these people will do their best to protect your information. The results of 
any new studies that use your extra samples and information may be published. 
No publication will use your name or identify you personally. 
17. We will do our best to protect your private information. 
Site: 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. 
Site: Any change to the following boxed 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. 

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Clinic staff will have access to your study records. Your records may also be 
reviewed by groups who watch over this study to see that we are protecting your 
rights, keeping you safe, and following the study plan. These groups include: 
 The US National Institutes of Health and its study monitors, 
 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 University of Massachusetts Medical School and the people who work for 
them, 
 The Infectious Disease Research Institute and the 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] 
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. 

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We may share information from the study with other researchers. We will not 
share your name or information that can identify you. 
A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov. 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. 
18. We may stop your injections or take you out of the study at any time. We 
may do this even if you want to stay in the study and even if you were 
scheduled for more injections.  
This may happen if: 
 you do not follow instructions, 
 we think that staying in the study might harm you, 
 you get HIV, 
 you enroll in a different research study where you get another study product, 
or 
 the study is stopped for any reason. 
If we stop your injections, we may ask you to stay in the study to complete other 
study procedures. 
19. We will stop your injections if you become pregnant. 
We will encourage you to stay in the study if you choose. We will discuss your 
study options with you. 
If you leave the study while you are still pregnant, we will contact you after your 
due date to ask some questions about your pregnancy and delivery. 
20. 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. Site: Modify the following sentence as appropriate. We 
will not provide or pay for any of your HIV care directly.  

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Other Risks 
21. There are other risks to being in this study. 
This section describes the other risks and restrictions we know about. There may 
also be unknown risks, even serious ones. We will tell you if we learn anything 
new that may affect your willingness to stay in the study. 
Risks of routine medical procedures:  
In this study, we will do some routine medical procedures. These are taking blood 
and giving injections. These procedures can cause bruising, pain, fainting, 
soreness, redness, swelling, itching, a sore, bleeding, and (rarely) muscle damage 
or infection where you got the injection. Taking blood can cause a low blood cell 
count (anemia), making you feel tired. 
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 vaccine 
may cause you to test positive on some types of HIV antibody tests, even if you 
are not infected with HIV. This is called vaccine-induced seropositivity (VISP). 
VISP means that after you get the study vaccine, a routine HIV test done outside 
this clinic may 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 vaccine. 
If you have a positive test result caused by the study vaccine at any time, we can 
arrange free HIV testing for as long as you need it. If this happens, we do not 
know how long you will test positive due to the study vaccine. 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.  

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

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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 vaccine 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 vaccine might affect your HIV infection or how long 
it takes to develop AIDS. 
We do not know if getting this study vaccine 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 vaccine. Currently, no HIV vaccine has 
been approved for use.  
We do not know how the study vaccine will affect a pregnant participant or a 
developing baby.  
Benefits 
22. The study may not benefit you. 
We do not know whether getting the study vaccine 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 
23. 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. 

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Leaving the study 
24. 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 
Site: Approval from HVTN Regulatory Affairs (at vtn.core.reg@hvtn.org) is needed 
for any change (other than those that the instructions specifically request or those 
previously approved by HVTN Regulatory Affairs) to the boxed text  
25. If you get sick or injured during the study, contact us immediately. 
Your health is important to us. (Site: 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 other ways that study-related injuries can be funded. 
We can give you more information if you would like. (Site: 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. 

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Questions  
26. If you have questions or problems at any time during your participation in 
this study, use the following important contacts. 
If you have questions about this study, contact 
[name or title and telephone number of the investigator or other study staff]. 
If you have any symptoms that you think may be related to this study, contact 
[name or title and telephone number of the investigator or other study staff]. 
This study has been reviewed and approved by a committee called the 
[name of local IRB/EC]. If you have questions about your rights as a research 
participant, or problems or concerns about how you are being treated in this study, 
contact 
[name or title and telephone number of person on IRB or other appropriate organization], 
at the committee. 
If you want to leave this study, contact 
[name or title and telephone number of the investigator or other study staff]. 
Your permissions and signature  
Site: Delete this section if using a separate consent for use of samples and 
information in other studies 
27. In Section 16 of this form, we told you about possible other uses of your extra 
samples and information, outside this study. Please choose only one of the 
options below and write your initials or make your mark in the box next to it. 
Whatever you choose, the HVTN keeps track of your decision about how 
your samples and information can be used. 
 

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I allow my extra samples and information to be used for other studies related to 
HIV, vaccines, the immune system, and other diseases. This may include 
genetic testing and keeping my cells growing over time.  
OR 
 
 
I agree to the option above and also to allow my extra samples and information 
to be used in genome wide studies. 
OR 
 
 
I do not allow my extra samples to be used in any other studies. This includes 
not allowing genetic testing, growing more of my cells, or genome wide studies.  
 
28. 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 
Sample informed consent form for Part B 
Title: A phase 1 clinical trial to evaluate the safety and immunogenicity of 
polyvalent env (A,B,C,A/E) / gag (C) DNA and gp120 (A,B,C,A/E) protein/GLA-
SE HIV-1 vaccines (PDPHV-201401) as a prime-boost regimen or co-
administered in repeated doses, in healthy, HIV-1–uninfected adult participants 
HVTN protocol number: HVTN 124 
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 2 HIV vaccines. HIV is the virus that causes AIDS. 
About 60 people will take part in this study at multiple sites, 12 in Part A and 48 
in Part B. The researcher in charge of this study at this clinic is 
[Insert name of site PI]. The US National Institutes of Health (NIH) is paying for 
the study.  
The results from the first 6 people enrolled in Part A showed that one of the 
vaccines did not cause safety problems, so we are continuing with Part B. We will 
first have 10 people join. After we see results from them, we will decide if the 
remaining 38 people should join the study. The decision on whether to move 
forward is always based on the safety of the participants and how they respond to 
the study products. 
You are being invited to join Part B of the study. Part B tests 2 vaccines and 
another study product called an adjuvant, which are described below. We will call 
the vaccines and study adjuvant the “study vaccines.” 
1. We are doing this study to answer several questions. 
 Are the study vaccines safe to give to people? 
 Are people able to take the study vaccines without becoming too 
uncomfortable? 
 How do people’s immune systems respond to the study vaccines? (Your 
immune system protects you from disease.) 

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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. 
Site: Any change to the following boxed text requires approval from HVTN 
Regulatory Affairs at vtn.core.reg@hvtn.org. 
Several studies have tested whether HIV vaccines can reduce the risk of getting 
HIV from another person. In some studies, people who got the vaccine seemed to 
have the same risk of getting HIV as people who did not get the vaccine. In one 
study, people who got the vaccine seemed to have a lower risk of getting HIV 
than people who did not get the vaccine. In 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. We can tell you about the differences.  
We do not know whether the vaccines in this study will affect your risk of getting 
HIV from another person. The risk could be higher, lower, or unchanged. It’s very 
important to avoid exposure to HIV during and after the study. We will tell you 
how to avoid HIV. 
4. The study vaccines are experimental. 
Experimental means we do not know if the vaccines and adjuvant will be safe to 
use in people, or if they will work to prevent HIV infection. These study vaccines 
are used only in research studies. 
There are 2 vaccines in Part B of the study. One of them is a DNA vaccine. It 
contains DNA made in a laboratory. DNA is a natural substance in the body that 
tells the body how to make proteins. Proteins are natural substances that the body 
uses to build and maintain itself, and also to protect itself against disease. The 
DNA in the vaccine tells the body to make 5 proteins that are found in HIV. The 
body’s immune system may respond to these proteins by making cells and 
antibodies that recognize and fight HIV. Antibodies are special proteins made by 
the body that can recognize and prevent infections. 
The second vaccine is a protein vaccine. The vaccine is made of 4 man-made 
proteins that are similar to proteins from the outer surface of the HIV virus. Your 
body’s immune system may respond to this study vaccine by making antibodies 
that recognize and fight against HIV proteins.  

