A Phase 1 Clinical Trial to Evaluate the Safety and Immunogenicity of EnvSeq-1 and CH505 M5 gp120 Envs Adjuvanted With GLA-SE in Healthy, HIV-Uninfected Adult Participants
Phase: PHASE1
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
 
PROTOCOL 
HVTN 115 
A phase 1 clinical trial to evaluate the safety and 
immunogenicity of EnvSeq-1 Envs adjuvanted with 
GLA-SE, administered alone or with DNA Mosaic-
Tre env, in healthy, HIV-uninfected adult 
participants 
DAIDS DOCUMENT ID 12042 
BB IND TBD HELD BY DAIDS 
CLINICAL TRIAL SPONSORED BY 
Division of AIDS (DAIDS) 
National Institute of Allergy and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
Department of Health and Human Services (DHHS) 
Bethesda, Maryland, USA 
STUDY PRODUCT(S) PROVIDED BY 
DAIDS, NIAID, NIH, DHHS 
Bethesda, Maryland, USA 
Infectious Disease Research Institute (IDRI) 
Seattle, Washington, USA 
May 2, 2017 
Final 
HVTN 115, Version 1.0 

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Contents 
1 
Ethical considerations .............................................................................................. 5 
2 
IRB/EC review considerations ................................................................................. 7 
2.1 
Minimized risks to participants ..................................................................... 7 
2.2 
Reasonable risk/benefit balance .................................................................... 7 
2.3 
Equitable participant selection ....................................................................... 7 
2.4 
Appropriate informed consent ....................................................................... 8 
2.5 
Adequate safety monitoring ........................................................................... 8 
2.6 
Protect privacy/confidentiality ....................................................................... 8 
3 
Overview .................................................................................................................. 9 
3.1 
Protocol Team .............................................................................................. 13 
4 
Background ............................................................................................................ 14 
4.1 
Rationale for trial concept ........................................................................... 14 
4.2 
CH505 Sequential Env (EnvSeq-1) ............................................................. 20 
4.3 
DNA Mosaic-Tre env vaccine ..................................................................... 21 
4.4 
GLA-SE adjuvant ........................................................................................ 23 
4.5 
Trial design rationale ................................................................................... 23 
4.6 
Plans for future product development and testing ....................................... 25 
4.7 
Preclinical safety studies .............................................................................. 26 
4.8 
Preclinical immunogenicity studies ............................................................. 28 
4.9 
Clinical studies ............................................................................................ 34 
4.10 Potential risks of study products and administration ................................... 40 
5 
Objectives and endpoints ....................................................................................... 41 
5.1 
Primary objectives and endpoints Part A ..................................................... 41 
5.2 
Secondary objectives and endpoints Part A ................................................. 41 
5.3 
Exploratory objectives Part A ...................................................................... 42 
5.4 
Primary objectives and endpoints Part B ..................................................... 42 
5.5 
Secondary objectives and endpoints Part B ................................................. 43 
5.6 
Exploratory objectives Part B ...................................................................... 44 
6 
Statistical considerations ........................................................................................ 45 
6.1 
Accrual and sample size calculations .......................................................... 45 
6.2 
Randomization ............................................................................................. 48 
6.3 
Blinding ....................................................................................................... 48 
6.4 
Statistical analyses ....................................................................................... 49 
7 
Selection and withdrawal of participants ............................................................... 56 
7.1 
Inclusion criteria .......................................................................................... 56 
7.2 
Exclusion criteria ......................................................................................... 58 
7.3 
Participant departure from vaccination schedule or withdrawal .................. 61 
8 
Study product preparation and administration ....................................................... 64 
8.1 
Vaccine regimen .......................................................................................... 64 
8.2 
Study product formulation ........................................................................... 70 
8.3 
Preparation of study products ...................................................................... 71 
8.4 
Administration ............................................................................................. 74 
8.5 
Acquisition of study products ...................................................................... 75 
8.6 
Pharmacy records......................................................................................... 75 
8.7 
Final disposition of study products .............................................................. 75 
9 
Clinical procedures ................................................................................................ 76 

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9.1 
Informed consent ......................................................................................... 76 
9.2 
Pre-enrollment procedures for Parts A and B .............................................. 78 
9.3 
Enrollment and vaccination visits ................................................................ 79 
9.4 
Follow-up visits ........................................................................................... 80 
9.5 
Contact at 6 months after last scheduled visit .............................................. 82 
9.6 
Stool sample collection in Part B ................................................................. 82 
9.7 
HIV counseling and testing ......................................................................... 83 
9.8 
Contraception status..................................................................................... 84 
9.9 
Urinalysis ..................................................................................................... 84 
9.10 Assessments of reactogenicity ..................................................................... 85 
9.11 Visit windows and missed visits .................................................................. 86 
9.12 Early termination visit ................................................................................. 87 
9.13 Pregnancy .................................................................................................... 87 
10 
Laboratory .............................................................................................................. 88 
10.1 HVTN CRS laboratory procedures .............................................................. 88 
10.2 Total blood volume ...................................................................................... 88 
10.3 Primary immunogenicity timepoints ........................................................... 88 
10.4 Endpoint assays: cellular ............................................................................. 89 
10.5 Endpoint assays: humoral ............................................................................ 89 
10.6 Lab assay algorithm ..................................................................................... 90 
10.7 Exploratory studies ...................................................................................... 90 
10.8 Other use of stored specimens ..................................................................... 90 
10.9 Biohazard containment ................................................................................ 91 
11 
Safety monitoring and safety review ..................................................................... 92 
11.1 Safety monitoring and oversight .................................................................. 92 
11.2 Safety reporting ........................................................................................... 93 
11.3 Safety reviews .............................................................................................. 95 
11.4 Safety pause and prompt PSRT AE review ................................................. 96 
11.5 Review of cumulative safety data ................................................................ 97 
11.6 Study termination......................................................................................... 97 
12 
Protocol conduct .................................................................................................... 99 
12.1 Social impacts .............................................................................................. 99 
12.2 Compliance with NIH guidelines for research involving products containing 
recombinant or synthetic Nucleic Acid Molecules .................................... 100 
12.3 Emergency communication with study participants .................................. 100 
13 
Version history ..................................................................................................... 101 
14 
Document references (other than literature citations) .......................................... 102 
15 
Acronyms and abbreviations ................................................................................ 104 
16 
Literature cited ..................................................................................................... 106 
Appendix A Sample informed consent form for Part A ................................................. 113 
Appendix B Sample informed consent form for Part B ................................................. 129 
Appendix C Approved birth control methods (for sample informed consent form) ...... 146 
Appendix D Sample consent form for use of samples and information in other studies 147 
Appendix E Injection schedule for part A sample informed consent form.................... 151 
Appendix F Injection schedule for part B sample informed consent form .................... 152 

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Appendix G Table of procedures for Part A (for sample informed consent form) ........ 154 
Appendix H Table of procedures for Part B (for sample informed consent form) ........ 155 
Appendix I Laboratory procedures for Part A .............................................................. 156 
Appendix J Laboratory procedures for Part B .............................................................. 157 
Appendix K Procedures at HVTN CRS for Part A ........................................................ 158 
Appendix L Procedures at HVTN CRS for Part B ........................................................ 160 
Appendix M Adverse events of special interest .............................................................. 163 
 

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

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 
HVTN research aims to benefit local communities by directly addressing the health 
and HIV prevention needs of those communities and by strengthening the capacity of 
the communities through training, support, shared knowledge, and equipment. 
Researchers involved in HVTN trials are able to conduct other critical research in 
their local research settings. 
 
The HVTN values the role of in-country Institutional Review Boards (IRBs), Ethics 
Committees (ECs), and other Regulatory Entities (REs) as custodians responsible for 
ensuring the ethical conduct of research in each setting. 

