A Phase 1 Clinical Trial to Evaluate the Safety and Immunogenicity of HIV-1 Vaccines Based on Chimpanzee Serotypes of Adenovirus Expressing Clade C gp140 and a CH505TF gp120 Protein Boost in Healthy, HIV- Uninfected Adult Participants
Phase: PHASE1
Conditions: HIV Infections
Sponsor: HIV Vaccine Trials Network

PROTOCOL 
HVTN 139 
A phase 1 clinical trial to evaluate the safety and 
immunogenicity of HIV-1 vaccines based on chimpanzee 
serotypes of adenovirus expressing clade C gp140 and 
a CH505TF gp120 protein boost in healthy, HIV- 
uninfected adult participants 
DAIDS DOCUMENT ID 12052 
A non-IND study 
CLINICAL TRIAL SPONSORED BY 
Division of AIDS (DAIDS) 
National Institute of Allergy and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
Department of Health and Human Services (DHHS) 
Bethesda, Maryland, USA 
STUDY PRODUCTS PROVIDED BY 
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 
February 23, 2021 
Final 
HVTN 139 
Version 1.0 

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Contents 
1 Overview ........................................................................................................................5 
1.1 
Protocol Team ................................................................................................9 
2 Ethical considerations ..................................................................................................10 
3 IRB/EC review considerations .....................................................................................12 
3.1 
Minimized risks to participants ....................................................................12 
3.2 
Reasonable risk/benefit balance ...................................................................12 
3.3 
Equitable participant selection .....................................................................13 
3.4 
Appropriate informed consent ......................................................................13 
3.5 
Adequate safety monitoring .........................................................................13 
3.6 
Protect privacy/confidentiality .....................................................................14 
4 Background ..................................................................................................................15 
4.1 
Rationale for trial concept ............................................................................15 
4.2 
AdC6-HIVgp140 ..........................................................................................17 
4.3 
AdC7-HIVgp140 ..........................................................................................18 
4.4 
CH505TF gp120 ...........................................................................................19 
4.5 
GLA-SE adjuvant .........................................................................................19 
4.6 
Trial design rationale ....................................................................................20 
4.7 
Plans for future product development and testing ........................................21 
4.8 
Preclinical safety studies ..............................................................................22 
4.9 
Preclinical immunogenicity studies .............................................................30 
4.10 Clinical studies .............................................................................................41 
4.11 Potential risks of study products and administration ...................................49 
5 Objectives and endpoints .............................................................................................50 
5.1 
Primary objectives and endpoints ................................................................50 
5.2 
Secondary objectives and endpoints ............................................................50 
5.3 
Exploratory objectives ..................................................................................52 
6 Statistical considerations ..............................................................................................53 
6.1 
Accrual and sample size calculations ...........................................................53 
6.2 
Randomization .............................................................................................55 
6.3 
Blinding ........................................................................................................55 
6.4 
Statistical analyses ........................................................................................56 
7 Selection and withdrawal of participants .....................................................................62 
7.1 
Inclusion criteria ...........................................................................................62 
7.2 
Exclusion criteria ..........................................................................................65 
7.3 
Participant departure from vaccination schedule or withdrawal ..................69 
8 Study product preparation and administration .............................................................72 
8.1 
Vaccine regimen ...........................................................................................72 
8.2 
Study product formulation ...........................................................................73 
8.3 
Preparation of study products .......................................................................74 
8.4 
Administration ..............................................................................................77 
8.5 
Acquisition of study products ......................................................................78 
8.6 
Pharmacy records .........................................................................................79 

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8.7 
Final disposition of study products ..............................................................79 
9 Clinical procedures ......................................................................................................80 
9.1 
Informed consent ..........................................................................................80 
9.2 
Pre-enrollment procedures ...........................................................................82 
9.3 
Enrollment and vaccination visits ................................................................84 
9.4 
Follow-up visits ............................................................................................85 
9.5 
Health Contacts ............................................................................................86 
9.6 
HIV counseling and testing ..........................................................................88 
9.7 
Contraception status .....................................................................................89 
9.8 
Urine testing .................................................................................................90 
9.9 
Assessments of reactogenicity .....................................................................90 
9.10 Visit windows and missed visits ..................................................................92 
9.11 Early termination visit ..................................................................................92 
9.12 Pregnancy .....................................................................................................92 
9.13 HIV infection during the study .....................................................................93 
10 Laboratory ....................................................................................................................94 
10.1 HVTN CRS laboratory procedures ..............................................................94 
10.2 Total blood volume ......................................................................................94 
10.3 Primary immunogenicity timepoint .............................................................94 
10.4 Endpoint assays: cellular ..............................................................................95 
10.5 Endpoint assays: humoral .............................................................................95 
10.6 HVTN Lab Center assay portfolio ...............................................................97 
10.7 Exploratory studies .......................................................................................97 
10.8 Specimen storage and other use of specimens .............................................97 
10.9 Biohazard containment .................................................................................98 
11 Safety monitoring and safety review ...........................................................................99 
11.1 Safety monitoring and oversight ..................................................................99 
11.2 Safety reporting ..........................................................................................100 
11.3 Safety reviews ............................................................................................103 
11.4 Safety pause and prompt PSRT AE review................................................104 
11.5 Review of cumulative safety data ..............................................................105 
11.6 Study termination .......................................................................................106 
12 Protocol conduct ........................................................................................................108 
12.1 Social impacts ............................................................................................109 
12.2 Compliance with NIH guidelines for research involving products containing 
recombinant or synthetic nucleic acid molecules .......................................109 
12.3 Emergency communication with study participants ..................................109 
13 Version history ...........................................................................................................111 
14 Document references (other than literature citations) ................................................112 
15 Acronyms and abbreviations......................................................................................115 
16 Literature cited ...........................................................................................................118 
Appendix A Sample informed consent form for Part A .................................................124 
Appendix B Sample informed consent form for Part B .................................................144 

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Appendix C Approved birth control methods for persons assigned female sex at birth 
(for sample informed consent form) ...........................................................165 
Appendix D Sample consent form for use of samples and information in other studies 166 
Appendix E Table of procedures for Part A (for sample informed consent form) .........171 
Appendix F Table of procedures for Part B (for sample informed consent form) .........172 
Appendix G Laboratory procedures Part A ....................................................................173 
Appendix H Laboratory procedures Part B ....................................................................175 
Appendix I Procedures at HVTN CRS for Part A .........................................................177 
Appendix J Procedures at HVTN CRS for Part B .........................................................179 
Appendix K HVTN 139 Visit Windows for Part A ........................................................181 
Appendix L HVTN 139 Visit Windows for Part B ........................................................182 
Appendix M HVTN low risk guidelines for Southern Africa .........................................183 
Appendix N Adverse events of special interest ..............................................................185 
Appendix O Protocol Signature Page .............................................................................186 
 

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1 
Overview 
Title  
A phase 1 clinical trial to evaluate the safety and immunogenicity of HIV-1 
vaccines based on chimpanzee serotypes of adenovirus expressing clade C gp140 
and a CH505TF gp120 protein boost in healthy, HIV- uninfected adult 
participants 
Primary objective 
To evaluate the safety and tolerability of AdC6-HIVgp140 and AdC7-HIVgp140 
at doses of 1 x 1010 virus particles (vp) and 5 x 1010 vp, alone and in combination 
with CH505TF gp120 adjuvanted with GLA-SE in HIV- uninfected adults. 
Study products and routes of administration 
▪ AdC6-HIVgp140: a chimpanzee-derived replication-defective adenovirus 
(Ad) vector expressing codon optimized gp140 of clade C isolate Du422 
administered at a dose of 1 x 1010 vp or 5 x 1010 vp. The vaccine dose will be 
divided equally into two separate 1mL intramuscular (IM) injections, 
administered into the deltoid of the non-dominant arm unless medically 
contraindicated. 
▪ AdC7-HIVgp140: a chimpanzee-derived replication-defective Ad vector 
expressing codon optimized gp140 of clade C isolate Du172 administered at a 
dose of 1 x 1010 vp or 5 x 1010 vp. The vaccine dose will be divided equally 
into two separate 1mL IM injections administered into the deltoid of the non-
dominant arm unless medically contraindicated. 
▪ CH505TF gp120: CH505 transmitted/founder gp120 mixed with GLA-SE 
[the immunological adjuvant Glucopyranosyl Lipid A (GLA) in an oil-in-
water stable emulsion (SE)], administered at a dose of 400 mcg with 10 mcg 
GLA-SE as a 1 mL injection in the thigh unless medically contraindicated. 
▪ Placebo control for AdC6 -HIVgp140 and AdC7-HIVgp140 vaccine: Sodium 
Chloride for Injection, 0.9% , administered as two separate 1 mL IM 
injections into the deltoid of the non-dominant arm unless medically 
contraindicated. 
▪ Placebo control for CH505TF gp120: Sodium Chloride for Injection, 0.9% 
administered as a 1 mL IM injection in the thigh unless medically 
contraindicated. 

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Table 1-1 Schema 
Study arm  
N 
AdC 
dose (vp) 
M0  
M3  
M6  
Part A: Low Dose 
 
 
 
Group 1 
5 
1x 1010 
AdC6-HIVgp140 
- 
- 
Group 2 
5 
1x 1010 
AdC7-HIVgp140 
- 
- 
Group 3 
2 
0 
Placebo 
- 
- 
Part B: High Dose 
 
 
 
Group 4 
10 
5 x 1010 
AdC6-HIVgp140 
AdC7-HIVgp140 
400 mcg CH505TF 
gp120/GLA-SE 
Group 5 
10 
5 x 1010 
AdC7-HIVgp140 
AdC6-HIVgp140 
400 mcg CH505TF 
gp120/GLA-SE 
Group 6 
2 
0 
Placebo 
Placebo 
Placebo 
Total 
34   (30 vaccinees / 4 placebos) 
Notes:  
Study is blinded as to Group assignment (Part assignment is not blinded). Enrollment will be stepwise 
starting with Part A. To ensure the safety of participants, a series of pre-planned enrollment pauses will 
occur. 
Safety Review #1: Low-dose Initial Vaccination. Enrollment for Part A will be restricted to a maximum of 
1 participant per day across all participating HVTN Clinical Research Sites (CRSs) until a total of 5 
participants have been enrolled. The HVTN Protocol Safety Review Team (PSRT) will review available 
safety and reactogenicity data reported for each of these 5 participants, up to and including the data reported 
for the first 72 hours postvaccination for the 5th enrolled participant, and determine whether it is safe to 
proceed with full enrollment in Part A.  
Safety Review #2: Low-dose (Part A) Safe-to-Proceed. The HVTN PSRT will review cumulative safety 
data, including at a minimum the 2-weeks following the vaccination visit, available on all 12 participants in 
Part A to determine whether dose-escalation may occur from Part A to Part B.  
Safety Review #3: Full Enrollment at Targeted Dose. The HVTN PSRT will also review cumulative safety 
data available on the first 12 participants enrolled in Part B, including the 2-week post Month 0 vaccination 
visit, to determine whether it is safe to proceed with full enrollment. 
 
Participants 
34 healthy, HIV– uninfected volunteers aged 18 through 50 years, inclusive; 30 
vaccinees, 4 placebo recipients 
Design 
Multicenter, randomized, controlled, double-blind trial 
Duration per participant 
Part A participants: 6 months of scheduled clinic visits (main study) followed by 
AESI (Adverse Events of Special Interest) health contacts at month 12, and then 
annual health contacts at month 24 and 36. 
Part B participants: 12 months of scheduled clinic visits (main study) followed by 
an AESI health contact at month 18, and then annual health contacts at month 24 
and 36.  

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Estimated total study duration 
48 months, includes enrollment, planned safety holds, AESI and annual health 
contacts. 
Clinical trial sponsor 
DAIDS, NIAID, NIH, DHHS (Bethesda, Maryland, USA) 
Study product providers 
▪ AdC6-HIVgp140: provided by DAIDS, NIAID, NIH, DHHS (Bethesda, 
Maryland, USA) 
▪ AdC7-HIVgp140: provided by DAIDS, NIAID, NIH, DHHS (Bethesda, 
Maryland, USA) 
▪ CH505TF gp120: DAIDS, NIAID, NIH, DHHS (Bethesda, Maryland, USA) 
▪ GLA-SE adjuvant:  DAIDS, NIAID, NIH, DHHS (Bethesda, Maryland, USA)  
HVTN Leadership Operations Center (LOC) operations 
HVTN Vaccine Leadership Group/Core Operations Center, Fred Hutchinson 
Cancer Research Center (Fred Hutch) (Seattle, Washington, USA) 
HVTN Statistical and Data Management Center (SDMC) 
Statistical Center for HIV/AIDS Research and Prevention (SCHARP), Fred Hutch 
(Seattle, Washington, USA) 
HVTN Laboratory Center (LC)  
HIV diagnostic laboratories 
HIV Sero-Molecular Laboratory-National Institute for Communicable Diseases 
(HSML-NICD) (Johannesburg, South Africa) 
University of Washington Virology Specialty Laboratory (UW-VSL) (Seattle, 
Washington, USA) 
Endpoint assay laboratories 
▪ Cape Town HVTN Immunology Laboratory (CHIL, Cape Town, Africa);  
▪ South African Immunology Laboratory-National Institute for Communicable 
Diseases (SAIL-NICD, Johannesburg, South Africa) 

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▪ Duke University Medical Center (Durham, North Carolina, USA) 
▪ Fred Hutch/University of Washington (Seattle, Washington, USA) 
▪ The Ertl Lab at the Wistar Institute Vaccine and Immunotherapy Center 
(Philadelphia, Pennsylvania, USA) 
Study sites 
HVTN Clinical Research Sites (HVTN CRSs) in South Africa to be specified in 
the Site Announcement Memo 
Safety monitoring 
HVTN 139 PSRT; HVTN Safety Monitoring Board (SMB) 

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1.1 
Protocol Team 
Protocol leadership 
Chair 
Ameena Goga 
HIV Prevention Research Unit, 
South African Medical Research 
Council 
+2712 339 8524 
+2782 302 3168 
Statistician 
Youyi Fong 
HVTN SDMC, Fred Hutch 
206-667-1093 
yfong@fredhutch.org 
Protocol Team leader 
William Hahn 
HVTN LOC, Fred Hutch 
206-667-3431 
whahn@fredhutch.org 
DAIDS Medical officer 
Edith Swann 
DAIDS, NIAID 
240-627-3035 
301-332-6435-BB 
swanne@niaid.nih.gov  
 
 
Laboratory lead 
Stephen De Rosa 
HVTN Laboratory Center 
206-667-1681 
sderosa@fredhutch.org 
Other contributors to the original protocol 
LOC medical monitor 
William Hahn 
HVTN LOC,  
Fred Hutch 
206-667-3431 
whahn@fredhutch.org 
DAIDS Product Lead 
Michael Pensiero 
DAIDS, NIAID 
301-435-3749 
mpensiero@niaid.nih.gov 
Study product 
developer 
representatives 
Hildegund Ertl 
Wistar Institute Vaccine and 
Immunotherapy Center 
Emmanuel (Chip) Walter 
Duke Human Vaccine Institute 
Zachary Sagawa 
Infectious Disease Research 
Institute 
DAIDS protocol 
pharmacist 
Oladapo Alli 
DAIDS, NIAID 
240-627-3593 
SDMC Associate 
director of lab science 
April Randhawa 
HVTN SDMC, Fred Hutch 
Laboratory Center 
Representative 
Lisa Sanders 
HVTN Laboratory Center,  
Fred Hutch 
Clinical trials manager 
Julie Hunt 
HVTN LOC, Fred Hutch 
Regulatory affairs 
associate 
Megan Brandon 
HVTN LOC, Fred Hutch 
Clinical safety specialist 
Maija Anderson 
HVTN LOC, Fred Hutch 
 
Community engagement 
unit representative 
Baepanye Kagisho 
HVTN LOC, Fred Hutch 
Regional Medical Liaison 
Azwi Takalani 
HVTN LOC, Fred Hutch 
Community 
educator/recruiter 
Mduduzi Ngubane 
Isipingo South African Medical 
Research Council  
Clinic coordinator 
Brodie Daniels 
Isipingo South African Medical 
Research Council  
Community Advisory 
Board (CAB) member 
Sphelelo Mqadi 
Isipingo South African Medical 
Research Council  
Clinical data manager 
Bhavesha O’Byrne 
HVTN SDMC, Fred Hutch 
 
Protocol development 
managers 
Kajari Mondal 
Daciana Margineantu 
HVTN LOC, Fred Hutch 
Statistical research 
associate 
 
Project coordinator  
Hua Zheng  
HVTN SDMC, Fred Hutch 
 
Haven Wilvich 
HVTN LOC, Fred Hutch 

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2 
Ethical considerations 
Multiple candidate HIV vaccines will need to be studied simultaneously in 
different populations around the world before a successful HIV preventive 
vaccine is found. It is critical that universally accepted ethical guidelines are 
followed at all sites involved in the conduct of these clinical trials. The HIV 
Vaccine Trials Network (HVTN) has addressed ethical concerns in the following 
ways: 
▪ HVTN trials are designed and conducted to enhance the knowledge base 
necessary to find a preventive vaccine, using methods that are scientifically 
rigorous and valid, and in accordance with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH) and/or other Good Clinical Practice (GCP) guidelines. 
▪ HVTN scientists and operational staff incorporate the philosophies underlying 
major codes (1-3), declarations, and other guidance documents relevant to 
human subjects research into the design and conduct of HIV vaccine clinical 
trials. 
▪ HVTN scientists and operational staff are committed to substantive 
community input—into the planning, conduct, and follow-up of its research—
to help ensure that locally appropriate cultural and linguistic needs of study 
populations are met. Community Advisory Boards (CAB) are required by 
DAIDS and supported at all HVTN research sites to ensure community input, 
in accordance with Good Participatory Practices (GPP) and all local and 
national guidelines. 
▪ HVTN clinical trial staff counsel study participants routinely on how to 
reduce HIV risk. Participants who become HIV-infected during the trial are 
provided counseling on notifying their partners and about HIV infection 
according to local guidelines. Staff members will also counsel them about 
reducing their risk of transmitting HIV to others. 
▪ Participants who become HIV-infected during the trial are referred to medical 
practitioners to manage their HIV infection and to identify potential clinical 
trials they may want to join. If a program for antiretroviral therapy (ART) 
provision is not available at a site and ART is needed, a privately established 
fund will be used to pay for access to treatment to the fullest extent possible. 
▪ The HVTN provides training so that all participating sites similarly ensure fair 
participant selection, protect the privacy of research participants, and obtain 
meaningful informed consent. During the study, participants will have their 
wellbeing monitored, and to the fullest extent possible, their privacy 
protected. Participants may withdraw from the study at any time. 

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▪ Prior to implementation, HVTN trials are rigorously reviewed by scientists 
who are not involved in the conduct of the trials under consideration. 
▪ HVTN trials are reviewed by local and national regulatory bodies and are 
conducted in compliance with all applicable national and local regulations. 
▪ The HVTN designs its research to minimize risk and maximize benefit to both 
study participants and their local communities. For example, HVTN protocols 
provide enhancement of participants’ knowledge of HIV and HIV prevention, 
as well as counseling, guidance, and assistance with any social impacts that 
may result from research participation. HVTN protocols also include careful 
medical review of each research participant’s health conditions and reactions 
to study products while in the study. 
▪ HVTN research aims to benefit local communities by directly addressing the 
health and HIV prevention needs of those communities and by strengthening 
the capacity of the communities through training, support, shared knowledge, 
and equipment. Researchers involved in HVTN trials are able to conduct other 
critical research in their local research settings. 
▪ The HVTN 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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3 
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. 
This trial is being conducted in countries outside of the United States, with 
funding from the US NIH among others. Due to this, the trial is subject to both 
US and local regulations and guidelines on the protection of human research 
subjects and ethical research conduct. Where there is a conflict in regulations or 
guidelines, the HVTN strives towards maximum protection of human research 
participants. 
In compliance with international and local (as appropriate) ICH and/or other GCP 
guidelines, each research location has a locally-based Principal Investigator (PI) 
who is qualified to conduct (and supervise the conduct of) the research. The 
investigators take responsibility for the conduct of the study and the control of the 
study products, including obtaining all appropriate regulatory and ethical reviews 
of the research. 
3.1 
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. 
3.2 
Reasonable risk/benefit balance 
45 CFR 46.111(a) 2 and 21 CFR 56.111(a) 2: Risks to subjects are 
reasonable in relation to anticipated benefits, if any, to subjects, and 

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the importance of the knowledge that may reasonably be expected to 
result. 
In all public health research, the risk-benefit ratio may be difficult to assess 
because the benefits to a healthy participant are not as apparent as they would be 
in treatment protocols, where a study participant may be ill and may have 
exhausted all conventional treatment options. However, this protocol is designed 
to minimize the risks to participants while maximizing the potential value of the 
knowledge it is designed to generate. 
3.3 
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. 
3.4 
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). As 
part of entering the HVTN, each site is provided training in informed consent by 
the HVTN and is required to have an SOP on the informed consent process. The 
HVTN requires a signed consent document for documentation, in addition to chart 
notes or a consent checklist. 
3.5 
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 LOC and routinely by the HVTN 139 Protocol Safety 

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Review Team (PSRT). In addition, the HVTN Safety Monitoring Board (SMB) 
periodically reviews study data. 
3.6 
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 they/their private life and the right to control access to 
individually identifiable information about him/her. The term “privacy” concerns 
research participants or potential research participants as individuals whereas the 
term “confidentiality” is used to refer to the treatment of information about those 
individuals. This protocol respects the privacy of participants by informing them 
about who will have access to their personal information and study data (see 
Appendix A 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 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. 
In some cases, a comparable confidentiality agreement process may be 
acceptable. Each study site participating in the protocol is required to have a 
standard operating procedure on how the staff members will protect the 
confidentiality of study participants. 

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4 
Background 
4.1 
Rationale for trial concept 
Adenovirus (‘Ad’ for short) vectors have been tested extensively, are well 
tolerated at immunogenic doses, induce very potent cellular responses, and are 
able to elicit potent and sustained humoral responses to a wide variety of 
transgene inserts. Nevertheless, pre-existing neutralizing antibodies (nAbs) to 
human serotypes of Ad vectors can impair immune responses to the transgene 
product to which a protective response is sought. This protocol will study 
replication-deficient Ad vectors derived from simian serotypes (AdC vectors), as 
a strategy of circumventing any pre-existing nAbs. Derived from Ad viruses 
isolated from a chimpanzee and known as AdC6 and AdC7 vectors (1), these 
products provide a novel approach to overcoming reduced vaccine efficacy and 
immunogenicity due to pre-existing nAbs. This trial is designed to test the safety 
and tolerability of two of these vectors, while also assessing immunogenicity 
using a relevant HIV-1 insert, gp140 of subtype C. The specific overall goal of 
this proposed trial is therefore to test two Ad vectors derived from chimpanzee 
serotypes 6 (AdC6) and 7 (AdC7) for safety and immunogenicity for the first time 
in humans. 
Adenoviral vectors have been used extensively as a vaccine platform for HIV-1. 
Human Ad serotype 5 (AdHu5) was tested as a single vaccine modality given 
repeatedly in the STEP/Phambili trials and combined with a DNA vaccine prime 
in HVTN505; both trials were designed to test for vaccine efficacy. The former 
vaccine was designed to induce T-cell responses to HIV-1, the latter to induce T- 
and B-cell responses. Neither trial achieved protection against HIV-1 acquisition 
or lowering of peak or setpoint viral loads in vaccinated individuals with 
breakthrough infection. In the STEP trial, uncircumcised male individuals with 
pre-existing AdHu5-specific nAbs showed a significant increase in HIV-1 
acquisition rates (2). 
Any theoretical risk of HIV acquisition related to the adenoviral vector (as 
observed in the STEP/Phambili trials) is mitigated by several important factors in 
the current protocol: 1.) The AdC6 and AdC7 vectors in this trial are biologically 
different from AdHu5 and derived from chimpanzees; 2.) .) this trial will enroll 
individuals at low risk for HIV infection; and 3.) the majority of humans lack 
nAbs to AdC6 and AdC7 viruses.  
As indicated above, one of the critical problems of using human adenoviral 
vectors as a vaccine platform is pre-existing humoral immunity. Extensive studies 
have been done with human sera to assess for the presence and titers of nAbs to 
AdC6 and AdC7 in comparison to human serotypes Ad vectors, eg, serotypes 5 
(AdHu5), and 26 (AdHu26) (3-5). These data show that nAbs to AdC viruses are 
rare in humans and people who carry such Abs generally have low titers. In 
contrast, nAbs to AdHu5 or AdHu26 are common in people living in developing 

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countries, and nAb titers to either of these viruses exceed those to the AdC viruses 
(3-5). T cells, as well as binding non-neutralizing Abs, cross-react between 
different Ad vectors of human or simian origin (6) as they are phylogenetically 
closely related (7), but neither affects vaccine immunogenicity (8-11). As we have 
shown (1), rhesus macaques (RMs) with pre-existing immunity to heterologous 
Ad viruses can readily be protected against chronic SIV infection by AdC vector 
immunization (see Section 4.9.1.7). AdC6 and AdC7 have not yet undergone 
clinical testing. As such they represent a novel vaccine platform. The combination 
of two distinct serotypes allows for fully circumventing any pre-existing nAbs 
including those elicited upon priming. 
The rationale for this protocol is also informed by the goal to combine the two 
serologically distinct AdC vectors in a heterologous prime-boost regimen. Such 
combinations are expected to outperform homologous prime-boost regimens in 
which nAbs elicited against the vector after priming may impair immune 
responses to a subsequent boost. Studies in nonhuman primates showed that 
priming with AdC7 followed by a boost with AdC6 resulted in slightly better 
protection against SIVmac challenge (12) than the reverse sequence of AdC6 
prime followed by an AdC7 boost.  
It is unknown if the human immune system will mirror these results. In this phase 
1 trial, human volunteers will therefore be primed with AdC6-HIVgp140 
followed by a boost with AdC7-HIVgp140. The reverse sequence will also be 
tested (AdC7-HIVgp140 followed by a boost with AdC6-HIVgp140).  
Another mechanism for circumventing pre-existing immunity to the vector is to 
boost with a heterologous immunogen, such as a recombinant protein. Studies in 
mice showed that a recombinant protein boost given to AdC7-gp140-immunized 
animals induces higher antibody responses than a prime with protein followed by 
an AdC7gp140 boost (13). We have additional evidence that the inclusion of a 
protein boost after sequential AdC priming (similar to the proposed regimen) 
leads to antibodies directed to the V1V2 region that were identified as a correlate 
of immunity in RV144 (14, 15). To maximize the potential immunogenicity of the 
regimen, we have included an additional boost with the GLA-SE adjuvanted 
CH505TF gp120 protein. 
AdC6 and AdC7 belong to the subfamily E of Ad, such as Ad of human serotype 
4 (which has been used as a vaccine platform in human trials (16, 17)). AdC 
vectors readily induce innate immune responses (18, 19) and thereby do not 
require addition of adjuvant. 
We developed recombinant AdC6 and AdC7 vectors expressing Env of HIV-1 
clade C. Du422 and Du172 were chosen as inserts because they are early infection 
clade C African isolates. The protein used for boosting is derived from yet another 
clade C isolate. We intentionally are using heterologous clade C Env immunogens 
to focus the immune response onto epitopes that are conserved between different 
HIV-1 clade C isolates. 

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HVTN 139 is a protocol designed to test whether a series of novel replication 
incompetent Chimpanzee adenoviruses could be advanced as a vaccine platform 
in the context of HIV. Pre-existing immunity to adenoviral vectors is associated 
with diminished immune responses and therefore the protocol is designed to test 
two chimpanzee adenoviruses (AdC6 and AdC7) given as a heterologous 
sequence. Evaluating the immune response to AdC6 and AdC7 vectors expressing 
clade C derived HIVgp140 Env followed by administration of CH505TF gp120 
Env protein is directly relevant to the South African population where the major 
circulating clade is subtype C. A vaccine based upon a Chimpanzee adenoviral 
vector from a different family (Chimpanzee Adenovirus 25) has recently had 
success within the context of COVID-19, as the ChadOx1 vaccine was recently 
licensed in the UK for the prevention of SARS-CoV-2 infection. 
4.2 
AdC6-HIVgp140 
The E1- and E3-deleted viral molecular clone of AdC6 was constructed by 
assembling gene fragments generated by restriction enzyme digest or PCR from 
the purified DNA of the AdC6 virus (ATCC-VR-592) into the pNEB193 vector 
using conventional cloning techniques (see Table 4-1, (20). AdC6-HIVgp140 is 
an E1- and partially E3-deleted AdC6 vector expressing gp140 of subtype C 
Du422. The insert Du422 (GenBank number: AAL05330.1) was chosen because 
subtype C is the dominant strain that circulates in Africa and the virus represents 
an early isolate of subtype C viruses. The transgene was cloned into pShuttle, 
which contains the cytomegalovirus promoter and other regulatory elements and 
from there into the parent AdC6 molecular clones using routine cloning 
procedures (see Figure 4-1). 
 
Figure 4-1 Maps of AdC6 recombinant virus (left) and AdC6-gp140Du422 pShuttle vector 
(right) 
Table 4-1 Nucleotide Numbers of the Deleted Portion of E1 and E3 Domain in the AdC6 
Vector  
Vector Name 
Nucleotide Numbers of E1 
Deleted Region* 
Nucleotide Numbers of E3 
Deleted Region* 

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AdC6-HIVgp140 
455 – 3022 bp 
27835 – 31052 bp 
Note: * Nucleotide numbers are based on GenBank accession numbers that are AY530877 for AdC6 (wildtype) 
virus 
The DNA plasmids encoding the viral vectors were purified by 3 rounds of 
phenol/chloroform extraction prior to transferring to SAFC Pharma Carlsbad 
(Carlsbad, California) for manufacturing the vaccines. The vaccine is vialed in 
2.5% Glycerol / 25 mM NaCl / 20 mM TRIS, pH 8.0. The vaccine was filled by 
IDT Biologika (Rockville, MD). 
4.3 
AdC7-HIVgp140 
AdC7-HIVgp140 is an E1- and partially E3-deleted AdC7 vector expressing 
gp140 of subtype C Du172. The parent virus was obtained from ATCC (AdC7 – 
ATCC-VR-593). To create an E1- and E3-deleted viral molecular clone of AdC7 
and then a recombinant virus expressing gp140, a similar cloning strategy as 
described above for AdC6 was adopted. (see Table 4-2 and Figure 4-2).  
 
Figure 4-2 Maps of AdC7 recombinant virus (left) and AdC7-gp140Du422 pShuttle vector 
(right) 
Table 4-2 Nucleotide Numbers of the Deleted Portion of E1 and E3 Domain in the rAdC 
Vectors 
Vector Name 
Nucleotide Numbers of E1 
Deleted Region* 
Nucleotide Numbers of E3 
Deleted Region* 
AdC7-HIVgp140 
455 – 3028 bp 
27775 – 31298 bp 
Note: * Nucleotide numbers are based on GenBank accession number AY530878 for AdC7 (wildtype) virus 
Manufacturing of the recombinant vector (AdC7-HIVgp140) was performed at 
SAFC Pharma Carlsbad (Carlsbad, California). The vaccine is vialed in 2.5% 
Glycerol / 25 mM NaCl / 20 mM TRIS, pH 8.0. The vaccine was filled by IDT 
Biologika (Rockville, MD). 