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The 2 vaccines were developed by scientists at the University of Massachusetts 
Medical School (Worcester, Massachusetts) with support from the Division of 
AIDS (DAIDS) at the National Institutes of Health (NIH).  
Sometimes vaccines work better when they are combined with another substance 
that helps to alert the immune system. These substances are called adjuvants. In 
this study, the protein vaccine is mixed with an adjuvant called GLA- SE. The 
study adjuvant was developed by Infectious Disease Research Institute (Seattle, 
Washington). 
We will call the protein vaccine mixed with the GLA-SE adjuvant the “protein 
vaccine.”  
The study vaccines have not been given to people before this study. They have 
been tested in mice and rabbits and appear safe. Even if something looks like it is 
safe or works in animals, it may not be true for people. Part A of this study tested 
the safety of the protein vaccine. This is the first study that will test the DNA and 
protein vaccines given together. 
The GLA-SE adjuvant has been tested in mice, guinea pigs, rats, and rabbits. It 
has also been given to over 900 people in research studies of vaccines for other 
diseases. In those studies, there were no serious safety concerns with the GLA-SE 
adjuvant. This is the first time the GLA-SE adjuvant has been tested with this 
protein vaccine against HIV. 
General risks of vaccines: 
All vaccines can cause fever, chills, rash, aches and pains, nausea, headache, 
dizziness, and feeling tired. Vaccines can also cause pain, redness, swelling, or 
itching where you got the injection. Most people can still do their planned 
activities after getting a vaccine. Rarely, people have side effects that limit their 
normal activities or make them go to the doctor. 
Rarely, a vaccine can cause an allergic reaction, including a rash, hives, or trouble 
breathing. Allergic reactions can be life-threatening. You should tell us if you 
have ever had a bad reaction to any injection or vaccine. 
Very rarely, a vaccine causes an autoimmune disease in a person, or makes an 
autoimmune disease worse. An autoimmune disease happens when your immune 
system attacks your own body, instead of attacking an infection. 
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 GLA-SE adjuvant may also cause the same risks as shown above for vaccines 
in general. It may also cause lack or loss of appetite. 

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Possible risks related to the study vaccines include muscle damage at the site of 
the injection, the production of antibodies which might react with normal body 
tissues and cause an autoimmune disease, temporary lab changes such as a low 
white blood cell count, and insertion of the study product’s DNA into the body’s 
DNA.  
Since 1995, thousands of people have received experimental DNA vaccines for 
diseases such as hepatitis, human papilloma virus (HPV, also known as genital 
warts), and HIV. In these people, the DNA vaccines have not caused serious side 
effects. We expect the risks of the study vaccines in this study to be similar to 
those of other DNA vaccines.  
In an earlier study, people received a similar DNA vaccine and similar protein 
vaccine, with a different adjuvant. Almost everyone had some injection site pain. 
A wide area of redness around the injection site was also common. After either 
vaccine, some people also had injection site swelling, fevers, body aches, 
tiredness, headache, and joint aches. After the DNA vaccine or the protein 
vaccine, a couple of days later, some people developed redness and swelling at a 
previous injection site. After receiving both vaccines, two people developed a 
kind of autoimmune disease called vasculitis that caused a rash in one person, and 
a rash along with kidney and liver injury in another person, who had had a similar 
illness before. These people recovered without any problem. We do not know if 
participants in this study will have similar effects, because the study vaccines and 
study adjuvant are different.  
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 get a study product. Being in more than one study 
may not be safe. 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 want 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: 

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 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. 
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.  
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. 
For the care that we cannot give, we will explain how we will help you get care 
elsewhere. For health problems that are unrelated to the study, we will not pay for 
care. 
8. If you were born female and could become pregnant, you must agree to use 
birth control to join this study. 
Site: If you want to include Appendix C, Approved birth control methods (for sample 
informed consent form), in this consent form, paste it below and delete paragraph 
below. 
You should not become pregnant during the study because we do not know how 
the study vaccines could affect the developing baby. You must agree to use 
effective birth control from 21 days before your first injection until after your last 
required protocol clinic visit. We will talk to you about effective birth control 
methods. They are listed on a handout that we will give to you.  
Being in the study 
If you meet the study requirements and want to join, here is what will happen: 

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9. You will come to the clinic for scheduled visits about [#] times over 
[Insert period of time]. 
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). 
Payments you receive for being in the study may be taxable. We may need to ask 
you for your Social Security number for tax reasons. 
You do not have to pay anything to be in this study. 
11. We will give you either the study vaccines or a placebo.  
Not everyone in this study will get the study vaccines. Some people will get a 
placebo, a substance that does not contain vaccine or adjuvant. We will compare 
the results from people who got the placebo with results from people who got the 
study vaccines. In this study, the placebo is sterile salt water. 
You have a 7-in-8 chance of getting the study vaccines. Whether you get the 
study vaccines or the placebo is completely random, like flipping a coin.  
We have no say in whether you get the study vaccines or the placebo. We will not 
know which one you are getting, and neither will you. Only the pharmacist at this 
clinic will have this information while the study is going on.  
You will have to wait until everyone completes their final study visits to find out 
whether you got the study vaccines or the placebo. This could be several years. 
But, if you have a serious medical problem and need to know what you got before 
the end of the study, we can tell you. 

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12. We will give you the study products on a schedule. 
You will be in Part B of the study, in 1 of 2 groups. You will not know which 
group you will be assigned to. You will get 2 injections of the study products or 
placebo, one in each upper arm. This will happen 5 times during the study. The 
injections are given with a needle and syringe. People in group 2 will get the 
products one at a time, and people in group 3 will get them together. 
Site: If a picture version of the injection schedule has been provided in a separate 
protocol appendix, you may insert it below in place of (or in addition to) the text 
version or give it as a separate document to volunteers if you believe it will be helpful 
to them. You are not required to do either. 
Part B 
Group* 
Month 0 
(Day 0) 
Month 1 
(Day 28) 
Month 3 
(Day 84) 
Month 6 
(Day 168) 
Month 8 
(Day 224) 
21 
people 
2 
DNA 
 + Placebo 
DNA 
+ Placebo 
DNA 
+ Placebo 
Protein with 
GLA-SE 
+ Placebo 
Protein 
with  
GLA-SE 
+ Placebo 
3 
people 
 
Placebo 
+ Placebo 
Placebo 
+ Placebo 
Placebo 
+ Placebo 
Placebo 
+ Placebo 
Placebo 
+ Placebo 
21 
people 
3 
DNA+ 
Protein 
with 
GLA-SE 
DNA+ 
Protein with 
GLA-SE 
DNA+ 
Protein with 
GLA-SE 
DNA+ 
Protein with 
GLA-SE 
DNA+ 
Protein 
with 
GLA-SE 
3 
people 
 
Placebo 
+ Placebo 
Placebo 
+ Placebo 
Placebo 
+ Placebo 
Placebo 
+ Placebo 
Placebo 
+ Placebo 
*(Group 1 was enrolled in Part A of the study.) 
You will have to wait in the clinic for about a half hour after each injection to see 
if there are any problems. Then for that night and for 7 more days, you will need 
to keep track of how you are feeling and if you have any symptoms. Within 3 
days of each injection, we will also ask know how you are doing. If you have a 
problem, we will continue to check on you until it goes away. 
Because this is the first study using these products in people, it is important for 
you to call us if you have any symptoms, issues, or concerns. We may ask you to 
return to the clinic. In the clinic, we may do some additional lab tests. If you have 
a reaction on your skin, we may take a picture of it. If we think it’s needed, we 
may send you to a specialist outside this clinic. You may be asked for your 
permission to take a skin biopsy. You will be given another consent form to 
explain this procedure. You will not have to pay for the specialist or for a skin 
biopsy. We will ask for these medical records to be shared with us so that we can 
use the information for this study.  
In addition to giving you the study products, we will:  
 Do regular HIV testing, as well as counseling on your results and on how to 
avoid getting HIV; 
 Do physical exams; 