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2 
IRB/EC review considerations 
US Food and Drug Administration (FDA) and other US federal regulations require 
IRBs/ECs/REs to ensure that certain requirements are satisfied on initial and continuing 
review of research (Title 45, Code of Federal Regulations (CFR), Part 46.111(a) 1-7; 21 
CFR 56.111(a) 1-7). The following section highlights how this protocol addresses each of 
these research requirements. Each HVTN Investigator welcomes IRB/EC/RE questions 
or concerns regarding these research requirements. 
2.1 
Minimized risks to participants 
45 CFR 46.111 (a) 1 and 21 CFR 56.111 (a) 1: Risks to subjects are minimized. 
This protocol minimizes risks to participants by (a) correctly and promptly informing 
participants about risks so that they can join in partnership with the researcher in 
recognizing and reporting harms; (b) respecting local/national blood draw limits; (c) 
performing direct observation of participants postvaccination and collecting information 
regarding side effects for several days postvaccination; (d) having staff properly trained 
in administering study procedures that may cause physical harm or psychological 
distress, such as blood draws, vaccinations, HIV testing and counseling and HIV risk 
reduction counseling; (e) providing HIV risk reduction counseling and checking on 
contraception use (for women); and (f) providing safety monitoring. 
2.2 
Reasonable risk/benefit balance 
45 CFR 46.111(a) 2 and 21 CFR 56.111(a) 2: Risks to subjects are reasonable in 
relation to anticipated benefits, if any, to subjects, and the importance of the 
knowledge that may reasonably be expected to result. 
In all public health research, the risk-benefit ratio may be difficult to assess because the 
benefits to a healthy participant are not as apparent as they would be in treatment 
protocols, where a study participant may be ill and may have exhausted all conventional 
treatment options. However, this protocol is designed to minimize the risks to participants 
while maximizing the potential value of the knowledge it is designed to generate.  
2.3 
Equitable participant selection 
45 CFR 46.111 (a) 3 and 21 CFR 56.111 (a) 3: Subject selection is equitable 
This protocol has specific inclusion and exclusion criteria for investigators to follow in 
admitting participants into the protocol. Participants are selected because of these criteria 
and not because of positions of vulnerability or privilege. Investigators are required to 
maintain screening and enrollment logs to document volunteers who screened into and 
out of the protocol and for what reasons. 

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2.4 
Appropriate informed consent 
45 CFR 46.111 (a) 4 & 5 and 21 CFR 56.111 (a) 4 & 5: Informed consent is sought 
from each prospective subject or the subject’s legally authorized representative as 
required by 45 CFR 46.116 and 21 CFR Part 50; informed consent is appropriately 
documented as required by 45 CFR 46.117 and 21 CFR 50.27 
The protocol specifies that informed consent must be obtained before any study 
procedures are initiated and assessed throughout the trial (see Section 9.1). Each site is 
provided training in informed consent by the HVTN as part of its entering the HVTN. 
The HVTN requires a signed consent document for documentation, in addition to chart 
notes or a consent checklist. 
2.5 
Adequate safety monitoring 
45 CFR 46.111 (a) 6 and 21 CFR 56.111 (a) 6: There is adequate provision for 
monitoring the data collected to ensure the safety of subjects. 
This protocol has extensive safety monitoring in place (see Section 11). Safety is 
monitored daily by HVTN Core and routinely by the HVTN 115 Protocol Safety Review 
Team (PSRT). In addition, the HVTN Safety Monitoring Board (SMB) periodically 
reviews study data. 
2.6 
Protect privacy/confidentiality 
45 CFR 46.111 (a) 7 and 21 CFR 56.111 (a) 7: There are adequate provisions to 
protect the privacy of subjects and maintain the confidentiality of data. 
Privacy refers to an individual’s right to be free from unauthorized or unreasonable 
intrusion into his/her private life and the right to control access to individually 
identifiable information about him/her. The term “privacy” concerns research participants 
or potential research participants as individuals whereas the term “confidentiality” is used 
to refer to the treatment of information about those individuals. This protocol respects the 
privacy of participants by informing them about who will have access to their personal 
information and study data (see Appendix A and Appendix B). The privacy of 
participants is protected by assigning unique identifiers in place of the participant’s name 
on study data and specimens. In the United States, research participants in HVTN 
protocols are protected by a Certificate of Confidentiality from the US NIH, which can 
prevent disclosure of study participation even when that information is requested by 
subpoena. Participants are told of the use and limits of the certificate in the study consent 
form. In addition, each staff member at each study site in this protocol signs an 
Agreement on Confidentiality and Use of Data and Specimens with the HVTN and each 
study site participating in the protocol is required to have a standard operating procedure 
on how the staff members will protect the confidentiality of study participants. 
 

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3 
Overview 
Title  
A phase 1 clinical trial to evaluate the safety and immunogenicity of EnvSeq-1 Envs 
adjuvanted with GLA-SE, administered alone or with DNA Mosaic-Tre env, in healthy, 
HIV-uninfected adult participants 
Primary objectives Part A 
 
To evaluate the safety and tolerability of different doses of CH505TF Env gp120 
in HIV-uninfected healthy adults 
 
To evaluate binding antibody responses elicited by different doses of the 
CH505TF gp120 vaccine 
Primary objectives Part B 
 
To evaluate the safety and tolerability of EnvSeq-1 vaccines administered with or 
without DNA Mosaic-Tre env in HIV-uninfected healthy adults 
 
To evaluate and compare vaccine-induced humoral responses elicited by 
EnvSeq-1 vaccines administered in sequential and additive protein 
immunizations, with and without DNA 
Study products and routes of administration 
 
CH505TF HIV gp120 transmitted/founder with GLA-SE SE (glucopyranosyl lipid 
adjuvant-stable emulsion (synthetic lipid A derivative mixed with squalene oil) 
 
CH505w53 HIV gp120 with GLA-SE 
 
CH505w78 HIV gp120 with GLA-SE 
 
CH505w100 HIV gp120 with GLA-SE 
 
(EnvSeq-1 refers to the 4 component gp120 vaccine including CH505TF, w53, w78, 
and w100 HIV gp120s) 
 
DNA Mosaic-Tre env: trivalent vaccine composed of mosaic HV13284, HV13285 
and HV13286 plasmids that are designed for global HIV-1 T-cell response coverage. 
All express gp160 Env protein. 
 
Placebo: Sodium Chloride for Injection, 0.9% USP 
 
All administrations will be intramuscular (IM) injections 

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Table 3-1 Schema 
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) 
 
 
 
 
 
 
 
 
 
 
 
 
Study arm 
N 
Month 0 
(Day 0) 
Month 2 
(Day 56) 
Month 4 
(Day 112) 
Month 8 
(Day 224) 
Month 12 
(Day 364) 
Month 16  
(Day 485) 
Part B 
 
 
 
 
 
 
 
Group 5 
20 
TBD mcg  
CH505TF 
+ placebo 
TBD mcg 
CH505w53 
+ placebo 
TBD mcg  
CH505w78 
+ placebo 
TBD mcg 
 CH505w100 
+ placebo 
TBD mcg 
CH505w100 
+ placebo 
TBD mcg 
 CH505w100 
+ placebo 
 
 
 
 
 
 
 
 
Group 6 
20 
TBD mcg 
CH505TF + 
4 mg 
DNA 
Mosaic-Tre 
TBD mcg 
CH505w53 
+ 4 mg 
DNA 
Mosaic-Tre 
TBD mcg 
CH505w78  
+ 4 mg 
DNA 
Mosaic-Tre 
TBD mcg 
CH505w100 
+ 4 mg 
DNA Mosaic-
Tre 
TBD mcg 
CH505w100 
+ 4 mg 
DNA 
Mosaic-Tre 
TBD mcg 
CH505w100 
+ 4 mg 
DNA Mosaic-
Tre 
 
 
 
 
 
 
 