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Both serotypes can be grown in cells transformed with E1 region of AdHu5 (such 
as HEK 293 cells). Differences in the E1 flanking region between E1 of AdC 
viruses and E1 of AdHu5 prevents outgrowth of replication competent Ad, which 
can be a problem upon growth of AdHu5 vectors on HEK 293 cells.  
Vectors were tested by western blotting of transduced cells and shown to express 
high levels of gp140. Genetic stability testing showed that the genomes of both 
AdC6 vectors expressing Du422 and AdC7 vectors expressing Du172 were stable 
after 12 sequential passages.  
4.4 
CH505TF gp120 
CH505TF gp120 protein is the transmitted/founder (TF) gp120 Env isolated from 
the HIV-infected African individual CH505 by Bart Haynes’s group (21). 
CH505TF is the first immunogen of the CH505 sequential envelope vaccine 
(EnvSeq-1) made up of 4 sequential Env gp120 components: the 
transmitted/founder (TF) CH505 Env (CH505TF gp120), the week 53 CH505 
Env (CH505w53 gp120), the week 78 CH505 Env (CH505w78 gp120), and the 
week 100 gp120 CH505 Env (CH505w100 gp120).  
CH505TF gp120 adjuvanted with GLA-SE is currently being evaluated in HVTN 
115 and HVTN 123 (see Section 4.10.2).  
4.5 
GLA-SE adjuvant 
GLA-SE is a synthetic TLR4 agonist formulated in a stable nano-emulsion of 
squalene oil and promotes a robust Th1-type immune response to vaccine 
antigens (22, 23). GLA-SE has been tested in over 2700 individuals in phase 1 
and 2 clinical trials with a variety of antigens, including CH505TF gp120 in Part 
A of HVTN 115 and HVTN 123 (see Section 4.10.2). No significant safety 
concerns were reported. Previous clinical trial experience with GLA-SE and other 
antigens is described in Section 4.10.4. 
The GLA-SE adjuvant has been used extensively in human phase 1 trials for 
influenza and leishmaniasis vaccines (24, 25). The 10 mcg dose of GLA-SE to be 
used in this clinical trial has been evaluated in 48 participants in 2 other clinical 
trials, 1 for a leishmaniasis vaccine candidate and 1 for a schistosomiasis vaccine 
candidate (ClinicalTrials.gov identifiers NCT02071758 and NCT01154049).  
CH505TF gp120 combined with 10 mcg GLA-SE adjuvant has been administered 
to 36 participants in HVTN 115 Part A and 30 participants in HVTN 123. Based 
on the interim safety data (see Section 4.10.2) and immunogenicity data from 2 
weeks after the 3rd immunization in HVTN 115 Part A, the dose for the protein 
vaccines in Part B will be 400 mcg. HVTN 115 Part A reached full enrollment 
with 42 participants in May 2018. As of January 27, 2020, vaccinations are 
complete and the study remains blinded. 

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4.6 
Trial design rationale 
With evidence that limitations in efficacy of human-derived Ad vector-based 
vaccines may be related to pre-existing nAbs to human Ad serotypes, this trial is 
designed to test safety and tolerability of two distinct replication-defective Ad 
vector vaccines derived from chimpanzee Ads. The trial is designed with a one-
dose vaccine regimen given into two intramuscular sites that provides for safety 
assessments prior to proceeding with second priming and a protein boost. 
Specifically, the two low dose groups (1 x 1010 vp) in Part A will receive a single 
dose of vaccine. As this is the first time AdC will be tested in humans, there are 
two planned enrollment pauses to ensure that it is safe to proceed to a higher dose 
(see Table 1-1 Schema). There is an additional planned enrollment pause with 
interim safety review prior to full enrollment in Part B (high dose).  
Group 4 and Group 5 will be given one dose of 5 x 1010 vp AdC6-HIVgp140 or 
AdC7-HIVgp140, respectively, and will be distributed equally between two 
injection sites in the same arm. Three months later Group 4 will be injected with 
one dose of 5 x 1010 vp of AdC7-HIVgp140 given to two sites in the same arm, 
and Group 5 will be injected with one dose of 5 x 1010 vp of AdC6-HIVgp140 
given to two sites in the same arm. Groups 4 and 5 will then receive (CH505TF 
gp120/GLA-SE) 6 months after the initial AdC6-HIVgp140 or AdC7-gp140 
injection. Injections of CH505 TF gp120/GLA-SE will be in the thigh.. 
4.6.1 
Dose (amount and number)  
Part A 
Group 1: Dose is 1 x 1010 vp of AdC6-HIVgp140  
Group 2: Dose is 1 x 1010 vp of AdC7-HIVgp140 
Group 3: Placebo control 
While the AdC6-HIVgp140 and AdC7-HIVgp140 have not been tested in 
humans, chimpanzee adenoviral vectors have been used as a vaccine platform in a 
variety of clinical trials (see Table 4-7). The dose of viral particles selected as the 
initial dose in Part A are as low as any dose selected for other chimpanzee 
adenoviral vectors.  
Part B 
Group 4: Dose is 5 x 1010 vp of AdC6-HIVgp140 followed by 5 x 1010 vp of 
AdC7-HIVgp140 (month 3) and 400 mcg CH505TF with 10 mcg 
GLA-SE (month 6) 
Group 5: Dose is 5 x 1010 vp of AdC7-HIVgp140 followed by 5 x 1010 vp of 
AdC6-HIVgp140 (month 3) and 400 mcg CH505TF with 10 mcg 
GLA-SE (month 6) 
Group 6: Placebo control 

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The target dose selected for immunogenicity analysis is in keeping with targeted 
doses of other chimpanzee adenoviral vectors (Table 4-7). The dose mirrors 
preclinical immunogenicity studies performed in non-human primates (see 
Section 4.9.1 below). 
4.6.2 
Schedule 
The primary objective of this study is safety. Part A begins with a low dose of 
both products and includes two planned safety reviews prior to dose escalation. 
These reviews include an enrollment limit of 1 participant per day for the first 5 
participants receiving either AdC6-HIVgp140 or AdC7-HIVgp140 because the 
products are very similar structurally and manufactured via nearly identical 
processes (please see the Investigator’s Brochure (IB) for more information); a 
second review occurs after all 12 participants have been enrolled in Part A. An 
additional safety review will occur after 12 participants have received the higher 
dose of AdC vaccines in Part B.  
The schedule in Part B is designed to also test the immunogenicity of a 
heterologous prime with different adenoviral vectors followed by a protein boost. 
It has been designed to mimic preclinical studies that demonstrate that a late 
vaccination with recombinant protein leads to increased antibody titers (see 
Section 4.9.2 below). 
4.6.3 
Prime-boost regimen 
Participants in Part B will receive a prime boost vaccine regimen consisting of 
two Ad vector primes followed by a protein boost with CH505TF. 
4.6.4 
Choice of control 
Control for AdC6-HIVgp140 or AdC7-HIVgp140, Sodium Chloride for Injection, 
0.9%  
Control for CH505TF gp120/GLA-SE adjuvanted protein: Sodium Chloride for 
Injection, 0.9%  
4.7 
Plans for future product development and testing 
Our long-term goal is to combine Env-expressing AdC vectors with AdC vectors 
expressing Gag for induction of cellular and humoral immune responses. 
Furthermore, to enhance immune responses we will combine the AdC7gag and 
AdC6gag vector mixtures in a prime-boost regimen. If the current study reveals 
promising immune responses, boosting with alternate recombinant HIV proteins 
would be natural follow-on studies. For example, we conducted studies with a 
trimeric Env protein (with the US Military HIV Research Program) used for 
priming or boosting of AdC vector-induced immune responses and our data 
showed that such regimens induce neutralizing antibodies in mice, especially if 

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the protein is used for boosting (13). Therefore, our long-term goal is to combine 
AdC vectors expressing Gag and Env of HIV-1 which are followed by protein 
vaccines. 
4.8 
Preclinical safety studies 
Table 4-3 Summary of preclinical safety studies 
Study 
number 
Product 
Type of study 
Animal 
N 
Dose groups 
Route 
Schedule 
S14487 
AdC6-
HIVgp140 
or AdC7-
HIVgp140 
Toxicity and 
Biodistribution 
New 
Zealand 
White 
Rabbits 
5M, 5F/ 
group 
Group 1: formulation 
buffer 
Group 2: AdC6-
HIVgp140 (1 x 1011 vp)  
Group 3: AdC7-
HIVgp140 (1 x 1011 vp)  
IM 
Day 
1:one 
dose 
split 
equally 
1726-
031 
CH505TF 
gp120/ 
GLA-SE 
Toxicity 
New 
Zealand 
White 
Rabbits 
10M, 10F/ 
group 
Group 1: Saline Control 
Group 2: CH505TF 
+GLA-SE 
Group 3: 
DNA+CH505TF+GLA-
SE 
Group 4: GLA-SE 
IM 
Day 1, 
15, 29, 
43, 57, 
71, 85 
4.8.1 
Toxicity and biodistribution study of AdC6-HIVgp140 and AdC7-
HIVgp140 in rabbits 
Toxicity studies in rabbits were conducted by Sinclair Research SRC Study No. 
S14487. The study contained 3 cohorts to assess early toxicity, toxicity after 
recovery, and extended biodistribution. Each cohort had three groups of 5 male 
and 5 female animals each, which received either placebo (formulation buffer), 1 
x 1011 vp of AdC6-HIVgp140 or 1 x 1011 vp of AdC7-HIVgp140 (see Table 4-3 
and Table 4-4). 

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Table 4-4 Experimental study design, toxicity and biodistribution study in rabbits 
Group 
Dose Route 
Treatment Dose 
Level (vp)A 
Main CohortB 
Recovery 
CohortC 
Extended 
Biodistribution 
CohortD 
1 
IM 
Vehicle Control 
5M + 5F 
5M + 5F 
5M + 5F 
2 
IM 
1 x 1011 AdC6-
HIVgp140 
5M + 5F 
5M + 5F 
5M + 5F 
3 
IM 
1 x 1011 AdC7-
HIVgp140 
5M + 5F 
5M + 5F 
5M + 5F 
A All animals were IM-administered 0.84 mL (two sites of ~ 0.42 mL) of their designated treatment. 
(Study Day (SD) 1). The total administered dose was equally administered between two separate injection 
locations in the same hind limb (left) spaced ~2.5 cm apart. 
B Main cohort euthanized four days after immunization (SD5). 
C Recovery cohort euthanized 28 days after immunization (SD29). 
D Extended biodistribution cohort 112 days after immunization (SD113). 
The majority of finding during routine follow up were minor and indicative of a 
mild inflammatory reaction to the vaccines. There were no significant 
pathological findings in tissues or tissue sections in the main or recovery groups. 
Two animals died post-dosing due to respiratory distress following phlebotomy. 
Clinical observations in all animals were superficial and unrelated to test article. 
Draize scores were no higher than 2 for any animals except 4 control animals on 
SD3 through SD7. Slight to moderate decreases in food consumption were 
observed on SD2 and SD3 in both treated groups, returning to normal by SD4 and 
remaining normal thereafter. Some animals had random episodes of low food 
consumption and were supplemented as necessary. These findings are not unusual 
in the species. There was no impact on body weights or gains or losses, with no 
significant differences between the control and treated animals. There were no 
ocular abnormalities observed. At 3 h and one day post-dosing, treated animals 
had increased temperatures relative to the control group, returning to normal 
thereafter. 
Several hematology parameters were changed in association with treatment 
including total white cells, neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils, attributed to receipt of a vaccine and considered clinically insignificant. 
Changes in coagulation factors of prothrombin time (PT) and activated partial 
thromboplastin time (APTT) were mild and insignificant, while changes in 
fibrinogen were considered due to an inflammatory reaction of vaccination and 
considered clinically insignificant. Serum chemistry changes included albumin to 
globulin ratio (A/G) and globulin, which are typical following vaccination. 
Changes in creatinine kinase (CK) were considered to be due to intramuscular 
injections, were mild, and considered to be clinically insignificant. No differences 
were observed in urinalysis. Immunogenicity was shown by ELISA at SD29 
(Figure 4-3), demonstrating that all treated animals responded positively to gp140, 
the transgene, post-vaccination, showing they were immunized with vaccine. 
Control animals did not have increased values at post-dosing timepoints (data not 
shown). These results verify dosing. 

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Figure 4-3 Anti-Ad antibodies in rabbits after single AdC6-HIVgp140 or AdC7-HIVgp140 
vectors. Antibody titer in rabbit serum measured by ELISA (1:100 serum dilution) in rabbits 
immunized with the Chimp Ad vectors. Data obtained with pre-immunization sera are shown in 
blue, data obtained with sera collected 28 days after immunization are shown in red. In all animals 
of groups 2 and 3 differences between pre- and post-immunization sera are statistically significant 
by multiple type 1 error corrected student t-test. 
Gross findings were not considered to be related to vaccination. Organ weights in 
group 2 females in the main cohort included adrenal glands that were statistically 
significantly decreased (28%) compared to group 1 females, as were adrenal to 
body (22%) and adrenal to brain (28%) weight ratios. These differences were not 
observed in the recovery cohort. However, in the recovery cohort, thymus gland 
weights were slightly increased compared to controls in group 2 females, as were 
thymus to body and thymus to brain weight ratios. These were not associated with 
microscopic lesions. The only relevant histopathological finding in the main or 
recovery cohorts were injection site local inflammation seen in the treated 
animals, as would be expected from vaccination and were considered normal 
reactions to injections. 
Biodistribution analyses were performed on the following tissues on SD5: lungs, 
liver, spleen, kidneys, bone marrow from the sternum, heart, testes, ovaries, 
injection site muscle, inguinal lymph nodes, brain (cerebellum), and blood. 
Positive tissues were tested from cohorts at SD29 and SD113. Copy numbers are 
presented per mg of tissue. Results showed that some vector DNA or RNA 
derived from transcription of the vector could be detected at some sites on SD5, 
SD29, and SD113 (4, 28, and 112 days after vector injection, respectively) 
(Figure 4-4). However, the number of animals with positive tissues and the copy 
numbers were decreasing throughout the study. Specifically, on SD5 low levels of 
DNA were detected in spleens of group 2 (10/10 animals, group mean 82.57 
copies) and group 3 (10/10 animals, group mean 332 copies), testis of group 3 
(1M [male]/5 animals, copy number of 756.12), ovaries of group 3 (1F [female]/5 
animals, copy number of 228.74), injection site of group 2 (3F [female], group 
mean of 97.08 copies) and group 3 (9/10 animals, group mean of 2001.83), lung 
of group 3 (1F with 21.72 copies), liver of group 3 (7/10 animals, group mean 
33.25 copies), and bone marrow of group 3 (2M). By SD29, vector DNA was 
detected in spleen of 10/10 animals of group 2 (group mean of 38.64) and 1M and 

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1F animal each of group 3 (copy numbers of 25.63 and 22.17, respectively, 
resulting in a group mean less than the LOD of the assay), as well as at the 
injection site in group 2 in 1F animal (5.51 copies) and in inguinal lymph nodes in 
group 2 in 1F animal (7.00 copies). By SD113, DNA was cleared from most 
animals with residual levels present as follows: spleen of 2F of group 2 (group 
mean below the limit of detection of the assay) and 8/10 animals of group 3 
(group mean of 34.45 copies), liver of 8/10 animals of group 3 (group mean of 
40.07 copies), and injection site of 2/10 animals of group 3 (group mean below 
assay LOD). 
On SD5, low levels of RNA were detected as follows: liver of group 2 (5/10 
animals, group mean of 18.85 copies) and group 3 (8/10 animals, group mean of 
53.77 copies), spleen of group 2 (10/10 animals, group mean of 260.40) and 
group 3 (5/10 animals, group mean of 11.49), testes of group 2 (3/5 M, group 
mean of 10.50 copies), ovaries of group 2 (1/5 F with copy number of 29.45), 
injection site of group 2 (9/10 animals, group mean of 5942.27 copies) and group 
3 (6/10 animals, group mean of 601.81). By SD29 RNA was detected in liver of 
1M animal of group 2 (77.43 copies) and 1M of group 3 (72.67 copies), in spleens 
of 8/10 animals of group 2 (group mean of 75.04) and 5/10 animals of group 3 
(group mean of 43.82), at the injection site of 1F animal of group 2 (copy number 
of 14.09), in inguinal lymph nodes of 4/10 animals of group 2 (group mean of 
157.65) and 1M animal of group 3 (47.65 copies). By SD113 RNA was detected 
in spleen of 3/10 animals of group 2 (group mean of 24.26), inguinal lymph node 
of 1M of group 2 (9.23 copies), and liver of 1M of group 3 (12.26 copies). 

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Figure 4-4 Vaccine-derived DNA (A) or RNA (B) tissue distribution. Mean copy number per mg 
of tissue shown for individual male (solid circles) or female (open circles) rabbits on days 5, 29 or 
113 after vaccination with 1011 vp of AdC6-HIVgp140 (group 2) or AdC7-HIVgp140 (group 3) 
vectors. 

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4.8.2 
Summary of a preclinical toxicity study of CH505TF gp120 
Eighty New Zealand White Rabbits, 13-15 weeks in age, were randomly assigned 
to 1 of 4 groups (5/sex/group) as outlined in Table 4-3. Group 3 included a DNA 
vaccine proposed for use in another clinical trial. The test formulations were 
administered bi-weekly (ie, Days 1, 15, 29, 43, 57, 71, and 85) during the study 
via intramuscular injection in dose volumes of 1 mL of protein and 1 mL of DNA. 
Doses were withdrawn into the syringe in the animal room and administered via 
bolus intramuscular injection into the quadriceps or biceps femoris muscle groups 
of the hind legs, with rotation between 4 injection sites. Animals were subjected 
to a full gross necropsy (5/group/sex) on SD 86. The remaining animals were 
necropsied on SD 113 following a 4-week no-treatment recovery period. 
Parameters evaluated during the study period included mortality, clinical and cage 
side observations, dermal grading observations, body weights, body temperatures, 
food consumption, ophthalmology, clinical pathology, immunology, 
immunogenicity, gross pathology, absolute and relative organ weights, and 
histopathology. 
Eight animals died or were euthanized in extremis during the course of the study. 
None of these deaths were considered to be directly related to test article toxicity, 
as the distribution of morbidity was equal across all groups, including controls, 
and none of the findings associated with morbidity or mortality in these animals 
were seen in animals surviving to term. 
Positive skin scores (very slight erythema and/or very slight edema) were 
observed following 6 out of 7 doses. The number of animals with positive dermal 
scores increased following the Day 57 dose administration, with a slight decrease 
following the Day 85 dose. Positive dermal scores were primarily noted in Group 
3 animals with only a few animals in Groups 1 and 2 having positive scores which 
correlated with a higher incidence of injection site findings in Group 3 animals at 
terminal necropsy. The severity of the positive skin scores did not increase with 
additional doses. These observations may be observed with the administration of 
vaccines and were not considered adverse due to the magnitude, low severity of 
microscopic findings, and trend toward reversibility noted microscopically at the 
recovery necropsy.  
Increased group mean body temperatures were observed across all groups 
(including controls) at 1 or more intervals, with a higher incidence observed in the 
vaccine-treated groups. In general, elevations (several outside of the protocol-
specified normal range of 38.3º to 39.4ºC) were noted between 6 and 24 hours 
post dose. Body temperatures for most animals had returned to normal by 48 
hours post dose. These elevations are a common finding following administration 
of a vaccine. 
Test article-related macroscopic observations were seen in the terminal Group 3 
males and females at injection sites 3 and 4 and consisted of swelling/thickening 
and red discoloration. These findings corresponded to microscopic findings of 
inflammation, edema, and/or fibrosis, or hemorrhage, for swelling/thickening and 

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discoloration, respectively. There were no macroscopic observations in the 
recovery animals. 
Test article-related microscopic findings were seen only at the injection sites for 
all terminal groups and all recovery groups and consisted of increased incidence 
and/or severity in all dosed groups compared to controls of a constellation of 
findings including: acute and chronic inflammation of the muscle; fibrosis; mixed 
cell infiltration/inflammation of the subcutaneous tissues; hemorrhage of the 
muscle and subcutaneous tissues; myofiber degeneration/necrosis; myofiber 
regeneration; and rare aggregates of vacuolated macrophages. While all groups 
had some degree of these findings, the DNA/CH505TF gp120/GLA-SE-dosed 
group (Group 3), had the overall highest incidence and/or severity of hemorrhage, 
muscle inflammation (both chronic and acute), and myofiber 
degeneration/necrosis seen across terminal males and females at injection sites 1 
and 2 combined. At injection sites 3 and 4 combined, Group 3 had the highest 
overall incidence and/or severity of the majority of the microscopic findings, 
including hemorrhage, edema, necrosis, vacuolated macrophages, muscle 
inflammation (both chronic and acute), subcutaneous infiltration/inflammation, 
and myofiber degeneration/necrosis and regeneration. Groups 2 and 4 were 
relatively similar to each other, with no clear trends in variation of incidence or 
severity of findings. At recovery, at all injection sites, there was a strong trend 
towards recovery in all groups, with generally reduced incidence and severity of 
most findings compared to terminal groups. Group 3 still had the highest overall 
incidence and/or severity of microscopic findings of vacuolated macrophages, 
chronic muscle inflammation, fibrosis, and subcutaneous 
infiltration/inflammation; with Group 2 and Group 4 being similar to each other 
and to Group 1 controls, albeit with slight increased incidence of vacuolated 
macrophages and, rarely, other findings consistent with resolving injection sites. 
The injection site findings were not considered to be adverse, given the generally 
low severity, lack of systemic findings, limited serum chemistry findings, and 
lack of associated clinical findings. 
Mild, generally reversible and transient test article-related increases in monocytes, 
fibrinogen, globulin, and CRP and decreases in albumin and albumin/globulin 
ratio were observed after each dose administration in both sexes in all treatment 
groups. These changes were comparable in magnitude in all groups. 
Potential test article-related statistically significant increases were seen in 
absolute and relative spleen weights of terminal Group 3 males and females. 
Notable absolute and relative spleen weight increases were also seen in the 
terminal Group 2 and 4 females. Spleen weight changes were similar between 
treatment groups and did not seem to vary to a notable degree between Groups 2, 
3, and 4. However, these changes in spleen weight were not accompanied by any 
consistent corresponding macroscopic or microscopic observations and the 
toxicologic significance of this finding is unclear. 

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Seven biweekly intramuscular injections of 400 mcg CH505TF gp120 with 20 
mcg GLA-SE adjuvant with or without a 4 mg DNA injection or 20 mcg GLA-SE 
alone to New Zealand White rabbits for 13 weeks was well tolerated. Test article-
related changes in dermal scores, clinical pathology parameters, and microscopic 
injection site findings were resolved/partially resolved and/or trending toward 
recovery by the recovery necropsy, and none of the test article-related changes 
were deemed adverse. 

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4.9 
Preclinical immunogenicity studies 
Table 4-5 Summary of preclinical immunogenicity studies 
Study 
number 
Product 
Animal 
N 
Dose groups 
Route 
Schedule 
Assay 
Study 
M1 
(13) 
gp145 protein 
+ 
AdC6-
HIVgp140 
+ 
AdC7-
HIVgp140 
mice 
10M, 
10F 
/group 
Group 1: gp145 protein + 1010 vp 
AdC7-HIVgp140 
Group 2: gp145 protein + 109 vp 
AdC7-HIVgp140 
Group 3: 1010 vp AdC7-
HIVgp140 + gp145 protein 
Group 4: 109 vp AdC7-HIVgp140 
+ gp145 protein 
Group 5: 1010 vp AdC7-
HIVgp140 + 1010 vp AdC6 
Group 6: 109 vp AdC7-HIVgp140 
+ 109 vp AdC6 
IM 
Group 1 and 
2: 0, 4, 8, 12 
weeks 
Group 3 and 
4: 0, 8, 12, 
18 weeks 
Group 5 and 
6: 0 and 8 
weeks 
Gp140-, 
V2-
specific 
Abs 
Study 
M2 
AdC6-
HIVgp140 
+ 
AdC7-
HIVgp140 
+ 
gp140 protein 
 
mice 
10M, 
10F 
/group 
Group 1: 1010 vp AdC7-
HIVgp140 + 1010 vp AdC6-
HIVgp140 + gp140 protein 
 
IM 
0, 8, 16 
weeks 
Gp140-, 
V1V2-
specific 
Abs 
NHP #1 
(26) 
AdC7gag37 + 
AdC6gag37 + 
AdHu5gag37 
RM 
4/group 
2/control 
 
Group 1: 1012 vp AdC7gag37 + 
1012 vp AdC6gag37 + 1012 vp 
AdHu5gag37 
Group 2: 1012 vp AdHu5gag37 + 
1012 vp AdC6gag37 + 1012 vp 
AdC7gag37 
Control: rabies virus glycoprotein 
 
IM 
0, 12, 24, 36 
weeks 
Gag-
specific 
Abs 
NHP #2 
(8) 
AdC6-
HIVgag 
+ 
AdC7-
HIVgag 
 
AdHu5-
HIVgag 
RM 
6/group 
2/control 
Group 1, 3: AdHu5-HIVgag pre-
exposed 
Group 2, 4: AdHu5-HIVgag non 
pre-exposed 
Regimen 1: 1011 vp AdC6-
HIVgag + 1011 vp AdC7-HIVgag 
+ 1011 vp AdC6-HIVgag + 1011 
vp AdC7-HIVgag (groups 1 and 
2) 
Regimen 2: 1011 vp AdHu5-
HIVgag + 1011 vp AdHu5-
HIVgag 
Control: AdHu5rab.gp 
 
IM 
Regimen 1: 
0, 32, 58 
weeks 
 
Regimen 2: 
0, 12 weeks 
T-cell 
respons
e 
 
Gag 
specific 
Ab 
 

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Study 
number 
Product 
Animal 
N 
Dose groups 
Route 
Schedule 
Assay 
NHP #3 
(27) 
AdC6-SIVgag 
+ AdC7-SIVgag 
+ 
MVASIVgagtat 
RM 
8/group; 
8/control 
1011vp AdC6-SIVgag 
+ 1011vp AdC7-
SIVgag + 
MVASIVgagtat 
Control: AdHu5rab.gp 
(2), no vector (6)  
IM 
0, 32, 58 
weeks 
Gag-specific 
T cells 
PSIV 
#1 
(12) 
AdC6-SIVgag/tat 
+ 
AdC7-SIVgag/tat 
RM 
10/group; 
10/control 
Group 1: AdC6-
SIVgag/tat+AdC7-
SIVgag/tat 
Group 2: AdC7-
SIVgag/tat+AdC6-
SIVgag/tat 
Group 3: control 
IM 
 
Ad vector: 
0, 24, 
SIVmac239: 
42 weeks, 1 
dose/2wks x 
15 
T-cell 
response 
Viral loads 
PSIV 
#2 
(1) 
Vectors: 
AdC6, AdC7 
AdH5, AdHu26 
Inserts: 
SIV Gag and 
gp140 
 
RM 
12/group 
All groups: AdHu 
control pre-exposure 
Group 1: AdC7-
gag/gp140 + AdC6- 
gag/gp140 
Group 2: AdHu26-
gag/gp140 + AdHu5-
gag/gp140 
Group 3: control 
IM 
 
Ad vector:0, 
4, 28, 
SIVmac239: 
52 weeks, 1 
dose/week x 
10 
T-cell 
response 
Viral loads 
F: female; M: male; IM: intramuscular; RM: rhesus macaques. 
4.9.1 
Immunogenicity and SIV protection studies of AdC6 and AdC7 
vectors expressing HIV-1 or SIV proteins 
We conducted a number of immunogenicity studies in mice and nonhuman 
primates. Antibody responses were tested using prime boost regimens. 
4.9.1.1 
Study M1: Immunogenicity of AdC6-HIVgp140 and AdC7-HIVgp140 
vectors with and without boosting with gp145 protein in mice 
This study has been published (13). Results show that priming with AdC7-
HIVgp140 induced HIV-1 Env-specific antibody responses, which further 
increased after a subsequent boost with AdC6-HIVgp140 or a partially trimeric 
clade C protein. Multiple booster immunizations with the alum-adjuvanted protein 
did not enhance antibody titers beyond those reached after the 1st protein boost. 
The Ab response was primarily composed of IgG2a and IgG2b isotypes, 
indicative of responses driven by type 1 T helper (Th1) cells. 
To assess Ab function, we performed TZM-bl neutralization assays against three 
tier 1 pseudoviruses (PVs), MW965 (subtype C), GS015 (subtype C), and TH023 
(CRF01_AE), and one tier 2 PV, TZBD 9/11 (subtype C). A PV containing the 
Env from murine leukemia virus (MuLV) was tested as a non-specific control. 
Sera from mice that had been boosted neutralized tier 1 but not tier 2 viruses. 
There was a trend towards higher titers of nAbs in mice primed with AdC7-
HIVgp140 and boosted with protein compared to mice that were sequentially 
immunized with the two AdC vectors. 

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The results from the RV144 Thai trial showed that Abs targeting the V2 region of 
gp120 correlated with decreased risk of HIV-1 acquisition. Anti-V2 Abs were 
detected in all vaccine groups. 
Conclusions: Priming with AdC followed by a protein boost or sequential 
immunizations with two AdC vectors induced HIV-1 Env-specific binding Abs 
including those to the V2 region as well as Abs that cross-neutralized tier 1 HIV-1 
from different subtypes. 
4.9.1.2 
Study M2: Immunogenicity of AdC6-HIVgp140 and AdC7-HIVgp140 
vectors with and without gp140 protein boost in mice 
In an unpublished study in mice (Study M2) we tested if a prime-boost regimen 
with AdC vector and protein induced antibodies to V1V2. We primed mice with 
1010 vp of AdC7-HIVgp140, boosted them 8 weeks later with the same dose of 
AdC6-HIVgp140 and then at week 16 of the study, boosted them with an alum-
adjuvanted baculovirus-derived gp140 protein of Du172. Mice were tested for 
antibodies to gp140 as above and for antibodies to the V1V2 loop on gp70-V1V2, 
a structurally confined V1V2 of a consensus clade C sequence on a scaffold 
protein composed of murine leukemia virus (MLV) glycoprotein which was also 
used to assess antibody responses in the RV144 trial. As shown in Figure 4-5 A, 
mice developed robust responses to gp140 after the boost with AdC6-HIVgp140, 
which only slightly increased after the protein boost. The protein boost achieved a 
marked increase in antibodies to the V1V2 sequence (Figure 4-5 B. Most 
importantly, although all regimens induced long-lasting responses to gp140 (> 1 
year, Figure 4-5 C) responses to the V1V2 loop only remained most significant in 
groups that have been primed with the AdC7-HIVgp140 vector, boosted with the 
AdC6-HIVgp140 vector, and then received a final boost with the gp140 protein 
(Figure 4-5 D). 