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 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; and 
 Take urine and blood samples; 
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 240 mL (1 tablespoon to 1 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 G, 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.  
13. If you agree, we will also collect saliva, rectal fluid, and cervical fluid or 
semen. 
We want to see how the study vaccines affect the parts of the body where people 
may be exposed to HIV: their mouth, rectum, vagina, and penis. At the end of this 
form we will ask if you allow us to collect saliva, 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. 
We will ask you to avoid some activities before we collect these samples. This 
will help make sure your samples give accurate lab readings. 
Saliva 
We will collect saliva from you at 3 visits. We will ask you to spit into a 
container. We may give you chewing wax if you need it to help you produce more 
saliva. We want to collect 3 to 5 mL, which is less than a teaspoon. 
For 1 hour before we collect your saliva, we will ask you to follow these 
instructions: 
 Do not smoke, eat, or drink anything but water, 

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 Do not brush your teeth or use mouthwash, 
 Do not chew gum or tobacco, Site: localize as needed 
 Do not kiss or perform oral sex. 
Rectal Fluid, Cervical Fluid, Semen 
We would also like to collect rectal fluid and cervical fluid (if you were born 
female) or semen (if you were born male). We would do this at 3 visits. If you 
were born female, we will test you for syphilis, gonorrhea, chlamydia, 
trichomonas vaginalis, bacterial vaginosis, and yeast when we collect them. If you 
were born male, we will test you for syphilis, gonorrhea, and chlamydia when we 
collect them. 
We will give you your test results. If you need care, we will tell you about the 
care we can give you here. We will also tell you about care we can help you get 
elsewhere. 
Rectal fluid 
Site: localize measurement units as needed 
We will collect rectal fluid by placing up to 3 small absorbent sponges or swabs 
in the rectum using a plastic tube about 2 cm wide (a little less than an inch). The 
tube will go in about 6½ cm (about 2½ inches) and stay in place for 5 minutes. 
For the 2 days before we collect your rectal fluid, we will ask you to follow these 
instructions:  
 Do not have receptive anal intercourse (having someone else’s penis in your 
anus). 
 Do not put anything into your anus, including cleaning products (creams, gels, 
lotions, pads, etc.), lubricant, enemas or douches (even with water). 
 Do not use any anti-inflammatory creams in or around your anus.  
 We will not collect rectal fluid if you are pregnant, or if we think you may 
have an anal or rectal infection. You should tell us if your rectal area is sore. 
We will not collect rectal fluid if you are menstruating or pregnant, or if we think 
you may have an infection of the rectum. If you are menstruating or have an 
infection, we may ask you to return to collect this sample at another time. 
Cervical fluid (for persons born female) 

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If you are 21 or older, you must have had a Pap smear within the last 3 to 5 years 
with the most recent result being normal. If you have not had a Pap smear within 
the last 3 years and would like to get one, we will tell you where you can get one. 
To collect cervical fluid, we will give you a menstrual cup (a small flexible plastic 
cup, shaped like a bell) to insert into your vagina. You will wear the cup for 6 
hours. The study staff will explain how to insert and remove the cup, or they can 
do it for you here. 
For the 2 days before we collect your cervical fluid, we will ask you these things:  
 Do not use any spermicide, lubricants, douche (even with water), or 
medication in or around your vagina;  
 Do not have vaginal intercourse or insert anything into your vagina.  
We will not collect cervical fluid if you are menstruating or pregnant or if we 
think you may have a cervical or vaginal infection. If you are menstruating or 
have an infection, we may ask you to return to collect this sample at another time. 
Semen (for persons born male) 
You may provide the semen at home or here. We will give you a plastic cup and 
ask you to ejaculate into it. We must receive the semen sample within 2 hours or 
less after it is collected. For at least 2 days before providing the semen, we will 
ask you: 
 not to have sex, including insertive oral sex (putting your penis in 
someone else’s mouth); 
 not to ejaculate; 
 not to use anything with lubricants; 
 not to put saliva on the penis.  
You should tell us if you think you have an infection on your penis. If you have 
an infection, we may ask you to return to collect this sample at another time. 
14. If you agree, we will also collect stool samples. 
At the end of this form, we will ask if you allow us to collect stool samples. 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 ask you to do this two times during this 
study.  

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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. If you would like, we can 
collect a stool sample in the clinic by doing rectal swabs. If that is what you 
choose, we will briefly insert sterile swabs into your rectum.  
You can decide not to give these samples and still be in the study. 
15. We will counsel you on avoiding HIV infection. 
We will ask you personal questions about your HIV risk factors such as sexual 
behavior, alcohol, and drug use. We will talk with you about ways to keep your 
risk of getting HIV low.  
16. The HVTN will test your samples to see how your immune system responds 
to the study products. 
We will send your samples (without your name) to labs approved by the HVTN 
for this study, which are located in the United States. In rare cases, some of your 
samples may be sent to labs approved by the HVTN in other countries for 
research related to this study. 
Researchers may also do genetic testing related to this study on your samples. 
Your genes are passed to you from your birth parents. They affect how you look 
and how your body works. The differences in people’s genes can help explain 
why some people get a disease while others do not. The genetic testing will only 
involve some of your genes, not all of your genes (your genome). The researchers 
will study only the genes related to the immune system and HIV and those that 
affect how people get HIV. 
If you become HIV infected, the researchers may look at all of the genes of the 
virus found in your samples. If you give stool, semen, saliva, cervical, 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.  
These tests done on your samples are for research purposes, not to check your 
health. The labs will not give the results to you or this clinic, because their tests 
are not approved for use in making health care decisions. These labs are only 
approved to do research tests.  
When your samples are no longer needed for this study, the HVTN will continue 
to store them. 

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Site: Delete next section if using separate consent for use of samples and information 
in other studies 
17. When samples are no longer needed for this study, the HVTN wants to use 
them in other studies and share them with other researchers. 
The HVTN calls these samples “extra samples”. The HVTN will only allow your 
extra samples to be used in other studies if you agree to this. You will mark your 
decision at the end of this form. If you have any questions, please ask. 
Do I have to agree? No. You are free to say yes or no, or to change your mind 
after you sign this form. At your request, we will destroy all extra samples that we 
have. Your decision will not affect your being in this study or have any negative 
consequences here.  
Where are the samples stored? Extra samples are stored in a secure central place 
called a repository. [Site: choose one of the following two sentences. African sites 
should choose the sentence referencing the repository in South Africa. All other 
sites should choose the sentence referencing the repository in the United States]. 
Your samples will be stored in the HVTN repository in South Africa. Your 
samples will be stored in the HVTN repository in the United States.  
How long will the samples be stored? There is no limit on how long your extra 
samples will be stored. [Site: Revise the previous sentence to insert limits if your 
regulatory authority imposes them.] 
Will I be paid for the use of my samples? No. Also, a researcher may make a new 
scientific discovery or product based on the use of your samples. If this happens, 
there is no plan to share any money with you. The researcher is not likely to ever 
know who you are. 
Will I benefit from allowing my samples to be used in other studies? Probably not. 
Results from these other studies are not given to you, this clinic, or your doctor. 
They are not part of your medical record. The studies are only being done for 
research purposes. 
Will the HVTN sell my samples and information? No, but the HVTN may share 
your samples with HVTN or other researchers. Once we share your samples and 
information, we may not be able to get them back. 
How do other researchers get my samples and information? When a researcher 
wants to use your samples and information, their research plan must be approved 
by the HVTN. Also, the researcher’s institutional review board (IRB) or ethics 
committee (EC) will review their plan. [Site: If review by your institution’s 
IRB/EC/RE is also required, insert a sentence stating this.] IRBs/ECs protect the 
rights and well-being of people in research. If the research plan is approved, the 
HVTN will send your samples to the researcher’s location.  