 
Group 7 
20 
TBD mcg 
CH505TF + 
placebo 
TBD mcg 
CH505TF, 
w53 
+ placebo 
TBD mcg 
CH505TF, 
w53, w78 
+ placebo 
TBD mcg 
CH505w53, 
w78, w100 
+ placebo 
TBD mcg 
CH505w78, 
w100 
+ placebo 
TBD mcg 
CH505w100 
+ placebo 
 
 
 
 
 
 
 
 
Group 8 
20 
TBD mcg 
CH505TF 
 + 4 mg 
DNA 
Mosaic-Tre 
TBD mcg 
CH505TF, 
w53 
+ 4 mg 
DNA 
Mosaic-Tre 
TBD mcg 
CH505TF, 
w53, w78 
+ 4 mg 
DNA 
Mosaic-Tre 
TBD mcg 
CH505w53, 
w78, w100 
+ 4 mg 
DNA 
Mosaic-Tre 
TBD mcg 
CH505w78, 
w100 
+ 4 mg 
DNA 
Mosaic-Tre 
TBD mcg 
CH505w100 
+ 4 mg 
DNA 
Mosaic-Tre 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Group 9 
10 
placebo 
+ placebo 
placebo 
+ placebo 
placebo 
+ placebo 
placebo 
+ placebo 
placebo 
+ placebo 
placebo 
+ placebo 
 
 
 
 
 
 
 
 
Total Part B 
90 
(80/10) 
 
 
 
 
 
 
Total Part A 
+ Part B 
132 
(116/16) 
 
 
 
 
 
 
Safety data and immune responses after Month 4 in Part A will inform the protein dose for Part B. 
GLA-SE will be admixed with all proteins. The total dose of GLA-SE will be 10 mcg at all 
timepoints. The total volume for protein plus adjuvant for injection is 1 mL, mixed 1:1 by volume. 

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If the dose of each protein in Groups 5 and 6 is 20 mcg, the total dose of each protein in Groups 7 and 
8 will also be 20 mcg. If the dose of each protein in Groups 5 and 6 is 100 mcg or 400 mcg, the dose 
of each protein in Groups 7 and 8 will be 100 mcg. 
All injections will be administered IM in the thigh. Part A injections will consist of 1 mL injections 
administered by needle and syringe. Part B injections will consist of 1 mL of protein or placebo 
administered by needle and syringe and 1 mL of DNA or placebo administered by Biojector 2000® 
Needle-Free Injection Management System™ (Biojector 2000®) into the same thigh. When 
necessary, the total protein volume will be supplemented with Sodium Chloride for Injection, 0.9% 
USP, at the time of mixing to make the total volume of injection 1 mL. 
Participants 
132 healthy, HIV-1–uninfected volunteers aged 18 to 50 years; In Part A, 36 vaccinees, 
6 placebo recipients; in Part B, 80 vaccinees, 10 placebo recipients 
Design 
Multicenter, randomized, placebo-controlled, double-blind trial 
Duration per participant 
Part A: 18 months of scheduled clinic visits (main study) followed by a health contact at 
month 24 
Part B: 22 months of scheduled clinic visits (main study) followed by a health contact at 
month 28 
Estimated total study duration 
48 months (includes enrollment, planned safety and immunogenicity holds, in-clinic 
follow-up, and health contact) 
Investigational New Drug (IND) sponsor 
DAIDS, NIAID, NIH, DHHS (Bethesda, Maryland, USA) 
Study product providers 
 
EnvSeq-1 (CH505TF, w53, w78, and w100) HIV gp120s: DAIDS, NIAID, NIH, 
DHHS (Bethesda, Maryland, USA) 
 
DNA Mosaic-Tre env trivalent vaccine: DAIDS, NIAID, NIH, DHHS (Bethesda, 
Maryland, USA) 
 
GLA-SE adjuvant: Infectious Disease Research Institute (IDRI) (Seattle, 
Washington, USA) 
Core operations 
HVTN Vaccine Leadership Group/Core Operations Center, Fred Hutchinson Cancer 
Research Center (FHCRC) (Seattle, Washington, USA) 

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Statistical and data management center (SDMC) 
Statistical Center for HIV/AIDS Research and Prevention (SCHARP), FHCRC (Seattle, 
Washington, USA) 
HIV diagnostic laboratory 
University of Washington Virology Specialty Laboratory (UW-VSL) (Seattle, 
Washington, USA) 
Endpoint assay laboratories 
 
Duke University Medical Center (Durham, North Carolina, USA) 
 
FHCRC/University of Washington (Seattle, Washington, USA) 
Study sites 
HVTN Clinical Research Sites (HVTN CRSs) to be specified in the Site Announcement 
Memo 
Safety monitoring 
HVTN 115 PSRT; HVTN Safety Monitoring Board (SMB) 

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3.1 
Protocol Team 
Protocol leadership 
Chair 
Magda Sobieszczyk 
Columbia University 
212-305-7185 
mes52@cumc.columbia.edu 
Statistician 
Paul Edlefsen 
SCHARP, FHCRC 
206-667-4086 
pedlefsen@gmail.com 
Co-chair 
James Kobie 
URMC-Rochester 
585-275-6632 
james_kobie@urmc.rochester.edu 
Medical officer 
Julia Hutter 
DAIDS, NIAID 
240-627-3039 
julia.hutter@nih.gov 
Protocol 
Team leader 
Cecilia Morgan 
HVTN Core, FHCRC 
206-667-5875 
cmorgan@fredhutch.org 
Laboratory lead 
David Montefiori 
Duke University 
919-684-5278 
monte@duke.edu 
Other contributors to the original protocol 
Core medical monitor 
Phillip Mann 
HVTN Core, 
FHCRC 
Clinical safety 
specialist 
Jill Zeller 
HVTN Core, 
FHCRC 
Vaccine developer 
representative 
Barton Haynes 
Duke University 
Clinical trials 
manager 
Charlie Gregor 
HVTN Core, 
FHCRC 
 
Zachary Sagawa 
IDRI 
Project manager 
Andrew Sigman 
SCHARP, FHCRC 
Laboratory Program 
representative 
Georgia Tomaras 
Duke University 
SCHARP Protocol 
operations manager 
Gina Escamilla 
SCHARP, FHCRC 
 
On Ho 
HVTN Laboratory 
Program, FHCRC 
DAIDS Project Officer 
Chris Butler 
DAIDS, NIAID 
Regulatory affairs 
Laurie Rinn 
HVTN Core, 
FHCRC 
Clinic coordinator 
Brett Gray 
Columbia 
DAIDS protocol 
pharmacist 
Oladapo Alli 
DAIDS, NIAID 
240-627-3593 
Protocol development 
manager 
Ramey Fair 
HVTN Core, 
FHCRC 
Community Advisory 
Board (CAB) 
members 
Ramil Sapinoro 
Rochester CAB 
Community 
engagement unit 
representative 
Jim Maynard  
HVTN Core, 
FHCRC 
 
Jonathan Kimble 
New York City CAB 
Community 
educator/recruiter 
Jorge Benitez 
Columbia CRS 
Statistical research 
associate 
Chenchen Yu 
SCHARP, FHCRC 
Technical editor 
Erik Schwab 
HVTN Core, 
FHCRC 
 
 
 
 
 