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Figure 4-5 Induction of antibodies to V1V2. Mice were primed with 1010 vp of AdC7-HIVgp140. 
Eight weeks later they were boosted once with 1010 vp of AdC6-HIVgp140 and then after an 
additional 8 weeks they were boosted with a clade C gp140 protein. Animals were bled before and 
after vaccination and sera were tested by ELISA for antibodies to gp140 clade C (A, C) or gp70-
V1V2 (B, D). The graphs show adsorbance at a 1:100 serum dilution. (A, B) show responses over 
time, (C, D) compare responses at baseline and at week 59 after priming. Significant differences 
were calculated by 2-way Anova (A, B) or multiple t-tests (C, D). Stars above line indicate degree of 
significance (*) – p >0.05, (**) p > 0.01, (***) p >0.001, (****) p > 0.0001. 
In summary, these data support the notion that induction of HIV-1 envelope-
specific antibodies that are high in magnitude, sustained over time, recognize 
crucial residues such as the V1V2 loop, and achieve cross-specific neutralization 
can best be achieved by multiple sequential immunizations. 
We conducted several studies in rhesus macaques (RM) to assess the efficacy of 
AdC vector immunization in inducing immune responses and providing 
protection against SIVmac challenges. 
4.9.1.3 
NHP #1: Immunogenicity of AdC7gag37 and AdC6gag37 vectors in NHPs 
In the NHP #1 study (26) two groups of 4 NHPs each were immunized with 1012 
vp of AdC7gag37 (a truncated form of gag), followed 8 months later by an 
injection of 1012 vp of AdC6gag37, and after an additional 4 month by a final 
boost with 1012 vp of AdHu5gag37. The 2nd group of 4 NHPs received the same 

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vectors but in the reverse order. Control animals were immunized with vectors 
expressing the rabies virus glycoprotein. Results showed that gag-specific 
antibody responses markedly increased after booster immunizations, 
demonstrating that AdC can serve as a vaccine platform capable of inducing 
robust humoral responses (26). 
4.9.1.4 
NHP #2: Immunogenicity of AdC6-HIVgag and AdC7-HIVgag vectors in 
NHPs  
In a second NHP study (NHP#2, (8)) we compared two vaccine regimens based 
on sequential use of AdHu5 vectors or two different chimpanzee-derived Ad 
vectors (AdC6 and AdC7) expressing HIV-1 gag in rhesus macaques that were 
AdHu5 seropositive or seronegative at the onset of vaccination. Our results show 
that heterologous booster immunizations with the chimpanzee-derived Ad vectors 
induced higher T- and B-cell responses than did repeated immunizations with the 
AdHu5 vector, especially in AdHu5-preexposed macaques (8).  
4.9.1.5 
NHP #3: Immunogenicity of AdC6-SIVgag and AdC6-SIVgag vectors in 
NHPs  
In a third NHP study (NHP #3, (27)) rhesus macaques were vaccinated 
intramuscularly with AdC6 and then boosted intramuscularly with AdC7 both 
expressing Gag of SIVmac239. Animals were subsequently boosted 
intramuscularly with a modified vaccinia Ankara (MVA) virus expressing Gag 
and Tat of the homologous SIV before mucosal challenge with a high dose of 
SIVmac239 given rectally. Animals developed robust T-cell responses after the 
boosts and the breadth of the response increased.  
4.9.1.6 
PSIVP #1: Preclinical SIV protection study using AdC6-SIV gag/tat and 
AdC7-SIV gag/tat vectors 
In the SIV protection study (12) we utilized two regimens of prime-boost 
immunizations with AdC6 and AdC7 expressing SIV Gag/Tat fusion protein to 
test their immunogenicity and ability to protect rhesus macaques (RMs) from a 
repeated low-dose SIVmac239 challenge. No significant protection from SIV 
transmission was observed in either AdC7/6- or AdC7/6-vaccinated RMs.  
4.9.1.7 
PSIVP #2: Preclinical SIV protection study using AdC6 and AdC7 vectors 
expressing Gag and gp160 of SIVmac239 
We tested two vaccine regimens based on prime-boosting with AdC7 and AdC6, 
or two distinct human serotype Ad vectors, AdHu5 and AdHu26, expressing Gag 
and gp160 of SIVmac239 in a nonhuman primate model (1).  
Role of pre-existing adenoviral immunity: To assess effects of pre-existing Abs 
to AdHu vectors, we first injected 36 Indian-origin RMs with AdHu vectors 
expressing an unrelated transgene. RMs of group 1, the AdC group, were 
vaccinated 4 weeks after the last AdHu exposure with 5 × 1010 virus particles (vp) 
of AdC7 expressing Gag (AdC7-gag) mixed with 5 × 1010 vp of AdC7 expressing 

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gp160 (AdC7-gp160). RMs of group 2, the AdHu group, were vaccinated with the 
same doses of AdHu26 vectors expressing the same inserts. Six months later RMs 
of the AdC7 and AdHu26 groups were boosted with AdC6 and AdHu5 vectors, 
respectively, expressing the same inserts and used at the same doses as the 
priming vectors. The control group was not vaccinated.  
Antibody-dependent cell-mediated cytotoxicity responses are improved in 
absence of pre-existing immunity: Env-specific Ab responses were low post-
priming, increased post-boost, and contracted by the time of challenges. Sera from 
MamuA*01/B17+ vaccinated RMs and from 6 control RMs were tested for 
antibody-dependent cell-mediated cytotoxicity (ADCC). In the AdC group most 
RMs scored positive while only 2/7 AdHu -vaccinated RMs showed low activity 
(<10% killing). Data for the AdC but not the AdHu groups were significantly 
different from those of the control group (p = 0.019 by 2-way Anova).  
Cellular Responses: Both vaccine regimens induced Gag-specific CD4+ and 
CD8+T-cell responses. Frequencies of the two CD4+T-cell subsets were 
comparable at all timepoints.  
Overall the NHP studies show that the AdC vectors are immunogenic and induce 
transgene product-specific T- and B-cell responses even in the presence of nAbs 
to human serotype Ad vectors.  
4.9.2 
Immunogenicity of the CH505 EnvSeq-1 vaccines 
NHP 79: Immunogenicity of the EnvSeq-1 gp120 Env proteins in rhesus 
macaques 
The EnvSeq-1 immunogens have been administered to 3 groups of rhesus 
macaques (NHP 79) with the GLA-SE TLR4 agonist adjuvant from IDRI: the 
CH505TF Env gp120 alone, the Envs given in a sequential regimen (CH505TF, 
CH505w53, CH505w78, and CH505w100), and an additive-immunization 
regimen consisting of CH505TF gp120 in combination with the evolved Env 
variants (CH505TF, then CH505TF + CH505w53, then CH505TF + CH505w53 
+ CH505w78, then CH505TF + CH505w53 + CH505w78 + CH505w100). 
From this study, the data indicate triggering of unmutated common ancestors 
(UCAs) of lineages capable of binding HIV Envs with wild type sequences but 
not going into bnAb evolution is possible (Figure 4-6 and Figure 4-7). In this 
study of 12 monkeys, 11/12 monkeys had differential binding antibodies isolated 
and overall the Env differential binding antibodies (bind to wild type CH505 Env 
gp120 but not to CH505 with a deletion of isoleucine at position 371 indicating 
CD4 binding site antibodies and a trait of the CH103 bnAbs) were subdominant 
and were 15% of the total number of antibodies.  

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Figure 4-6 Binding specificities of 417 HIV-1 CH505 Env-induced antibodies isolated from 
rhesus macaques immunized with the CH505 4-valent sequential Envs (NHP79). Differential 
binders are antibodies that bind to the CH505 wild type gp120, but not the ΔI371 gp120, which is 
indicative of putative CD4-binding site broadly neutralizing antibodies. Antibodies generated via 
small scale transient transfection were screened for binding in ELISA. 
 
Figure 4-7 Plasma neutralization profile post sixth immunization in CH505-vaccinated 
macaques. Plasma was screened for neutralization of HIV-1 isolates via the TZM-bl assay. ID50 
positivity cutoff was ≥20 or 3x> background neutralization of MuLV. *40-49% virus neutralization; 
less than 50% required to generate an ID50 value. 
Using the following 4 criteria of the CH103 UCA characteristics, the Haynes 
team determined whether this 4-valent immunogen of CH505 Envs administered 
to rhesus macaques induced triggering of the UCA of a lineage with bnAb 
characteristics of: 1) no neutralization of the tier 2 CH505 TF virus; 2) 
neutralization of the tier 1A CH505 TF variant 4.3; 3) differentially binds to the 
CH505 TF gp120 but not to the mutated CH505 gp120 Env variants with a 
deletion of isoleucine at 371 (ΔI371); and 4) the lineage precursors are 
subdominant to other CH505 Env-binding lineages. Out of 412 Env-reactive 
antibodies isolated from rhesus macaques immunized with the CH505 4-valent 
sequential Envs, 60 (15%) antibodies fit this profile (Figure 4-6). Of the 60 CD4-
binding site antibodies, the Haynes team has isolated a CH505 gp120/CH505 
gp120ΔI371 differential-binding antibody, DH522, which not only neutralized the 
tier 1A CH505 TF variant 4.3 but also neutralized tier 1b viruses such as 
B.SS1196 C.6644, and AG.DJ263. Most importantly, this antibody is the first 
1 5 %   (6 3 /4 1 7 )  C H 5 0 5 -D iffe re n tia ls
8 5 %   (3 5 4 /4 1 7 ) C H 5 0 5  N o n -d iffe re n tia ls
T o ta l:
4 17
H IV -1  A b s
Vaccine groups 
Animal 
ID
Neutralization (ID50)
CH505
(Tier 2)
CH505.w4.3
(Tier 1b)
C.MW965
(Tier 1)
B.SF162
(Tier 1)
B.SS1196
(Tier 1b)
C.6644
(Tier 1b)
D.57128
(Tier 2)
MuLV
Group 1 –
CH505 T/F Env 
alone
17
<20
359
958
20
<20
46
<20
<20
18
<20
577
138
48
<20
<20
<20
<20
19
<20
68
81
<20
<20
<20
<20
<20
20
<20
1453
3470
302
49
67
<20*
<20
Group 4 –
CH505 
Sequential Envs
21
<20
990
1775
49
24
37
<20*
<20
22
<20
539
335
<20
48
36
22
21
23
<20
293
293
29
<20
<20
<20*
<20
24
<20
1908
1255
78
<20
34
22
<20
Group 5 - CH505 
Additive Envs
25
<20
296
469
34
<20
<20
<20
<20
26
<20
341
264
47
24
26
<20*
<20
27
<20
470
318
55
<20
25
<20
<20
28
<20
130
329
<20
<20
<20
<20
<20
ID50 reciprocal dilutions
<20
20-100
101-1,000
1,001-10,000

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example of an antibody isolated in a vaccinated monkey that has tier 2 
heterologous virus neutralization and neutralizes tier 2 HIV-1 strains; D.57128 
and M.CON-S (Figure 4-8). Remarkably, the DH522 antibody VH in rhesus 
macaques is the VH4 gene that is most similar (92% identical) to the human VH4-
59 that is used by CH103 CD4 binding site bnAb. This antibody was induced in 
the additive-immunization group in the non-human primate (NHP) study. 
Additionally, further characterization of antibodies isolated from the additive 
immunization NHP group (macaque 5556) has led to the identification of 2 
additional members of a DH522 clonal lineage (Figure 4-9). The DH522 antibody 
was found to block the binding of soluble CD4 as well as CH103 Abs to CH505 
Env, and also exhibited differential binding to CH505 Env versus the 
∆I371/P363N mutant as well as YU2 wild-type versus YU2 D368R. DH522 also 
utilized the rhesus heavy chain most closely related to human VH4-59 (the VH 
used by CH103) and has a VH mutation frequency of 3.4%. The frequency of the 
DH522 heterologous tier 2 neutralizing antibody lineage members is 2/412 (0.5%) 
of Env-specific antibodies. 
 
Figure 4-8 Neutralization profile of DH522 and other lineage members. 
 
IC50 (µg/mL)
0.01-1
1.0-10.0
10.0-50.0
>50
Virus Isolates 
IC50 (µg/ml)
ID
Tier
DH522 
UCA
DH522IA1.2 DH522
DH564_ 
565
CH103 
UCA
CH103
CH505 T/F
2
>50
>50
>50
>50
>50
1.3
CH505.w4.3
1b
2.4
0.1
0.2
0.1
24.2
0.1
C.6644
1b
>50
2.0
4.3
9.5
>50
0.1
B.SS1196
1b
>50
14.6
22.9
19.4
>50
0.8
AG.DJ263
1b
>50
10.5
11.9
5.7
>50
0.9
D.57128
2
>50
14.0
15.6
13.8
>50
>50
M.CON-S
2
41
21.1
42.3
15.7
>50
3.0
MuLV
-
>50
>50
>50
>50
>50
>50

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Figure 4-9 Three DH522 clonal lineage members from an NHP receiving the additive 
immunization regimen (NHP #79). 
We determined the neutralization profile of DH522 and found that it neutralized 2 
out of 31 primary isolates (6%), specifically D.57128 and M.CON-S (Figure 4-8). 
We also performed an alignment of DH522 and CH103 and determined the light 
chain CH103 contacts that are shared with the vaccine-induced DH522 binding 
site antibody (Figure 4-10). We found that a shared mutation in contact region 
E50 in LCDR2 forms an H bond with N280 in loop D, and additionally shared 
contact K66 in light chain FR3 forms a salt bridge with D461 in V5 in CH103. 
 
Figure 4-10 Alignment of DH522 and CH103: mutations to shared amino acids. 
Thus, the CH103 human antibody and the DH522 rhesus antibody show 
convergent evolution with the same amino acids at gp120 contact sites. Finally, 
we characterized a fourth CH505 Env differential binder mAb (DH566) from 
post-fourth immunization sequential immunization in macaque 5553 (summarized 
in Table 4-6). 
CH103UCA_VL    SGDKLGDKYA C...WYQQKP GQSPVLVIYQ DSKRPSGIPE RFSGSNSGNT ATL 
DH522UCA
T-TSSDIGGY NGVS----HS -TA-R-L--E V------VSD -----K---- -S-
DH522IA1.2     S-TSSDIGAY NGVS---HHS -TA-R-L--E V------VSD -----K---- -S-
DH522L         S-TSSDIGAY NGVS---HHS -TA-R-L--E V------VSD -----K---- -S-
DH564_565L     S-TTNDIGAY NGVS---HHS DTA-R-L--E VN-----VSD -----K---- -S-
CH103_VL       S-A...STNV -...---V-- ----EV--FE NY-------D -----K--S- ---
***
* ***
****

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Table 4-6 Characteristics of CH505 Env differential binder DH566, post-fourth immunization 
(macaque 5553) 
• 
VH3-30 (like HCDR3 binder CD4bs 
bnAb CH98) 
• 
HCDR3 = 18 
• 
Binds CH505 gp120, not CH505 
∆I371; binds RSC3 but not 
RSC3∆I371, P363N gp120s 
• 
Neutralization in TZM-bl: 
CH505TF = <20 CH505 4.3 = 0.2 mcg 
MW965 = 0. 2 mcg SF162 = 43 mcg/mL 
AG.DJ263 = 7.3 mcg/mL 
C.6644 = 3.0 mcg MuLV = <20 
• 
VH mutations = 8.5%, IgG1 
Note: HCDR3: long heavy chain third complementarity determining regions 
NHP 106 Study: Dose ranging study of EnvSeq-1 vaccine proteins administered 
with GLA-SE adjuvant in rhesus macaques 
A dose ranging study was performed in rhesus macaques using CH505TF gp120 
in 25 mcg GLA-SE with a dose of 5 to 600 mcg of gp120 Env with each dose 
administered 3 times. Env binding antibody (Figure 4-11) and CD4-binding site 
antibody (Figure 4-12) were determined and the CH505TF gp120 was 
immunogenic after 2 immunizations. Moreover, it was noted that after 2 
immunizations the 300 and 600 mcg doses of the protein were optimal with 
respect to inducing binding antibodies; after 3 immunizations the binding 
antibody responses were similar for all doses. With tier 1 neutralization, we found 
that while after 2 immunizations (Figure 4-13) there was a linear increase in 
neutralization titers with increasing gp120 dose, after 3 immunizations, there was 
no statistical difference between the tier 1 antibody neutralizing titers (Figure 
4-14). 
Preliminary data from the NHP 106 study included both plasma antibody and 
flow cytometric quantification of memory B cells that displayed differential 
binding; analysis of both measures indicated that 300 mcg/dose was optimal in 
NHP. For that reason, we expect that the validated assay primary outcome data 
and the secondary outcome data from flow cytometry will give a concordant 
answer. 
 
 
Figure 4-11 Inhibition of CH106 CD4bs binding to B.63521 gp120 Env by NHP 106 plasma 
from immunization with 5 different doses of CH505TF gp120. 
0
2
6
1 4
0
2 0
4 0
6 0
8 0
1 0 0
W e e k
B lo ck in g  (% )
G ro u p  1 : C H 0 5 0 5  5  u g
G ro u p  2 : C H 0 5 0 5  2 0  u g
G ro u p  3 : C H 0 5 0 5  1 0 0  u g
G ro u p  4 : C H 0 5 0 5  3 0 0  u g
G ro u p  5 : C H 0 5 0 5  6 0 0  u g

HVTN 139 Version 1.0 / February 23, 2021 
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Figure 4-12. Binding of NHP 106 plasma to CHO-derived CH505TF gp120. 
 
Figure 4-13 Tier 1 HIV neutralization in the TZM-Bl assay after 2 immunizations with 
CH505TF gp120 doses. Group 1, 5 mcg; Group 2, 20 mcg; Group 3, 100 mcg; Group 4; 300 mcg; 
Group 5, 600 mcg. 

HVTN 139 Version 1.0 / February 23, 2021 
HVTN139_v1.0_FINAL / Page 41 of 186 
 
 
Figure 4-14 Tier 1 HIV neutralization in the TZM-Bl assay after 3 immunizations with 
CH505TF gp120 doses. Group 1, 5 mcg; Group 2, 20 mcg; Group 3, 100 mcg; Group 4; 300 mcg; 
Group 5, 600 mcg. 
 
 
Figure 4-15 Gating strategy for B cell analysis. An example of NHP B-cell data shown for pre-
immune and post third immunization samples. Few double positive (red gate gp120-reactive) or 
differential positive (black gate) cells are found in the pre-immune sample; both double positive and 
differential B cells are found two weeks after the third immunization. 
4.10 
Clinical studies 
4.10.1 
Clinical studies of Chimpanzee Ad vectors targeting diverse 
pathogens 
The AdC6-HIVgp140 and AdC7-HIVgp140 vectors have not yet been tested in 
humans. 
Chimpanzee Ad vectors of different serotypes (AdC63, AdC3) with inserts 
targeting other pathogens have been tested in human adults administered 
intramuscularly (see Table 4-7). None of the trials reported serious adverse 
events, even in trials with vectors used at higher doses than those planned in this 
trial. 

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Table 4-7 Summary of clinical trials that used chimpanzee Ad vectors of different serotypes 
Vaccine 
Doses (vp) 
Number of subjects 
Disease 
Ref. 
AdC63 
5 x 109 
8 
Malaria 
(28) 
5 x 1010 
8 
AdC3 
2.5 x 1010 
5 
Hepatitis C 
(29) 
7.5 x 1010 
5 
AdC3 
2.5 x 1010 
9 
Hepatitis C 
(30) 
AdC3 
1 x 1010 
10 
Ebola 
(31) 
2.5 x 1010 
35 
5 x 1010 
20 
1 x 1011 
11 
AdC63 
1 x 1010 
4 
Malaria 
(32) 
5 x 1010 
8 
2 x 1011 
10 
AdC3 
2 x 1010 
10 
Ebola 
(33) 
2 x 1011 
10 
AdC63  
5 x 1010+Matrix-M 50 mcg 
10 
Malaria 
(34) 
5 x 1010+Matrix-M 50 mcg 
10 
AdC63 
5 x 109 
3 
Malaria 
(35) 
4.10.2 
Clinical studies of CH505TF gp120 /GLA-SE vaccine 
4.10.2.1 
HVTN 115, Part A 
The CH505TF gp120/GLA-SE vaccine has been administered at different doses 
in the HVTN 115 Part A trial. This was a dose escalation study, evaluating 
CH505TF gp120 /GLA-SE at protein doses of 20, 100, and 400 mcg adjuvanted 
with 10 mcg of GLA-SE adjuvant, respectively.  
Table 4-8 Schema of HVTN 115, Part A 
Study arm 
N 
Month 0 
 (Day 0) 
Month 2 
(Day 56) 
Month 4 
(Day 112) 
Month 8 
(Day 224) 
Month 12 (Day 
364) 
Part A 
 
 
 
 
 
 
Group 1 
12 
20 mcg 
CH505TF 
20 mcg 
CH505TF 
20 mcg 
CH505TF 
20 mcg 
CH505TF 
20 mcg 
CH505TF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Group 2 
12 
100 mcg 
CH505TF 
100 mcg 
CH505TF 
100 mcg 
CH505TF 
100 mcg 
CH505TF 
100 mcg 
CH505TF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Group 3 
12 
400 mcg 
CH505TF 
400 mcg 
CH505TF 
400 mcg 
CH505TF 
400 mcg 
CH505TF 
400 mcg 
CH505TF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Group 4 
6 
placebo 
placebo 
placebo 
Placebo 
placebo 
 
 
 
 
 
 
 
Total Part A 
42 (36/6) 
 
 
 
 
 

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Based on the interim safety data and immunogenicity data from 2 weeks after the 
3rd immunization in Part A, the dose for the protein vaccines in Part B will be 
400 mcg, the same as in this study. HVTN 115 Part A reached full enrollment 
with 42 participants in May 2018. As of January 27, 2020, vaccinations are 
complete and the study remains blinded. Most participants reported no or mild 
local signs and symptoms after vaccine administrations. There have been 2 cases 
of severe (grade 3) erythema and induration, which resolved within days, and one 
case of severe (grade 3) pain. One of those participants experienced moderate 
injection site cellulitis, which resolved with oral antibiotics. Most participants 
reported no or mild systemic reactogenicity signs or symptoms after vaccinations. 
Two cases of severe (grade 3) headache were reported during the reactogenicity 
period. Beyond the reactogenicity period, there have been no severe adverse 
events related to study product. 
4.10.2.2 
HVTN 123  
The HVTN 123 study is a double-blind, randomized clinical trial comparing the 
safety, tolerability and immunogenicity of CH505TF gp120 produced from stably 
transfected cells to CH505TF gp120 produced from transiently transfected cells. 
In this study CH505TF gp120 is used at 100 mcg dose in combination with 10 
mcg GLA-SE.  
HVTN 123 reached full enrollment with 30 participants in January 2020. As of 4 
March 2020, vaccinations are ongoing, all 30 participants have received their 1st 
vaccination, 22 participants have received their 2nd vaccination and 13 
participants have received their 3rd vaccination. The study remains blinded. Most 
participants experienced none or mild reactogenicity after vaccine 
administrations. There was no severe or potentially life-threatening 
reactogenicity. As of March 4, 2020, 17 mild and moderate adverse events have 
occurred in 10 of 30 participants. Of those, 1 moderate adverse event was 
designated as related to study product. This participant had grade 2 axillary 
lymphadenopathy that resolved by day 4 after vaccination. 
Table 4-9 Schema of HVTN 123 
Study arm 
n 
 
Month 0 
Month 2 
Month 6 
Group 1 
15 
 
100 mcg 
CH505TF gp120 
Stable 
 
100 mcg 
CH505TF gp120 
Stable 
100 mcg 
CH505TF gp120 
Stable 
Group 2 
15 
 
100 mcg 
CH505TF gp120 
Transient 
100 mcg 
CH505TF gp120 
Transient 
100 mcg 
CH505TF gp120 
Transient 
Total 
30 
 
 
 
 

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4.10.3 
Clinical studies of gp120 Env protein vaccines 
Although CH505TF gp120 has already been evaluated in humans without 
identification of safety issues, there is additional extensive clinical trial 
experience with other gp120 Env proteins evaluated either alone or in 
combination with a prime or boost. 
To date, there is considerable experience from phase 1 and phase 2 studies 
evaluating gp120/160 alone or in combination with pox vectors (36, 37). The 
AIDS Vaccine Evaluation Group conducted an analysis of safety data from over 
15 clinical trials of gp120 and gp160 proteins administered to over 500 
individuals demonstrating that overall, all HIV Env proteins at doses up to 640 
mcg were well tolerated. The majority, if not all of the local and systemic 
reactions were deemed associated with adjuvant components of the vaccine rather 
than the Env proteins (38). 
The monovalent subtype B and bivalent subtype B/E (CRF01_AE) recombinant 
glycoprotein 120 HIV-1 vaccine (AIDSVAX B/E) was evaluated in an efficacy 
study conducted among injection drug users in Thailand. A total of 600 mcg of 
AIDSVAX B/E was administered with alum as a stand-alone vaccination. The 
most commonly reported adverse event was tenderness at the injection site 
(71.0% vaccine recipients versus 65.7% placebo recipients), which did not 
increase with multiple injections. There were no differences between vaccine and 
placebo recipients with respect to the number of serious adverse events (39). 
The RV144 Thai study evaluated the same gp120 vaccine in a heterologous 
prime-boost vaccination strategy consisting of a recombinant canarypox vector 
vaccine expressing gag, pol, and env (ALVAC-HIV) followed by the gp120 
subunit boost. Over 8,000 participants received multiple combined doses of 600 
mcg of gp120 (300 mcg each of 2 different clade B and E gp120s) in combination 
with ALVAC-HIV (vCP1521). This trial showed partial efficacy (31%) in 
protection from HIV-1 infection. Local and systemic reactogenicity noted after 
the gp120 protein (AIDSVAX B/E) was mostly mild and resulted in few serious 
adverse events (40). 
Previous clinical experience comparing various doses of gp120 and gp160 
proteins did not identify significant differences in safety profile when the protein 
dose was altered and adjuvant dose remained constant. For example, in a study 
evaluating AIDSVAX B/E gp120 at 100 mcg (n=31), 300 mcg (n=31) and 600 
mcg (n=30) of protein in alum, majority (80%) of participants reported at least 
one reactogenicity event, the most common being injection site pain/tenderness, 
but all of the symptoms were mild to moderate and self-limited. Moreover, while 
there were fewer reactogenicity events at the lowest dose, the safety profile in the 
300 mcg and 600 mcg groups was similar (41). A study of recombinant gp160 
VaxSyn formulated with an aluminium phosphate gel adjuvant compared two 
doses of 160 mcg (N=20) and 640 mcg (N=21) of the protein administered as 4 
injections over 12 months. Both doses were generally well tolerated. Local 
reactogenicity (injection site erythema/induration) was frequent but self-limited, 

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lasting less than 48 hours; and the frequency of local reactogenicity was similar 
between the two groups. There were no significant differences in severe local or 
systemic reactions between the dose groups. And importantly, there were no 
significant differences in laboratory abnormalities [hepatic, hematologic and renal 
function] between the different protein doses (42). 
Taken together, the combined evidence from the large numbers of trial 
participants in these and other studies (43-47) demonstrates that gp120 
recombinant protein vaccines administered in combined doses of up to 600 mcg 
were immunogenic and well tolerated. There was 1 case of anaphylaxis deemed 
related to the vaccine. There were no other unusual or serious vaccine-associated 
adverse events (SAE) reported. 
4.10.4 
Clinical studies of the GLA-SE adjuvant and protein combinations 
GLA-SE is a synthetic TLR4 agonist formulated in a stable nano-emulsion of 
squalene oil and promotes a strong Th1-type immune response to vaccine 
antigens (22, 23). CH505TF gp120 has been tested in combination with 10 mcg 
GLA-SE in part A of HVTN 115, HVTN 123 and HVTN124 (see Section 4.10.2). 
There is considerable clinical trial experience with the GLA-SE adjuvant in 
combination with other antigens. These data are summarized below and in Table 
4-10 and Table 4-11.  
Over 2700 individuals have received at least one dose of the GLA-SE adjuvant at 
doses ranging from 0.5 to 20 mcg with no significant safety concerns identified to 
date. Please see the Investigator’s Brochure (IB) for additional details of the 
clinical trials performed with GLA-SE.  
In addition to HVTN 115, HVTN 123, and HVTN 124 five other studies have 
included the 10 mcg dose of the GLA-SE adjuvant, the same dose as proposed for 
this study. The first was an open-label phase 1 clinical trial conducted in Brazil 
with a Schistosoma mansoni antigen (Sm14) (48). Twenty healthy males received 
3 IM doses of 50 mcg Sm14 + 10 mcg GLA-SE at one-month intervals. The 
vaccine was safe and generally well tolerated with no serious adverse events 
(SAEs) or Grade 4 adverse events (AEs) (48). Injection site pain was commonly 
reported (80%, 50%, and 41% after the first, second, and third dose, respectively), 
but generally mild and self-limited. There were no abnormalities in physical 
exams, serum chemistries, and hematology values related to study product. 
Humoral and CD4+ T-cell responses to Sm14 were reported (48). 
The second clinical trial using the 10 mcg dose of GLA-SE was a phase 1, open-
label evaluation of the safety, open-label evaluation of the safety, tolerability, and 
immunogenicity of a Leishmania vaccine (LEISH-F3) in combination with SLA-
SE (second generation glucopyranosyl lipid A in stable oil-in-water emulsion) 
adjuvant compared to LEISH-F3 with GLA-SE in healthy adults (NCT02071758; 
Protocol IDRI-LVVPX-117). The SLA-SE adjuvant is a next generation TLR4 
adjuvant formulation. Thirty-nine participants were randomized to 4 arms: high 
dose LEISH-F3 (20 mcg) and low dose SLA-SE (5 mcg); high dose LEISH-F3 

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and high dose GLA-SE adjuvant (10 mcg); low dose LEISH-F3 (5 mcg) and high 
dose GLA-SE adjuvant (10 mcg); and high dose LEISH-F3 and high dose SLA-
SE adjuvant (10 mcg). Participants received 3 injections at one-month intervals. 
The LEISH-F3 + GLA-SE and LEISH-F3 + SLA-SE vaccines were safe and well 
tolerated in adult subjects. No deaths, no dose-limiting toxicities (DLTs), no 
Grade 3 or 4 AEs, no SAEs, and no AE of special interest (AESIs) occurred 
during the study. All study injection reactions were Grade 1 or Grade 2. The most 
frequently reported reactions were injection site tenderness/pain and fatigue. 
Three other clinical trials are evaluating 10 mcg or higher doses of GLA-SE in 
oncology. Two ongoing trials are investigating GLA-SE alone as an 
immunotherapy and one trial tested GLA-SE in combination with a prostate 
cancer antigen. No data are currently available from these trials. 
Clinical experience with GLA-SE as an adjuvant for other vaccines at doses 
ranging from 1 mcg to 5 mcg suggests that it is safe and well-tolerated. Treanor et 
al. (24) tested an avian influenza hemagglutinin (H5) subunit vaccine at a range of 
doses with and without a fixed dose of GLA-SE (1 mcg) and reported mild to 
moderate injection site pain and/or tenderness in 50–70% of H5 + GLA-SE 
recipients, with myalgias and headaches reported by a minority (25-27%) of 
vaccinees. No other safety findings were noted, and the GLA-SE adjuvant 
substantially increased the immunogenicity of the vaccine (24). 
A recent phase 1 clinical trial of a respiratory syncytial virus (RSV) vaccine in 
older adults (≥ 60 years of age) found that a combination of the RSV fusion (F) 
protein at three different doses with 2.5 mcg of GLA-SE was safe, well-tolerated, 
and immunogenic. Compared with the unadjuvanted vaccine, GLA-SE increased 
local reactogenicity, with 40-65% of subjects reporting mild-to-moderate, self-
limited injection site pain and/or tenderness (49). No other safety concerns were 
reported. Immune responses were F protein dose-dependent, and the adjuvant 
enhanced both humoral and cellular immune responses (49). A follow-up study 
using a higher dose of F protein and three doses of GLA-SE has been completed 
(NCT02289820). The vaccine was safe, tolerable, and immunogenic and the data 
supported the selection of 120 mcg F protein /5 mcg of GLA-SE for further 
evaluation (50). 
GLA-SE was also found to be safe and well-tolerated at doses of 2 mcg and 5 
mcg in a phase 1 trial of LEISH-F3 given three times at one-month intervals (25). 
Injection site pain and/or tenderness was quite common (90-100%) with fatigue 
noted by 40-60% of vaccinees receiving the adjuvanted product versus 33% of 
subjects who received unadjuvanted vaccine (25). The unadjuvanted LEISH-F3 
was essentially non-immunogenic while antibody and cytokine responses were 
noted in vaccinees in both dose groups of GLA-SE (25). 
GLA-SE at a 5 mcg dose has also been tested together with protein antigens in 
several other clinical trials which are included in the tables below. 