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What information is shared with HVTN or other researchers? The samples and 
information will be labeled with a code number. Your name will not be part of the 
information. However, some information that we share may be personal, such as 
your race, ethnicity, sex, health information from the study, and HIV status. We 
may share information about the study product you received and how your body 
responded to the study product.  
What kind of studies might be done with my extra samples and information? The 
studies will be related to HIV, vaccines, the immune system and other diseases.  
Researchers may also do genetic testing on your samples.  
In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to contribute to this study.  
If you agree, your samples could also be used for genome wide studies. In these 
studies, researchers will look at all of your genes (your genome). The researchers 
compare the genomes of many people, looking for common patterns of genes that 
could help them understand diseases. The researchers may put the information 
from the genome-wide studies into a protected database so that other researchers 
can access it. Usually, no one would be able to look at your genome and link it to 
you as a person. However, if another database exists that also has information on 
your genome and your name, someone might be able to compare the databases 
and identify you. If others found out, it could lead to discrimination or other 
problems. The risk of this is very small. 
Who will have access to my information in studies using my extra samples?  
People who may see your information are: 
 Researchers who use your extra samples and information for other research 
 Government agencies that fund or monitor the research using your extra 
samples and information 
 The researcher’s Institutional Review Board or Ethics Committee 
 The people who work with the researcher  
All of these people will do their best to protect your information. The results of 
any new studies that use your extra samples and information may be published. 
No publication will use your name or identify you personally. 
18. We will do our best to protect your private information. 
Site: 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 

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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. 
Site: Any change to the following boxed text requires approval from HVTN 
Regulatory Affairs.  
We do need to share your name with the HVTN in case you need proof in the 
future that you participated in an HIV vaccine study. The HVTN will keep your 
name in a secure file with these items:  
 The name of your study  
 Your age or date of birth  
 Your study ID number  
 What study product(s) you received  
There are no HIV test results kept in this file. The HVTN will not share any 
information that could identify you without your agreement. The HVTN will 
remove your name from the file if you do not want it there. 
Clinic staff will have access to your study records. Your records may also be 
reviewed by groups who watch over this study to see that we are protecting your 
rights, keeping you safe, and following the study plan. These groups include: 
 The US National Institutes of Health and its study monitors, 
 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 University of Massachusetts Medical School and people who work for 
them, 
 The Infectious Disease Research Institute 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. 

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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] 
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. 
A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov. This website will not include information that can 
identify you. At most, the website will include a summary of the results. You can 
search this website at any time. 
19. We may stop your injections or take you out of the study at any time. We 
may do this even if you want to stay in the study and even if you were 
scheduled for more injections.  
This may happen if: 
 you do not follow instructions, 
 we think that staying in the study might harm you, 
 you get HIV, 
 you enroll in a different research study where you get another study product, 
or 
 the study is stopped for any reason. 

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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. 
We will encourage you to stay in the study if you choose. We will discuss your 
study options with you. 
If you leave the study while you are still pregnant, we will contact you after your 
due date to ask some questions about your pregnancy and delivery. 
21. If you get infected with HIV during the study, we will 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. 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 where you got the injection. Taking blood can cause a low blood cell 
count (anemia), making you feel tired. 
Risks of collecting semen, rectal and cervical fluids: 
For semen collection, you may be asked not to ejaculate for a few days before 
providing the sample. You may find this inconvenient.  
You may have some discomfort during sample collection, and minor bleeding 
during collection of rectal fluids. This does not usually last very long. 
During any of these procedures, you may feel anxious or embarrassed. If you feel 
uncomfortable in any way, please tell us and we will try to help you. 
Risks of rectal swab: 

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If you choose to provide a stool sample by rectal swabbing, you may feel pressure 
as the swab is inserted into your rectum, but it is usually not painful. Some people 
might have a little bit of bleeding.  
Personal problems/discrimination/testing HIV antibody positive: 
About 10 to 20% of people who join HVTN studies report personal problems or 
discrimination because of joining an HIV vaccine study. Family or friends may 
worry, get upset or angry, or assume that you are infected with HIV or at high risk 
and treat you unfairly as a result. Rarely, a person has lost a job because the study 
took too much time away from work, or because their employer thought they had 
HIV.  
The body makes antibodies to fight or prevent infection. Most vaccines cause the 
body to make antibodies as a way of preventing infection. Your body may make 
antibodies to HIV because you received HIV study vaccines. The study vaccines 
may cause you to test positive on some types of HIV antibody 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 may 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 have a positive test result caused by the study vaccines at any time, we can 
arrange free HIV testing for as long as you need it. If this happens, we do not 
know how long you will test positive due to the study vaccines. If you receive a 
positive HIV test result and we determine it is because you have HIV, we will 
refer you for follow-up care. 
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, in some countries, you could be denied medical or dental 
care, employment, insurance, a visa, or entry into the military. 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 

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danger to the baby, and they go away over time. For most babies antibodies from 
the mother last for about six months. 
You should always tell the delivery staff if you have VISP. However, you may 
still be tested for HIV using the antibody test when you deliver your baby. If your 
test is positive and the delivery staff believes you have an HIV infection, your 
baby may be started on antiretroviral treatment when it is not needed. If this 
happens, we can arrange for you and the baby to have a test that can tell the 
difference between true HIV infection and a VISP result. If you or the baby 
continue to have VISP, we can arrange this testing for free for as long as it is 
needed. 
Embarrassment/anxiety:  
You may feel embarrassed when we ask about your HIV risks, such as having sex 
and using drugs. Also, waiting for your HIV test results or other health test results 
could make you feel anxious. You could feel worried if your test results show that 
you are infected with HIV. If you feel embarrassed or anxious, please tell us and 
we will try to help you. 
Risks of disclosure of your personal information: 
We will take several steps to protect your personal information. Although the risk 
is very low, it is possible that your personal information could be given to 
someone who should not have it. If that happened, you could face discrimination, 
stress, and embarrassment. We can tell you more about how we will protect your 
personal information if you would like it.  
Risks of genetic testing: 
It is unlikely, but the genetic tests done on your samples could show you may be 
at risk for certain diseases. If others found out, it could lead to discrimination or 
other problems. However, it is almost impossible for you or others to know your 
test results from the genetic testing. The results are not part of your study records 
and are not given to you.  
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. 

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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.  
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. 

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Injuries 
Site: Approval from HVTN Regulatory Affairs (at vtn.core.reg@hvtn.org) is needed 
for any change (other than those that the instructions specifically request or those 
previously approved by HVTN Regulatory Affairs) to the following section . 
26. If you get sick or injured during the study, contact us immediately. 
Your health is important to us. (Site: 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 other ways that study-related injuries can be funded. 
We can give you more information if you would like. (Site: insert locale- 
appropriate medical insurance language in the following sentence) If the injury is 
not study related, then you and your health insurance will be responsible for 
treatment costs.  
Some injuries are not physical. For example, you might be harmed emotionally by 
being in an HIV vaccine study. Or you might lose wages because you cannot go 
to work. However, there are no funds to pay for these kinds of injuries, even if 
they are study related. 
You may disagree with the decision about whether your injury is study related. If 
you wish, the HVTN will ask independent experts to review the decision. You 
always have the right to use the court system if you are not satisfied. 
Questions  
27. If you have questions or problems at any time during your participation in 
this study, use the following important contacts. 
If you have questions about this study, contact 
[name or title and telephone number of the investigator or other study staff]. 
If you have any symptoms that you think may be related to this study, contact 
[name or title and telephone number of the investigator or other study staff]. 
This study has been reviewed and approved by a committee called the 
[name of local IRB/EC]. If you have questions about your rights as a research 
participant, or problems or concerns about how you are being treated in this study, 
contact 

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[name or title and telephone number of person on IRB or other appropriate organization], 
at the committee. 
If you want to leave this study, contact 
[name or title and telephone number of the investigator or other study staff]. 
Your permissions and signature  
Site: Delete this section if using a separate consent for use of samples and 
information in other studies 
28. In Section 17 of this form, we told you about possible other uses of your extra 
samples and information, outside this study. Please choose only one of the 
options below and write your initials or make your mark in the box next to it. 
Whatever you choose, the HVTN keeps track of your decision about how 
your samples and information can be used. 
 