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4 
Background 
4.1 
Rationale for trial concept 
One of the major obstacles to developing an efficacious preventive HIV-1 vaccine is the 
challenge of inducing broadly neutralizing antibodies (bnAbs) against the virus. There are 
several reasons why eliciting bnAbs has been challenging and these include the 
conformational structure of the viral envelope, molecular mimicry of host antigens by 
conserved epitopes which may lead to the suppression of potentially useful antibody 
responses, and the high level of somatic mutations in the variable domains and the 
requirement for complex maturation pathways [4-6]. It has been shown that 
approximately 15% of HIV-1 – infected individuals develop high levels of very bnAbs 
that are detected 2-4 years after infection. To date, all bnAbs have 1 or more of these 
unusual antibody traits: high levels of somatic mutation, autoreactivity with host 
antigens, and long heavy chain third complementarity determining regions (HCDR3s)—
all traits that are controlled or modified by host immunoregulatory mechanisms. Thus, the 
hypothesis has been put forth that typical vaccinations of single invariant immunogen 
primes and boosts will not suffice to be able to induce bnAbs; rather, it will take 
sequential immunizations with different Env immunogens, perhaps over a prolonged 
period of time, to mimic the bnAb induction that occurs in chronically infected 
individuals [7]. 
The B-cell lineage immunogen design tested in this trial is a process to give the bnAb 
lineages that are typically subdominant in infected patients a survival advantage  wherein 
sequential Env immunogens are chosen that have high affinities for the B cell receptors 
of the unmutated common ancestor (UCA) or germline gene of the bnAb clonal lineage 
(see Figure 4-1) [8]. Envs for immunization can either be selected for binding or derived 
from the evolutionary pathways of Envs that actually give rise to bnAbs in vivo. Liao and 
colleagues, using serum samples of HIV-infected individuals collected over time under 
the CHAVI-ID program, recently described the co-evolution of HIV-1 and a CD4-
binding site (CD4bs) bnAb from the time of seroconversion to the development of 
plasma bnAb induction, thereby presenting an opportunity to map out the pathways that 
lead to generation of this type of CD4bs bnAb (see Figure 4-2) [9].  

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Figure 4-1. Steps of a B-cell-lineage-based approach to vaccine design 
 
 
Figure 4-2. Schema of co-evolution of HIV-1 and broadly neutralizing antibodies in HIV-1–
infected individuals. Most HIV-I infected individuals make either no or low levels of plasma 
broadly neutralizing antibodies, while ~15% of HIV-1–infected individuals will eventually make high 
levels of very broadly neutralizing plasma antibodies. The goal of this protocol is attempt to 
recreate this process by sequential Env vaccination. 

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This study demonstrated that the single transmitted/founder virus was able to bind to the 
bnAb UCA, and identified a series of evolved envelope proteins of the founder virus that 
were likely stimulators of the bnAb lineage. Analysis of the frequency of the B cell 
immunoglobulin gene variable-diversity-joining gene segment (VDJ) recombinations that 
occurred in this B cell lineage (the VH4-59, Vλ3-1, CH103 CD4bs bnAb lineage) through 
collaborative studies of Bart Haynes and Tom Kepler (Boston University) has revealed 
that we can expect similar germline precursors in most vaccinated individuals. 
Specifically, the analysis found these precursors in 9/9 individuals tested by next 
generation sequencing. Thus, this work presents the HVTN with an opportunity to 
vaccinate with naturally derived viral envelopes that could drive the desired B-cell 
responses and induce the development of broad and potent neutralizing antibodies. While 
the human antibody repertoire is diverse, it has been found that only a few types of B-cell 
lineages can lead to bnAb development, and that these lineages are similar across a 
number of individuals [10,11]. Thus, it is feasible that use of Envs from 1 individual will 
generalize to others. 
The approach in this study to address the challenge of eliciting bnAbs involves recreating 
the Env immunogens that induced a CD4bs bnAb clonal lineage in an HIV-infected 
individual, by making sequential recombinant Envs from that individual and using these 
Envs for vaccination. The B-cell lineage vaccine strategy thus includes designing 
immunogens based on unmutated ancestors as well as intermediate ancestors of known 
bnAb lineages. A candidate vaccine could use transmitted/founder virus envelopes to, at 
first, stimulate the beginning stages of a bnAb lineage, and subsequently boost with 
evolved Env variants to recapitulate the high level of somatic mutation needed for 
affinity maturation and bnAb activity. The goal of such a strategy is to selectively drive 
desired bnAb pathways. 
4.1.1 
B-cell lineage immunogen design 
Over the past 5 years the HIV vaccine development field has realized that immunization 
with a single HIV envelope protein is not going to be successful for induction of broadly 
neutralizing antibodies [4]. Moreover, the biology of bnAbs has also become 
considerably clearer, with the evidence for a role of the host immune tolerance control 
mechanisms in limiting the induction of bnAbs (reviewed in [4,12]). While the role of the 
structure of the Env immunogens is undoubtedly important, ie, the Env must contain 
sufficiently native bnAb epitopes to bind in nM affinities to the unmutated common 
ancestor (naïve B cell receptors) of bnAb lineages [7,13], it is as yet unknown whether a 
native trimer is needed for this purpose or if a highly antigenic Env subunit will suffice. 
Studies in mice in basic B cell biology have demonstrated, however, that what is 
important for B cell survival in the germinal center (GC) is the affinity of the immunogen 
for the GC B cell receptor [14,15]. 
Thus, the Haynes group has proposed the concept of B cell lineage immunogen design, 
whereby lineages of bnAbs are elucidated, and Envs are chosen for sequential 
immunizations based on optimized affinity of Env immunogens for B-cell receptor 
(BCR) at sequential steps of the affinity maturation pathway of bnAb lineages (see Figure 
4-1) [7]. While Envs have been designed for reacting with UCAs of heterologous bnAb 
lineages [13,16], in order to take the guessing out of Env selection, Haynes et al. have 
taken the approach of defining in select HIV-infected individuals, who make bnAbs, the 
natural sequence of Envs that in that individual induced the bnAb lineage. Thus, from the 
HIV-infected African individual CH505, both sequential Envs and bnAbs were isolated 
over time and the co-evolution of the CH103 CD4 binding site bnAb lineage was mapped 

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(see Figure 4-2)[9]. The Haynes group first screened thirty CH505 Env mutants, and of 
this group 4 candidates were found that reacted with the UCA, intermediate antibodies, 
and mature antibodies of the CH103 bnAb lineage. The proteins that optimally reacted 
with each step of the CH103 lineage were the transmitted/founder (TF) Env, the week 
53.16 Env, the week 78.33 Env, and the week 100.B6 Env. In surface plasmon resonance 
(SPR) assays, the TF Env gp120 reacted with the UCA of the CH103 lineage with a KD 
of ~200 nM. 
4.1.2 
Rationale for this study 
This proposed study represents an important step to learning how to induce bnAbs in a 
vaccine recipient, by using a strategy of immunization to attempt to recreate the natural 
evolution of Env that promotes CD4 binding site-specific antibody evolution. This is the 
first time this concept will be studied in humans, and it will be undertaken in a stepwise 
approach. The vaccine is called the CH505 sequential envelope vaccine or the EnvSeq-1 
vaccine. It is made up of 4 Env gp120 components, the transmitted/founder (TF) gp120 
Env (CH505TF), the CH505 week 53 gp120 Env (CH505w53), the week 78 gp120 Env 
(CH505w78) and the week 100 gp120 Env (CH505w100). Gp120 forms of Env were 
chosen because a) the efficiency of immunization is related to binding affinity to B cell 
receptors of responding B cells [14,15], b) the gp120 forms bound with nM affinity to the 
unmutated ancestor antibody of the bnAb lineage and as well bound with nM affinities to 
other bnAb lineage intermediates, and c) it was desirable to leave out gp41 so as not to 
divert the immune response to non-neutralizing gp41 determinants. 
The first step in the clinical trial is a dose-ranging study that will evaluate the induced 
antibodies to determine if the early stages of bnAb lineage can be stimulated with TF 
virus envelope (Part A of this proposal). This will be followed by a second part (Part B) 
that will assess boosting of CH505TF gp120 with evolved Env variants (CH505w53, 
w78, and w100) in order to attempt to recreate the Env diversity observed during in vivo 
affinity maturation in the CH505 individual. The second part of the study will also 
incorporate administration of a DNA with mosaic env insert together with the CH505 
EnvSeq-1 variants. The rationale for this strategy is to provide T-cell help from 
heterologous Envs using the mosaic Envs designed to overcome virus diversity and to 
provide “universal CD4 T-cell help” (see Section 4.1.3 on Rationale for DNA Mosaic-
Tre env as a universal helper immunogen) [17-19]. Our overall aim is to trigger the 
desired CD4 binding site bnAb lineage. We hypothesize that this can be accomplished in 
a clinical study, given the nonhuman primate (NHP) data (see Section 4.8 on Preclinical 
immunogenicity studies) demonstrating that it is possible to initiate the CH103-like CD4 
binding site lineage in rhesus macaques. 
The overarching aims of the proposed trial are to determine the safety and 
immunogenicity of CH505 EnvSeq-1 vaccine administered in combination with the 
GLA-SE adjuvant. The specific aim of Part A of the study is to make a rational choice for 
the optimal dose of gp120 Env protein that will be used in the other groups. The dose-
ranging study of this vaccine product with GLA-SE in NHP (NHP 106; see Section 4.8.1 
on Preclinical immunogenicity studies) demonstrated that after the second injection there 
was clearly a hierarchy of doses with respect to inducing Env binding as well as 
neutralizing antibodies and thus, the first part of this study will be a critical first step 
leading to the selection of a protein dose in humans and to Part B of the trial. The other 
important aspect of Part A is to evaluate the immunogenicity of CH505TF gp120 and 
compare to responses induced with the different combinations of the 4 Env mutant 
proteins in order to assess whether Env mutants, and not just CH505TF gp120 alone, are 