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Table 4-10 Completed clinical trials using IDRI GLA‐SE adjuvant formulations in combination with other 
vaccines (as of February 14, 2020) 
Sponsor/Partner 
Disease Area/Antigen 
GLA-SE 
Dose 
# Receiving 
GLA-SE 
# Total in 
Study 
Oswaldo Cruz Foundation / IDRI 
NCT01154049  
Schistosomiasis (Sm14)  
10 mcg  
20 
20 
Oswaldo Cruz Foundation / IDRI 
NCT03041766 
Schistosomiasis (Sm14)  
5 mcg  
30 
30 
Oswaldo Cruz Foundation / IDRI 
NCT03799510 
Schistosomiasis (Sm14) 
2.5 mcg 
64 
95 
IDRI / Rockefeller University 
NCT01397604 and NCT01864876  
Adjuvant only 
2 mcg  
5 mcg  
10 
7 
49 
IDRI  
NCT01484548  
Leishmaniasis (LEISH-F3)  
2 mcg  
5 mcg  
12 
12 
36 
NIAID / IDRI  
NCT01751048  
Leishmaniasis (LEISH-F3)  
5 mcg  
16 
 
48 
IDRI 
NCT02071758  
Leishmaniasis (LEISH-F3)  
10 mcg 
18 
39 
IDRI  
NCT03302897 
Leprosy (LEP-F1)  
5 mcg  
24 
24 
WRAIR / IDRI 
NCT01540474  
Malaria (CelTOS)  
2 mcg  
5 mcg  
10 
20 
30 
European Vaccine Initiative / IDRI 
NCT01949909  
Malaria (p27A)  
2.5 mcg 
5 mcg  
24 
8 
56 
European Vaccine Initiative / IDRI 
NCT02014727  
Malaria (AMA-1 DiCo)  
2.5 mcg  
33 
66 
University Hospital Tuebingen / 
IDRI 
NCT02647489 
Malaria (PAMVAC) 
5 mcg 
 
21 
 
63 
Institut National de la Santé et de la 
Recherche Médicale / IDRI 
NCT02658253 
Malaria (PRIMVAC) 
2.5 mcg 
29 
68 
IDRI / Aeras 
NCT01599897  
TB (ID93)  
2 mcg  
5 mcg  
24 
24 
60 
IDRI / Aeras 
NCT01927159 
TB (ID93) 
2 mcg 
5 mcg 
39 
15 
66 
IDRI  
NCT02465216 
TB (ID93) 
2 mcg 
5 mcg 
20 
28 
60 
NIH/NIAID/DMID / IDRI 
NCT02508376 
TB (ID93) 
5 mcg 
 
20 
 
70 
CONFIDENTIAL  
Seasonal influenza  
0.5 mcg  
1 mcg  
2.5 mcg  
5 mcg  
6 
12 
36 
4 
96 
Protein Sciences / Immune Design  
NCT01147068  
Pandemic influenza 
(recombinant protein)  
1 mcg  
220 
392 
Novavax / Immune Design 
NCT01596725  
Pandemic influenza (H5-
VLP)  
2.5 mcg  
169 
333 

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Sponsor/Partner 
Disease Area/Antigen 
GLA-SE 
Dose 
# Receiving 
GLA-SE 
# Total in 
Study 
Medicago / Immune Design 
NCT01991561  
Pandemic influenza (H5-
VLP)  
5 mcg  
130 
390 
Immune Design 
NCT02015416 
Cancer (NY-ESO-1) 
2 mcg 
5 mcg 
10 mcg 
3 
3 
6 
12 
Immune Design 
NCT02035657 
Merkel cell carcinoma 
5 mcg 
9 
9 
Immune Design  
NCT02387125 
Cancer (CMB305, G305) 
Not 
Available 
 
 
Immune Design  
NCT02609984 
Cancer (CMB305) 
Not 
Available 
 
 
Immune Design  
NCT02501473 
Non-Hodgkins lymphoma  
5 mcg 
10 mcg 
20 mcg 
Unknown 
Unknown 
Immune Design  
NCT02180698 
Sarcoma  
5 mcg 
10 mcg 
20 mcg 
4 
4 
4 
12 
Immune Design  
NCT02320305 
Melanoma (MART1) 
Not 
Available 
 
 
Medimmune / Immune Design 
NCT02115815  
Respiratory syncytial virus 
(sF) 
2.5 mcg 
60 
144 
Medimmune / Immune Design 
NCT02289820  
Respiratory syncytial virus 
(sF) 
1 mcg 
2.5 mcg 
5 mcg 
39 
99 
79 
261 
Medimmune / Immune Design 
NCT02508194 
Respiratory syncytial virus 
(sF) 
5 mcg 
946 
1894 

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Table 4-11 Ongoing clinical trials using IDRI GLA-SE adjuvant formulations in combination with other 
vaccines (as of February 14, 2020)  
Sponsor/Partner 
Disease Area/Antigen 
GLA-SE 
Dose 
# Receiving 
GLA-SE 
# Total in 
Study  
IDRI  
NCT03722472 
TB (ID93) 
5 mcg  
48 
48 
Quratis / IDRI 
NCT03806686 
TB (ID93) 
5 mcg 
96 
144 
Quratis / IDRI 
NCT03806699 
TB (ID93) 
5 mcg 
24 
36 
Immune Design 
NCT03450122 
Sarcoma (CMB305) 
Not 
Available 
 
 
Immune Design 
NCT02406781 
Sarcoma (G100) 
Not 
Available 
 
 
HVTN 115 / IDRI 
NCT03220724 
HIV Vaccine (CH505TF 
gp120) 
10 mcg 
96 
107 
HVTN 123 / IDRI 
NCT03856996 
HIV Vaccine (CH505TF 
gp120) 
10 mcg 
30 
30 
HVTN 124 / IDRI 
NCT03409276 
HIV Vaccine (PDPHV) 
10 mcg 
52 
60 
4.11 
Potential risks of study products and administration 
Table 4-12 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 
• 
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 
• 
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 
Theoretical risks 
• 
Autoimmune disease  
• 
Effects on a participant’s response to an approved HIV vaccine 
administered in the future 
• 
Effects on susceptibility to HIV, if the participant is exposed to HIV 
• 
Effects on the course of HIV infection/disease, if the participant is infected 
with HIV 
• 
Effects on the fetus and on pregnancy 

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5 
Objectives and endpoints 
5.1 
Primary objectives and endpoints 
Primary objective 1: 
To evaluate the safety and tolerability of AdC6-HIVgp140 and AdC7-HIVgp140 
at doses of 1 x 1010 virus particles (vp) and 5 x 1010 vp, alone and in combination 
with CH505TF gp120 adjuvanted with GLA-SE in HIV- uninfected adults. 
Primary endpoint 1: 
Local and systemic reactogenicity signs and symptoms for a minimum of seven 
days following receipt of any study product. All adverse events for thirty days 
after any receipt of study vaccination. All serious adverse events (SAEs), 
medically attended adverse events (MAAEs), and adverse events of special 
interest (AESIs) will be collected for twelve months following any receipt of 
study product. 
5.2 
Secondary objectives and endpoints 
Secondary objective 1: 
To evaluate and compare immune responses elicited by single administration of 
AdC6-HIVgp140 or AdC7-HIVgp140 at two different dose levels 
Secondary endpoints 1: 
• Response rate, magnitude, and breadth of HIV-specific serum IgG binding 
antibodies assessed 4 weeks after a single vaccination (Part A) or the first 
vaccination (Part B)  
• Response rate, magnitude, and polyfunctionality of HIV-specific CD4+ 
and CD8+ T-cell responses assessed 4 weeks after a single vaccination 
(Part A) or the first vaccination (Part B) 
• Response rate, magnitude, and breadth of serum neutralizing antibodies 
against tier 1 and if applicable, other heterologous tier 2 HIV-1 isolates 
assessed 4 weeks after a single vaccination (Part A) or the first vaccination 
(Part B)  
Secondary objective 2: 
To evaluate and compare immune responses elicited by sequential administration 
of AdC7-HIVgp140 followed by AdC6-HIVgp140 and AdC7-HIVgp140 
followed by a dose of AdC6-HIVgp140 at 5 x 1010 vp 

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Secondary endpoints 2: 
• Response rate, magnitude, and breadth of HIV-specific serum IgG binding 
antibodies assessed 4 weeks after the second vaccination (Part B) 
• Response rate, magnitude, and polyfunctionality of HIV-specific CD4+ 
and CD8+ T-cell responses assessed 4 weeks after the second vaccination 
(Part B) 
• Response rate, magnitude, and breadth of serum neutralizing antibodies 
against tier 1 and if applicable, other heterologous tier 2 HIV-1 isolates 
assessed 4 weeks after the second vaccination (Part B) 
Secondary objective 3: 
To evaluate and compare immune responses elicited by heterologous AdC7-
HIVgp140 followed by AdC6-HIVgp140 or AdC7-HIVgp140 followed by AdC6-
HIVgp140 prime followed with CH505TF gp120 / GLA-SE boost 
Secondary endpoints 3: 
• Response rate, magnitude, and breadth of HIV-specific serum IgG binding 
antibodies assessed 2 weeks after the third vaccination (Part B) 
• Response rate, magnitude, and polyfunctionality of HIV-specific CD4+ 
and CD8+ T-cell responses assessed 2 weeks after the third vaccination 
(Part B) 
• Response rate, magnitude, and breadth of serum neutralizing antibodies 
against tier 1 and if applicable, other heterologous tier 2 HIV-1 isolates 
assessed 2 weeks after the third vaccination (Part B) 
Secondary objective 4: 
To evaluate vector-specific antibodies both before and after vaccination.  
Secondary endpoint 4: 
Magnitude of serum antibody neutralization of AdC6 and AdC7 vectors as 
assessed by adenovirus neutralization assay at baseline (Parts A and B), 4 weeks 
after the first vaccination (Parts A and B), and 4 weeks after the second 
vaccination (Part B) 

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5.3 
Exploratory objectives 
Exploratory objective 1: 
To characterize antibody avidity and/or Fc-mediated antibody functions (infected 
cells antibody binding assay [ICABA], antibody-dependent cellular cytotoxicity 
[ADCC], antibody dependent cellular phagocytosis [ADCP], antibody dependent 
neutrophil phagocytosis [ADNP], and FcR-binding) 
Exploratory objective 2: 
To assess the impacts of vaccination on B-cell subset distribution in blood 
Exploratory objective 3: 
To conduct analyses related to furthering the understanding of HIV, immunology, 
vaccines, and clinical trial conduct 
Exploratory objective 4: 
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 Center assay portfolio 

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6 
Statistical considerations 
6.1 
Accrual and sample size calculations  
Recruitment will target enrolling 34 healthy, HIV-uninfected adult participants 
aged 18 through 50 years. Part A and B are single- and multiple-administration 
groups, respectively. Enrollment to the groups in the two parts will have a series 
of pre-planned enrollment pauses as indicated in Section 1. 
To ensure balance of both sexes assigned at birth, the trial will enroll at least 
approximately 40% of each sex assigned at birth across all treatment groups. The 
study team will work closely with the sites to monitor enrollment progress to 
ensure appropriate balance. 
Since enrollment is concurrent with receiving the first study vaccination, all 
participants will provide some safety data. However, for immunogenicity 
analyses, it is possible that data may be missing for various reasons, such as 
participants terminating from the study early, problems in shipping specimens, 
low cell viability of processed peripheral blood mononuclear cells (PBMCs), or 
high assay background. Immunogenicity data from 17 phase 1 and 2 phase 2a 
HVTN vaccine trials, which began enrolling after June 2005 (data as of 
September 2014), indicate that 10% is a reasonable estimate for the rate of 
missing data. For this reason, the sample size calculations in Section 6.1.2 account 
for 10% 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 10, Table 6-1) can be expressed by the true 
event rate above which at least 1 SAE would likely be observed and the true event 
rate below which no events would likely be observed. Specifically, for each 
vaccine arm of the study in Part A (n =5), there is at least an 83% chance of 
observing at least 1 event if the true rate of such an event is 30% or more; and 
there is at least a 95% chance of observing no events if the true rate is 1% or less. 
As a reference, in HVTN vaccine trials from April 2008 through March 2018, 
about 1.6% of participants who received placebos experienced an SAE. 
Binomial probabilities of observing 0, 1 or more, and 2 or more events among 
arms of size 5 and 10 are presented in Table 6-1 for a range of possible true 
adverse event rates. Ten participants does not account for historical potential 
dropout because every enrolled subject provides some safety data. These 
calculations provide a more complete picture of the sensitivity of this study design 
to identify potential safety problems with the vaccine. 

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Table 6-1 Probability of observing 0 events, 1 or more events, and 2 or more events, among 
arms of size 5 or 10, for different true event rates 
True event rate (%) 
Pr(0/5) 
Pr(1+/5) 
Pr(2+/5) 
Pr(0/10) 
Pr(1+/10) 
Pr(2+/10) 
1 
0.95 
0.05 
<0.01 
0.90 
0.10 
<0.01 
3.5 
0.84 
0.16 
0.01 
0.70 
0.30 
0.05 
5 
0.77 
0.23 
0.02 
0.60 
0.40 
0.09 
10 
0.59 
0.41 
0.08 
0.35 
0.65 
0.26 
20 
0.33 
0.67 
0.26 
0.11 
0.89 
0.62 
30 
0.17 
0.83 
0.47 
0.03 
0.97 
0.85 
40 
0.08 
0.92 
0.66 
0.01 
0.99 
0.95 
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 (51, 52). If none of the 10 participants receiving 
a vaccine regimen experience a safety event, the 95% 2-sided upper confidence 
bound for the true rate of such events in the total vaccinated population is 27.8%. 
Table 6-2 Two-sided 95% confidence intervals for the probability of observing a safety event 
based on observing a particular rate of safety endpoints for arms of sizes 5 and 10 
Observed event rate 
95% Confidence interval (%) 
0/5 
0.0 – 43.4 
1/5 
1.0 – 62.4 
2/5 
11.8 – 76.9 
 
 
0/10 
0.0 – 27.8 
1/10 
0.5 – 40.4 
2/10 
5.7 – 51.0 
6.1.2 
Sample size calculations for immunogenicity 
The main goals of this trial regarding immunogenicity outcomes involve a 
preliminary estimation of response rates based on data from the BAMA assays 
among vaccinees. 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 (51). The n = 9 
assumes 10% missing immunogenicity data. 

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Table 6-3 Two-sided 95% confidence intervals for the true response rate based on observing 
a particular rate of responses in the vaccinees (n = 9, assuming 10% missing data) 
No. of responses 
Observed response rate (%) 
95% Confidence interval 
5 
56 
[26.7, 81.1] 
6 
67 
[35.4, 87.9] 
7 
78 
[45.3, 93.7] 
8 
89 
[56.5, 99.4] 
9 
100 
[70.1, 100.0] 
6.2 
Randomization  
A participant’s randomization assignment will be computer generated and 
provided to the HVTN CRS pharmacist through a Web-based randomization 
system. At each institution, the pharmacist with primary responsibility for 
dispensing study products is charged with maintaining security of the treatment 
assignments (except in emergency situations as specified in the HVTN MOP). 
6.3 
Blinding 
Participants and site staff (except for site pharmacists and other staff designated 
for pharmacy quality control) will be blinded as to participant treatment group 
assignments (eg, vaccine or control) but not to study part. Safety assessments will 
be made in a blinded fashion until the planned unblinding occurs (see Appendix 
E, Appendix F, Appendix I, and Appendix J). 
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 excepted for designated staff used solely for the 
purposes of quality control. The HVTN SMB members also are unblinded to 
treatment assignment in order to conduct review of trial safety. 
When a participant leaves the trial prior to study completion, the participant will 
be told he or she must wait until all participants are unblinded to learn his or her 
treatment assignment. 
In some cases, the CRS, PSRT, or study sponsor may believe unblinding of the 
site PI and participant would be appropriate to facilitate the clinical management 
of an AE or SAE. The HVTN Unblinding MOP specifies procedures for 
emergency unblinding, and for early unblinding for medical reasons. 

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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 and immunogenicity 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 

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systemic symptoms will be calculated. Kruskal-Wallis tests will be used to test for 
differences in severity between arms. 
6.4.3.2 
AEs and SAEs 
AEs will be summarized using MedDRA System Organ Class and preferred 
terms. Tables will show by treatment arm the number and percentage of 
participants experiencing an AE within a System Organ Class or within preferred 
term 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. 
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 post-enrollment 
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 9.9) will be tabulated by treatment arm for each 
postvaccination timepoint. Reportable clinical laboratory abnormalities without an 
associated clinical diagnosis will also be included in the tabulation of AEs 
described above. 
6.4.3.4 
Reasons for vaccination discontinuation and early study termination 
The number and percentage of participants who discontinue vaccination and who 
terminate the study early will be tabulated by reason and treatment arm. 
6.4.4 
Immunogenicity analysis 
6.4.4.1 
General approach 
For the statistical analysis of immunogenicity endpoints, data from enrolled 
participants will be used according to the initial randomization assignment 
regardless of how many injections they received. Additional analyses may be 

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performed, limited to participants who received all scheduled injections per 
protocol. Assay results that are unreliable are excluded; results from specimens 
collected outside of the visit window, or from HIV-infected participants post-
infection, may be 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 and difference between treatment arms will be presented with their 
corresponding 95% confidence interval estimates calculated using the score test 
method (51). 
For quantitative assay data, 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 study arms. 
Typically, the results will be shown for each vaccine arm and for the set of control 
arms pooled into one group. 
Mean or median (if normality assumption severely violated) assay readouts will 
be compared between arms and bootstrap confidence intervals will be estimated. 
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. 
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 heatmap 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 
(53). 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 

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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 
The area-under-the-magnitude-breadth curve (AUC-MB) to a global panel of viral 
isolates (54) will be computed for each participant with evaluable neutralization 
data, as described in (55). AUC-MB to a vaccine-matched panel may also be 
computed when the panel consists of at least 3 isolates. Tier 1A viral isolates will 
not be included in AUC-MB analyses. Dunnett’s procedure will be applied with 
2-sided alpha = 0.05 to determine which of the [n] vaccine groups have a 
significantly higher mean AUC-MB than that of the pooled placebo groups, as 
described in (52) (see their formula (1.1)). This procedure will be applied to 
construct 95% CIs about the [n] differences in mean AUC-MB for each vaccine 
regimen versus the pooled placebo groups (vaccine – placebo), which 
simultaneously have at least 95% coverage probability. 
6.4.4.4 
Analysis of CD4+ and CD8+ T-cell responses 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 (56) 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 

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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 (57) 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. 
6.4.4.5 
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. Response breadth is defined as the number of 
antigens, peptides, and/or isolates with associated magnitudes above the assay-
specific positivity threshold. 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 AUC-MB 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 
Analyses and data sharing prior to end of scheduled follow-up visits 
Any analyses conducted prior to the end of the scheduled follow-up visits should 
not compromise the integrity of the trial in terms of participant retention or safety 
or immunogenicity endpoint assessments. In particular, early unblinded analyses 
by treatment assignment require careful consideration and should be made 
available on a need to know basis in accordance with Sections 6.4.5.1. Interim 
blinded safety and immunogenicity data should not be shared outside of the SMB, 
HVTN 139 PSRT, the protocol team leadership, the HVTN Executive 
Management Team, the study product developer, and the study sponsor and/or its 
designee(s) for their regulatory reporting unless approved by the protocol 
leadership and the HVTN leadership. 
6.4.5.1 
Safety analyses 
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 1, for 

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review by the SMB. Ad hoc safety reports may also be prepared for SMB review 
at the request of the HVTN 139 PSRT. Refer to the process described in the 
HVTN Unblinding MOP for any requests for unblinded safety data prior to the 
end of the scheduled follow-up visits. 
6.4.5.2 
Immunogenicity analyses 
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 reaches the aforementioned 
threshold. The HVTN Laboratory Center will review the analysis report prior to 
distribution to the protocol chairs, DAIDS, study product developer, and other key 
HVTN members and investigators. Reports for distribution or presentation should 
use PubIDs and not PTIDs for individual responses. 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 information available at the time of 
enrollment, including results of screening laboratory tests, medical history, 
physical examinations, and answers to self-administered and/or interview 
questions. 
Investigators should always use good clinical judgment in considering a 
volunteer’s overall fitness for trial participation. Some volunteers may not be 
appropriate for enrollment even if they meet all inclusion/exclusion criteria. 
Medical, psychiatric, occupational, or other conditions may make evaluation of 
safety and/or immunogenicity difficult, and some volunteers may be poor 
candidates for retention.  
Determination of eligibility, taking into account all inclusion and exclusion 
criteria, must be made within 56 days prior to enrollment unless otherwise noted 
in Sections 7.1 and 7.2. 
7.1 
Inclusion criteria 
General and Demographic Criteria 
1. Age of 18 through 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. 
4. Assessment of understanding: volunteer demonstrates understanding of this 
study and that in a previous trial with an adenovirus type 5 (Ad5) vector there was 
an association of increased HIV acquisition with receipt of that study product; 
completes a questionnaire prior to first vaccination with verbal demonstration of 
understanding of all questionnaire items answered incorrectly. 
5. Willing to be contacted annually after completion of scheduled clinic visits for a 
total of 3 years following initial study injection. 
6. Agrees not to enroll in another study of an investigational research agent until 
the last scheduled clinic visit. 
7. Good general health as shown by medical history, physical exam, and screening 
laboratory tests. 

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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 as “low risk” for HIV acquisition per low risk guidelines (see Appendix 
M), agrees to discuss HIV infection risks, agrees to risk reduction counseling, and 
agrees to avoid behavior associated with high risk of HIV exposure through the 
final study visit. Low risk may include persons stably taking PrEP as prescribed 
for 6 months or longer. 
Laboratory Inclusion Values 
Hemogram/Complete blood count (CBC) 
11. Hemoglobin  
≥ 11.0 g/dL for volunteers who were assigned female sex at birth 
≥ 13.0 g/dL for volunteers who were assigned male sex at birth and transgender 
male who have been on hormone therapy for more than 6 consecutive months 
≥ 12.0 g/dL for transgender female who have been on hormone therapy for more 
than 6 consecutive months 
For transgender participants who have been on hormone therapy for less than 6 
consecutive months, determine hemoglobin eligibility based on the sex assigned at 
birth  
12. White blood cell count = 2,500 to 12,000 cells/mm3 with normal differential, or 
differential approved by Investigator of Record (IoR) or designee as not clinically 
significant 
13. Total lymphocyte count ≥ 650 cells/mm3 with normal differential, or differential 
approved by Investigator of Record (IoR) or designee as not clinically significant 
14. Remaining differential either within institutional normal range or with site 
physician approval. 
15. Platelets = 125,000 to 550,000 cells/mm3. 
Chemistry 
16. Alanine aminotransferase (ALT) < 1.25 times the institutional upper limit of 
normal; 

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17. Creatinine <1.1 times the institutional upper limit of normal  
Virology 
18. Negative HIV-1 and -2 blood test: US volunteers must have a negative FDA-
approved enzyme immunoassay (EIA) or chemiluminescent microparticle 
immunoassay (CMIA).  
19. Negative Hepatitis B surface antigen (HBsAg). 
20. Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV 
nucleic acid test if the anti-HCV is positive 
Urine 
21. Normal urine: 
▪ Negative or trace urine protein, and 
▪ Negative, trace, or 1+ blood/hemoglobin on urine dipstick. If 1+ hemoglobin 
is present on dipstick, a microscopic urinalysis with red blood cells levels 
within institutional normal range is required. 
Reproductive Status 
22. Volunteers who were assigned female sex at birth: negative serum or urine beta 
human chorionic gonadotropin (β-HCG) pregnancy test at screening (ie, prior to 
randomization) and prior to study product administration on the day of study 
product administration. Persons who are NOT of reproductive potential due to 
having undergone hysterectomy or bilateral oophorectomy (verified by medical 
records), are not required to undergo pregnancy testing. 
23. Reproductive status: A volunteer who was assigned female sex at birth: 
Must agree to use effective contraception for sexual activity that could lead to 
pregnancy from at least 21 days prior to enrollment until two months following 
final product administration. 
▪ Condoms (male or female) with or without a spermicide, 
▪ Diaphragm or cervical cap with spermicide, 
▪ Intrauterine device (IUD), 
▪ Hormonal contraception,  
▪ Tubal ligation, or 
▪ Any other contraceptive method approved by the HVTN 139 PSRT 

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▪ Successful vasectomy in any partner assigned male sex at birth 
(considered successful if a volunteer reports that a male partner has [1] 
documentation of azoospermia by microscopy, or [2] a vasectomy more 
than 2 years ago with no resultant pregnancy despite sexual activity 
postvasectomy); 
▪ Or not be of reproductive potential, such as having reached menopause (no 
menses for 1 year) or having undergone hysterectomy, or bilateral 
oophorectomy; 
▪ Or be sexually abstinent. 
24. Volunteers who were assigned female sex at birth must also agree not to seek 
pregnancy through alternative methods, such as artificial insemination or in 
vitro fertilization until two months after the last product administration 
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 tobacco 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 139 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 139 PSRT will 
determine eligibility on a case-by-case basis. 
8. Previous receipt of monoclonal antibodies (mAbs), whether licensed or 
investigational. Exceptions may be made by the HVTN 139 PSRT on a case-by-
case basis. 

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9. Non-HIV experimental vaccine(s) received within the last 1 year in a prior 
vaccine trial. Exceptions may be made by the HVTN 139 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 139 PSRT 
will determine eligibility on a case-by-case basis. For volunteers who have 
received an experimental vaccine(s) greater than 1 years ago, eligibility for 
enrollment will be determined by the HVTN 139 PSRT on a case-by-case basis. 
10. Live attenuated vaccines received within 30 days before first vaccination or 
scheduled within 28 days after injection (eg, measles, mumps, and rubella 
[MMR]; oral polio vaccine [OPV]; varicella; yellow fever; live attenuated 
influenza vaccine). 
11. 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). 
12. Allergy treatment with antigen injections within 30 days before first 
vaccination or that are scheduled within 14 days after first vaccination. 
Immune System  
13. Immunosuppressive medications received within 168 days before first 
vaccination (Not exclusionary: [1] corticosteroid nasal spray; [2] inhaled 
corticosteroids; [3] topical corticosteroids for mild, uncomplicated dermatologic 
condition; or [4] a single course of oral/parenteral prednisone or equivalent at 
doses < 60 mg/day and length of therapy < 11 days with completion at least 30 
days prior to enrollment). 
14. Serious adverse reactions to vaccines or to vaccine components such as 
glycerol, sodium chloride, tris (hydroxymethyl)aminomethane including history 
of anaphylaxis and related symptoms such as hives, respiratory difficulty, 
angioedema, and/or abdominal pain. (Not excluded from participation: a 
volunteer who had a nonanaphylactic adverse reaction to pertussis vaccine as a 
child). 
15. Immunoglobulin received within 90 days before first vaccination (for mAb see 
criterion 8 above). 
16. Autoimmune disease, current or history. (Not exclusionary: well-controlled 
psoriasis that does not require systemic therapy) 
17. AESIs  
Volunteers who currently have, or have a history of, any condition that could be 
considered an AESI for the products administered in this protocol (representative 
examples are listed in Appendix N). The exception to Appendix N is well-
controlled psoriasis, which is not exclusionary (as above) 

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18. Immunodeficiency. 
Clinically significant medical conditions 
19. 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. 
20. 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. 
21. 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. 
22. Current anti-tuberculosis (TB) prophylaxis or therapy. 
23. Asthma exclusion criteria: 
Asthma is excluded if the participant has ANY of the following: 
• Required either oral or parenteral corticosteroids for an exacerbation two 
or more times within the past year; OR 
• Needed emergency care, urgent care, hospitalization, or intubation for 
asthma within the past year; OR 
• Uses a short-acting rescue inhaler more than 2 days/week; OR 
• Uses medium-to-high dose inhaled corticosteroids (greater than 250 mcg 
fluticasone or therapeutic equivalent) or more than one medication for 

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maintenance therapy daily. For example, potential participants taking long 
acting bronchodilator/inhaled corticosteroid combinations for daily 
maintenance are excluded. [Note: Maintenance monotherapy with 
cromolyn, leukotriene receptor antagonist, or theophylline is not 
exclusionary.]; OR 
• Meets any other asthma-related criteria that, in the judgement of the 
investigator, could lead to interference with study participation. 
24. Diabetes mellitus type 1 or type 2. (Not exclusionary: type 2 cases controlled 
with diet alone or a history of isolated gestational diabetes) 
25. Thyroidectomy, or thyroid disease (Not exclusionary: well-controlled non-
autoimmune thyroid disease as defined in HVTN 139 Study Specific Procedures 
(SSP)) 
26. 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 in this protocol as 
consistently < 140 mm Hg systolic and < 90 mm Hg diastolic, with or without 
medication, with only isolated, brief instances of higher readings, which must 
be ≤ 150 mm Hg systolic and ≤ 100 mm Hg diastolic. For these volunteers, 
blood pressure must be < 140 mm Hg systolic and < 90 mm Hg diastolic at 
enrollment. 
▪ If a person has NOT been found to have elevated blood pressure or 
hypertension during screening or previously, exclude for systolic blood 
pressure ≥ 150 mm Hg at enrollment or diastolic blood pressure ≥ 100 mm Hg 
at enrollment. 
27. Bleeding disorder (eg, factor deficiency, coagulopathy, or platelet disorder 
requiring special precautions) 
28. 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). 
29. 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. 
30. Asplenia: any condition resulting in the absence of a functional spleen. 
31. History of angioedema, or anaphylaxis. (Not exclusionary: angioedema or 
anaphylaxis with known trigger and no episodes within five years.) 

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32. History of generalized urticaria within past five years. 
7.3 
Participant departure from vaccination schedule or withdrawal 
This section concerns an individual participant’s departure from the study product 
administration schedule. Pause rules for the trial 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) 
▪ Prevaccination abnormal vital signs or clinical symptoms that may mask 
assessment of vaccine reaction 
Vaccinations should not be administered outside the visit window HVTN 139. 
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 products 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 

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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 139 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) 
▪ HIV infection 
▪ Any grade 4 local or systemic reactogenicity symptom, lab abnormality, or 
AE that is subsequently considered to be related to vaccination 
▪ Any grade 3 lab abnormality that is subsequently considered to be related 
to vaccination 
▪ Other grade 3 clinical AE that is subsequently considered to be related to 
vaccination with the exception of fever and subjective local and systemic 
symptoms. For grade 3 injection site erythema and/or induration, upon 
review, the PSRT may allow continuation of vaccination 
▪ SAE that is subsequently considered to be related to vaccination 
▪ Clinically significant type 1 hypersensitivity reaction associated with 
study vaccination. Consultation with the HVTN 139 PSRT is required 
prior to subsequent vaccinations following any type 1 hypersensitivity 
reaction associated with study vaccination 
▪ Investigator determination in consultation with Protocol Team leadership (eg, 
for repeated nonadherence to study staff instructions) 
Participants discontinuing study product for reasons other than HIV infection 
should be counseled on the importance of continuing with the study and strongly 
encouraged to participate in follow-up visits and protocol-related procedures per 
the protocol for the remainder of the trial, unless medically contraindicated (see 
HVTN 139 SSP). 
Participants diagnosed with HIV infection during the study should be encouraged 
to participate in follow-up visits as indicated in Section 9.13. 