 
I allow my extra samples and information to be used for other studies related to 
HIV, vaccines, the immune system, and other diseases. This may include 
genetic testing and keeping my cells growing over time.  
OR 
 
 
I agree to the option above and also to allow my extra samples and information 
to be used in genome wide studies. 
OR 
 
 
I do not allow my extra samples to be used in any other studies. This includes 
not allowing genetic testing, growing more of my cells, or genome wide studies.  
 
29. In sections 13 and 14 of this form, we told you about optional collection of 
stool samples, saliva, 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 saliva. 
 
 
I do not agree to provide 
saliva. 
 

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I agree to provide rectal 
fluid. 
 
 
I do not agree to provide rectal 
fluid. 
 
 
I agree to provide semen or cervical 
fluid. 
 
 
I do not agree to provide semen or cervical fluid
 
 
 
I agree to provide stool samples. 
 
 
I do not agree to provide stool 
samples. 
30. If you agree to join this study, you will need to sign or make your mark 
below. Before you sign or make your mark on this consent form, make sure 
of the following: 
 You have read this consent form, or someone has read it to you. 
 You feel that you understand what the study is about and what will happen to 
you if you join. You understand what the possible risks and benefits are. 
 You have had your questions answered and know that you can ask more. 
 You agree to join this study. 
You will not be giving up any of your rights by signing this consent form. 

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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 C 
Approved birth control methods (for sample 
informed consent form) 
Site: Any change to the following boxed text requires approval from HVTN 
Regulatory Affairs at vtn.core.reg@hvtn.org. 
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 21 days before your first 
injection until after your last required protocol clinic visit. 
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; 
 Intrauterine device (IUD); or 
 Any other contraceptive method approved by the researchers. 
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. 
If you join the study, we will test you for pregnancy at some visits, including 
before each study injection. 

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Appendix D 
Sample consent form for use of samples and 
information in other studies 
Title: A phase 1 clinical trial to evaluate the safety and immunogenicity of 
polyvalent env (A,B,C,A/E) / gag (C) DNA and gp120 (A,B,C,A/E) protein/GLA-
SE HIV-1 vaccines (PDPHV-201401) as a prime-boost regimen or co-
administered in repeated doses, in healthy, HIV-1–uninfected adult participants 
HVTN protocol number: HVTN 124 
Site: [Insert site name] 
When samples are no longer needed for this study, the HVTN wants to use them 
in other studies and share them with other researchers. 
The HVTN calls these samples “extra samples”. The HVTN will only allow your 
extra samples to be used in other studies if you agree to this. You will mark your 
decision at the end of this form. If you have any questions, please ask.  
1. Do I have to agree?  
No. You are free to say yes or no, or to change your mind after you sign this form. 
At your request, we will destroy all extra samples that we have. Your decision 
will not affect your being in this study or have any negative consequences here.  
2. Where are the samples stored?  
Extra samples are stored in a secure central place called a repository. Your 
samples will be stored in the HVTN repository in the United States. 
3. How long will the samples be stored?  
There is no limit on how long your extra samples will be stored. [Site: Revise the 
previous sentence to insert limits if your regulatory authority imposes them.] 
4. Will I be paid for the use of my samples?  
No. Also, a researcher may make a new scientific discovery or product based on 
the use of your samples. If this happens, there is no plan to share any money with 
you. The researcher is not likely to ever know who you are. 
5. Will I benefit from allowing my samples to be used in other studies?  
Probably not. Results from these other studies are not given to you, this clinic, or 
your doctor. They are not part of your medical record. The studies are only being 
done for research purposes. 

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6. Will the HVTN sell my samples and information?  
No, but the HVTN may share your samples with HVTN or other researchers. 
Once we share your samples and information, we may not be able to get them 
back. 
7. How do other researchers get my samples and information?  
When a researcher wants to use your samples and information, their research plan 
must be approved by the HVTN. Also, the researcher’s institutional review board 
(IRB) or ethics committee (EC) will review their plan. [Site: If review by your 
institution’s IRB/EC/RE is also required, insert a sentence stating this.] IRBs/ECs 
protect the rights and well-being of people in research. If the research plan is 
approved, the HVTN will send your samples to the researcher’s location. 
8. What information is shared with HVTN or other researchers?  
The samples and information will be labeled with a code number. Your name will 
not be part of the information. However, some information that we share may be 
personal, such as your race, ethnicity, gender, health information from the study, 
and HIV status. We may share information about the study product you received 
and how your body responded to the study product.  
9. What kind of studies might be done with my extra samples and information?  
The studies will be related to HIV, vaccines, the immune system and other 
diseases.  
Researchers may also do genetic testing on your samples.  
In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to contribute to this study. 
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? 
It is unlikely, but the genetic tests done on your samples could show you may be 
at risk for certain diseases. If others found out, it could lead to discrimination or 
other problems. However, it is almost impossible for you or others to know your 

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test results from the genetic testing. The results are not part of your study records 
and are not given to you.  
In the very unlikely event that your genetic information becomes linked to your 
name, a federal law called the Genetic Information Nondiscrimination Act 
(GINA) helps protect you. GINA keeps health insurance companies and 
employers from seeing results of genetic testing when deciding about giving you 
health insurance or offering you work. GINA does not help or protect you against 
discrimination by companies that sell life, disability or long-term care insurance.  
11. Who will have access to my information in studies using my extra samples? 
People who may see your information are: 
 Researchers who use your extra samples and information for other research 
 Government agencies that fund or monitor the research using your extra 
samples and information 
 The researcher’s Institutional Review Board or Ethics Committee 
 The people who work with the researcher  
All of these people will do their best to protect your information. The results of 
any new studies that use your extra samples and information may be published. 
No publication will use your name or identify you personally. 
Questions  
12. If you have questions or problems about allowing your samples and 
information to be used in other studies, use the following important contacts. 
If you have questions about the use of your samples or information or if you want 
to change your mind about their use, contact 
[name or title and telephone number of the investigator or other study staff]. 
If you think you may have been harmed because of studies using your samples or 
information, contact 
[name or title and telephone number of the investigator or other study staff]. 
If you have questions about your rights as a research participant, contact 
[name or title and telephone number of person on IRB or other appropriate organization]. 

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13. Please choose only one of the options below and write your initials or make 
your mark in the box next to it. Whatever you choose, the HVTN keeps track 
of your choice about how your samples and information can be used. 
 
I allow my extra samples and information to be used for other studies related to 
HIV, vaccines, the immune system, and other diseases. This may include 
genetic testing and keeping my cells growing over time.  
OR 
 
 
I agree to the option above and also to allow my extra samples and information 
to be used in genome wide studies. 
 
OR 
 
 
I do not allow my extra samples to be used in any other studies. This includes 
not allowing genetic testing, growing more of my cells, or genome wide studies.  
 
 
 
 
 
 
 
 
 
 
Participant’s name (print) 
 
Participant’s signature or mark 
 
Date 
 
Time 
 
 
 
 
 
 
 
Clinic staff conducting consent 
discussion (print) 
 
Clinic staff signature 
 
Date 
 
Time 
For participants who are unable to read or write, a witness should complete the signature 
block below: 
 
 
 
 
 
 
 
Witness’s name (print) 
 
Witness’s signature  
 
Date 
 
Time 
*Witness is impartial and was present for the consent process.