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needed to induce the desired lineage. The second part of the study will allow us to focus 
in on the essence of the concept of how to induce the desired bnAb pathways. And thus, 
the aims of the second part of the strategy (Part B) will be to assess the ability of the 
CH505 gp120 EnvSeq-1 mutant variants to induce CD4-binding site bnAb lineages. The 
EnvSeq-1 proteins will be administered either by combining the proteins with an additive 
approach with overlapping exposure to antigens (mimicking the coexistence of antigens 
in the environment in which they evolved naturally) and in a sequential immunization 
approach with each of the proteins administered separately in the order in which they 
evolved. An important secondary objective will be to explore the repertoire of B cell 
responses and isolate clones of the desired bnAb lineage. 
Exploratory objectives proposed for this study will investigate the correlation between B-
cell responses to the gp120 Env variants and the diversity of responses to the antigens 
present in gut flora. The role of the gut microbiome on the maturation of the immune 
system and the pathogenesis of chronic HIV infection has been well described [20-22] 
and there are emerging data about the role of gut microbiome in shaping the initial 
response to HIV. It has been shown, for example, that the initial antibody response to 
HIV infection is directed against gp41 and does not control early viremia [23]. Previous 
work demonstrated that immunization with DNA prime, rAd5 boost HIV-1 vaccine 
regimen selectively recruited a dominant gp41 memory B-cell response that was cross 
reactive with intestinal commensal-bacterial antigens [24]. Specific composition of the 
microbiota is thus an important factor influencing the host immune system and individual 
differences in the human microbiome can modulate vaccine-induced responses. This 
proposal will explore further how immune responses to this vaccine correlate with gut 
flora responses and whether the composition of gut microbiota in a vaccine recipient 
selects for cross-reactive responses similar to what has been previously noted. 
4.1.3 
Rationale for DNA Mosaic-Tre env as a universal helper immunogen 
It is known that considerable T-cell help is required for the amount of affinity maturation 
needed to drive bnAbs and that those individuals chronically infected with HIV who 
spontaneously make bnAbs have higher levels of blood CD4 T cells that are 
phenotypically similar to T follicular helper T cells (Tfh) [25]. Previous work in non-
human primates suggested that including a DNA vaccine with the protein can increase 
the quantity and quality of the induced antibody response compared to immunization with 
protein alone [26,27]. Furthermore co-administration of DNA and protein in the same 
limb elicited higher systemic binding and neutralizing antibodies compared to DNA 
alone or DNA prime followed by an antibody boost [26]. Pavlakis and colleagues 
illustrated the potential immunologic advantages of co-administration of protein with 
DNA in non-human primate studies whereby the animals that received DNA vaccine 
(either alone or co-administered with a protein) had higher levels of vaccine-induced T-
cell responses. Moreover, the group that received DNA concurrently with protein had 
higher binding Ab responses than DNA or protein alone [28,29]. Pissani, et al. also 
showed in rabbits that DNA and protein co-administration increased the magnitude, 
avidity, and neutralizing potency compared to administration of protein alone. In 
addition, their study indicated that antibody responses using a mismatched DNA and 
protein elicited comparable or higher responses compared to matched vaccines [27]. 
These data support inclusion of a DNA vaccine in the regimen to assess and compare 
binding antibody responses and differential binding induced by immunization with and 
without the DNA. We hypothesize that the combined administration of DNA and protein 
will elicit stronger humoral and cellular responses than the protein alone. 

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Previous work demonstrated that immunization with a DNA prime/rAd5 boost HIV-1 
vaccine regimen induced a non-neutralizing dominant Env gp41-reactive Ab response 
directed to non-neutralizing epitopes [24]. Although the DNA Mosaic-Tre vaccine in this 
protocol contains gp41 epitopes, a couple of key characteristics distinguish it from the 
DNA vaccine made by the Vaccine Research Center (VRC) which may result in a 
different quality of responses: 1) the mosaic gp160 DNA (DNA Mosaic-Tre) vaccine has 
been optimized for T cell diversity and CD4 (as well as CD8) epitopes; and 2) it is 
expected that this DNA gp160s product will form more native Env trimers compared to 
the VRC gp140 CFI misfolded proteins used in the DNA/rAd5 regimen. Importantly, 
current design of Part B will permit comparison of the immune responses induced by the 
protein + DNA Mosaic-Tre (Groups 6 and 8) vs. protein alone (Groups 5 and 7) to 
evaluate the effect of gp41 and whether or not co-administration of DNA results in 
diverting the immune response to non-neutralizing gp41 determinants. 
Therefore, in this study we will evaluate and compare the immunogenicity of the CH505 
gp120 proteins in sequential and additive immunization regimens administered with or 
without the DNA Mosaic-Tre env vaccine. 
4.1.4 
Rationale for GLA-SE adjuvant 
The EnvSeq-1 proteins will be formulated in the GLA-SE adjuvant that has been used 
extensively in human phase 1 trials for influenza and leishmaniasis vaccines [30,31]. 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). And importantly, when administered with CH505TF gp120 in guinea 
pigs and NHP studies, the GLA-SE adjuvant has been shown to be a potent adjuvant in 
induction of binding and neutralizing antibodies [B. Haynes, unpublished]. In the guinea 
pig study, GLA-SE adjuvant was necessary for optimal immune responses to gp120 at all 
doses (Figure 4-3). The 10 mcg dose in this clinical trial was selected based upon the 
preclinical record of safety and immunogenicity of the CH505 gp120 + GLA-SE vaccine 
in guinea pigs and rhesus macaques, and the established safety profile of the GLA-SE 
adjuvant in human clinical trials. 

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Figure 4-3. A dose study of both GLA-SE (0 to 25 mcg per immunization) and 1-50 mcg per 
immunization of CH505 gp120 IM was performed with 4 guinea pigs per group. Data show 
that for each dose of gp120, the response to the unadjuvanted protein was lower than the 
adjuvanted. Thus, the adjuvant is required for optimal response to gp120. 
4.2 
CH505 Sequential Env (EnvSeq-1) 
The 4 individual EnvSeq-1 vaccine Envs used in this study are called CH505TF, 
CH505w53, CH505w78, and CH505w100 and were chosen based on their binding 
affinity in assays such as shown in Figure 4-4, which demonstrates the binding of the 
CH103 lineage versus a panel of recombinantly expressed sequential Envs. 