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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 declines 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, 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 1-1. See the Investigator’s Brochures for further 
information about study products. 
8.1 
Vaccine regimen 
The schedule of vaccination is shown in Section 1 and additional information is 
given below. 
Part A: Low Dose Arm 
Treatment 1 (T1): 1 x 1010 vp AdC6-HIVgp140 to be administered as two 
separate 1 mL IM injections into the deltoid of the non-dominant arm unless 
medically contraindicated at month 0. 
Treatment 2 (T2): 1 x 1010 vp AdC7-HIVgp140 to be administered as two 
separate 1 mL IM injections into the deltoid of the non-dominant arm unless 
medically contraindicated at month 0.  
Control 3 (C3): Placebo for AdC6-HIVgp140 or AdC7-HIVgp140 (labeled as 
Sodium Chloride for Injection, 0.9%) to be administered as two separate 1 mL IM 
injections into the deltoid of the non-dominant arm unless medically 
contraindicated at month 0. 
Part B: High Dose Arm 
Treatment 4 (T4): 5 x 1010 vp AdC6-HIVgp140 to be administered as two 
separate 1 mL IM injections into the deltoid of the non-dominant arm unless 
medically contraindicated at month 0. 
Then 
5 x 1010 vp AdC7-HIVgp140 to be administered as two separate 1 mL IM 
injections into the deltoid of the non-dominant arm unless medically 
contraindicated at month 3. 
Then 
400 mcg CH505TF gp120 admixed with 10 mcg GLA-SE administered as a 1mL 
IM injection into either thigh unless medically contraindicated at month 6. 
Treatment 5 (T5): 5 x 1010 vp AdC7-HIVgp140 to be administered as two 
separate 1 mL IM injections into the deltoid of the non-dominant arm unless 
medically contraindicated at month 0.  

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Then 
5 x 1010 vp AdC6-HIVgp140 to be administered as two separate 1 mL IM 
injections into the deltoid of the non-dominant arm unless medically 
contraindicated at month 3. 
Then 
400 mcg CH505TF gp120 admixed with 10 mcg GLA-SE administered as a 1mL 
IM injection into either thigh unless medically contraindicated at month 6. 
Control 6 (C6): Placebo for AdC6-HIVgp140and AdC7-HIVgp140 (labeled as 
Sodium Chloride for Injection, 0.9%) to be administered as two separate 1 mL IM 
injections into the deltoid of the non-dominant arm unless medically 
contraindicated at month 0 and 3. Placebo for CH505TF/GLA-SE (labeled as 
Sodium Chloride for Injection, 0.9% ) to be administered as 1 mL IM injection 
into either thigh at month 6. 
8.2 
Study product formulation 
8.2.1 
AdC6-HIVgp140 and AdC7-HIVgp140  
Both products are diluted in 2.5% Glycerol/25 mM NaCl/20 mM TRIS, pH 8.0 
formulation buffer to a concentration of 1.2 x 1011 vp/mL and filled at 0.3 mL for 
AdC6-HIVgp140 and 0.6 mL for AdC7-HIVgp140 into a 2 mL Type 1 glass vial 
and stoppered with a gray chlorobutyl rubber stopper. Both products are clear to 
slightly cloudy liquid, essentially free of visible particles. 
Both AdC6-HIVgp140 and AdC7-HIVgp140 should be stored at ≤ -65°C prior to 
use/preparation.  
The study products are described in further detail in the Investigator’s Brochure 
(IB). 
8.2.2 
CH505TF gp120 
CH505TF gp120 is formulated in 20 mM sodium phosphate, 150 mM NaCl, 
0.02% polysorbate 80 (PS80), pH 6.5, supplied as a frozen liquid in 2 mL glass 
vials. Each 2 mL vial contains 0.75 mL of formulated gp120 at a concentration of 
0.8 mg/mL and is stored at ≤ -65°C. 
8.2.3 
GLA-SE (glucopyranosyl lipid A – stable emulsion; [labeled as AP 10-
201]) 
The GLA-SE adjuvant will be provided as vials containing 20 mcg/mL GLA in a 
4% oil-in-water emulsion. Each sterile, single use vial contains 0.4 mL of product. 

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Product appears as a milky-white liquid. GLA-SE must be stored at 2° to 8°C and 
must not be frozen. The study product is described in further detail within the IB. 
8.2.4 
Placebo will be Sodium Chloride for Injection, 0.9%, will be used as the placebo. 
It must be stored as recommended by the manufacturer. 
8.3 
Preparation of study products 
Aseptic technique should be used for the preparation of all study products 
described in this section. 
8.3.1 
AdC6-HIVgp140 
One vial of AdC6-HIVgp140 and Sodium Chloride for Injection, 0.9% , will be 
needed to prepare the low dose of 1 x 1010 vp for Part A. 
Two vials of AdC6-HIVgp140 and Sodium Chloride for Injection, 0.9% , will be 
needed to prepare the high dose of 5 x 1010 vp for Part B. 
Prior to admixture, the pharmacist will remove the appropriate number of vials of 
AdC6-HIVgp140 from the freezer and allow to thaw completely at room 
temperature. Once thawed, mix using a vortexer machine at high speed for one 
second.  
Low Dose: 
1. Withdraw 0.25 mL of AdC6-HIVgp140 from 1 vial, and add to an 
empty sterile vial. 
2. Add 5.75 ml of sodium chloride for injection to the vial containing 
0.25 mL of AdC6-HIVgp140. 
3. Vortex the preparation at high speed for one second. 
High Dose: 
1. Withdraw 0.5 mL of AdC6-HIVgp140 from the two vials and add 
to an empty sterile vial.  
2. Add 1.9 ml of sodium chloride for injection to the vial containing 
0.5 mL of AdC6-HIVgp140. 
3. Vortex the preparation at high speed for one second. 
Finally, using two 3 or 5 mL syringes, withdraw 1 mL of the diluted vaccine into 
each syringe, remove the needle and cap the syringe.  

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The final syringe(s) for administration must be covered with an overlay and 
labeled as: 
“AdC6-HIVgp140 or placebo syringe 1 of 2 and AdC6-HIVgp140 or placebo 
syringe 2 of 2”. The syringe must also be labeled for IM administration into 
deltoid, with an expiration date and time of 2 hours following thawing. 
The preparation must be stored at 2° to 8°C in the refrigerator immediately after 
labeling each syringe, until the time of administration. 
Any unused portion of vials or expired prefilled syringes should be disposed of in 
accordance with institutional or pharmacy policy. 
8.3.2 
AdC7-HIVgp140  
One vial of AdC7-HIVgp140 and Sodium Chloride for Injection, 0.9% will be 
needed to prepare the dose.  
Prior to admixture, the pharmacist will remove one vial of AdC7-HIVgp140 from 
the freezer and allow to thaw completely at room temperature. Once thawed, mix 
using a vortexer machine at high speed for one second. 
Low Dose: 
1. Withdraw 0.25 ml of AdC7-HIVgp140 from 1 vial,. and add to an empty 
sterile vial.  
2. Add 5.75 ml of sodium chloride for injection to the vial containing 0.25 mL of 
AdC7-HIVgp140. 
3. Vortex the preparation at high speed for one second. 
High Dose: 
1. Withdraw 0.5 mL of AdC7-HIVgp140 from 1 vial and add to an empty sterile 
vial. 
2. Add 1.9 ml of sodium chloride for injection to the vial containing 0.5 mL of 
AdC7-HIVgp140.  
3. Vortex the preparation at high speed for one second. 
Finally, using two 3 or 5 mL syringes, withdraw 1 mL of the diluted vaccine into 
each syringe, remove the needle and cap the syringe.  
The final syringe(s) for administration must be covered with an overlay and 
labeled as: 

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“AdC7-HIVgp140 or placebo syringe 1 of 2 and AdC7-HIVgp140 or placebo 
syringe 2 of 2”. The syringe must also be labeled for IM administration into 
deltoid, with an expiration date and time of 2 hours following thawing.  
The preparation must be stored at 2° to 8°C in the refrigerator immediately after 
labeling each syringe, until the time of administration. 
Any unused portion of vials or expired prefilled syringes should be disposed of in 
accordance with institutional or pharmacy policy.  
8.3.3 
CH505TF gp120 + GLA-SE  
One vial of CH505TF gp120 (0.8 mg/mL) and two vials of GLA-SE (20 mcg/mL) 
will be needed to prepare the dose. 
Prior to admixture, the pharmacist will remove the CH505TF gp120 vial from the 
freezer and allow to thaw completely at room temperature. Once thawed 
completely, invert the vial 10 times to ensure a homogeneous product. Remove 
two vials of GLA-SE from the refrigerator and allow to equilibrate to room 
temperature. 
1. Add 0.2 ml of GLA-SE to another vial of GLA-SE. This vial now contains 0.6 
mL of GLA-SE. 
2. Add 0.6 mL of CH505TF gp120 to the vial containing 0.6 mL of GLA-SE and 
mix thoroughly using a vortexer machine at high speed for 3 seconds. 
The final concentration of the admixture is 400 mcg/mL of CH505TF gp120 and 
10 mcg/mL of GLA-SE. 
3. Withdraw 1 mL from the vial containing 400 mcg/mL CH505TF gp120 and 
10 mcg/mL GLA-SE, using a 3 or 5 mL syringe. Remove the needle and cap 
syringe. 
The final syringe for administration must be covered with an overlay and then 
labeled as “CH505TF/GLA-SE or placebo”. The syringe must also be labeled for 
IM administration into either thigh, with an expiration date and time of 8 hours 
following the last mixing procedure. 
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 AdC6-HIVgp140 and AdC7-HIVgp140  
Withdraw 1 mL of Sodium Chloride for Injection, 0.9% into two separate 3 or 5 
mL syringes, remove the needle and cap each syringe. 

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The final syringes for administration must be covered with an overlay and labeled 
as: 
“AdC6-HIVgp140/placebo or AdC7-HIVgp140/placebo” (depending on 
treatment allocation) syringe 1 of 2 and syringe 2 of 2. The syringe must also be 
labeled for IM administration into deltoid, with an expiration date and time of 2 
hours.  
The preparation must be stored at 2°C to 8°C in the refrigerator immediately after 
labeling each syringe, until the time of administration. 
8.3.5 
Placebo for CH505TF/GLA-SE 
Withdraw 1 mL of Sodium Chloride for Injection, 0.9% into a 3 or 5 mL syringe, 
remove the needle and cap the syringe. 
The final syringe for administration must be covered with an overlay and then 
labeled as “CH505TF/GLA-SE or placebo”. The syringe must also be labeled for 
IM administration into either thigh, with an expiration date and time of 8 hours 
following the last mixing procedure. 
8.4 
Administration 
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. 
Any administrator of study product will be blinded to the individual participant's 
treatment assignment. 

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8.4.1 
AdC6-HIVgp140: will be administered at a dose of 1 x 1010 vp in Part A and a 
dose of 5 x 1010 vp in Part B of the study. The vaccine dose will be divided 
equally into two separate 1 mL intramuscular (IM) injections, administered into 
the deltoid of the non-dominant arm unless medically contraindicated. 
8.4.2 
AdC7-HIVgp140: will be administered at a dose of 1 x 1010 vp in Part A and a 
dose of 5 x 1010 vp in Part B of the study. The vaccine dose will be divided 
equally into two separate 1 mL IM injections administered into the deltoid of the 
non-dominant arm unless medically contraindicated. 
8.4.3 
CH505TF gp120: will be administered at a dose of 400 mcg protein with 10 mcg 
GLA-SE as a 1mL intramuscular (IM) injection, into either thigh unless medically 
contraindicated. 
8.4.4 
Placebo control for AdC6-HIVgp140 or AdC7-HIVgp140 vaccine: Sodium 
Chloride for Injection, 0.9%, administered as two separate 1 mL IM injections 
into the deltoid of the non-dominant arm unless medically contraindicated. 
8.4.5 
Placebo control for CH505TF gp120: Sodium Chloride for Injection, 0.9%, 
administered as a 1 mL IM injection into either thigh unless medically 
contraindicated. 
8.5 
Acquisition of study products 
AdC6-HIVgp140 was manufactured by IDT Biologika (Rockville, Maryland, 
USA) and will be provided by DAIDS, NIAID, NIH, DHHS (Bethesda, 
Maryland, USA). 
AdC7-HIVgp140 was manufactured by IDT Biologika (Rockville, Maryland, 
USA) and will be provided by DAIDS, NIAID, NIH, DHHS (Bethesda, 
Maryland, USA). 
CH505TF gp120 was manufactured by Berkshire Sterile Manufacturing (Lee, 
Massachusetts, USA) and will be provided by DAIDS, NIAID, NIH, DHHS 
(Bethesda, Maryland, USA). 
GLA-SE adjuvant: was manufactured by Infectious Disease Research Institute 
(IDRI) (Seattle, Washington, USA) and will be provided by DAIDS, NIAID, 
NIH, DHHS (Bethesda, Maryland, USA). 
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 outlined in Pharmacy Guidelines 
and Instructions for DAIDS Clinical Trials Networks. 

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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 
For US clinical research sites, all unused study products must be returned to the 
CRPMC after the study is completed or terminated unless otherwise instructed by 
the study sponsor. For non-US clinical research sites, all unused study products 
must be destroyed after the study is completed or terminated unless otherwise 
instructed by the study sponsor. The procedures are included in the Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks. 

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9 
Clinical procedures 
The schedule of clinical procedures is shown in Appendix I and Appendix J. 
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, as well as per 
the CRS’s SOP on the informed consent process. 
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 as 
directed by the IRB/EC. 
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 
entity/body that has the power to regulate which includes authorities that review 
submitted clinical data and those that conduct inspections. These are sometimes 
referred to as competent authorities. These are entities/bodies whose 
approval/authorization/acknowledgment of a clinical trial is required for 
conducting a clinical trial. Any organization whose approval is required prior to a 
CRS's participation in DAIDS funded and/or Sponsored Clinical Trial. Includes 
but not limited to approvals from state/national health systems and administrative 
bodies, drug agencies etc. (DAIDS adopted from ICH E6(R2)”. CRSs are 
responsible for knowing the requirements of their applicable REs. 

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9.1.1 
Screening consent form 
Without a general screening consent, screening for a specific study cannot take 
place until the site receives protocol registration from the DAIDS RSC Protocol 
Registration Office. 
Some HVTN CRSs have approval from their IRB/EC and any applicable RE to 
use a general screening consent form that allows screening for an unspecified HIV 
vaccine trial. In this way, HVTN CRS staff can continually screen potential 
participants and, when needed, proceed quickly to obtain protocol-specific 
enrollment consent. Sites conducting general screening or prescreening approved 
by their IRB/EC and any applicable RE may use the results from this screening to 
determine eligibility for this protocol, provided the tests are conducted within the 
time periods specified in the eligibility criteria. 
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. 
Sample protocol-specific consent forms for the main study of Part A and Part B 
are located in Appendix A and Appendix B, respectively. A separate sample 
consent form for other uses of specimens is located in Appendix D. 
Each HVTN CRS is responsible for developing a protocol-specific consent 
form(s) for local use, based on the sample protocol-specific consent forms in 
Appendix A and Appendix B. The consent form(s) must be developed in 
accordance with requirements of the following: 
• CRS’s IRB/EC and any applicable REs, 
• CRS’s institution, and 
• Elements of informed consent as described in Title 45, CFR Part 46 
and Title 21 CFR, Part 50, and in ICH E6(R2), 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(s) include instructions for developing specific 
content. 
Regarding protocol registration, sites should follow procedures outlined in the 
current version of the DAIDS Protocol Registration Manual. 

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9.1.3 
Assessment of Understanding 
Study staff are responsible for ensuring that participants fully understand the 
study before enrolling them. This process involves reviewing the informed 
consent form with the participant, allowing time for the participant to reflect on 
the procedures and issues presented, and answering all questions completely. 
An Assessment of Understanding is used to document the participant’s 
understanding of key concepts in this HIV vaccine trial and that in a previous trial 
with an adenovirus type 5 (Ad5) vector there was a statistically significant 
increase of HIV acquisition with receipt of that study product. 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). Screening results will be reviewed 
with the volunteer. 
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 whether the volunteer is at low risk for HIV infection (see 
Appendix M). 
• 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 

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• Laboratory tests, including: 
▪ Screening HIV test 
▪ Complete blood count (CBC) with differential and platelets 
▪ Limited chemistry panel (ALT and creatinine) 
▪ Hepatitis B surface antigen (HBsAg) 
▪ Anti-Hepatitis C (HCV) antibodies 
▪ Urine or serum pregnancy test 
• Administration of behavioral risk assessment questionnaire 
• Obtaining of volunteer demographics in compliance with the NIH Policy and 
Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical 
Research, November 28, 2017 Amendment (available at 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-014.html)  
• Counseling on HIV testing and risk reduction, performed in compliance with 
the US Centers for Disease Control and Prevention (CDC)’s current 
guidelines or other local guidelines for HIV counseling, testing, and referral as 
described in Section 9.6 
• Discussion with participants regarding need to refrain from blood or tissue 
donation while being enrolled in this trial due to potential for inadvertent 
unblinding from HIV-antibody testing. 
• Discussion of reproductive status and contraception. A pregnant or 
breastfeeding person may not be enrolled in this trial. Specific criteria and 
assessment of contraception and reproductive status are described in study 
inclusion criteria. Discussion of contraception includes advising a participant 
who was assigned female sex at birth and who reports no current sexual 
activity that could lead to that participant becoming pregnant to have a plan to 
begin adequate birth control. This plan would be put to use if, during the 
study, the participant becomes sexually active in a way that could lead to that 
participant becoming pregnant. 
9.2.1 
Use of screening results from another HVTN study 
If a participant screens for an HVTN study at the same HVTN CRS but then does 
not join that study, screening results from that effort may be applied to the 
screening for this protocol, as long as the screening was done under participant 
consent, the participant has signed a consent form to begin screening for this 
study, and the tests were conducted within the time periods specified in the 
eligibility criteria (see Sections 7.1 and 7.2). 

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9.3 
Enrollment and vaccination visits 
Once a volunteer has consented to trial participation and is found to meet all 
eligibility criteria (see Sections 7.1 and 7.2), the HVTN CRS requests the 
randomization assignment via a Web-based randomization system. Enrollment is 
simultaneous with first vaccination. 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. Clinically important lab results 
will be reviewed with the participant at any visit, as needed. 
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 
• Urine or serum pregnancy test (for participants who were assigned female sex 
at birth). Persons who are NOT of reproductive potential due to having 
undergone hysterectomy or bilateral oophorectomy (verified by medical 
records), are not required to undergo pregnancy testing. For pregnant 
participants, see Section 9.12 
Following completion of all procedures in the preceding list, and if results 
indicate that vaccination may proceed, vaccination is administered (see Section 
8.3). 
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 a 
minimum of 60 minutes for observation and initial reactogenicity assessment. 
Before leaving the clinic, the participant is given the Participant Diary and is 
instructed on how to complete it. The site will make arrangements to be in contact 
with the participant during the reactogenicity period (as described in Section 9.9). 
The following procedures will be performed at all vaccination visits. These 
procedures may be performed prior to or following vaccination: 
• HIV risk reduction counseling (as described in Section 9.6) 

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• Contraception status assessment (as described in Section 9.2 and 9.7). During 
follow-up in persons who are confirmed pregnant, contraception status 
assessment is not required 
• 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 I and Appendix J:  
• Confirm that participants received HIV test results from previous visit. If not, 
provide test results and post-test counseling as appropriate 
• Specimen collection (should be completed prior to vaccination) 
9.4 
Follow-up visits 
The following procedures are performed at all scheduled follow-up visits: 
• HIV risk reduction counseling (as described in Section 9.6); 
• 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 I and Appendix J: 
• Contraception status assessment (as described in Section 9.2 and 9.7). During 
follow-up in persons who are confirmed pregnant, contraception status 
assessment is not required 
• 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 

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• HIV infection assessment including pretest counseling and HIV testing. 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 
• Clinically important lab results will be reviewed with the participant, as 
needed 
• 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 
• Clinical laboratory tests including: 
▪ CBC with differential 
▪ Chemistry panel (see Section 9.2) 
▪ Urine dipstick (urinalysis if appropriate; see Section 9.4) 
• Urine or serum pregnancy test (for participants who were assigned female sex 
at birth). Persons who are NOT of reproductive potential due to having 
undergone hysterectomy or bilateral oophorectomy (verified by medical 
records), are not required to undergo pregnancy testing. During follow-up in 
persons who are confirmed pregnant, pregnancy testing is not required, unless 
clinically indicated.  
9.5 
Health Contacts 
9.5.1 
AESI Contact  
CRS staff will contact study participants 12 months after the final study product 
administration to collect the information listed below. Clinic visits will only be 
required if HIV confirmatory testing is necessary (see Section 9.6.1); however, a 
clinic visit may be arranged for other reasons (eg, AESI assessment and referral). 
Confirmation of vital status: 
If deceased, attempt to learn cause and date of death. 

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If participant is alive, record the following events: 
▪ SAEs 
▪ AEs of special interest (AESI, see Section 11.2.2). A sample list of AESI 
is provided in Appendix N 
▪ New diagnosis of HIV infection 
▪ Pregnancies and outcomes, including congenital anomalies/birth defects 
▪ Medically attended adverse events (MAAE), defined as any adverse 
events leading to an unscheduled visit to a healthcare professional (see 
HVTN 139 SSP) 
All such events will be recorded. 
9.5.2 
Annual Health Contacts  
In addition to the AESI contact, participants will be contacted annually at 2 years 
and 3 years (month 24 and month 36) following initial study injection (see and 
Appendix I and Appendix J). At these contacts, CRS staff will collect the 
information listed below. Clinic visits will only be required if HIV confirmatory 
testing is necessary (see Section 9.6.1); 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, record the participant’s responses to questions regarding 
any occurrence of the following events since the last HVTN study contact: 
▪ Life-threatening adverse experiences 
▪ Persistent or significant disability/incapacity 
▪ Hospitalizations and reasons 
▪ Other important medical events that may jeopardize the participant or may 
require intervention to prevent 1 of the other outcomes listed above 
▪ New chronic conditions requiring more than 30 days of medical 
intervention or medication 
▪ New diagnosis of HIV infection 
▪ Pregnancies and outcomes, including congenital anomalies/birth defects 
All such events will be recorded, and adverse events will be assessed for 
relationship to study products. 
9.5.3 
Interim contacts 
CRSs may report safety information obtained at a contact other than the annual 
contact. These contacts are reported as interim visits. 

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9.6 
HIV counseling and testing 
HIV counseling will be performed in compliance with the CDC’s guidelines or 
other local guidelines for HIV counseling and referral. HIV testing will be 
performed in accordance with the current HVTN HIV testing algorithm following 
enrollment. 
Participants will be counseled routinely during the trial on the avoidance of HIV 
infection and on the potential negative social impacts of testing 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. Potential and enrolled participants identified as being HIV-infected will 
be referred for medical treatment, counseling, and management of the HIV 
infection. Participants who are found to be HIV-infected after enrollment will not 
receive any additional study product but will continue to be followed in the study 
for safety assessments. These individuals may also be referred to appropriate 
ongoing clinical trials or observational studies. 
9.6.1 
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: 

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• Participants will have physical examinations at visits specified in Appendix I 
and Appendix J. Signs or symptoms of an acute HIV infection syndrome, an 
intercurrent illness consistent with HIV 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 G, Appendix H, Appendix I, and Appendix J). The Laboratory 
Program (or approved diagnostic laboratory) will follow the HVTN HIV 
testing algorithm (see HVTN 139 SSP), which is able to distinguish vaccine-
induced antibody responses from actual HIV infections. 
• All participants can receive HIV 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 serology (as measured by the standard anti-HIV 
antibody screening tests) at or after the study is unblinded will be offered 
poststudy HIV diagnostic testing (per the HVTN poststudy HIV 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. 
9.6.2 
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) (see Section 9.6.1). In order to provide 
poststudy HIV testing to distinguish between VISP and HIV infection, and to 
mitigate potential social harms resulting from VISP in HIV vaccine recipients 
who are not infected with HIV, the HVTN has created a VISP registry. Following 
study unblinding, the registry will allow trained staff to verify that an individual 
has received an HIV vaccine, and therefore has the potential for VISP. 
Information in the VISP registry will not be used for research. Rather, the registry 
exists to support provision of poststudy testing and counseling services to HIV 
vaccine recipients. The registry contains the names of all study participants, 
unless they request that their names be removed. 
9.7 
Contraception status 
Contraception status is assessed and documented as shown in Appendix I and 
Appendix J for a participant who was assigned female sex at birth and who is 
sexually active in a way that could cause that participant to become pregnant. 
Prior to enrollment and throughout the study, staff will ask participants to verbally 
confirm their use of adequate contraceptive methods. A participant who was 

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assigned female sex at birth and is sexually active in a way that could cause that 
participant to become pregnant should be reminded at scheduled clinic visits of 
the importance of using contraception and should be referred to specific 
counseling, information, and advice as needed. (Specific contraception 
requirements are listed in Section 7.1.) This reminder should be documented in 
the participant’s study record. 
Self-reported infertility—including having reached menopause (no menses for 1 
year) or having undergone hysterectomy, bilateral oophorectomy, or tubal 
ligation—must be documented in the participant’s study record. 
9.8 
Urine testing 
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 non-urinary bleeding (eg, 
menstruation) or infection, document this issue in the participant’s source 
documentation. For infection, provide appropriate treatment and/or referral and 
document this in the participant's chart. Following resolution, repeat the dipstick 
and, if within the eligibility limits specified in the protocol, the participant may be 
enrolled. 
Follow-up visit dipstick testing should be deferred if a participant is experiencing 
non-urinary bleeding (eg, menstruation), but should be performed as soon as 
possible. If a follow-up visit dipstick is abnormal due to a participant’s non-
urinary bleeding (eg, menstruation), document in the comment section of the case 
report form (CRF) and repeat the dipstick once the participant is no longer 
experiencing non-urinary bleeding. A micro-urinalysis is not required. If a follow-
up visit dipstick or micro-urinalysis is abnormal due to infection, provide 
appropriate treatment and/or referral and document this in the participant's source 
documentation. See the Urine Testing MOP for further details. 
9.9 
Assessments of reactogenicity 
For all participants, baseline assessments are performed before and reactogenicity 
assessments are performed after each vaccination. All reactogenicity symptoms 
are followed until resolution and graded according to the Division of AIDS Table 
for Grading the Severity of Adult and Pediatric Adverse Events, Corrected 
Version 2.1, 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 Participant Diary. Contacts between the participant and the site 
staff should take place at least once between 1-3 days postvaccination (for Part A 

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participants, please refer to HVTN 139 SSP). 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, and vaccine-related lesions. Events not listed on a 
CRF, or with an onset after the reactogenicity assessment period (day of 
vaccination and 7 full days after), or those meeting SAE/adverse events requiring 
expedited reporting according 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 clinician 
 
Early: At least 60 minutes after 
vaccination 
HVTN CRS clinician 
 
Between early assessment and 11:59pm 
day 0 
HVTN CRS clinician or 
participant 
1-7b 
Between 12:00am and 11:59pm on the 
respective day 
HVTN CRS clinician or 
participant 
a Day of vaccination 
b New or unresolved reactogenicity symptoms present on day 7 are followed until resolution 
9.9.1 
Assessment of systemic and local symptoms 
Systemic symptoms include increased body temperature, malaise and/or fatigue, 
myalgia, headache, chills, arthralgia, and nausea. Local symptoms include pain 
and/or tenderness at the injection site. The daily maximum severity reached for 
each symptom during the assessment period is reported.  
Body temperature is measured by oral or infrared thermometry. All temperatures 
must be measured by non-axillary thermometry. This includes temperatures taken 
in the clinic, as well as temperatures taken by participants during the 
reactogenicity period. 
Temperature is reported in degrees Celsius. A measurement is taken once daily 
during the assessment period and should be repeated if participant is feeling 
feverish. 
9.9.2 
Assessment of injection site 
Typical injection site reactions are erythema/redness and induration/swelling. The 
maximum diameter for all injection site reactions is recorded. 

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All injection site reactions are monitored until resolution. Reactions with 
diameters ≥5 cm are followed daily; otherwise, the frequency of follow-up is 
based on clinician judgment. See HVTN 139 SSP for detail. 
9.10 
Visit windows and missed visits 
Visit windows are included in Appendix K (Part A) and Appendix L (Part B). The 
procedures for documenting missed visits and out of window visits are described 
in HVTN 139 SSP. 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. 
9.11 
Early termination visit 
In the event of early participant termination, site staff should consider if the 
following assessments are appropriate: a final physical examination, clinical 
laboratory tests (including urine dipstick, CBC with differential, and chemistry 
panel), pregnancy testing (note: for persons who are confirmed pregnant, 
pregnancy testing is not required, unless clinically indicated), social impact 
assessment, and HIV test. For participants who have a confirmed diagnosis of 
HIV infection, see Section 9.13. 
9.12 
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. During follow-up in persons who 
are confirmed pregnant, pregnancy testing is not required, unless clinically 
indicated. 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 as described in the HVTN 139 SSP section on Pregnancy 
Management and Reporting. If the participant is no longer pregnant, refer to 
Section 7.3.3. 

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9.13 
HIV infection during the study 
If a participant becomes HIV-infected during the course of the study, no 
additional study product will be administered. Participants will be encouraged to 
continue scheduled study visits for 12-weeks following their last study product 
administration. Follow-up duration for participants diagnosed with HIV infection 
may be adjusted in consultation with the CRS investigator and the HVTN 139 
PSRT (eg, to avoid interference with participant initiation of HIV treatment). At 
post-infection follow-up visits, only specimens required for protocol-specified 
safety laboratory tests, urinalysis, and pregnancy tests will be collected (note: for 
persons who are confirmed pregnant, pregnancy testing is not required, unless 
clinically indicated); in addition, some clinic procedures may be modified or 
discontinued (see Appendix I and Appendix J). 

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10 
Laboratory 
10.1 
HVTN CRS laboratory procedures 
The HVTN 139 Site Processing 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 G and Appendix H. For 
tests performed locally, the local lab may assign appropriate tube types. 
In specific situations, the blood collection tubes may be redirected to another 
laboratory or may require study-specific processing techniques. In these cases, 
laboratory special instructions will be posted on the protocol-specific section of 
the HVTN website. 
Of note, all assays described below are performed as research assays to evaluate 
the ability of the vaccine to induce immune responses, and are not approved for 
use in medical care. Results from these assays are not made available to 
participants or medical professionals to guide treatment decisions 
10.2 
Total blood volume 
Required blood volumes per visit are shown in Appendix G and Appendix H. 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 for Part A occur at 1 month post-
vaccination; and for Part B at 1 month post first vaccination, 1 month post-second 
vaccination, and 2 weeks after the protein boost. Endpoint assays may be 
performed on specimens collected from participants at the primary 
immunogenicity timepoint and samples collected at baseline and other timepoints. 