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Appendix E 
Injection schedule for Part A and B sample 
informed consent forms 
 

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Appendix F 
Table of procedures for Part A (for sample 
informed consent form) 
 
 
 
Time after first injection visit  
Procedure 
Screening 
visit(s) 
First 
injection 
visit  
2 weeks 
2 months 
2.5 months 
5 months 
8 months 
1 year + 2 
months 
Injections 
 
√ 
 
√ 
 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
Complete physical 
√ 
 
 
 
 
 
√ 
 
Brief physical 
 
√ 
√ 
√ 
√ 
√ 
 
 
Urine test 
√ 
 
√ 
 
√ 
 
 
 
Blood drawn 
√ 
√ 
√ 
 
√ 
√ 
√ 
 
Pregnancy test 
(participants born 
female)* 
√ 
√ 
 
√ 
 
√ 
 
 
HIV testing & pretest 
counseling 
√ 
 
 
 
√ 
√ 
√ 
 
Risk reduction 
counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Interview/questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Health contact 
 
 
 
 
 
 
 
√ 
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.  
*Persons who had a total hysterectomy (removal of the uterus) or removal of both ovaries (verified by medical 
records), are not required to have a pregnancy test.

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Appendix G 
Table of procedures for Part B (for sample informed consent form) 
 
 
 
Time after first injection visit  
Procedure 
Part B  
Eligibility  
visit(s) 
First 
injection 
visit  
2 weeks 
1 month 
6 weeks 
3 months 
3½ months 
6 months 
6½ months 
8 months 
8 months + 1 
week 
8½ months 
11 months 
1 year + 2 
months 
1 year + 8 
months 
Injections 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
 
Brief physical 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Urine test 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
√ 
 
 
 
Blood drawn 
√ 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
√ 
√ 
√ 
 
Pregnancy test 
(participants born 
female)1 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√2 
√ 
√2 
 
HIV testing & pretest 
counseling 
√ 
 
 
 
 
 
√ 
 
√ 
 
 
√ 
√ 
√ 
 
Risk reduction 
counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Interview/questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Saliva, semen, cervical, 
and rectal fluid 
(optional) 
 
√ 
 
 
 
 
 
 
 
 
 
√ 
 
√ 
 
Genital Tract Infection 
testing (blood, urine 
and/or swabs) for 
people who agree to 
provide the optional 
samples 
 
√ 
 
 
 
 
 
 
 
 
 
√ 
 
√ 
 
Stool samples (optional) 
 
√ 
 
 
 
 
 
 
 
 
 
√ 
 
 
 
Health contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
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.  
1Persons who had a total hysterectomy (removal of the uterus) or removal of both ovaries (verified by medical records), are not required to have a pregnancy test 
2Only for participants who agree to provide optional rectal and cervical fluid samples 
 

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Appendix H 
Laboratory procedures – Part A (1 of 2) 
Visit:
1
2
3
4
5
6
7
810
Day:
D0
D14
D56
D70
D140
D224
D425
Week:
W0
W2
W8
W10
W20
W32
W61
Month:
M0
M0.5
M2
M2.5
M5
M8
M14
VAC1
VAC2
Procedure
Ship to1
Tube4
Tube size (vol. 
capacity)4
BLOOD COLLECTION
Screening or diagnostic assays
     Screening HIV test
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
5
     HBsAg/anti-HCV
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
5
     Syphilis
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
5
     HIV diagnostics 9
UW-VSL
UW-VSL
EDTA
10mL
—
—
—
—
10
10
209
—
40
Safety labs
     CBC/ Diff/ platelets
Local lab
Local lab
EDTA
5mL
5
—
5
—
5
5
—
—
20
     Chemistry panel5
Local lab
Local lab
SST
5mL
5
—
5
—
5
5
—
—
20
Immunogenicity assays 6
     Host genetics 7
CSR
HVTN Labs
ACD
8.5mL
—
17
—
—
—
—
—
—
17
     Cellular assays
          ICS
CSR
HVTN Labs
ACD
8.5mL
—
—
—
—
42.5
—
—
—
42.5
     Humoral assays
          Binding Ab
CSR
HVTN Labs
SST
8.5mL
—
8.5
8.5
—
8.5
—
8.5
—
34
Specimen storage
     PBMC
CSR
ACD
8.5mL
—
119
102
—
76.5
—
102
—
399.5
     Serum
CSR
SST
8.5mL
—
17
17
—
17
—
17
—
68
Visit total
25
161.5
137.5
0
164.5
20
148
0
656
56-Day total
25
186.5
324
324
302
20
148
0
URINE COLLECTION
      Urine dipstick11
Local lab
Local lab
X
—
X
—
X
—
—
—
      Pregnancy test8
Local lab
Local lab
X
X
—
X
—
X
—
—
Tube volume (mL)
Total
Screening 
visit3
Assay Location2
 
 
 
 

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Footnotes for Laboratory procedures – Part A (2 of 2) 
1CSR = Central Specimen Repository; UW-VSL = University of Washington Virology Specialty Laboratory (Seattle, Washington, USA). 
2HVTN Laboratories include: Fred Hutchinson Cancer Research Center (Seattle, Washington, USA); Duke University Medical Center (Durham, North Carolina, USA). 
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 M2.5. 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 participants born female. Pregnancy test may be performed on blood specimens. Persons who are NOT of reproductive potential due to having undergone total 
hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing. 
9At an early termination visit for a withdrawn or terminated participant (see Section 9.14), blood should be drawn for HIV diagnostic testing, as shown for visit 7 above.  
10For information concerning the Month 14 health contact, see Section 9.7. Clinic visits are not required except that any participant reporting a diagnosis of HIV infection from 
testing outside of the HVTN will be asked to come to the clinic to collect specimens for HIV testing with HVTN HIV diagnostic algorithms. 
11And microscopy if needed. 

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Appendix I 
Laboratory procedures – Part B (1 of 2) 
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1514
Day:
D0
D14
D28
D42
D84
D98
D168
D182
D224
D231
D238
D334
D425
D607
Week:
W0
W2
W4
W6
W12
W14
W24
W26
W32
W33
W34
W48
W61
W87
Month:
M0
M0.5
M1
M1.5
M3
M3.5
M6
M6.5
M8
M8.25
M8.5
M11
M14
M20
VAC1
VAC2
VAC3
VAC4
VAC5
Procedure
Ship to1
Tube4
Tube size (vol. 
capacity)4
BLOOD COLLECTION
Screening or diagnostic assays
     Screening HIV test
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     HBsAg/anti-HCV
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     Syphilis
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
511
—
511
—
15
     HIV diagnostics 9
UW-VSL
UW-VSL
EDTA
10mL
—
—
—
—
—
—
10
—
10
—
—
10
10
209
—
60
Safety labs
     CBC/ Diff/ platelets
Local lab
Local lab
EDTA
5mL
5
—
5
—
5
—
5
—
5
—
—
5
5
—
—
35
     Chemistry panel5
Local lab
Local lab
SST
5mL
5
—
5
—
5
—
5
—
5
—
—
5
5
—
—
35
Immunogenicity assays 6
     Host genetics 7
CSR
HVTN Labs
ACD
8.5mL
—
17
—
—
—
—
—
—
—
—
—
—
—
—
—
17
     Cellular assays
          ICS
CSR
HVTN Labs
ACD
8.5mL
—
—
—
—
—
—
42.5
—
42.5
—
—
42.5
—
68
—
195.5
          pTfh and plasmablasts
CSR
HVTN Labs
ACD
8.5mL
—
42.5
—
—
—
—
—
—
—
—
42.5
—
—
—
—
85
          B-cell ELISpot
CSR
HVTN Labs
ACD
8.5mL
—
17
—
—
—
—
17
—
17
—
—
17
—
17
—
85
          B-cell phenotyping
CSR
HVTN Labs
ACD
8.5mL
—
17
—
—
—
—
17
—
17
—
—
17
—
17
—
85
     Humoral assays
          Binding Ab
CSR
HVTN Labs
SST
8.5mL
—
8.5
—
—
—
—
8.5
—
8.5
—
—
8.5
—
8.5
—
42.5
          Neutralizing Ab
CSR
HVTN Labs
SST
8.5mL
—
8.5
—
—
—
—
8.5
—
8.5
—
—
8.5
—
8.5
—
42.5
          ADCC
CSR
HVTN Labs
SST
8.5mL
—
y
—
—
—
—
y
—
y
—
—
y
—
y
—
0
Specimen storage
     PBMC
CSR
ACD
8.5mL
—
76.5
—
—
76.5
—
76.5
—
68
—
25.5
76.5
—
76.5
—
476
     Serum
CSR
SST
8.5mL
—
17
—
—
17
—
17
—
8.5
—
8.5
17
—
17
—
102
Visit total
25
204
10
0
103.5
0
207
0
190
0
76.5
212
20
237.5
0
1285.5
56-Day total
25
229
239
239
342.5
103.5
310.5
0
190
190
266.5
478.5
20
237.5
0
URINE COLLECTION
      Urine dipstick15
Local lab
Local lab
X
—
X
—
X
—
X
—
X
—
—
X
—
—
—
      Pregnancy test8
Local lab
Local lab
X
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)
      Saliva
CSR
HVTN Labs
—
X13
—
—
—
—
—
—
—
—
—
X
—
X
—
      Semen
CSR
HVTN Labs
—
X13
—
—
—
—
—
—
—
—
—
X
—
X
—
      Cervical Secretions
CSR
HVTN Labs
—
X13
—
—
—
—
—
—
—
—
—
X
—
X
—
      Rectal Secretions
CSR
HVTN Labs
—
X13
—
—
—
—
—
—
—
—
—
X
—
X
—
STOOL COLLECTION (OPTIONAL)
      Stool 
CSR
HVTN Labs
—
X16
—
—
—
—
—
—
—
—
—
X
—
—
—
Screening 
visit3
Assay Location2
Total
Tube volume (mL)
 