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Figure 4-4. Binding of CH103 lineage antibodies to autologous CH505 Envs. Choice of 
transmitted/founder and week 53, 78, and 100 CH505 Envs by binding EC50 levels to recombinant 
sequential CH505 Envs. Data are in EC50 binding levels in ELISA. (Red shading highlights the 
selected antigens and the antibodies they bind to.) 
The EnvSeq-1 immunogen is composed of 4 recombinant protein Env gp120s, each with 
an N-terminal deletion to facilitate production by decreasing protein dimer formation and 
increasing production yield [32]. The individual components of the immunogen are the 
transmitted/founder CH505 Env (called CH505TF), the week 53 CH505 Env (called 
CH505w53), the week 78 CH505 Env (called CH505w78), and the week 100 CH505 Env 
(called CH505w100). They are all derived from the African clade C transmitted founder 
virus CH505 as described by Liao and colleagues [9]. 
4.3 
DNA Mosaic-Tre env vaccine 
This is a trivalent mosaic vaccine, Mosaic-Tre env, composed of mosaic HV13284, 
HV13285 and HV13286 envs that optimize global coverage. The individual Env 
components are termed TCM3.1 (plasmid name HV13284), TCM3.2 (plasmid name 
HV13285) and TCM3.3 (plasmid name HV13286). The mosaic immunogens are 
designed by in silico homologous recombinations to result in 3 env genes that a) have 
natural joining sites for CD4 and CD8 T cell epitopes, and b) provide the most extensive 
coverage of all the isolates possible in the Los Alamos HIV Sequence Database. Figure 
4-5 shows the comparison of the coverage predicted for the Mosaic-Tre env versus the 
coverage with group M consensus CON-S env and a wild-type env B.1059. Figure 4-6 
shows Mosaic-Tre env coverage for 9-mer coverage (CD8 cells) and 12-mer coverage 
(CD4 cells). The Mosaic-Tre env, optimized for 9-mers, is composed of 3 mosaic gp160s 
with transmembrane and cytoplasmic domain regions, and are encoded in the VRC8400 
plasmid. 

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Figure 4-5. Average coverage of 9-mers in the Los Alamos database by different HIV-1 Env 
vaccine antigens used in this study. The red bar indicates the fraction of 9-mers that were 
perfectly matched by a 9-mer included in the vaccine, the orange adds on the frequency of 9-mers 
with an 8 of 9 match, and the yellow a match of 7 of 9. This plot is alignment independent, based 
on splintering all M group proteins, 1 sequence per person, into all possible 9-mers, attending to 
their frequencies, and then calculating the frequency of matches and near matches in the full data 
base to each vaccine antigen or protein cocktail. Each vaccine is summarized 4 ways. The “total” 
represents all sequences in the database alignment at the time these sequences were designed 
(2008). The “B” is just the subset that are B clade, “C” the subset that are C clade, and “Other” are 
the remaining M group sequences that are not B or C clade (all other clades and recombinants). 
Mosaics were optimized such that they maximized the red bar on the left, the exact matches in full, 
or total, dataset, but they provide excellent coverage of B clade, C clade, and other sequences. 
The best single natural TF virus, B.1059, was also selected to maximize the number of exact 
matches in the full database, given the constraints of selecting form among TF viruses and using a 
natural sequence. The single best natural is of course a B Env, as B clade dominates the data 
base, and thus the B clade has the best coverage for B.1059, with C and other having markedly 
reduced coverage. Con S, as expected, provides much more even coverage for all clades. 
 

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Figure 4-6. Comparison of the coverage of the 9-mers and 12-mers in the Los Alamos 
database using 9-mer and 12-mer optimized mosaics. The mosaic algorithm [17] requires the 
use of a string of specified length for optimization, and we typically use 9-mers, as that is the most 
common size of CD8+ T-cells epitopes, so 9 is a biologically motivated choice. However the 
optimal solution for 9-mers will be a near optimal solution for 8 to 12-mers [33]. Here we compare 
9-mers and 12-mers in terms of the mosaic solution given the optimization criteria, versus the level 
of coverage obtained. CD4+ T cells tend to have longer epitopes, but 9–mer optimization provides 
excellent coverage of all epitope lengths. 
4.4 
GLA-SE adjuvant 
The IDRI GLA-SE adjuvant is a glucopyranosyl lipid adjuvant-stable emulsion (synthetic 
lipid A derivative mixed with squalene oil). The Clinical studies section outlines previous 
experience with GLA-SE and other antigens (see Section 4.9). This adjuvant, however, 
has not yet been been administered to humans in combination with the EnvSeq-1 and the 
DNA Mosaic-Tre vaccines and therefore safety and tolerability of these products will be 
closely monitored. 
4.5 
Trial design rationale 
An important goal for the vaccine field is to address the challenge of inducing broadly 
neutralizing antibodies against HIV-1. This study addresses this question by testing 
immunogens capable of recreating the natural evolution of Env that promote CD4 
binding site specific antibody evolution. The first step in Part A of the study will be to 
compare the safety and immunogenicity of different doses of CH505TF gp120, including 
binding antibody responses and differential binding of antibodies to the wild type CH505 
TF gp120 envelope compared to the IΔ371 mutant CH505 Env. These data will be used 
to determine the optimal dose of the protein to be used in the additive and sequential 
approach proposed in Part B. In the next step, we will build on the data from Part A to 
evaluate immune responses induced by the envelope variants which will be delivered 
either sequentially or with overlap (Table 3-1). This study aims to be the first of multiple 
iterative experimental trials to test the ability of these Envs to initiate bnAb lineages and 
to use the isolated B cells from the vaccinees to identify the lineages induced. Since it has 
been shown that DNA co-immunization with protein increased T-cell help and the 

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magnitude and quality of antibody responses, a trivalent mosaic DNA Env vaccine will 
be combined with the sequential immunization and the additive immunization schemes. 
CH505TF gp120 protein will be available for clinical use approximately 6-7 months 
before the additional 3 proteins (CH505w53, w78, and w100 gp120s, representing 
variants from later timepoints in infection) are available. The IND will be established 
with the CH505TF gp120 protein information. Safety and immunogenicity data from 
after the third injection in Part A will be used to determine the protein doses to be used in 
Part B. Updated product documentation for the 3 later proteins and dose information for 
Part B will be submitted to the FDA prior to opening Part B for enrollment. 
4.5.1 
Dose (amount and number) and schedule 
Part A, the dose-finding portion of the study, will involve 5 immunizations IM with the 
CH505TF gp120 at 0, 2, 4, 8, and 12 months. The doses of the protein will be 20 mcg 
(group 1), 100 mcg (group 2), and 400 mcg (group 3). GLA-SE will be admixed with all 
proteins and the total dose of GLA-SE will be 10 mcg at all timepoints. The total volume 
for protein plus adjuvant for injection will be 1 mL, mixed 1:1 by volume. 
Part B will include an additive and a sequential approach to EnvSeq-1 protein 
administration, both with and without the DNA Mosaic-Tre env vaccine. The additive 
approach administers CH505TF, followed by CH505TF and w53 at month 2, CH505TF 
+ w53 + w78 at month 4, CH505w53 + w78 + w100 at month 8, CH505w78 + w100 at 
month 12, and CH505w100 at month 16 as follows: 
Month 0 
Month 2 
Month 4 
Month 8 
Month 12 
Month 16 
TF 
TF 
TF 
 