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10.4 
Endpoint assays: cellular 
10.4.1 
Flow cytometry 
Intracellular cytokine staining (ICS) 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 vaccines, or with peptides that 
encompass HIV sequence diversity (such as PTE peptides). Data will be reported 
as percentages of CD4+ or CD8+ T cells responding to a specific peptide pool. 
Additional cell surface markers, cytokines, or functional markers may also be 
analyzed. 
10.4.2 
Antigen-specific B cell and plasmablast phenotyping 
HIV-1 antigen-specific memory B cells and plasmablasts 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 and plasmablasts will be enumerated and may be further 
characterized for expression of memory, activation, inhibitory or other markers of 
interest. 
10.5 
Endpoint assays: humoral 
10.5.1 
Binding antibody multiplex assay (BAMA) 
HIV-1–specific total IgG binding antibodies to vaccine-matched antigens as well 
as non-matched antigens will be assessed on serum samples from study 
participants. In addition, HIV-1–specific IgA and IgG subclass (IgG1, IgG2, 
IgG3, and IgG4) binding antibodies may also be assessed.  
10.5.2 
Antibody avidity  
Antibody avidity may be measured using BAMA with the addition of a 
dissociation step to calculate the antibody avidity index (BAMA-AI). Biolayer 
Interferometry (BLI) and/or Surface Plasmon Resonance (SPR) technologies may 
also be used to define antibody avidity. 
10.5.3 
HIV-1- specific neutralizing antibody assay (NAb) 
HIV-1–specific nAb assays will be performed on serum samples from study 
participants. The TZM-bl assay will test neutralization of the vaccine strain(s) 
Du422, Du172, CH505TF and a single highly neutralization-sensitive tier 1 virus 
as a positive control (eg, MW965.25). The global panel and/or clade-specific 
panels may be used to assess tier 2 neutralization (54, 58). 

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10.5.4 
Antibody-dependent cellular cytotoxicity assay (ADCC) 
ADCC activity may be assessed using serum samples from study participants 
using one or both of the assays listed here. For the Granzyme B flow-based 
cytotoxicity assay, participant sera are incubated with effector cells sourced from 
human PBMCs and gp120-coated CEM.NKR.CCR5 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 CEM.NKR.CCR5 cells 
and percent killing is measured through the use of Viviren luminescence.  
10.5.5 
Antibody-dependent cellular phagocytosis (ADCP) 
To assess the ability of vaccine-elicited antibodies to engage cellular FcR for 
potential antiviral function, ADCP may be measured using serum samples from 
study participants taken at baseline and at a primary immunogenicity timepoint. 
ADCP is measured by assessing the ability of vaccine elicited antibodies to 
mediate monocyte phagocytosis of HIV-1 antigen coated fluorescent beads by 
flow cytometry (59, 60). An array of antigens or viruses in addition to specimens 
from other timepoints may also be analyzed at the discretion of the HVTN 
Laboratory Center, which may be contingent on the results of the primary 
immunogenicity timepoint. 
10.5.6 
Antibody-dependent neutrophil phagocytosis (ADNP)  
To assess the ability of vaccine-elicited antibodies to engage cellular FcR for 
potential antiviral function, ADNP may be measured using serum samples from 
study participants at a primary immunogenicity timepoint and compared to 
placebo controls. ADNP is measured by assessing the ability of vaccine elicited 
antibodies to mediate neutrophil cell line phagocytosis of HIV-1 antigen coated 
fluorescent beads by flow cytometry (61). An array of antigens or viruses in 
addition to specimens from other timepoints may also be analyzed at the 
discretion of the HVTN Laboratory Center, which may be contingent on the 
results of the primary immunogenicity timepoint. 
10.5.7 
Fc receptor binding  
The ability of vaccine elicited antibodies to bind to cellular Fc receptors enables 
characterization of the antibody Fc profile that results in antiviral function (ie, 
includes subclass and glycans). HIV-specific antibody binding to FcγR proteins 
will be assessed by the FcR BAMA. The FCR BAMA is a modification of the 
binding assay where fluorescently labeled FcR proteins are utilized as the 
detection reagent for serum antibodies bound to HIV proteins on microspheres. 
The readout may include the magnitude and/or avidity for an array of Fc receptors 
involved in mediating antiviral activity. 

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10.5.8 
Infected cells antibody binding assay (ICABA)  
The capacity of vaccine elicited antibodies to recognize epitopes exposed on the 
surface of infected cells may be assessed using serum samples from study 
participants. This assay measures the capacity of vaccine elicited antibodies to 
recognize HIV envelope on the surface of infected cells (ie, the first step in 
mediating antibody Fc effector function) with a readout by flow cytometry. 
10.5.9 
Antivector antibody studies (AdC6- and AdC7-specific neutralizing 
antibodies) 
Adenovirus neutralization assays will be performed on serum samples from study 
participants. These assays will be conducted by incubating a dose of diluted GFP-
expressing AdC6 or AdC7 vector with diluted sera. The vector-serum mixture 
will be mixed with HEK 293 cells and transferred into culture wells to incubate; 
the cells will be screened visually for green fluorescence by microscopy. The titer 
of neutralizing antibodies to AdC6 and AdC7 will be determined as the reciprocal 
serum dilution that causes an ∼50% reduction of fluorescence in comparison to 
fluorescence of the control wells infected with vector only. 
10.6 
HVTN Lab Center assay portfolio 
Additional assays may be performed per the HVTN Laboratory Center assay 
portfolio, which includes immune assessments such as those for cellular, humoral, 
and innate immune responses and host genetics. The assay portfolio will be 
updated periodically to include new assays and adjust qualification levels of 
existing assays. 
10.7 
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 
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 form for the main 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. 

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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 IRBs/ECs/REs of 
the CRSs if required. 
As part of consenting for the study, participants document their initial decision to 
allow or not allow their specimens to be used in other research, and they may 
change their decision at any time. The participant’s initial decision about other 
use of their specimens, and any later change to that decision, is recorded by their 
CRS in a Web-based tool that documents their current decisions for other use of 
their specimens. The HVTN will only allow other research to be done on 
specimens from participants who allow such use. 
CRSs must notify HVTN Regulatory Affairs if institutional or local governmental 
requirements pose a conflict with or impose restrictions on specimen storage or 
other use of specimens. 
10.9 
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 139 PSRT 
The HVTN 139 PSRT is composed of the following members: 
▪ DAIDS medical officer representative 
▪ Protocol chair / medical monitor  
▪ Protocol cochair 
▪ Protocol Team leader 
▪ Regional Medical Liaison 
▪ Clinical safety specialist 
The clinician members of HVTN 139 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 
139 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 during the main study (as defined in Section 1); for safety reviews 
during the annual health contacts period, see Section 11.5.3. 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 139 PSRT. 
Study sites will receive SMB summary minutes and are responsible for 
forwarding them to their IRB/EC and any applicable RE. 

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11.1.3 
SDMC roles and responsibilities in safety monitoring  
The roles and responsibilities of the SDMC in relation to safety monitoring 
include: 
• Maintaining a central database management system for HVTN clinical data 
• Providing reports of clinical data to appropriate groups such as the HVTN 139 
PSRT (see Section 11.1.1) and HVTN SMB (see Section 11.1.2) 
11.1.4 
HVTN LOC roles and responsibilities in safety monitoring 
• Daily monitoring of clinical data for events that meet the safety pause and 
HVTN 139 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 
• Providing support to the HVTN 139 PSRT 
11.2 
Safety reporting 
11.2.1 
Submission of safety forms to SDMC 
Site staff must submit all safety forms (eg, reactogenicity, adverse experience, 
urinalysis, local lab results, and concomitant medications) within 3 business days 
of the site being notified, or sooner per Table 11-1. The forms should not be held 
in anticipation of additional information at a later date. If additional information is 
received at a later date, the forms should be updated and resubmitted before the 
end of the next business day after receiving the new information. For the case of a 
longer site holiday closure, site staff must submit the data by the end of the 5th 
day (local time) after receiving the information even if this day is a holiday. 
For example: If the site becomes aware of an AE on Thursday (Day 0), the site 
must submit the data by the end of the next business day, on Friday. If there is a 
longer site holiday closure, then this AE must be reported no later than the end of 
the fifth day, Monday (Day 4). If Monday is a holiday as well, all safety forms 
still need to be submitted by the end of Monday (Day 4). 
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 

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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 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-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 
139 Study Specific Procedures); 
• Injection Site Erythema or Redness and Injection Site Induration or Swelling 
will not consider surface area and interference with usual social and functional 
activities such that: 
▪ Grade 1 is: 2.5 to < 5 cm in diameter; 
▪ Grade 2 is: ≥ 5 to < 10 cm in diameter; 
▪ Grade 3 is: ≥ 10 cm in diameter 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); 
• Creatinine is required to be reported as an AE only if it is gradable per the 
increase from local lab ULN parameter. Do not grade elevated creatinine 
based on the change from the baseline parameter; 
• Creatinine clearance or estimated glomerular filtration rate (eGFR) is required 
to be reported based only on the reported value or if dialysis is needed. Do not 
grade Creatinine clearance or eGFR based on the change from the baseline 
parameter. 
Unsolicited AEs will be collected over a period of 30 days after each vaccination 
visit. All collected AEs are reported to the SDMC on the appropriate CRF. Clinic 
staff should evaluate every AE to determine if (1) the AE meets the requirements 
for expedited reporting (see Section 11.2.3), (2) if the AE meets the criteria for a 
safety pause/prompt AE review (see Section 11.4), and (3) if the AE is a potential 
immune-mediated disease that may be listed as an AE of special interest (AESI). 
A sample list of AESI is provided in Appendix N. 
Certain AEs will be collected and reported throughout the study until 12 months 
following final study product administration: 
▪ SAEs/EAEs, 
▪ AESIs, 

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▪ Medically Attended Adverse Events (MAAEs) 
▪ New chronic conditions requiring medical intervention for ≥ 30 days, 
▪ Newly diagnosed or treated STIs, 
▪ AEs leading to early participant withdrawal or early discontinuation of 
study product(s) administration. 
Report the subset of AEs bulleted in Section 9.5.1 until the AESI health contact is 
complete and the subset of AEs bulleted in Section 9.5.2 until the last annual 
health contact is complete. 
Sites are expected to notify HVTN clinical safety staff of any serious safety 
concern requiring their attention (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/hvtn139). Concerns requiring immediate 
attention should be communicated by calling the clinical safety phone. 
In the case of email notification, clinical safety staff will reply within one 
business day. Serious events that meet pause rule criteria will be addressed 
immediately (as outlined in Table 11-1). If email service is not available, the CRS 
should notify clinical safety staff of the event by telephone, and 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 https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-
reporting-adverse-events-daids.  
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 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. 
For questions about DAERS, please contact CRMSsupport@niaid.nih.gov or 
from within the DAERS application itself. 
For questions about EAE reporting, please contact the DAIDS RSC Safety Office 
at (DAIDSRSCSafetyOffice@tech-res.com). 

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The study products for which expedited reporting are required are:  
• AdC6-HIVgp140 
• AdC7-HIVgp140 
• CH505TF gp120 
• GLA-SE adjuvant 
From enrollment until 12 months following final study product administration, the 
SAE Reporting Category will be used.  
From 12 months following final study product administration until completion of 
the month 36 annual health contact, the SUSAR Reporting Category will be used. 
After the participant has completed the month 36 annual health contact and is off 
study, sites must report SUSARs if the study site staff becomes aware of the 
events on a passive basis (eg, from publicly available information). 
The NIAID/DAIDS will report all unexpected SAEs related to the study products 
observed in this clinical trial to the South African Health Products Regulatory 
Authority (SAHPRA). However, because safety is a primary study endpoint, the 
study 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 SAHPRA based on the blinded 
attribution assessment. 
In some cases, the PSRT or CRS may believe unblinding of the site PI or their 
designee and participant would be appropriate to facilitate the clinical 
management of an AE or SAE. The HVTN MOP specifies procedures for 
emergency unblinding, and for early unblinding for medical reasons. 
11.3 
Safety reviews 
11.3.1 
Safety review # 1: Low-dose Initial Vaccination 
Enrollment across all participating HVTN CRSs will be restricted to a maximum 
of 1 participant per day and restricted until 5 participants have been enrolled in 
Part A (Groups 1-3). Enrollment will then pause. The HVTN 139 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 
5 participants, and will determine whether it is safe to proceed with full 
enrollment in Part A. 

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11.3.2 
Safety review # 2: Low-dose (Part A) Safe-to-Proceed 
In addition to monitoring participant safety throughout the study period, the 
HVTN 139 PSRT will review cumulative safety data available on all 12 Part A 
participants up to and including the 2-week visit after the final participant receives 
a vaccination to determine whether dose escalation and enrollment in Part B may 
occur. The HVTN 139 PSRT may consult with the HVTN SMB on an ad hoc 
basis for these evaluations. 
11.3.3 
Safety review # 3: Full Enrollment at Targeted Dose 
Enrollment will start in Part B for Groups 4 -6 and pause after the first 12 
participants have enrolled. In addition to monitoring participant safety throughout 
the study period, the HVTN 139 PSRT will review all cumulative safety data 
available up to and including the 2-week visit after the vaccination in the first 12 
participants enrolled in Part B. Based on the assessment of this safety data, the 
HVTN 139 PSRT will determine whether it is safe to proceed with full enrollment 
in Part B. The HVTN SMB may perform an additional unblinded review of this 
safety data to make the final determination based on safety for proceeding with 
full enrollment in Part B. 
11.4 
Safety pause and prompt PSRT AE review 
When a trial is placed on an unplanned safety pause, all enrollment and 
vaccinations 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 139 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 139 PSRT, participant safety 
may be threatened. Criteria for an individual participant’s departure from the 
schedule of vaccinations are listed in Section 7.3. 
Table 11-1 AE notification and safety pause/AE review rules 
Event and 
relationship to study 
products 
Severity 
HVTN CRS actiona 
HVTN LOC 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 PSRT notification 
SAE, related 
Grade 3, 2, 
or 1 
Email and submit forms 
immediately 
Immediate PSRT notification and 
prompt PSRT AE review to 
consider pause 
AEb, related 
Grade 4 or 
3 
Email and submit forms 
immediately 
Immediate PSRT notification and 
prompt PSRT AE review to 
consider pause 
a Phone numbers and email addresses are found on the Protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/hvtn139). 
b Does not include the following Grade 3 subjective reactogenicity symptoms: injection site pain, tenderness, 
fatigue/malaise, myalgia, arthralgia, chills, headache, nausea (unless IV rehydration required). 

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For all safety pauses, HVTN LOC notifies the HVTN 139 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 LOC notifies the SMB. 
Once a trial is paused, the HVTN 139 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 LOC 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 139 PSRT assessment, DAIDS RAB 
notifies the SAHPRA as needed. 
If an immediate HVTN 139 PSRT notification or prompt HVTN 139 PSRT AE 
review is triggered, HVTN LOC notifies the HVTN 139 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 139 PSRT AE 
review cannot be completed within 72 hours of notification (excluding weekends 
and US federal holidays), an automatic safety pause occurs. 
The HVTN requires that each CRS submit to its IRB/EC and any applicable RE 
protocol-related safety information (such as IND safety reports, notification of 
vaccine holds due to the pause rules, unanticipated problems involving risks to 
participants or others, and notification of other unplanned safety pauses). CRSs 
must also follow all applicable RE reporting requirements. 
In addition, all other AEs are reviewed routinely by the HVTN 139 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 LOC for events 
requiring expedited reporting to DAIDS, and events that meet safety pause criteria 
or prompt HVTN 139 PSRT AE review criteria. 

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11.5.2 
Weekly review 
During the injection phase of the trial, the HVTN 139 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 139 PSRT. HVTN LOC reviews reports of clinical and laboratory 
AEs. Events identified during the review that are considered questionable, 
inconsistent, or unexplained are referred to the HVTN CRS clinic coordinator for 
verification. 
11.5.3 
Annual Health Contacts quarterly review 
After the main study period, a monitoring team reviews safety reports quarterly 
during the annual health contacts period. This monitoring team comprises a 
DAIDS Medical Officer, LOC medical monitor, and an HVTN clinical safety 
staff member. 
11.6 
Study termination 
NIAID reserves the right to terminate or curtail a clinical study for any reason, 
including but not limited to the following (reference: 
https://grants.nih.gov/grants/guide/rfa-files/RFA-AI-12-012.html): 
• 
risk to subject safety 
• 
the scientific question is no longer relevant or the objectives will not be met 
(ie slow accrual) 
• 
failure to comply with GCP, US Federal regulations, or Terms and Conditions 
of Award 
• 
occurrence of unforeseen drug safety issues or data from preclinical studies 
indicate a presence of unanticipated toxicity 
• 
risks that cannot be adequately quantified 
• 
ethical concerns raised by the local community or local medical care/health 
care authorities 
• 
failure to remedy deficiencies identified through site monitoring 
• 
substandard data 
• 
reaching a major study endpoint substantially before schedule with persuasive 
statistical significance 

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This study may also be terminated early by the determination of the HVTN 139 
PSRT, a pertinent national regulatory authority, SAHPRA, NIH, Office for 
Human Research Protections (OHRP), or study product developers. 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 (ICH E6 (R2)), 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 139 SSP. 

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12.1 
Social impacts 
Participants in this study risk experiencing discrimination or other personal 
problems that may result from study participation itself or from the development 
of VISP: these are known collectively as negative social impacts. 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 negative 
social impact, a designated NIAID or HVTN Core representative can be 
contacted. 
Participants may also experience positive social impacts as a benefit of study 
participation. When asked, participants say that being in a study made them feel 
good about helping others, increased their knowledge about HIV, and improved 
their self-esteem. 
Negative social impacts are tabulated by the SDMC and are subjected to 
descriptive analysis. The goals are to reduce the incidence of negative social 
impacts and enhance the ability of study staff to mitigate them when possible. 
Reports of positive social impacts may assist sites in providing participants with a 
favorable experience. 
Summary tables of all negative 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 or synthetic nucleic acid molecules 
Because this study is evaluating products containing recombinant or synthetic 
nucleic acid molecules, it must comply with regulations set forth in the NIH’s 
Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid 
Molecules (April 2019). Information about the study must be submitted to the 
Institutional Biosafety Committee (IBC) for each CRS. Investigators at each CRS 
are responsible for obtaining IBC approval per NIH guideline section IV-B7-a-(1). 
IBC review and approval must be documented by the investigator and submitted 
as part of DAIDS’s initial protocol registration for this trial before participants are 
enrolled at the CRS. If this protocol is amended, investigators should follow the 
requirements of their respective IBC. 
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. 

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When such communication is needed, the CRS will request that its IRB/EC and 
any applicable RE expedite review of the message. If this review cannot be 
completed in a timeframe consistent with the urgency of the required 
communication, the site can contact the participant without IRB/EC approval if 
such communication is necessary to avoid imminent harm to the study participant. 
The CRS must notify the IRB/EC and any applicable RE of the matter as soon as 
possible. 

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13 
Version history 
The Protocol Team may modify the original version of the protocol. 
Modifications are made to HVTN protocols via clarification memos, letters of 
amendment, or full protocol amendments. 
The version history of, and modifications to, Protocol HVTN 139 are described 
below. 
Protocol history and modifications 
Date: February 23, 2021 
Protocol version: Version 1.0 
Protocol modification: 
 
Original protocol 
 

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14 
Document references (other than literature 
citations) 
Other documents referred to in this protocol, and containing information relevant 
to the conduct of this study, include: 
▪ Assessment of Understanding. Accessible through the HVTN protocol-
specific website. 
▪ Current CDC Guidelines: 
▪ Revised Recommendations for HIV Testing of Adults, Adolescents, and 
Pregnant Women in Health-Care Settings. Available at 
http://www.cdc.gov/mmwr/PDF/rr/rr5514.pdf  
▪ Revised Guidelines for HIV Counseling, Testing, and Referral. Available 
at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5019a1.htm 
▪ Division of AIDS (DAIDS) Clinical Research Policies and Standard 
Procedures Documents. Available at 
https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-
procedures 
▪ Division of AIDS Protocol Registration Manual. Available at 
https://www.niaid.nih.gov/sites/default/files/prmanual.pdf  
▪ Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events. Corrected Version 2.1, July 2017. Available at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-
tables 
▪ The Manual for Expedited Reporting of Adverse Events to DAIDS. Version 
2.0, January 2010. Available at https://rsc.niaid.nih.gov/clinical-research-
sites/manual-expedited-reporting-adverse-events-daids 
▪ HVTN Certificate of Confidentiality. Accessible through the HVTN website. 
▪ HVTN 139 Special Instructions. Accessible through the HVTN protocol-
specific website. 
▪ HVTN 139 Study Specific Procedures. Accessible through the HVTN 
protocol-specific website. 
▪ HVTN 139 Site Processing Laboratory Instructions. Accessible through the 
HVTN protocol-specific website. 
▪ HVTN Manual of Operations. Accessible through the HVTN website. 

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▪ Dangerous Goods Regulations (updated annually), International Air Transport 
Association. Available for purchase at 
https://www.iata.org/publications/dgr/Pages/index.aspx 
▪ HVTN Lab Center assay portfolio (available upon request). 
▪ International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E6(R2), Guideline for Good Clinical 
Practice: Section 4.8, Informed consent of trial subjects. Available at 
http://www.ich.org/products/guidelines/efficacy/article/efficacy-
guidelines.html 
▪ Participants’ Bill of Rights and Responsibilities. Accessible through the 
HVTN website. 
▪ NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic 
Acid Molecules. Available at http://osp.od.nih.gov/office-biotechnology-
activities/biosafety/nih-guidelines 
▪ NIH Policy and Guidelines on the Inclusion of Women and Minorities as 
Subjects in Clinical Research, November 28, 2017 Amendment (available at 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-014.html) 
▪ Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks, 
March 2016. 
▪ 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 (2018 requirements). Current 
requirements available at https://www.hhs.gov/ohrp/regulations-and-
policy/regulations/45-cfr-46/index.html 
▪ Guidelines for Phase I clinical trials, The Association of the British 
Pharmaceutical Industry. Available at 
https://www.abpi.org.uk/publications/guidelines-for-phase-i-clinical-trials-
2018-edition/ 
▪ The Protection of Personal Information Act (POPIA, South Africa, 2013). 
Available at 
https://www.gov.za/sites/default/files/gcis_document/201409/3706726-
11act4of2013protectionofpersonalinforcorrect.pdf 

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See Section 16 for literature cited in the background and statistics sections of this 
protocol. 

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15 
Acronyms and abbreviations 
A/G 
 
albumin/globulin (ratio) 
Ab 
 
antibody 
Ad 
 
adenovirus 
AdC6 
 
Ad vectors derived from chimpanzee serotypes 6 
AdC7 
 
Ad vectors derived from chimpanzee serotypes 7 
ADCC 
 
antibody-dependent cellular cytotoxicity 
ADCP 
 
antibody-dependent cellular phagocytosis 
ADNP 
 
antibody-dependent neutrophil phagocytosis 
AE 
 
adverse event 
AESI 
 
adverse events of special interest 
ALT 
 
alanine aminotransferase 
ANOVA  
analysis of variance 
ART 
 
antiretroviral therapy 
AUC-MB  
area-under-the-magnitude-breadth 
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 
CI 
 
confidence intervals 
CIOMS 
 
Council for International Organizations of Medical Sciences 
COMPASS 
Combinatorial Polyfunctionality analysis of Antigen-Specific 
T-cell Subsets 
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 
eGFR 
 
estimated glomerular filtration rate 
EIA 
 
enzyme immunoassay 
ELISA 
 
enzyme-linked immunosorbent assay 

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Fc 
 
fragment crystallizable 
FcR 
 
Fc receptor 
FDA 
 
US Food and Drug Administration 
FPR 
 
false positive rate 
Fred Hutch 
Fred Hutchinson Cancer Research Center 
GLA 
 
glucopyranosyl lipid A 
GCP 
 
Good Clinical Practice 
GPP 
 
Good Participatory Practices 
HBsAg 
 
hepatitis B surface antigen 
HCDR3 
 
heavy chain complementarity-determining region 3 
HCV 
 
hepatitis C virus 
HIPAA 
 
Health Insurance Portability and Accountability Act 
HIV 
 
human immunodeficiency virus 
HLA 
 
human leukocyte antigen 
HVTN 
 
HIV Vaccine Trials Network 
IB 
 
Investigator’s Brochure 
IBC 
 
Institutional Biosafety Committee 
ICH 
 
International Council on Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ICABA 
 
infected cells antibody binding assay 
ICS 
 
intracellular cytokine staining 
IDRI 
 
Infectious Disease Research Institute 
IgG 
 
immunoglobulin subtype G 
IM 
 
intramuscular (injection) 
IND 
 
Investigational New Drug 
IRB 
 
Institutional Review Board 
IUD 
 
intrauterine device 
LOC 
 
HVTN Leadership Operations Center 
LOD 
 
limit of detection 
mAb 
 
monoclonal antibody 
MAR 
 
missing at random 
MCAR 
 
missing completely at random 
MIMOSA  
Mixture Models for Single-cell Assays 
MMR 
 
measles, mumps, and rubella 
nAb 
 
neutralizing antibody 
NHP 
 
nonhuman primate 
NIAID 
 
National Institute of Allergy and Infectious Diseases (US NIH) 
NIH 
 
US National Institutes of Health 
OBA 
 
NIH Office of Biotechnology Activities 

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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 
PCA 
 
principal component analysis 
PCR 
 
polymerase chain reaction 
PFS 
 
polyfunctionality score 
PI 
 
Principal Investigator 
PrEP 
 
pre-exposure prophylaxis 
PSRT 
 
Protocol Safety Review Team 
PTE 
 
potential T-cell epitope 
PV 
 
pseudovirus 
RAB 
 
DAIDS Regulatory Affairs Branch 
RAC 
 
NIH Recombinant DNA Advisory Committee 
RE 
 
regulatory entity 
RM 
 
Rhesus Macaque 
RSC 
 
DAIDS Regulatory Support Center 
SAE 
 
serious adverse event 
SAHPRA  
South African Health Products Regulatory Authority 
SAP 
 
Statistical Analysis Plan 
SCHARP  
Statistical Center for HIV/AIDS Research and Prevention 
SD 
 
Study Day 
SDMC 
 
statistical and data management center 
SIV 
 
simian immunodeficiency virus 
SMB 
 
Safety Monitoring Board 
SPT 
 
DAIDS Safety and Pharmacovigilance Team 
SSP 
 
Study Specific Procedures 
SUSAR 
 
Suspected Unexpected Serious Adverse Reaction 
TB 
 
tuberculosis 
UCA 
 
unmutated common ancestor 
UW-VSL  
University of Washington Virology Specialty Laboratory 
VISP 
 
Vaccine induced seropositivity 
VLP 
 
virus-like particle 
VP 
 
virus particle 
VRC 
 
Vaccine Research Center (NIAID) 
 

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16 
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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 HIV-1 
vaccines based on chimpanzee serotypes of adenovirus expressing clade C gp140 
and a CH505TF gp120 protein boost in healthy, HIV- uninfected adult 
participants 
HVTN protocol number: HVTN 139 
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. 
Key information 
▪ Being in this research study is voluntary. It is your choice. 
▪ You are being asked to take part in this study because you are 18-50 years old, 
HIV negative and healthy.  
▪ The purpose of this study is to see if the study vaccines are safe, if people are 
able to take them without becoming too uncomfortable, and to see how a 
person’s immune system responds to the study vaccines.  
▪ Your participation in this study will include about 6 months of clinic visits. 
After that, there will be annual health contacts by phone or message at one 
year, two years, and three years after you got the study injection.  
▪ Procedures will include blood draws and two injections of a study vaccine or 
placebo given at one study visit. 
▪ There are risks from participating.  
▪ We will tell you more information about risks later in this consent form. 
▪ This is the first study to give these study vaccines to people. Because these 
study vaccines have not been given to people yet, we do not know what all 
of the risks may be. 
▪ We do not expect the study vaccines to benefit you in any way. 

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About the study 
The HIV Vaccine Trials Network (HVTN) and [Insert site name] are doing a 
study to test three study products. HIV is the virus that causes AIDS. 
About 34 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 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 results from Part A, we will decide 
whether or not to do Part B of the study. If we decide to do Part B, 22 more 
people will join. 
You are being invited to join Part A of the study, which will only test 2 of the 3 
study products. 
1. We are doing this study to answer several questions. 
▪ Are the study vaccines safe to give to people? 
▪ Are people able to take the study vaccines without becoming too 
uncomfortable? 
▪ How do people’s immune systems respond to the study vaccines? (Your 
immune system protects you from disease.) 
2. The study vaccines cannot give you HIV. 
The study vaccines are not made from actual HIV. It is impossible for the study 
vaccines to give you HIV. Also, they cannot cause you to give HIV to someone 
else. 
3. We do not know if the study vaccines will decrease, increase, or not change 
your risk of getting 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. You can remove the box around the text. 
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. 

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The studies that found a higher risk of HIV infection were testing a vaccine made 
from a weakened common cold virus called adenovirus type 5 (Ad5). 
In one study, the group of men at higher risk had some things in common. In 
addition to getting the vaccine, they either: 
• had antibodies to Ad5 (your body makes antibodies to fight infection), 
• or they were uncircumcised (still had the foreskin on their penises), 
• or both. 
Men who were circumcised and did not have these antibodies did not have higher 
risk when they got the vaccine. In the group with higher risk after vaccination, the 
risk seemed to lessen after about a year and a half. 
Only a few women in that study got HIV, so we can’t tell if the vaccine affected 
their risk. 
In another study, men who got the vaccine had higher risk whether or not they 
were circumcised or had antibodies to Ad5. Many women got HIV during the 
study but we can’t tell if the vaccine affected their risk. 
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. These study vaccines are experimental. 
The study vaccines in Part A are called AdC6-HIVgp140 and AdC7-HIVgp140. 
From here on, we will call them AdC6 and AdC7 vaccines or the study vaccines. 
The study vaccines have not been given to people before. They are experimental 
HIV vaccines. That means we do not know if the study vaccines will be safe to 
use in people, or if they will work to prevent HIV infection. These vaccines are 
used only in research studies. 
The study vaccines have been tested in animals and appear safe. Even if 
something looks like it is safe or works in animals, it may not be true for people.  
The vaccines were developed by the Division of AIDS (DAIDS) at the US 
National Institutes of Health (NIH).  
The AdC6 and AdC7 study vaccines are “adenoviral vector” vaccines. They are 
made from two kinds of adenovirus. Adenoviruses cause colds, coughs, and 

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diarrhea. The adenoviruses used in these study vaccines are from chimpanzees so 
they should not cause infections in people. The adenoviruses in the vaccines have 
been changed so that they will not spread in your body or to people around you. 
You cannot become infected with HIV or AIDS from the study vaccines. 
The AdC6 and AdC7 study vaccines have been made in a lab to tell your body to 
make a small amount of some proteins that are found in HIV. Your body’s 
immune system might recognize these proteins and prepare itself to fight HIV by 
making antibodies and T cells. Antibodies and T cells are parts of an immune 
response. Immune responses are part of the body’s natural defense against 
disease. 
Some people will get a placebo, a substance that does not contain vaccine. In this 
study, the placebo is sterile salt water. 
In Part A of the study, we are looking to see if the AdC6 or AdC7 study vaccines 
are safe when given in a small amount. We will also measure your body’s 
immune responses. 
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. Anyone can get 
an autoimmune disease. It is possible but unlikely that a vaccine can lead to an 
autoimmune disease or make one worse. 
Risks of the AdC6 and AdC7 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. 
These AdC6 and AdC7 study vaccines have not been given to people before. 
Studies in animals showed that these vaccines are safe. Even if something looks 
like it is safe or works in animals, it may not be true for people. Other chimpanzee 
adenovirus vaccines have been used in other research studies for other diseases 

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and did not cause serious health problems, even when given at higher doses than 
will be used in this study. 
Some people who get a study product may have changes in their blood or urine 
that can only be seen in laboratory tests. These changes usually go away on their 
own in a few days but sometimes require more testing.  
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. We check to make sure that you are not in more than one study 
by taking your fingerprint on an electronic system. This information is only 
accessed by a few members of the study team using a secure password. 
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 ask you about medications you are taking, including HIV pre-exposure 
prophylaxis (PrEP). We will ask you about behaviors that might put you at risk 

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for getting HIV. If you were assigned female sex at birth, 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 assigned female sex at birth and could become pregnant, you 
must agree to use birth control to join this study. 
Site: If you want to include Appendix 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 2 months after 
your last study injection. We will talk to you about effective birth control 
methods. They are listed on a handout that we will give to you. 
Being in the study 
If you meet the study requirements and want to join, here is what will happen: 
9. You will come to the clinic for scheduled visits about [#] times over 6 months. 
Site: Insert number of visits and range of visit lengths. (There is site-specific variation 
in screening protocols and in the number of possible follow-up visits between 
protocol-mandated visits.) 
Visits can last from [#] to [#] hours. 
You may have to come for more visits if you have a lab or health issue. 
We will contact you after the main study ends to check your health, and to tell 
you about the study results. 