 
 

Version 1.0 / September 28, 2017 
HVTN124_v1.0_FINAL.docx / Page 165 of 171 
Footnotes for Laboratory procedures – Part B (2 of 2) 
1CSR Central Specimen Repository; UW-VSL = University of Washington Virology Specialty Laboratory (Seattle, Washington, USA). 
2HVTN Laboratories include Fred Hutchinson Cancer Research Center (Seattle, Washington, USA); Duke University Medical Center (Durham, North Carolina, USA). 
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 M8.5. 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 participants born female. Pregnancy test may be performed on blood specimens. Persons who are NOT of reproductive potential due to having undergone total 
hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing. 
9At an early termination visit for a withdrawn or terminated participant (see Section 9.14), blood should be drawn for HIV diagnostic testing, as shown for visit 14 above.  
10Pregnancy testing at the indicated visit is only required of participants who are born female and are providing a cervical and/or rectal fluid sample. 
11Syphilis testing by serology and Chlamydia and Gonorrhea testing by urine will only be performed if the participant agrees to provide a semen, cervical, or rectal mucosal 
sample. 
12Cervical/vaginal swabs will only be collected from participants who agree to provide a cervical fluid sample and for yeast if clinically indicated. 
13Optional mucosal specimens may be collected as part of screening and prior to the enrollment visit once the participant has been found to have met mucosal specimen 
collection criteria as specified in Section 9.5. 
14For information concerning the Month 20 health contact, see Section 9.7. Clinic visits are not required except that any participant reporting a diagnosis of HIV infection from 
testing outside of the HVTN will be asked to come to the clinic to collect specimens for HIV testing with HVTN HIV diagnostic algorithms. 
15And microscopy if needed. 
16Optional stool specimen must be collected prior to first vaccination. 
y = SST collected for binding Ab and neutralizing Ab assays will also cover specimen needs for ADCC; no separate blood draw is needed. 

Version 1.0 / September 28, 2017 
HVTN124_v1.0_FINAL.docx / Page 166 of 171 
Appendix J 
Procedures at HVTN CRS - Part A (1 of 2) 
Visit: 
011,2 
022 
03 
04 
05 
06 
7 
83 
Post 
Day: 
 
D0 
D14 
D56 
D70 
D140 
D224 
D425 
 
Month: 
 
M0 
M0.5 
M2 
M2.5 
M5 
M8 
M14 
 
Procedure 
Scr. 
VAC1 
 
VAC2 
 
 
 
 
 
Study procedures 
 
 
 
 
 
 
 
 
 
Signed screening consent (if used) 
X 
— 
— 
— 
— 
— 
— 
— 
— 
Assessment of understanding 
X 
— 
— 
— 
— 
— 
— 
— 
— 
Signed protocol consent 
X 
— 
— 
— 
— 
— 
— 
— 
— 
Medical history  
X 
— 
— 
— 
— 
— 
— 
— 
— 
Complete physical exam 
X 
— 
— 
— 
— 
— 
X 
— 
— 
Abbreviated physical exam 
— 
X 
X 
X 
X 
X 
 
— 
— 
Risk reduction counseling 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Pregnancy assessment4 
X 
X 
— 
X 
— 
X 
— 
— 
— 
Pregnancy prevention assessment5 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Behavioral risk assessment 
X 
— 
— 
— 
— 
X 
X 
— 
— 
Confirm eligibility, obtain 
demographics, randomize  
X 
— 
— 
— 
— 
— 
— 
— 
— 
Social impact assessment 
— 
X 
X 
X 
X 
X 
X 
— 
— 
Social impact assessment 
questionnaire 
— 
— 
— 
X 
— 
— 
X 
— 
— 
Outside testing and belief 
questionnaire 
— 
— 
— 
— 
— 
X 
X 
— 
— 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Intercurrent illness/adverse 
experience 
— 
X 
X 
X 
X 
X 
X 
— 
— 
HIV infection assessment6 
X 
— 
— 
— 
X 
X 
X 
— 
— 
Confirm HIV test results provided 
to participant 
— 
X 
— 
— 
— 
X 
X 
X 
— 
Health contact 
— 
— 
— 
— 
— 
— 
— 
X 
— 
Specimen collection7 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Vaccination procedures 
 
 
 
 
 
 
 
 
 
Vaccination8 
— 
X 
— 
X 
— 
— 
— 
— 
— 
Reactogenicity assessments9 
— 
X 
— 
X 
— 
— 
— 
— 
— 
Poststudy 
 
 
 
 
 
 
 
 
 
Unblind participant 
— 
— 
— 
— 
— 
— 
— 
— 
X 

Version 1.0 / September 28, 2017 
HVTN124_v1.0_FINAL.docx / Page 167 of 171 
Footnotes for Procedures at HVTN CRS – Part A (2 of 2) 
1Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination. 
2Specimens indicated for day 0 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 
3See Section 9.7. Clinic visits are not required except that any participant reporting a diagnosis of HIV infection 
from testing outside of the HVTN will be asked to come to the clinic to collect specimens for HIV testing with 
HVTN HIV diagnostic algorithms.  
4For 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. 
5Pregnancy prevention assessment is required only for participants who were born female and are capable of 
becoming pregnant. 
6Includes pre-test counseling. A subsequent follow-up contact is conducted to provide post-test counseling and 
to report results to participant. 
7See Clinical procedures sections 9.2, 9.3, 9.4, 9.5, 9.6, Laboratory procedures section 10, and Appendix H. 
8Blood 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. 
9Reactogenicity assessments performed daily for at least 7 days post vaccination (see Section 9.11).