 
 
 
w53 
w53 
w53 
 
 
 
 
w78 
w78 
w78 
 
 
 
 
w100 
w100 
w100 
This additive immunization strategy mimics natural infection with proteins being 
administered in the order that they evolved naturally along with some overlap with 
preceding mutant Envs. This strategy also ensures that each protein is administered 3 
times, which may be needed for optimal immune response to each immunogen to drive 
the desired B cell maturation. 
The sequential approach will start with the CH505TF, then administer CH505w53 at 
month 2, CH505w78 at month 4, and CH505w100 at months 8, 12, and 16. The 
sequential approach also administers the Env mutants in the order that they evolved 
naturally, but does not include overlapping protein vaccinations. If the sequential 
approach is as effective as the additive approach, the simplified immunization schedule 
would be preferable. The immunization schedule is attempting to compress the process of 
recreating the evolution of antibody responses to the CD4 binding site in a much shorter 
timeframe than the 2 years it took for them to develop in natural infection. Data from 
NHP studies support the approach. This is the first clinical study evaluating this approach 
in humans. As mentioned above, the dose of the proteins will be determined by the safety 
and immunogenicity following the third immunization in Part A. 
In Part B, the vaccines will be administered at months 0, 2, 4, 8, 12, and 16 and 10 mcg 
of GLA-SE adjuvant will be admixed with all proteins at all timepoints. In addition, some 
groups will also receive co-administration of 4 mg of DNA Mosaic-Tre env [17] to 

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compare the immunogenicity of the EnvSeq-1 vaccines with and without the DNA. The 
primary immunogenicity timepoints in Part B will occur after the fourth injection to 
permit sufficient time for the development of peak nAb titers and after the last 
vaccination to be able to evaluate whether the full regimens lead to the development of 
broadly neutralizing antibodies. 
GLA-SE will be admixed with all proteins. The total dose of GLA-SE will be 10 mcg at 
all timepoints. The total volume for protein + adjuvant for injection is 1 mL, mixed 1:1 
by volume. 
If Part A indicates that the dose of each protein should be 20 mcg in Part B, the total dose 
of each protein in Groups 7 and 8 with the additive approach will also be 20 mcg. If the 
dose of each protein is determined to be 100 mcg or 400 mcg, the dose of each protein in 
Groups 7 and 8 will be 100 mcg to avoid going over 400 mcg of total protein at any 
timepoint.  
All injections will be administered IM in the thigh. Part A injections will be administered 
as 1 mL of protein or placebo administered by needle and syringe. Part B injections will 
consist of 1 mL of protein or placebo administered by needle and syringe and 1 mL of 
DNA or placebo administered by needleless Biojector® into the same thigh. The rationale 
for injecting both products into the same limb is to ensure that both immunogens reach 
the same draining lymph nodes to optimize the amount of T-cell help available to 
promote B-cell differentiation and proliferation within the germinal center. Data from 
non-human primates (with different vaccine products) demonstrate that same limb co-
immunization with DNA/gp120 protein/GLA-SE adjuvant vaccines resulted in enhanced 
humoral immune responses and polyfunctional cellular immune responses [28,34]. 
Adult immunizations are usually administered in 0.5 to 1 mL doses. There is, however, 
experience with the Hepatitis B vaccine Engerix-B, which has been safely given as a 2 
mL injection in hemodialysis patients [29]. Similarly, multiple injections of licensed 
vaccines have been administered safely in the same limb, either the deltoid or the thigh 
[35,36]. As the 2 mL combined volume of the protein and DNA injections exceeds the 
typical volume administered in the deltoid, the larger vastus lateralis muscle will be used 
as the site of injection. To maintain comparability and blinding across groups, all groups 
will have all injections administered in the thigh. 
4.5.2 
Choice of control 
Sodium chloride for injection USP, 0.9% will be used as placebo. 
4.6 
Plans for future product development and testing 
This study will be the first trial of sequential Envs to attempt to initiate CD4-binding site 
neutralizing antibodies. The task is to begin the process of iterative human clinical trials 
to learn how to induce broadly neutralizing antibodies. Considerable data have been 
reported that bnAb precursors are rare and subdominant and, in some cases, are made so 
by tolerance controls of bnAb precursors in bone marrow [4,7,12]. Other types of bnAb 
such as membrane-proximal external region (MPER) antibodies (in addition to CD4 
binding site antibodies) are also likely controlled in the periphery by peripheral immune 
tolerance control mechanisms because of bnAb acquisition of polyreactivity or 
autoreactivity [37]. Thus, this trial represents the first in a series of iterative phase 1 

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clinical studies to begin learning how to induce bnAbs in vaccinees. The goal of this trial 
is to be able to test immunogens capable of inducing HIV-1 bnAbs in humans. 
4.7 
Preclinical safety studies 
Table 4-1 Summary of preclinical safety study 
Study 
number 
Product 
Type of 
study 
Animal 
N 
Dose groups 
Route 
Schedule 
1726-031 
CH505TF 
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 
4.7.1 
Summary of preclinical safety studies related to the vaccines used in this study 
Eighty New Zealand White Rabbits, 13-15 weeks in age, were randomly assigned to 1 of 
4 groups (5/sex/group) as outlined in the table above. 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, and were rotated 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 

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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 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/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.  
Seven biweekly intramuscular injections of 400 mcg CH505 TF gp120 with 20 mcg 
GLA-SE adjuvant with or without a 4 mg DNA booster injection or 20 mcg GLA-SE 
alone to New Zealand White rabbits for 13 weeks was well tolerated. Test article-related 

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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. 
4.8 
Preclinical immunogenicity studies 
Table 4-2 Summary of preclinical immunogenicity studies 
Study 
number 
Product 
Animal 
N 
Dose groups 
Route 
Schedule 
Assay 
NHP 
79 
EnvSeq-
1 gp120 
Env with 
GLA-SE 
RM 
N=4 NHPs 
per group 
 100 g CH505TF gp120 only 
 100 g CH505 sequential Envs 
 100 g CH505 additive Envs 
 
IM 
wk 0, 6, 
12, 19, 
24, 57 
Neuts, 
binding, 
blocking 
NHP 
106 
EnvSeq-
1 gp120 
Env with 
GLA-SE 
RM 
N=3 NHPs 
per group 
 5 g CH505TF Env 
 20 g CH505TF Env 
 100 g CH505TF Env 
 300 g CH505TF Env 
 600 g CH505TF Env 
IM 
wk 0, 4, 
12, 29, 
37 
Neuts, 
binding, 
blocking 
4.8.1 
Immunogenicity of the CH505 Env 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 UCAs of lineages capable of binding HIV 
Envs with wild type sequences but not going into bnAb evolution is possible (Figure 4-7 
and Figure 4-8). In this study of 12 monkeys, 11/12 monkeys had differential binding 
antibodies isolated and overall the Env differential binding antibodies (binds 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 4-7. 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 WT gp 120, but not the Δ371 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 4-8. 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 1B 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 (IΔ371); 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 4-7). Of the 60 CD4-binding 
site antibodies, the Haynes team has isolated a CH505 gp120/CH505 gp120IΔ371 
differential-binding antibody, DH522, which not only neutralized the Tier 1b CH505 TF 
variant 4.3 but also neutralized other tier 1b viruses such as B.SS1196 C.6644, and 
AG.DJ263. Most importantly, this antibody is the first example of an antibody isolated in 
a vaccinated monkey that has tier 2 heterologous virus neutralization and neutralizes tier 
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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2 HIV-1 strains; D.57128 and M.CON-S (Figure 4-9). 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 4-10). The DH522 antibody was found to 
block the binding of sCD4 as well as CH103 Abs to CH505 Env, and also exhibited 
differential binding to CH505 Env versus the ∆371/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 4-9. Neutralization profile of DH522 and other lineage members. 
 