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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). 
You do not have to pay anything to be in this study. 
11. We will give you one of the study vaccines or a placebo. 
Not everyone in this study will get a study vaccine. Some people will get a 
placebo. We will compare the results from people who got the placebo with 
results from people who got the study vaccines. 
You have about an 83% chance of getting one of the study vaccines. Site: Modify 
the randomization metaphor in the next sentence as appropriate to your local 
culture. Whether you get a study vaccine or the placebo is completely random, 
like flipping a coin. 
We have no say in whether you get a 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 main 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. 
12. We will give you the study products on a schedule. 
You will be in one of 3 groups. You will get 2 injections into the same upper arm 
at one clinic visit. 
 
Part A 
Group 
N 
Dose 
Enrollment Visit 
1 
5 
Low dose 
AdC6 
2 
5 
Low dose 
AdC7 
3 
2 
None 
Placebo 
You will have to wait in the clinic for at least an hour after the injections to see if 
there are any problems. Then for that night and for 7 more days, you will need to 
keep track of how you are feeling and if you have any symptoms. Site: Customize 
the next sentence based on how you collect reactogenicity information. You will 
bring this information back to the clinic at your next visit. Within 3 days of the 
injection, we will also need to be in contact with you to ask how you are doing. 

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Contact the clinic staff if you have any issues or concerns after getting an 
injection. If you have a problem, we will continue to check on you until it goes 
away. 
13. In addition to giving you the study products, we will: 
▪ Do regular HIV testing, as well as counseling on your results and on how to 
avoid getting HIV 
▪ Do physical exams 
▪ Do pregnancy tests if you were assigned female sex at birth 
▪ Ask questions about your health, including medications you may be taking 
▪ Ask questions about any personal problems or benefits you may have from 
being in the study 
▪ 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 190 mL (about 1 tablespoon to a little 
less than 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 E, 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 about protecting yourself from HIV. 
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. 
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 South Africa and in the United States. In rare 

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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 get HIV, 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 products. 
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 South 
Africa.  
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.] 

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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. The key to the code will stay at 
this clinic. It will not be shared with anyone who does not need to know your 
name. Your name will not be part of the information. However, some information 
that we share may be personal, such as your race, ethnicity, sex, health 
information from the study, and HIV status. We may share information about the 
study product you received and how your body responded to the study product. 
What kind of studies might be done with my extra samples and information? The 
studies will be related to HIV, vaccines, the immune system and other diseases. 
Researchers may also do genetic testing on your samples. 
In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to do research with them. 
If you agree, your samples could also be used for genome-wide studies. In these 
studies, researchers will look at all of your genes (your genome). The researchers 
compare the genomes of many people, looking for common patterns of genes that 
could help them understand diseases. The researchers may put the information 
from the genome-wide studies into a protected database so that other researchers 
can access it, but your name and other personal information will not be included. 
Usually, no one would be able to look at your genome and link it to you as a 
person. However, if another database exists that also has information on your 
genome and your name, someone might be able to compare the databases and 

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identify you. If others found out, it could lead to discrimination or other problems. 
The risk of this is very small. There may be other unknown risks. 
Who will have access to my information in studies using my extra samples? 
People who may see your information are: 
▪ Researchers who use your extra samples and information for other research 
▪ Government agencies that fund or monitor the research using your extra 
samples and information 
▪ The researcher’s Institutional Review Board or Ethics Committee 
▪ Any regulatory agency that reviews clinical trials 
▪ 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. 
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. You can remove the box around the text.  
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, 
▪ Any regulatory agency that reviews clinical trials, 
▪ [Insert name of local IRB/EC] , 
▪ [Insert name of local and/or national regulatory authority as appropriate], 
▪ Wistar Institute and people who work for them, 
▪ Duke University and people who work for them, 
▪ IDRI and people who work for them, 
▪ The Division of AIDS and people who work for them, 
▪ The HVTN and people who work for them, 
▪ The 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. If you are found to have a medical 
condition that we are required to report by law, then some of your information 
may be shared. 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.) If your site does not have public health or legal reporting 
requirements, you may delete the last sentence in the paragraph above, along with 
the bullets below. 
▪ [Item 1] 
▪ [Item 2] 
▪ [Item 3] 
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. If you become pregnant or get HIV during the study, we will discuss your 
options for participation with you. 
We will encourage you to stay in the study if you choose. This means that we may 
still take blood and urine samples and ask you to come to scheduled clinic visits. 
We will also call you once a year for 3 years after your injection to check on your 
safety.  
If you leave the study while you are still pregnant, we would like to contact you 
after your due date to ask some questions about your pregnancy and delivery.  
If you get HIV, we will help you get care and support. We will counsel you about 
having HIV and about telling your partner(s). Site: Modify the following sentence 
as appropriate. We will not provide or pay for any of your HIV care directly.  
19. We may take you out of the study at any time.  
We may take you out of the study if: 
▪ you do not follow instructions, 
▪ we think that staying in the study might harm you,or 
▪ the study is stopped for any reason. 
Other Risks 
20. There are other risks to being in this study. 
This section describes the other risks and restrictions we know about. There may 
also be unknown risks, even serious ones. We will tell you if we learn anything 
new that may affect your willingness to stay in the study. 
Risks of routine medical procedures: 
In this study, we will do some routine medical procedures. These are taking blood 
and giving injections. These procedures can cause bruising, pain, fainting, 
soreness, redness, swelling, itching, 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. 

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Personal problems/discrimination/testing HIV antibody positive: 
Most people who join HVTN studies report no problems or discrimination as a 
result of their participation in an HIV vaccine study. Most problems that were 
reported were with personal relationships. These problems can include family or 
friends worrying, getting upset or angry, or assuming that you have HIV or are at 
high risk and treating you unfairly as a result. Most problems that were reported 
by participants had minimal impact on their lives. 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. A study vaccine 
may cause you to test positive on some types of HIV antibody tests, even if you 
do not have HIV. This is called vaccine-induced seropositivity (VISP). VISP 
means that after you get a 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 a 
study vaccine. 
If you have a positive test result caused by a 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 a 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. 
Site: Modify the following paragraph if applicable. If someone believes you have 
HIV even if you do 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. We may also show you 
a video to help you think about these VISP issues. 
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. 

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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 HIV, 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 have 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 getting HIV if exposed. If you get HIV, we do not know how the study 
vaccines might affect your HIV infection or how long it takes to develop AIDS. 
We do not know if getting the study vaccines will affect how you respond to any 
future approved HIV vaccine. Currently, no HIV vaccine has been approved for 
use. 

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We do not know how the study vaccines will affect a pregnant participant or a 
developing baby. 
Benefits 
21. The study may not benefit you. 
We do not expect the study vaccines to 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. 
When asked, most study participants say that participating in a study made them 
feel good about helping others, increased their knowledge about HIV, and 
improved their self-esteem. 
This study may help in the search for a vaccine to prevent HIV. However, if the 
study vaccines later become approved and sold, there are no plans to share any 
money with you. 
Your rights and responsibilities 
22. If you join the study, you have rights and responsibilities. 
You have many rights that we will respect. You also have responsibilities. We list 
these in the Bill of Rights and Responsibilities (BRR) for HIV Research. We will 
give you a copy of it. 
Leaving the study 
23. Tell us if you decide to leave the study. 
You are free to leave the study at any time and for any reason. Your care at this 
clinic and your legal rights will not be affected, but it is important for you to let us 
know. 
Previously collected information about you will remain in the study records and 
will be included in the analysis of results. Your information can not be removed 
from the study records. 
We may 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 may 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 
Sites: 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. You can remove 
the box around the text. 
24. If you get sick or injured during the study, contact us immediately. 
Your health is important to us. (Sites: adjust the following 2 sentences if 
applicable to the care available at your site) We will tell you about the care that 
we can give 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, the HVTN has 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. 
In this study, our clinic has insurance to cover your medical treatment in the case 
of a study-related injury. We will follow the Association of the British 
Pharmaceutical Industry guidelines for payment of study-related injury. We 
can give you a copy of these guidelines. In rare cases, the insurance funds may 
not be enough. 
The HVTN has limited funds to pay medical costs that it determines are 
reasonable. (Sites: insert locale- appropriate medical insurance language in the 
following sentence) If the injury is not study related, then you and/or 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. 
 
Annual health contacts  
25. After your clinic visits end, we will contact you once a year until 3 years after 
your injection to check your health  
We will contact you once a year to ask questions about your health.  

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If we have any concerns about your health, we may need to have more contact 
with you. You are also welcome to contact us at any time if you have concerns 
about your health related to being in the study. 
If we ask you to come to the clinic, we will give you 
[Site: Insert compensation amount] for each visit. This amount is to cover the 
costs of [Site: Insert text]. 
If someone outside this study clinic told you that you have HIV, we will ask you 
to come back to the clinic for another HIV test. We will draw about 15 mL (1 
tablespoon) of blood. We may ask you to come back more than once for this 
testing. 
Because we will want to contact you once a year, please tell us if your contact 
information changes, if you are moving away, or if you do not want us to contact 
you anymore. 
You can tell us at any time that you don’t want any more annual health contacts. 
If you do so, you will not lose any benefits or rights you would normally have. 
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/EC] , at the 
committee. 
The study has been structured in accordance with the Declaration of Helsinki (last 
updated October 2013) which deals with the recommendations guiding doctors in 
biomedical research involving human participants, the Ethics in Health Research: 
Principles, Structures and Processes Second Edition 2015, and Guidelines for 
Good Practice in the Conduct of Clinical Trials in Human Participants in South 
Africa. We can provide you with copies of these guidelines if you wish to review 
them. In addition, the recent Protection of Personal Information Act (POPIA) 
ensures that all South African institutions conducts themselves in a responsible 
manner when collecting, processing, storing and sharing another entity’s personal 
information by holding them accountable should they abuse or compromise your 
personal information in any way. 

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If you want to leave this study, contact 
[name or title and telephone number of the investigator or other study staff]. 
You can reach a study staff member 24 hours a day at [telephone number]. 
If you have questions about this trial you should first discuss them with your 
doctor or the ethics committee (contact details as provided on this form). After 
you have consulted your doctor or the ethics committee and if they have not 
provided you with answers to your satisfaction, you should write to the South 
African Healthcare Products Regulatory Authority (SAHPRA) at: 
The Chief Executive Officer 
Dr Boitumelo Semete-Makokotlela 
South African Health Products Regulatory Authority Private Bag X828 
PRETORIA 
0001 
Tel: (012) 501 0410/13 
e-mail: Boitumelo.Semete@sahpra.org.za 
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. You can change your mind after 
signing this form. 
 

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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 entire discussion of this consent form. 
 
 

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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 HIV-1 
vaccines based on chimpanzee serotypes of adenovirus expressing clade C gp140 
and a CH505TF gp120 protein boost in healthy, HIV- uninfected adult 
participants 
HVTN protocol number: HVTN 139 
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. 
Key information  
Being in this research study is voluntary. It is your choice. 
▪ You are being asked to take part in this study because you are 18-50 years old, 
HIV negative and healthy.  
▪ The purpose of this study is to see if the study products are safe, if people are 
able to take them without becoming too uncomfortable, and to see how a 
person’s immune system responds to the study products. 
▪ Two of the study vaccines were tested in Part A at a lower dose and were 
found to be safe to continue testing in this part of the study.  
▪ Your participation in this study will include about 12 months of clinic visits. 
After that, there will be health contacts by phone or message at 18 months, 2 
years, and 3 years after your first study injection. 
▪ Procedures will include blood draws and injections of the study products or a 
placebo at three study visits.  
▪ There are risks from participating.  
▪ We will tell you more information about risks later in this consent form. 
▪ Part A of this study was the first time two of the study vaccines have been 
given to people. Because these vaccines have not been given to very many 
people yet, we do not know what all of the risks may be. 
▪ We do not expect the study vaccines to benefit you in any way.  

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About the study 
The HIV Vaccine Trials Network (HVTN) and [Insert site name] are doing a 
study to test three study vaccines. HIV is the virus that causes AIDS. 
About 34 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 is divided into two parts, Part A and Part B. About 12 people took part 
in Part A of this study. The safety data from participants in Part A was reviewed, 
and we believe it is safe to continue with Part B. In Part B, 22 more people will 
join. 
You are being invited to join Part B of the study. 
1. We are doing this study to answer several questions. 
▪ Are the study products safe to give to people? 
▪ Are people able to take the study products without becoming too 
uncomfortable? 
▪ How do people’s immune systems respond to the study products? (Your 
immune system protects you from disease.) 
2. The study products cannot give you HIV. 
The study products are not made from actual HIV. It is impossible for the study 
products to give you HIV. Also, they cannot cause you to give HIV to someone 
else. 
3. We do not know if the study products will decrease, increase, or not change 
your risk of getting 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. You can remove the box around the text. 
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. 
The studies that found a higher risk of HIV infection were testing a vaccine made 
from a weakened common cold virus called adenovirus type 5 (Ad5). 

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In one study, the group of men at higher risk had some things in common. In 
addition to getting the vaccine, they either: 
• had antibodies to Ad5 (your body makes antibodies to fight infection), 
• or they were uncircumcised (still had the foreskin on their penises), 
• or both. 
Men who were circumcised and did not have these antibodies did not have higher 
risk when they got the vaccine. In the group with higher risk after vaccination, the 
risk seemed to lessen after about a year and a half. 
Only a few women in that study got HIV, so we can’t tell if the vaccine affected 
their risk. 
In another study, men who got the vaccine had higher risk whether or not they 
were circumcised or had antibodies to Ad5. Many women got HIV during the 
study but we can’t tell if the vaccine affected their risk. 
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. These study products are experimental. 
The study products in Part B are called AdC6-HIVgp140, AdC7-HIVgp140, and 
CH505TF gp120. From here on, we will call them AdC6, AdC7, CH505TF or the 
study vaccines. The AdC6 and AdC7 study vaccines have not been given to 
people before Part A of this study. They are experimental HIV vaccines. That 
means we do not know if the study vaccines will be safe to use in people, or if 
they will work to prevent HIV infection. These vaccines are used only in research 
studies. The vaccines were developed by the Division of AIDS (DAIDS) at the 
National Institutes of Health (NIH). 
The AdC6 and AdC7 study vaccines have been tested in animals and appear safe. 
Even if something looks like it is safe or works in animals, it may not be true for 
people.  
The AdC6 and AdC7 study vaccines are “adenoviral vector” vaccines. They are 
made from two kinds of adenovirus. Adenoviruses cause colds, coughs, and 
diarrhea. The adenoviruses used in these study vaccines are from chimpanzees so 
they should not cause infections in people. The adenoviruses in the vaccines have 

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been changed so that they will not spread in your body or to people around you. 
You cannot become infected with HIV or AIDS from the study vaccines. 
The AdC6 and AdC7 study vaccines have been made in a lab to tell your body to 
make a small amount of some proteins that are found in HIV. Your body’s 
immune system might recognize these proteins and prepare itself to fight HIV by 
making antibodies and T cells. Antibodies and T cells are parts of an immune 
response. Immune responses are part of the body’s natural defense against 
disease. 
The CH505TF study vaccine has man-made pieces of protein that look like part of 
a protein found in HIV. Your body’s immune system might learn to recognize this 
protein and prepare itself to fight HIV. This is called an immune response. 
The CH505TF study vaccine is mixed with an adjuvant. An adjuvant is a 
substance that should help the immune system respond better. The adjuvant in this 
study is called GLA-SE. GLA-SE was made by the Infectious Disease Research 
Institute (IDRI). The CH505TF study vaccine and GLA-SE study adjuvant have 
been given to 72 people in two other ongoing HVTN studies. So far they have not 
made people too uncomfortable or caused serious health problems. 
Some people will get a placebo, a substance that does not contain vaccine. In this 
study, the placebo is sterile salt water. 
In part A of the study, we looked to see if the AdC6 and AdC7 study vaccines 
were safe when given once at a low dose, and then we measured people’s immune 
responses. There were about 12 people in Part A and the results showed that it is 
safe to move ahead with Part B of the study. 
In part B of the study, we are looking to see if the AdC6 and AdC7 study vaccines 
are safe when given at a higher dose, in combination, and when followed by the 
CH505TF study vaccine. We will measure your body’s immune responses. By 
giving the combination of the 3 study vaccines, we hope the immune system 
develops responses that can better teach the body to fight 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. 

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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. Anyone can get 
an autoimmune disease. It is possible but unlikely that a vaccine can lead to an 
autoimmune disease or make one worse. 
Risks of the AdC6 and AdC7 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. 
Studies in animals showed that these vaccines are safe. Even if something looks 
like it is safe or works in animals, it may not be true for people. Other chimpanzee 
adenovirus vaccines have been used in other research studies for other diseases 
and did not cause serious health problems, even when given at higher doses than 
will be used in this study. 
Risks of the CH505TF study vaccine: 
In one study, the CH505TF study vaccine and GLA-SE adjuvant were given to 12 
people at the same dose that will be given to people in this study. Thirty other 
people in that study got different doses of the CH505TF study vaccine and GLA-
SE adjuvant or placebo. That study is still ongoing and we don’t know who got 
the vaccine and adjuvant, or who got the placebo. The most common complaints 
were pain or tenderness where people were injected. One person had a skin 
infection where they got the injection, which went away within 5 days after taking 
medication (antibiotics). It did not affect that person’s daily routine. Two people 
had bad headaches that went away in a few days. In a second study, 30 
participants received CH505TF at a lower dose than we are testing in this study. 
That study is also ongoing so we do not know the results, but we do know that as 
of March 4, 2020, there have been no serious health problems reported. 
The study adjuvant, GLA-SE, has also been tested in people with vaccines for 
other diseases. The most common complaints were pain and tenderness at the 
place where you got the injection, and feeling tired. 
Some people who get a study product may have changes in their blood or urine 
that can only be seen in laboratory tests. These changes usually go away on their 
own in a few days but sometimes require more testing.  
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 

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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. We check to make sure that you are not in more than one study 
by taking your fingerprint on an electronic system. This information is only 
accessed by a few members of the study team using a secure password. 
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 ask you about medications you are taking, including HIV pre-exposure 
prophylaxis (PrEP). We will ask you about behaviors that might put you at risk 
for getting HIV. If you were assigned female sex at birth, we will test you for 
pregnancy. 
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. 

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8. If you were assigned female sex at birth and could become pregnant, you 
must agree to use birth control to join this study. 
Site: If you want to include Appendix 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 products could affect the developing baby. You must agree to use 
effective birth control from 21 days before your first injection until 2 months after 
your last study injection. We will talk to you about effective birth control 
methods. They are listed on a handout that we will give to you. 
Being in the study 
If you meet the study requirements and want to join, here is what will happen: 
9. You will come to the clinic for scheduled visits about [#] times over 12 
months. 
Site: Insert number of visits and range of visit lengths. (There is site-specific variation 
in screening protocols and in the number of possible follow-up visits between 
protocol-mandated visits.) 
Visits can last from [#] to [#] hours. 
You may have to come for more visits if you have a lab or health issue. 
We will contact you after the main study ends to check your health, and 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). 
You do not have to pay anything to be in this study. 
11. We will give you either the study products or a placebo. 
Not everyone in this study will get the study products. Some people will get a 
placebo. We will compare the results from people who got the placebo with 
results from people who got the study products. 

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You have about a 90% chance of getting the study products. Site: Modify the 
randomization metaphor in the next sentence as appropriate to your local culture. 
Whether you get the study products or the placebo is completely random, like 
flipping a coin. 
We have no say in whether you get the study products or the placebo. We will not 
know which 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 B completes their final main study 
visits to find out whether you got the study products 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. 
12. We will give you the study products on a schedule. 
You will be in one of 3 groups. At the first two injection visits, you will get 2 
injections into the same upper arm. At the third injection visit, you will get 1 
injection into the upper thigh. 
 
Part B 
Group 
N 
Dose 
Enrollment visit 
3 months 
6 months 
4 
10 
Higher dose 
AdC6 
AdC7 
CH505TF + GLA-
SE 
5 
10 
Higher dose 
AdC7 
AdC6 
CH505TF+ GLA-
SE 
6 
2 
None 
Placebo 
Placebo 
Placebo 
You will have to wait in the clinic for at least an 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. Site: Customize 
the next sentence based on how you collect reactogenicity information. You will 
bring this information back to the clinic at your next visit. Within 3 days of each 
injection, we will also need to be in contact with you to ask how you are doing. 
Contact the clinic staff if you have any issues or concerns after getting an 
injection. If you have a problem, we will continue to check on you until it goes 
away. 
13. In addition to giving you the study products, we will: 
▪ Do regular HIV testing, as well as counseling on your results and on how to 
avoid getting HIV 
▪ Do physical exams 
▪ Do pregnancy tests if you were assigned female sex at birth 
▪ Ask questions about your health, including medications you may be taking 

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▪ Ask questions about any personal problems or benefits you may have from 
being in the study 
▪ 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 190 mL (1 tablespoon to a little less 
than 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 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 about protecting yourself from HIV. 
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. 
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 South Africa and 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 get HIV, 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 products. 

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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 South 
Africa.  
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. 

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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. The key to the code will stay at 
this clinic. It will not be shared with anyone who does not need to know your 
name. Your name will not be part of the information. However, some information 
that we share may be personal, such as your race, ethnicity, sex, health 
information from the study, and HIV status. We may share information about the 
study product you received and how your body responded to the study product. 
What kind of studies might be done with my extra samples and information? The 
studies will be related to HIV, vaccines, the immune system and other diseases. 
Researchers may also do genetic testing on your samples. 
In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to do research with them. 
If you agree, your samples could also be used for genome-wide studies. In these 
studies, researchers will look at all of your genes (your genome). The researchers 
compare the genomes of many people, looking for common patterns of genes that 
could help them understand diseases. The researchers may put the information 
from the genome-wide studies into a protected database so that other researchers 
can access it, but your name and other personal information will not be included. 
Usually, no one would be able to look at your genome and link it to you as a 
person. However, if another database exists that also has information on your 
genome and your name, someone might be able to compare the databases and 
identify you. If others found out, it could lead to discrimination or other problems. 
The risk of this is very small. There may be other unknown risks. 
Who will have access to my information in studies using my extra samples? 
People who may see your information are: 
▪ Researchers who use your extra samples and information for other research 
▪ Government agencies that fund or monitor the research using your extra 
samples and information 
▪ The researcher’s Institutional Review Board or Ethics Committee 
▪ Any regulatory agency that reviews clinical trials 

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▪ 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. 
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. You can remove the box around the text.  
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, 
▪ Any regulatory agency that reviews clinical trials, 
▪ [Insert name of local IRB/EC] , 
▪ [Insert name of local and/or national regulatory authority as appropriate], 
▪ Wistar Institute and people who work for them, 
▪ Duke University and people who work for them, 

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▪ IDRI and people who work for them, 
▪ The Division of AIDS and people who work for them, 
▪ The HVTN and people who work for them, 
▪ The 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. If you are found to have a medical 
condition that we are required to report by law, then some of your information 
may be shared. 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.) If your site does not have public health or legal reporting 
requirements, you may delete the last sentence in the paragraph above, along with 
the bullets below. 
▪ [Item 1] 
▪ [Item 2] 
▪ [Item 3] 
The results of this study may be published. No publication will use your name or 
identify you personally. 
We may share information from the study with other researchers. We will not 
share your name or information that can identify you. 
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. There are several reasons why we may stop your injections. We may stop 
them even if you want to stay in the study and even if you were scheduled for 
more injections. 
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. 

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We will stop your injections if you get HIV. We will also take fewer samples, and 
we will help you get care and support. We will encourage you to stay in the study, 
including annual contacts to check your health for 3 years after your first injection 
if you choose. We will discuss your study options with you. We will counsel you 
about having HIV and about telling your partner(s). Site: Modify the following 
sentence as appropriate. We will not provide or pay for any of your HIV care 
directly.  
If we stop your injections, we may ask you to stay in the study to complete other 
study procedures. 
19. We may take you out of the study at any time.  
We may take you out of the study if: 
▪ you do not follow instructions, 
▪ we think that staying in the study might harm you, or 
▪ the study is stopped for any reason. 
Other Risks 
20. There are other risks to being in this study. 
This section describes the other risks and restrictions we know about. There may 
also be unknown risks, even serious ones. We will tell you if we learn anything 
new that may affect your willingness to stay in the study. 
Risks of routine medical procedures: 
In this study, we will do some routine medical procedures. These are taking blood 
and giving injections. These procedures can cause bruising, pain, fainting, 
soreness, redness, swelling, itching, 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: 
Most people who join HVTN studies report no problems or discrimination as a 
result of their participation in an HIV vaccine study. Most problems that were 
reported were with personal relationships. These problems can include family or 
friends worrying, getting upset or angry, or assuming that you have HIV or are at 
high risk and treating you unfairly as a result. Most problems that were reported 
by participants had minimal impact on their lives. 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. 

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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 
do not have 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. 
Site: Modify the following paragraph if applicable. If someone believes you have 
HIV even if you do 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. We may also show you 
a video to help you think about these VISP issues. 
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 HIV, 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: 

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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 have 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 products will increase, decrease, or not change your 
risk of getting HIV if exposed. If you get HIV, we do not know how the study 
vaccines might affect your HIV infection or how long it takes to develop AIDS. 
We do not know if getting the study products will affect how you respond to any 
future approved HIV vaccine. Currently, no HIV vaccine has been approved for 
use. 
We do not know how the study products will affect a pregnant participant or a 
developing baby. 
Benefits 
21. The study may not benefit you. 
We do not expect the study products to 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 

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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. 
When asked, most study participants say that participating in a study made them 
feel good about helping others, increased their knowledge about HIV, and 
improved their self-esteem. 
This study may help in the search for a vaccine to prevent HIV. However, if the 
study products later become approved and sold, there are no plans to share any 
money with you. 
Your rights and responsibilities 
22. If you join the study, you have rights and responsibilities. 
You have many rights that we will respect. You also have responsibilities. We list 
these in the Bill of Rights and Responsibilities (BRR) for HIV Research. We will 
give you a copy of it. 
Leaving the study 
23. Tell us if you decide to leave the study. 
You are free to leave the study at any time and for any reason. Your care at this 
clinic and your legal rights will not be affected, but it is important for you to let us 
know. 
Previously collected information about you will remain in the study records and 
will be included in the analysis of results. Your information can not be removed 
from the study records. 
We may 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 may also ask about any 
personal problems or benefits you have experienced from being in the study. We 
believe these steps are important to protecting your health, but it is up to you 
whether to complete them. 
Injuries 
Sites: 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. You can remove 
the box around the text. 

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24. If you get sick or injured during the study, contact us immediately. 
Your health is important to us. (Sites: adjust the following 2 sentences if 
applicable to the care available at your site) We will tell you about the care that 
we can give 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, the HVTN has 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. 
In this study, our clinic has insurance to cover your medical treatment in the case 
of a study-related injury. We will follow the Association of the British 
Pharmaceutical Industry guidelines for payment of study-related injury. We 
can give you a copy of these guidelines. In rare cases, the insurance funds may 
not be enough. 
The HVTN has limited funds to pay medical costs that it determines are 
reasonable. (Sites: insert locale- appropriate medical insurance language in the 
following sentence) If the injury is not study related, then you and/or 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. 
 
Annual health contacts  
25. After your clinic visits end, we will contact you at 18 months, two years, and 
3 years after your first injection to check your health.  
We will contact you once a year or to ask questions about your health 
If we have any concerns about your health, we may need to have more contact 
with you. You are also welcome to contact us at any time if you have concerns 
about your health related to being in the study. 
If we ask you to come to the clinic, we will give you 
[Site: Insert compensation amount] for each visit. This amount is to cover the 
costs of [Site: Insert text]. 

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If someone outside this study clinic told you that you have HIV, we will ask you 
to come back to the clinic for another HIV test. We will draw about 15 mL (1 
tablespoon) of blood. We may ask you to come back more than once for this 
testing. 
Because we will want to contact you once a year, please tell us if your contact 
information changes, if you are moving away, or if you do not want us to contact 
you anymore. 
You can tell us at any time that you don’t want any more annual health contacts. 
If you do so, you will not lose any benefits or rights you would normally have. 
 
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/EC] , at the 
committee. 
The study has been structured in accordance with the Declaration of Helsinki (last 
updated October 2013) which deals with the recommendations guiding doctors in 
biomedical research involving human participants, the Ethics in Health Research: 
Principles, Structures and Processes Second Edition 2015, and Guidelines for 
Good Practice in the Conduct of Clinical Trials in Human Participants in South 
Africa. We can provide you with copies of these guidelines if you wish to review 
them. In addition, the recent Protection of Personal Information Act (POPIA) 
ensures that all South African institutions conducts themselves in a responsible 
manner when collecting, processing, storing and sharing another entity’s personal 
information by holding them accountable should they abuse or compromise your 
personal information in any way. 
If you want to leave this study, contact 
[name or title and telephone number of the investigator or other study staff]. 
You can reach a study staff member 24 hours a day at [telephone number]. 

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If you have questions about this trial you should first discuss them with your 
doctor or the ethics committee (contact details as provided on this form). After 
you have consulted your doctor or the ethics committee and if they have not 
provided you with answers to your satisfaction, you should write to the South 
African Healthcare Products Regulatory Authority (SAHPRA) at: 
The Chief Executive Officer 
Dr Boitumelo Semete-Makokotlela 
South African Health Products Regulatory Authority Private Bag X828 
PRETORIA 
0001 
Tel: (012) 501 0410/13 
e-mail: Boitumelo.Semete@sahpra.org.za 
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. You can change your mind after 
signing this form. 
 
 
I allow my extra samples and information to be used for other studies related to HIV, 
vaccines, the immune system, and other diseases. This may include genetic testing and 
keeping my cells growing over time.  
OR 
 
 
I agree to the option above and also to allow my extra samples and information to be 
used in genome wide studies. 
OR 
 
 
I do not allow my extra samples to be used in any other studies. This includes not 
allowing genetic testing, growing more of my cells, or genome wide studies.  
 
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. 

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▪ You feel that you understand what the study is about and what will happen to 
you if you join. You understand what the possible risks and benefits are. 
▪ You have had your questions answered and know that you can ask more. 
▪ You agree to join this study. 
You will not be giving up any of your rights by signing this consent form. 
 
 
 
 
 
 
 
Participant’s name (print) 
 
Participant’s signature or mark 
 
Date 
 
Time 
 
 
 
 
 
 
 
Clinic staff conducting consent 
discussion (print) 
 
Clinic staff signature 
 
Date 
 
Time 
For participants who are unable to read or write, a witness should complete the 
signature block below: 
 
 
 
 
 
 
 
Witness’s name (print) 
 
Witness’s signature  
 
Date 
 
Time 
*Witness is impartial and was present for the entire discussion of this consent form. 
 