Version 1.0 / September 28, 2017 
HVTN124_v1.0_FINAL.docx / Page 168 of 171 
Appendix K 
Procedures at HVTN CRS - Part B (1 of 2) 
Visit: 
011,2 
022 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
153 
Post 
Day: 
 
D0 
D14 
D28 
D42 
D84 
D98 
D168 
D182 
D224 
D231 
D238 
D334 
D425 
D607 
 
Month: 
 
M0 
M0.5 
M1 
M1.5 
M3 
M3.5 
M6 
M6.5 
M8 
M8.25 
M8.5 
M11 
M14 
M20 
 
Procedure 
Scr. 
VAC1 
 
VAC2 
 
VAC3 
 
VAC4 
 
VAC5 
 
 
 
 
 
 
Study procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed screening consent (if used) 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Assessment of understanding 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Signed protocol consent 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Medical history  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Complete physical exam 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
Abbreviated physical exam 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
— 
Risk reduction counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Pregnancy assessment4 
X 
X 
— 
X 
— 
X 
— 
X 
— 
X 
— 
X5 
X 
X5 
— 
— 
Pregnancy prevention assessment6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Behavioral risk assessment 
X 
— 
— 
— 
— 
X 
— 
X 
— 
— 
— 
— 
X 
X 
— 
— 
Confirm eligibility, obtain 
demographics, randomize  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Social impact assessment 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Social impact assessment 
questionnaire 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
— 
X 
X 
— 
— 
Outside testing and belief 
questionnaire 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
— 
X 
X 
— 
— 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Intercurrent illness/adverse 
experience 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
HIV infection assessment7 
X 
— 
— 
— 
— 
— 
X 
— 
X 
— 
— 
X 
X 
X 
— 
— 
Confirm HIV test results provided 
to participant 
— 
X 
— 
— 
— 
— 
— 
X 
— 
X 
— 
— 
X 
X 
X 
— 
Stool sample (optional) 
— 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
— 
Dietary and GI symptom 
questionnaire8 
— 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
— 
Health contact 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 

Version 1.0 / September 28, 2017 
HVTN124_v1.0_FINAL.docx / Page 169 of 171 
Procedures at HVTN CRS – Part B (2 of 2) 
Visit:
011,2 
022 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
153 
Post 
Day:
 
D0 
D14 
D28 
D42 
D84 
D98 
D168 
D182 
D224 
D231 
D238 
D334 
D425 
D607 
 
Month:
 
M0 
M0,5 
M1 
M1.5 
M3 
M3.5 
M6 
M6.5 
M8 
M8.25 
M8.5 
M11 
M14 
M20 
 
Procedure
Scr. 
VAC1 
 
VAC2 
 
VAC3 
 
VAC4 
 
VAC5 
 
 
 
 
 
 
Specimen collection9  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vaccination procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination10 
— 
X 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
— 
— 
— 
— 
Reactogenicity assessment11 
— 
X 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
— 
— 
— 
— 
Poststudy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblind participant 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
 
1Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination. 
2Specimens indicated for day 0 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. 
3See Section 9.7. Clinic visits are not required except that any participant reporting a diagnosis of HIV infection from testing outside of the HVTN will be asked to come to the 
clinic to collect specimens for HIV testing with HVTN HIV diagnostic algorithms.  
4For 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 
5Pregnancy testing at the indicated visits is only required of participants who are born female and are providing a cervical and/or rectal fluid sample. 
6Pregnancy prevention assessment is required only for participants who were born female and are capable of becoming pregnant. 
7Includes pre-test counseling. A subsequent follow-up contact is conducted to provide post-test counseling and to report results to participant. 
8For participants providing optional stool sample. 
9See Clinical procedures sections 9.2, 9.3, 9.4, 9.5, 9.6, Laboratory procedures section 10, and Appendix I. 
10Blood 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. 
11Reactogenicity assessments performed daily for at least 7 days post vaccination (see Section 9.11).

Version 1.0 / September 28, 2017 
HVTN124_v1.0_FINAL.docx / Page 170 of 171 
Appendix L 
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 124 Study Specific Procedures. 
Gastrointestinal disorders 
Liver disorders 
Metabolic diseases 
 
Celiac disease 
 
Crohn’s disease 
 
Ulcerative colitis 
 
Ulcerative proctitis 
 
Autoimmune cholangitis 
 
Autoimmune hepatitis 
 
Primary biliary cirrhosis 
 
Primary sclerosing cholangitis 
 
Addison’s disease 
 
Autoimmune thyroiditis 
(including Hashimoto 
thyroiditis) 
 
Diabetes mellitus type I 
 
Grave’s or Basedow’s 
disease 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
 
Acute disseminated encephalomyelitis, 
including site specific variants (eg, non-
infectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculomyelitis) 
 
Cranial nerve disorders, included 
paralyses/paresis (eg, Bell’s palsy) 
 
Guillain-Barré syndrome, including 
Miller Fisher syndrome and other 
variants 
 
Immune-mediated peripheral 
neuropathies and plexopathies, 
including chronic inflammatory 
demyelinating polyneuropathy, 
multifocal motor neuropathy and 
polyneuropathies associated with 
monoclonal gammopathy 
 
Multiple sclerosis 
 
Myasthenia gravis, including Eaton-
Lambert syndrome 
 
Narcolepsy 
 
Optic neuritis 
 
Transverse Myelitis 
 
Antisynthetase syndrome 
 
Dermatomyositis 
 
Juvenile chronic arthritis (including 
Still’s disease) 
 
Mixed connective tissue disorder 
 
Polymyalgia rheumatic 
 
Polymyositis 
 
Psoriatic arthropathy 
 
Relapsing polychondritis 
 
Rheumatoid arthritis 
 
Scleroderma, including diffuse 
systemic form and CREST 
syndrome 
 
Spondyloarthritis, including 
ankylosing spondylitis, reactive 
arthritis (Reiter’s Syndrome) and 
undifferentiated spondyloarthritis 
 
Systemic lupus erythematosus 
 
Systemic sclerosis 
 
Alopecia areata 
 
Autoimmune bullous skin 
diseases, including 
pemphigus, pemphigoid and 
dermatitis herpetiformis 
 
Cutaneous lupus 
erythematosus 
 
Erythema nodosum 
 
Morphoea 
 
Lichen planus 
 
Psoriasis 
 
Sweet’s syndrome 
 
Vitiligo 
Vasculitides 
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 
 
Antiphospholipid syndrome 
 
Autoimmune hemolytic anemia 
 
Autoimmune glomerulonephritis (including IgA nephropathy, 
glomerulonephritis rapidly progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and mesangioproliferative 
glomerulonephritis) 
 
Autoimmune myocarditis/cardiomyopathy 
 
Autoimmune thrombocytopenia 
 
Goodpasture syndrome 
 
Idiopathic pulmonary fibrosis 
 
Pernicious anemia 
 
Raynaud’s phenomenon 
 
Sarcoidosis 
 
Sjögren’s syndrome 
 
Stevens-Johnson syndrome 
 
Uveitis 
 

Version 1.0 / September 28, 2017 
HVTN124_v1.0_FINAL.docx / Page 171 of 171 
Appendix M 
Protocol Signature Page 
A phase 1 clinical trial to evaluate the safety and immunogenicity of polyvalent env 
(A,B,C,A/E) / gag (C) DNA and gp120 (A,B,C,A/E) protein/GLA-SE HIV-1 
vaccines (PDPHV-201401) as a prime-boost regimen or co-administered in repeated 
doses, in healthy, HIV-1–uninfected adult participants 
I will conduct the study in accordance with the provisions of this protocol and all 
applicable protocol-related documents. I agree to conduct this study in compliance with 
United States (US) Health and Human Service regulations (45 CFR 46); applicable U.S. 
Food and Drug Administration regulations; standards of the International Conference on 
Harmonization Guideline for Good Clinical Practice (E6); Institutional Review 
Board/Ethics Committee determinations; all applicable in-country, state, and local laws 
and regulations; and other applicable requirements (e.g., US National Institutes of Health, 
Division of AIDS) and institutional policies 
 
 
 
 
 
 
 
 
 
Investigator of Record Name (print) 
 
Investigator of Record Signature 
 
Date 
 
 
DAIDS Protocol Number: HVTN 124 
DAIDS Protocol Version: Version 1.0 
Protocol Date: September 28, 2017