 

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Appendix C 
Approved birth control methods for persons 
assigned female sex at birth (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 can remove the box around the text. 
You should not become pregnant during the study because we do not know how 
the study products could affect the developing baby. 
You must agree to use effective birth control from 21 days before your first 
injection until 2 months after your last study injection. This includes not seeking 
pregnancy through alternative methods such as artificial insemination or in vitro 
fertilization. 
Effective birth control means using any of the following methods every time you 
have sex in a way that could lead to pregnancy: 
• Birth control drugs that prevent pregnancy—given by pills, shots, patches, 
vaginal rings, or inserts under the skin; 
• Internal or external 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 sexually abstinent (no sex at all). 
Remember: If you are having sex, male and female condoms are the only birth 
control methods that also provide protection against HIV and other sexually 
transmitted infections. 
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 HIV-1 
vaccines based on chimpanzee serotypes of adenovirus expressing clade C gp140 
and a CH505TF gp120 protein boost in healthy, HIV- uninfected adult 
participants 
HVTN protocol number: HVTN 139 
Site: [Insert site name] 
Key Information 
These are some of the things you should know about the use of your samples and 
information for other studies: 
▪ The extra samples will be labeled with a code number. They will not be 
labeled with your name. The extra samples are stored in a secure place. At 
your request, the HVTN will destroy all your extra samples. You can still join 
the main study even if you do not agree to use of your extra samples in other 
studies. 
▪ Researchers may do genetic testing on your samples, which could include 
genome wide studies. It is unlikely, but these tests could show you may be at 
risk for certain diseases. In the very unlikely event that others found out, this 
could lead to discrimination or other problems.  
▪ You will not be paid or otherwise benefit from allowing your extra samples to 
be used in other studies.  
The rest of this form gives more information about use of your extra samples for 
other studies. Please read it carefully. 
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. 

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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 South Africa. 
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. 
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. The key to the 
code will stay at this clinic. It will not be shared with anyone who does not need 
to know your name. 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. 

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9. What kind of studies might be done with my extra samples and information? 
The studies will be related to HIV, vaccines, the immune system and other 
diseases. 
Researchers may also do genetic testing on your samples. 
In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to do research with them. 
If you agree, your samples could also be used for genome wide studies. In these 
studies, researchers will look at all of your genes (your genome). The researchers 
compare the genomes of many people, looking for common patterns of genes that 
could help them understand diseases. The researchers may put the information 
from the genome-wide studies into a protected database so that other researchers 
can access it, but your name and other personal information will not be included. 
Usually, no one would be able to look at your genome and link it to you as a 
person. However, if another database exists that also has information on your 
genome and your name, someone might be able to compare the databases and 
identify you. If others found out, it could lead to discrimination or other problems. 
The risk of this is very small. There may be other unknown risks. 
10. What are the risks of genetic testing? 
It is unlikely, but the genetic tests done on your samples could show you may be 
at risk for certain diseases. If others found out, it could lead to discrimination or 
other problems. However, it is almost impossible for you or others to know your 
test results from the genetic testing. The results are not part of your study records 
and are not given to you. 
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 
▪ Any regulatory agency that reviews clinical trials 
▪ 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. 

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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/EC . 
The study has been structured in accordance with the Declaration of Helsinki (last 
updated October 2013) which deals with the recommendations guiding doctors in 
biomedical research involving human participants, the Ethics in Health Research: 
Principles, Structures and Processes Second Edition 2015, and Guidelines for 
Good Practice in the Conduct of Clinical Trials in Human Participants in South 
Africa. We can provide you with copies of these guidelines if you wish to review 
them. In addition, the recent Protection of Personal Information Act (POPIA) 
ensures that all South African institutions conducts themselves in a responsible 
manner when collecting, processing, storing and sharing another entity’s personal 
information by holding them accountable should they abuse or compromise your 
personal information in any way. 
You can reach a study staff member 24 hours a day at [telephone number]. 
If you have questions about this trial you should first discuss them with your 
doctor or the ethics committee (contact details as provided on this form). After 
you have consulted your doctor or the ethics committee and if they have not 
provided you with answers to your satisfaction, you should write to the South 
African Healthcare Products Regulatory Authority (SAHPRA) at: 
The Chief Executive Officer 
Dr Boitumelo Semete-Makokotlela 
South African Health Products Regulatory Authority Private Bag X828 
PRETORIA 
0001 
Tel: (012) 501 0410/13 
e-mail: Boitumelo.Semete@sahpra.org.za 
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 

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of your choice about how your samples and information can be used. You can 
change your mind after signing this form. 
 
 
I allow my extra samples and information to be used for other studies related to 
HIV, vaccines, the immune system, and other diseases. This may include 
genetic testing and keeping my cells growing over time. 
OR 
 
 
I agree to the option above and also to allow my extra samples and information 
to be used in genome wide studies. 
 
OR 
 
 
I do not allow my extra samples to be used in any other studies. This includes 
not allowing genetic testing, growing more of my cells, or genome wide studies.  
 
 
 
 
 
 
 
 
 
 
Participant’s name (print) 
 
Participant’s signature or mark 
 
Date 
 
Time 
 
 
 
 
 
 
 
Clinic staff conducting consent 
discussion (print) 
 
Clinic staff signature 
 
Date 
 
Time 
For participants who are unable to read or write, a witness should complete the 
signature block below: 
 
 
 
 
 
 
 
Witness’s name (print) 
 
Witness’s signature  
 
Date 
 
Time 
*Witness is impartial and was present for the entire discussion of this consent form. 
 

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Appendix E 
Table of procedures for Part A (for sample informed consent form) 
 
Procedure 
Screening visit 
Enrollment visit 
2 weeks 
1 month 
6 months 
1 year 
2 years 
3 years 
Injection 
 
√ 
 
 
 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
Complete physical 
√ 
 
 
 
√ 
 
 
 
Brief physical 
 
√ 
√ 
√ 
 
 
 
 
Urine test 
√ 
 
√ 
 
 
 
 
 
Blood drawn 
√ 
√ 
√ 
√ 
√ 
 
 
 
Pregnancy test (participants assigned 
female sex at birth)* 
√ 
√ 
 
√ 
 
 
 
 
HIV testing and pretest counseling 
√ 
 
 
 
√ 
 
 
 
Risk reduction counseling 
√ 
√ 
√ 
√ 
√ 
 
 
 
Interview/questionnaire 
√ 
√ 
√ 
√ 
√ 
 
 
 
Health contact** 
 
 
 
 
 
√ 
√ 
√ 
Unblinding*** 
 
 
 
 
√ 
 
 
 
 
* Persons who had a hysterectomy (removal of the uterus) or removal of both ovaries (verified by medical records) are not required to have a pregnancy test. 
** Phone contact about one, two, and three years after injection to check on certain aspects of participant health.  
*** Participants find out if they got the vaccines or placebo as soon as the data are available after the 6 month visit. 
 

HVTN 139 Version 1.0 / February 23, 2021 
HVTN139_v1.0_FINAL / Page 172 of 186 
Appendix F 
Table of procedures for Part B (for sample informed consent form) 
 
Procedure 
Screening 
visit 
Enrollment 
visit 
2 
weeks 
1 
month 
3 
months 
3½ 
months   
4 
months 
6 
months 
6½ 
months  
1 year 
1½ 
years  
2 years 
3 
years  
Injection 
 
√ 
 
 
√ 
 
 
√ 
 
 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
√ 
 
 
 
 
 
 
 
 
√ 
 
 
 
Brief physical 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
 
Urine test 
√ 
 
√ 
 
 
√ 
 
 
√ 
 
 
 
 
Blood drawn 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Pregnancy test 
(participants assigned 
female sex at birth)* 
√ 
√ 
 
 
√ 
 
 
√ 
 
 
 
 
 
HIV testing and pretest 
counseling 
√ 
 
 
 
√ 
 
 
√ 
 
√ 
 
 
 
Risk reduction 
counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Interview/questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Health contact** 
 
 
 
 
 
 
 
 
 
 
√ 
√ 
√ 
Unblinding*** 
 
 
 
 
 
 
 
 
 
√ 
 
 
 
 
* Persons who had a hysterectomy (removal of the uterus) or removal of both ovaries (verified by medical records) are not required to have a pregnancy test. 
** Phone contact about one and a half, two, and three years after the first injection to check on certain aspects of participant health. 
*** Participants find out if they got the vaccines or placebo as soon as the data are available after the 1 year visit. 

HVTN 139 Version 1.0 / February 23, 2021 
HVTN139_v1.0_FINAL / Page 173 of 186 
Appendix G 
Laboratory procedures Part A 
 
 
1 CSR = Central Specimen Repository; HSML-NICD = HIV Sero-Molecular Laboratory-National Institute for Communicable Diseases (Johannesburg, South Africa); UW-VSL = 
University of Washington Virology Specialty Laboratory (Seattle, Washington, USA) 
Visit
1
210
3
4
5
AESI11
Day
D0
D14
D28
D168
D364
Week
W0
W2
W4
W24
W52
Month
M0
M0.5
M1
M6
M12
AdC6HIVgp140 OR
AdC7HIVgp140 OR
Placebo
Procedure
Send to1,2
Assay location2
Tube 
Type4
Tube size          
(vol. capacity)4
Total
BLOOD COLLECTION
Screening/Diagnostic
HIV Screening test
Local lab
Local lab
SST
5mL
5
—
—
—
—
—
5
HBsAg/anti-HCV
Local lab
Local lab
SST
5mL
5
—
—
—
—
—
5
HIV diagnostics 7
HSML-NICD / UW-
VSL
HSML-NICD / UW-
VSL
EDTA
10mL
—
—
—
—
20
—
20
Safety labs8
CBC/ Diff/ platelets
Local lab
Local lab
EDTA
5mL
5
—
5
—
—
—
10
Chemistry panel5
Local lab
Local lab
SST
5mL
5
—
5
—
—
—
10
Immunogenicity & Virologic assays
Cellular assays
ICS
CSR
HVTN Labs
ACD
8.5mL
—
42.5
—
42.5
42.5
—
128
Humoral assays
Binding Ab Assay
CSR
HVTN Labs
SST
8.5mL
—
8.5
—
8.5
8.5
—
26
Neutralizing Ab Assay
CSR
HVTN Labs
SST
8.5mL
—
8.5
—
8.5
8.5
—
26
AdC6 and AdC7 Titer
AdC6 and AdC7 Neutralizing Ab Assay
CSR
Non-HVTN Labs
SST
8.5mL
—
8.5
—
8.5
—
—
17
Storage
PBMC
CSR
ACD
8.5mL
—
59.5
—
42.5
68
—
170
Serum
CSR
SST
8.5mL
—
17
—
17
17
—
51
Visit total
20
145
10
128
165
0
467
56-Day total
20
165
175
302
165
0
URINE COLLECTION8
Urine dipstick9
Local lab
Local lab
X
—
X
—
—
—
—
Pregnancy Test6
Local lab
Local lab
X
X
—
X
—
—
—
Screening 
visit3

HVTN 139 Version 1.0 / February 23, 2021 
HVTN139_v1.0_FINAL / Page 174 of 186 
2 HVTN Laboratories include: Cape Town HVTN Immunology Laboratory (CHIL, Cape Town, Africa); South African Immunology Laboratory-National Institute for 
Communicable Diseases (SAIL-NICD, Johannesburg, South Africa); Fred Hutchinson Cancer Research Center (Seattle, Washington, USA); Duke University Medical Center 
(Durham, North Carolina, USA). Non-HVTN Laboratories include: Wistar Institute's Vaccine and Immunotherapy Center (Philadelphia, PA). 
3 Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination. 
4 Local labs may assign appropriate alternative tube types for locally performed tests. 
5 Chemistry panels are defined in Section 9.2 (pre-enrollment) and section 9.4 (post-enrollment).  
6 For a participant who was assigned female sex at birth, pregnancy test must be performed on urine or blood specimens within 24 hours of vaccination with negative results 
received prior to vaccination. Persons who have undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy 
testing. 
7 At an early termination visit for a withdrawn or terminated participant who is not HIV-infected (see Section 9.11), blood should be drawn for HIV diagnostic testing, as shown for 
visit 5 above. If a participant has a confirmed diagnosis of HIV infection, do not collect blood for HIV diagnostic testing (see Section 9.13). 
8 For participants with confirmed diagnosis of HIV infection, only specimens required for protocol-specified safety laboratory tests, urinalysis and pregnancy tests will be collected. 
9 And microscopy if needed. 
10 Specimens indicated for Day 0 (except the pregnancy test) may be obtained within the 14 days prior to vaccination. 
11Clinic visit is not required for AESI Health Contact except for conditions specified in Protocol Section 9.5.1. 
 

HVTN 139, Version 1.0 / February 23, 2021 
HVTN139_v1.0_FINAL / Page 175 of 186 
Appendix H 
Laboratory procedures Part B 
Visit
1
211
3
4
5
6
7
8
9
10
AESI10
Day
D0
D14
D28
D84
D98
D112
D168
D182
D364
D546
Week
W0
W2
W4
W12
W14
W16
W24
W26
W52
W78
Month
M0
M0.5
M1
M3
M3.5
M4
M6
M6.5
M12
M18
AdC6HIVgp140 OR 
AdC7HIVgp140 OR  
Placebo
AdC7HIVgp140 OR 
AdC6HIVgp140 OR 
Placebo
CH505TF gp120/ 
GLA-SE OR
Placebo
Procedure
Send to1,2
Assay location2
Tube 
Type4
Tube size          
(vol. capacity)4
BLOOD COLLECTION
Screening/Diagnostic
HIV Screening test
Local lab
Local lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
5
HBsAg/anti-HCV
Local lab
Local lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
5
HIV diagnostics 7
HSML-NICD / UW-
VSL
HSML-NICD / UW-
VSL
EDTA
10mL
—
—
—
—
10
—
—
10
—
20
—
40
Safety labs8
CBC/ Diff/ platelets
Local lab
Local lab
EDTA
5mL
5
—
5
—
5
5
—
—
5
—
—
25
Chemistry panel5
Local lab
Local lab
SST
5mL
5
—
5
—
5
5
—
—
5
—
—
25
Immunogenicity & Virologic assays
Cellular assays
ICS
CSR
HVTN Labs
ACD
8.5mL
—
42.5
—
42.5
—
—
42.5
—
42.5
42.5
—
213
Ag-specific B-cell phenotyping
CSR
HVTN Labs
ACD
8.5mL
—
34
—
—
—
—
34
—
34
17
—
119
Humoral assays
Binding Ab Assay
CSR
HVTN Labs
SST
8.5mL
—
8.5
—
8.5
—
—
8.5
—
8.5
8.5
—
43
Neutralizing Ab Assay
CSR
HVTN Labs
SST
8.5mL
—
8.5
—
8.5
—
—
8.5
—
8.5
8.5
—
43
Fc-mediated antibody functions 12
CSR
HVTN Labs
SST
8.5mL
—
y
—
—
—
—
y
—
y
y
—
AdC6 and AdC7 Titer
AdC6 and AdC7 Neutralizing Ab Assay
CSR
Non-HVTN Labs
SST
8.5mL
—
8.5
—
8.5
—
—
8.5
—
—
—
—
26
Storage
PBMC
CSR
ACD
8.5mL
—
59.5
—
42.5
—
—
42.5
—
42.5
68
—
255
Serum
CSR
SST
8.5mL
—
25.5
—
17
—
—
17
—
17
17
—
94
Visit total
20
187
10
128
20
10
162
10
163
182
0
891
56-Day total
20
207
217
345
148
30
192
172
173
182
0
URINE COLLECTION8
Urine dipstick9
Local lab
Local lab
X
—
X
—
—
X
—
—
X
—
—
—
Pregnancy Test6
Local lab
Local lab
X
X
—
—
X
—
—
X
—
—
—
—
Screening 
visit3
Total
 
 
1 CSR = Central Specimen Repository; HSML-NICD = HIV Sero-Molecular Laboratory-National Institute for Communicable Diseases (Johannesburg, South Africa); UW-VSL = 
University of Washington Virology Specialty Laboratory (Seattle, Washington, USA) 
2 HVTN Laboratories include: Cape Town HVTN Immunology Laboratory (CHIL, Cape Town, Africa); South African Immunology Laboratory-National Institute for 
Communicable Diseases (SAIL-NICD, Johannesburg, South Africa); Fred Hutchinson Cancer Research Center (Seattle, Washington, USA); Duke University Medical Center 
(Durham, North Carolina, USA). 
Non-HVTN Laboratories include: Wistar Institute's Vaccine and Immunotherapy Center (Philadelphia, PA). 
3 Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination. 
4 Local labs may assign appropriate alternative tube types for locally performed tests. 

HVTN 139, Version 1.0 / February 23, 2021 
HVTN139_v1.0_FINAL / Page 176 of 186 
5 Chemistry panels are defined in Section 9.2 (pre-enrollment) and Section 9.4 (post-enrollment).  
6 For a participant who was assigned female sex at birth, pregnancy test must be performed on urine or blood specimens within 24 hours of vaccination with negative results 
received prior to vaccination. Persons who have undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy 
testing. 
7 At an early termination visit for a withdrawn or terminated participant who is not HIV-infected (see Section 9.11), blood should be drawn for HIV diagnostic testing, as shown for 
visit 10 above. If a participant has a confirmed diagnosis of HIV infection, do not collect blood for HIV diagnostic testing (see Section 9.13). 
8 For participants with confirmed diagnosis of HIV infection, only specimens required for protocol-specified safety laboratory tests, urinalysis, and pregnancy tests will be 
collected. 
9 And microscopy if needed. 
10 Clinic visit is not required for AESI Health Contact except for conditions specified in Protocol Section 9.5.1.  
11 Specimens indicated for Day 0 (except the pregnancy test) may be obtained within the 14 days prior to vaccination. 
12 Fc-mediated Ab functions may include ADCC, ADNP, ADCP, Fc-binding assays, and ICABA. 
y = SST blood collected for the Binding Ab and Neutralizing Ab assays and for storage will also cover specimen needs for the Fc-mediated antibody functions and antibody avidity 
assays; no separate blood draw is needed 
.

HVTN 139, Version 1.0 / February 23, 2021 
HVTN139_v1.0_FINAL / Page 177 of 186 
Appendix I 
Procedures at HVTN CRS for Part A  
 
 
 
Visit: 
011 
02 
03 
04 
05 
066 
076 
086 
Day: 
 
D0 
D14 
D28 
D168 
D364 
D728 
D1092 
Month: 
 
M0 
M0.5 
M1 
M6 
M12 
M24 
M36 
Procedure 
Scr. 
VAC 
 
 
 
 
 
 
Study procedures 
 
 
 
 
 
 
 
 
Screening consent (if used) 
✓ 
– 
– 
– 
– 
– 
– 
– 
Assessment of understanding 
✓ 
– 
– 
– 
– 
– 
– 
– 
Protocol consent 
✓ 
– 
– 
– 
– 
– 
– 
– 
Medical history 
✓ 
– 
– 
– 
– 
– 
– 
– 
Complete physical exam 
✓ 
– 
– 
– 
✓ 
– 
– 
– 
Contraception status assessment2 
✓ 
✓ 
✓ 
✓ 
– 
– 
– 
– 
Behavioral risk assessment3 
✓ 
– 
– 
– 
✓ 
– 
– 
– 
Risk reduction counseling4 
✓ 
✓ 
✓ 
✓ 
✓ 
– 
– 
– 
Confirm eligibility 
✓ 
– 
– 
– 
– 
– 
– 
– 
Obtain demographics 
✓ 
– 
– 
– 
– 
– 
– 
– 
Randomize 
✓ 
– 
– 
– 
– 
– 
– 
– 
Concomitant medications 
✓ 
✓ 
✓ 
✓ 
✓ 
– 
– 
– 
HIV infection assessment5 
✓ 
– 
– 
– 
✓ 
– 
– 
– 
Abbreviated physical exam 
– 
✓ 
✓ 
✓ 
– 
– 
– 
– 
Intercurrent illness/adverse experience 
– 
✓ 
✓ 
✓ 
✓ 
– 
– 
 
Social impact assessment 
– 
✓ 
✓ 
✓ 
✓ 
– 
– 
– 
Social impact assessment questionnaire 
– 
– 
– 
– 
✓ 
– 
– 
– 
Outside testing and belief questionnaire 
– 
– 
– 
– 
✓ 
– 
– 
– 
AESI Health Contact6 
– 
– 
– 
– 
– 
✓ 
– 
– 
Annual Health Contacts6  
– 
– 
– 
– 
– 
– 
✓ 
✓ 
Specimen collection7 
✓ 
✓ 
✓ 
✓ 
✓ 
– 
– 
– 
Vaccination procedures8 
 
 
 
 
 
 
 
 
Vaccination9 
– 
✓ 
– 
– 
– 
– 
– 
– 
Reactogenicity assessments10 
– 
✓ 
– 
– 
– 
– 
– 
– 
 Unblind participant11 
– 
– 
– 
– 
✓ 
– 
– 
– 

HVTN 139, Version 1.0 / February 23, 2021 
HVTN139_v1.0_FINAL / Page 178 of 186 
1 Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination. 
2 Contraception status assessment is required only for participants who were assigned female sex at birth and are capable of becoming pregnant. Persons who are confirmed 
pregnant, pregnancy testing is not required, unless clinically indicated. 
3 Not applicable to HIV-infected participants. Conduct before Risk Reduction Counseling if both occur at same visit. 
4 Includes transmission risk reduction counseling for HIV-infected participants. Conduct after BRA questionnaire if both occur at same visit. 
5 Includes pretest counseling and HIV testing. A subsequent follow-up contact is conducted to provide post-test counseling and to report results to participant. If a participant has a 
confirmed diagnosis of HIV infection, do not perform HIV infection assessment. 
6 Clinic visits are not required, except that any participant reporting a diagnosis of HIV infection will be asked to come to the clinic so that HIV status can be confirmed. Month 12 
is an AESI health contact, Month 24 and 36 are annual health contacts (see Sections 9.5.1 and 9.5.2).  
7 For specimen collection requirements, see Appendix G. For participants with a confirmed diagnosis of HIV infection, specimens listed under “Safety labs” in Appendix G, 
urinalysis, and urine pregnancy tests will be collected per the protocol schedule. 
8 Not applicable to HIV-infected participants. 
9 Blood draws required at vaccination visits must be performed prior to vaccination; however, it is not necessary to have results prior to vaccination, except for results of a urine or 
serum pregnancy test, if indicated. See Appendix G. 
10 Reactogenicity assessments performed daily for at least 7 days postvaccination (see Section 9.9). 
11 Unblinding will occur after the Month 6 visit when data are available; timing of unblinding may vary among participants. 
 

HVTN 139, Version 1.0 / February 23, 2021 
HVTN139_v1.0_FINAL / Page 179 of 186 
Appendix J 
Procedures at HVTN CRS for Part B  
Visit: 
011 
02 
03 
04 
05 
06 
07 
08 
09 
10 
116 
126 
136 
Day: 
 
D0 
D14 
D28 
D84 
D98 
D112 
D168 
D182 
D364 
D546 
D728 
D1092 
Month: 
 
M0 
M0.5 
M1 
M3 
M3.5 
M4 
M6 
M6.5 
M12 
M18 
M24 
M36 
Procedure 
Scr. 
VAC
1 
 
 
VAC
2 
 
 
VAC
3 
 
 
 
 
 
Study procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening consent (if used) 
✓ 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Assessment of understanding 
✓ 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Protocol consent 
✓ 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Medical history 
✓ 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Complete physical exam 
✓ 
– 
– 
– 
– 
– 
– 
– 
– 
✓ 
– 
– 
– 
Contraception status assessment2 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
– 
– 
– 
– 
Behavioral risk assessment3 
✓ 
– 
– 
– 
– 
– 
– 
– 
– 
✓ 
– 
– 
– 
Risk reduction counseling4 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
– 
– 
– 
Confirm eligibility 
✓ 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Obtain demographics 
✓ 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Randomize  
✓ 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Concomitant medications 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
– 
– 
– 
HIV infection assessment5 
✓ 
– 
– 
– 
✓ 
– 
– 
✓ 
– 
✓ 
– 
– 
– 
Abbreviated physical exam 
– 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
– 
– 
– 
– 
Intercurrent illness/adverse experience 
– 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
– 
– 
– 
Social impact assessment 
– 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
– 
– 
– 
Social impact assessment questionnaire 
– 
– 
– 
– 
✓ 
– 
– 
✓ 
– 
✓ 
– 
– 
– 
Outside testing and belief 
questionnaire 
– 
– 
– 
– 
– 
– 
– 
✓ 
– 
✓ 
– 
– 
– 
AESI Health Contact6 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
✓ 
– 
– 
Annual Health Contacts6 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
✓ 
✓ 
Specimen collection7 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
– 
– 
– 
Vaccination procedures8 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination9 
– 
✓ 
– 
– 
✓ 
– 
– 
✓ 
– 
– 
– 
– 
– 
Reactogenicity assessments10 
– 
✓ 
– 
– 
✓ 
– 
– 
✓ 
– 
– 
– 
– 
– 
Unblind participant11 
– 
– 
– 
– 
– 
– 
– 
– 
– 
✓ 
– 
– 
– 

HVTN 139, Version 1.0 / February 23, 2021 
HVTN139_v1.0_FINAL / Page 180 of 186 
1 Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination. 
2 Contraception status assessment is required only for participants who were assigned female sex at birth and are capable of becoming pregnant. Persons who are confirmed 
pregnant, pregnancy testing is not required, unless clinically indicated. 
3 Not applicable to HIV-infected participants. Conduct before Risk Reduction Counseling if both occur at same visit. 
4 Includes transmission risk reduction counseling for HIV-infected participants. Conduct after BRA questionnaire if both occur at same visit. 
5 Includes pretest counseling and HIV testing. A subsequent follow-up contact is conducted to provide post-test counseling and to report results to participant. If a participant has a 
confirmed diagnosis of HIV infection, do not perform HIV infection assessment. 
6 Clinic visits are not required, except that any participant reporting a diagnosis of HIV infection will be asked to come to the clinic so that HIV status can be confirmed (see 
Section 9.5.2). Month 18 is an AESI contact, Month 24 and 36 are annual health contacts (see Sections 9.5.1 and 9.5.2). 
7 For specimen collection requirements, see Appendix H. For participants with a confirmed diagnosis of HIV infection, specimens listed under “Safety labs” in Appendix H, 
urinalysis, and urine pregnancy tests will be collected per the protocol schedule. 
8 Not applicable to HIV-infected participants. 
9 Blood draws required at vaccination visits must be performed prior to vaccination; however, it is not necessary to have results prior to vaccination, except for results of a urine or 
serum pregnancy test, if indicated. See Appendix H. 
10 Reactogenicity assessments performed daily for at least 7 days postvaccination (see Section 9.9). 
11 Unblinding will occur after the Month 12 visit when data are available; timing of unblinding may vary among participants. 
 
 

HVTN 139, Version 1.0 / February 23, 2021 
HVTN139_v1.0_FINAL / Page 181 of 186 
Appendix K 
HVTN 139 Visit Windows for Part A 
 
Visit 
Number 
Visit Type 
Lower 
Allowable 
Window  
Lower Target 
Day 
Target 
Day 
Upper Target 
Day 
Upper Allowable 
Window  
01.0 
Screening 
-56 
- 
 
- 
- 
02.0 
Enrollment 
- 
- 
0 
- 
- 
03.0 
2 Weeks Post-Vaccination 
- 
-4 
14 
+4 
+7 
04.0 
Follow-up 
Primary Immunogenicity 
-10 
-4 
28 
+7 
+14 
05.0 
Follow-up 
-28 
-14 
168 
+14 
+28 
06.0 
AESI Contact 
- 
-85 
364 
+85 
- 
07.0 
Health Contact 
- 
-85 
728 
+85 
- 
08.0 
Health Contact 
- 
-85 
1092 
+85 
- 
Note: 
Target dates are relative to Day 0 (Enrollment). 
 

HVTN 139, Version 1.0 / February 23, 2021 
HVTN139_v1.0_FINAL / Page 182 of 186 
Appendix L 
HVTN 139 Visit Windows for Part B 
 
Visit 
Number 
Visit Type 
Lower 
Allowable 
Window  
Lower Target 
Day 
Target 
Day 
Upper Target 
Day 
Upper Allowable 
Window  
01.0 
Screening 
-56 
- 
 
- 
- 
02.0 
Enrollment 
- 
- 
0 
- 
- 
03.0 
2 Weeks Post-Vaccination 
- 
-4 
14 
+4 
+7 
04.0 
Follow-up 
Primary Immunogenicity 
-10 
-4 
28 
+7 
+14 
05.0 
Vaccination 2 
-21 
-14 
84 
+14 
+21 
06.0 
2 Weeks Post-Vaccination 
- 
-4 
98 
+4 
+7 
07.0 
Follow-up 
Primary Immunogenicity 
-10 
-4 
112 
+7 
+14 
08.0 
Vaccination 3 
-28 
-14 
168 
+14 
+28 
09.0 
2 Weeks Post-Vaccination 
Primary Immunogenicity 
- 
-4 
182 
+4 
+7 
10.0 
Follow-up 
-28 
-14 
364 
+14 
+28 
11.0 
AESI Contact 
- 
-84 
546 
+84 
- 
12.0 
Health Contact 
- 
-84 
728 
+84 
- 
13.0 
Health Contact 
- 
-84 
1092 
+84 
- 
Note: Target dates are relative to Day 0 (Enrollment), with the exception of visits 6.0 and 9.0, which are relative 
to the prior vaccination visit. 
 

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Appendix M 
HVTN low risk guidelines for Southern Africa 
 
For South African Volunteers on Pre-exposure prophylaxis 
(PrEP) 
1. PrEP ASSESSMENT 
• Reports equal to or greater than six consecutive months of protective PrEP use 
• Commits to maintaining protective PrEP use throughout trial 
• Participant reports equal to or greater than 70% when asked the following: 
“Thinking about the past 4 weeks, what percent of the time were you able to 
take all your PrEP medications?” 
2. SEXUAL BEHAVIORS 

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• Persons stably taking PrEP as prescribed above for 6 months or longer are 
considered low risk of HIV infection, regardless of any sexual behavior that 
might otherwise be associated with high risk of HIV exposure. 
3. NON-SEXUAL BEHAVIORS 
In the last 12 months did not: 
• Inject drugs or other substances without a prescription 
• Use cocaine, methamphetamine, or excessive alcohol, which in the 
investigator’s judgment, rendered the participant at greater than low risk for 
acquiring HIV infection. 
The investigator’s judgment should consider local epidemiologic information about 
HIV prevalence in the area and community networks. 
 

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Appendix N 
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 139 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 
• 
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 
 

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Appendix O 
Protocol Signature Page 
 
A phase 1 clinical trial to evaluate the safety and immunogenicity of HIV-1 
vaccines based on chimpanzee serotypes of adenovirus expressing clade C gp140 
and a CH505TF gp120 protein boost in healthy, HIV- uninfected adult 
participants 
I will conduct the study in accordance with the provisions of this protocol and all 
applicable protocol-related documents. I agree to conduct this study in 
compliance with United States (U.S.) 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(R2)); Institutional Review Board/Ethics Committee determinations; 
all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (eg, U.S. National Institutes of Health, Division of AIDS) 
and institutional policies. 
 
 
 
 
 
 
 
 
 
Investigator of Record Name (print) 
 
Investigator of Record Signature 
 
Date 
 
DAIDS Protocol Number: HVTN 139 
DAIDS Protocol Version: Version 1.0 
Protocol Date: February 23, 2021