 
Figure 4-10. Three DH522 clonal lineage members from an NHP receiving the additive 
immunization regimen (NHP #79). 
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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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 4-9). 
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 4-11). 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 4-11. 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 4-3). 
Table 4-3 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 
∆371; binds RSC3 but not 
RSC3∆371, 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 
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 Env with each dose administered 3 times. 
Env binding antibody (Figure 4-12) and CD4-binding site antibody (Figure 4-13) were 
determined and the CH505 TF 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 4-14) there was a linear increase in 
neutralization titers with increasing Env dose, after 3 immunizations, there was no 
statistical difference between the tier 1 antibody neutralizing titers (Figure 4-15). 
In the dose ranging portion of this clinical trial, (Part A) we will evaluate the binding Ab 
responses as the primary endpoint and quantify the frequency of the memory B cells that 
display differential binding to wild type CH505 TF gp120 envelope compared to mutant 
CH505 Env IΔ371 (Figure 4-16) induced after the third dose of CH505 TF gp120 vaccine 
to inform the protein dose for the second part of the study. The dose in Part A that will be 
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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chosen for the dose in the arms of Part B will be determined by analysis of antibody 
binding data from a validated assay and will additionally be informed by the assay of 
memory B-cell receptor binding to CH505TF gp120 and differential binding to the 
CH505 IΔ371 gp120 Env. 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 mgc/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 4-12. Inhibition of CH106 CD4 bs binding to B.63521 gp120 Env by NHP 106 plasma 
from immunization with 5 different doses of CH505TF gp120. 
 
Figure 4-13. Binding of NHP 106 plasma to CHO-derived 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

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Figure 4-14. Tier 1 HIV neutralization in the TZM-Bl assay after 2 immunizations with 
CH505TF doses. Group 1, 5 mcg; Group 2, 20 mcg; Group 3, 100 mcg; Group 4; 300 mcg; 
Group 5, 600 mcg. 
 
Figure 4-15. Tier 1 HIV neutralization in the TZM-Bl assay after 3 immunizations with 
CH505TF doses. Group 1, 5 mcg; Group 2, 20 mcg; Group 3, 100 mcg; Group 4; 300 mcg; 
Group 5, 600 mcg. 
 
 
Figure 4-16 Gating strategy for B cell analysis. An example of NHP B cell data shown for 
preimmune and post third immunization samples. Few double positive (red gate gp120-
reactive) or differential positive (black gate) cells are found in the preimmune sample; both 
double positive and differential B cells are found two weeks after the third immunization 

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4.9 
Clinical studies 
4.9.1 
Clinical studies of gp120 Env protein vaccines 
Although the EnvSeq-1 vaccines (CH505TF, CH505w53, CH505w78, and CH505w100 
gp120 Env variants) have never been evaluated in humans before, there is 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 [38,39]. 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. Majority, if not 
all of the local and systemic reactions were deemed associated with adjuvant components 
of the vaccine rather than the Env proteins [40]. 
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 [41]. 
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 8000 
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 [42]. 
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, most common 
one being injection site pain/tenderness, but all of the symptoms were mild to moderate 
and self-limited. Moreover, while there were fewer reactogenicty events at the lowest 
dose, the safety profile in the 300 mcg and 600 mcg groups was similar [43]. 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 
reactogenicty (injection site erythema/induration) was frequent but self-limited, 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 [44]. 

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Taken together, the combined evidence from the large numbers of trial participants in 
these and other studies [45-49] 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. In Part A of the 
current study, the dose finding study for CH505TF gp120 will test doses ranging from 20, 
100, to 400 mcg/dose with real-time safety evaluations. The protein dose for Part B of the 
study will be determined based on the safety and immunogenicity of the vaccine products 
in Part A of this trial. 
4.9.2 
Clinical studies of the GLA-SE adjuvant and protein combinations 
Although the EnvSeq-1 vaccines in combination with GLA-SE has never been evaluated 
in humans, there is considerable clinical trial experience with the GLA-SE adjuvant in 
combination with other antigens. These data are summarized below and in Table 4-4 and 
Table 4-5. 
Two previous studies evaluated the 10 mcg dose of the GLA-SE adjuvant proposed for 
this study. A phase 1 clinical trial was undertaken in Brazil with a Schistosoma mansoni 
antigen (Sm14; NCT01154049). Twenty healthy males received 3 doses of 50 mcg Sm14 
+ 10 mcg GLA-SE at 1-month intervals. There was no control group. The vaccine was 
safe and generally well tolerated with no SAEs or Grade 4 AEs (reported by the study 
PI). All AEs were rare with the exception of injection site pain (80%, 50%, and 41% after 
the first, second, and third dose, respectively). There were no abnormalities in physical 
exams, serum chemistries, and hematology values that were considered related to study 
vaccine. 
The other trial is an ongoing phase 1, open-label evaluation of the safety, tolerability, and 
immunogenicity of the leishmaniasis vaccine (LEISH-F3) in combination with SLA-SE 
adjuvant compared to LEISH-F3 with GLA-SE in healthy adults (NCT02071758; 
Protocol IDRI-LVVPX-117). The SLA-SE adjuvant is the next generation TLR4 
adjuvant formulation. Thirty-nine participants were randomized to 4 arms: high dose of 
antigen (20 mcg) and low dose of SLA-SE (5 mcg); high dose of antigen and high dose 
of GLA-SE adjuvant (10 mcg); low dose antigen (5 mcg) and high dose of GLA-SE 
adjuvant (10 mcg); and high dose of antigen and high dose of SLA-SE adjuvant (10 
mcg). Participants received 3 injections at 1-month intervals. To date, all subjects have 
completed the treatment phase of the study and are in follow-up. There have been no 
Grade 3 or 4 AEs reported. Among the reported Grade 1 or 2 adverse events were: 
 
Local reactogenicity AEs: injection site tenderness (89%), pain (59%), induration 
(15%), erythema (15%), warmth (13%), pruritus (8%), and ecchymosis (5%) 
 
Systemic reactogenicity AEs: fatigue (41%), headache (26%), myalgia (21%), 
decreased appetite (18%), and chills (8%) 
 
Other AEs occurring in at least 2 subjects: hemoglobin decreased (15%), upper 
respiratory infection (13%), decreased potassium (5%), and emesis (5%) 
GLA-SE at a 5 mcg dose has also been tested together with protein antigens in several 
other clinical trials which are included in Table 4-4 and Table 4-5. 

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Clinical experience with non-HIV protein antigens administered in combination with the 
GLA-SE adjuvant demonstrated that altering the dose of protein did not result in 
differences in the safety and tolerability of the vaccines [50,51] (Z Sagawa, personal 
communication). In a phase 1 study of a mycobacterium tuberculosis (Mtb) vaccine, sixty 
individuals received 3 doses of increasing dose of Mtb polyprotein from 2 mcg to 10 mcg 
in combination with GLA-SE from 2 mcg to 5 mcg [50]. Majority of adverse events were 
mild; most common were injection site pain, headache and fatigue. Importantly, there 
was no apparent increase in frequency or severity of adverse events with successive doses 
or higher doses of the antigen or GLA-SE. 

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Table 4-4. Completed clinical trials using IDRI GLA‐SE adjuvant formulations in combination 
with other vaccines 
Sponsor/Partner 
Disease Area/Antigen 
Adjuvant Formulation 
Dose 
Oswaldo Cruz 
Foundation 
NCT01154049 
Schistosomiasis (Sm14) 
GLA-SE 
10 mcg 
Rockefeller University/ 
IDRI 
NCT01397604 and 
NCT01864876 
Adjuvant 
GLA-SE, GLA-AF, SE 
2 mcg 
5 mcg 
IDRI 
NCT01484548 
Leishmaniasis (LEISH-
F3) 
GLA-SE 
2 mcg 
5 mcg 
WRAIR 
NCT01540474 
Malaria (CelTOS) 
GLA-SE 
2 mcg 
5 mcg 
Aeras / IDRI 
NCT01599897 
TB (ID93) 
GLA-SE 
2 mcg 
5 mcg 
CONFIDENTIAL 
Seasonal influenza 
GLA-SE 
0.5 mcg 
1.0 mcg 
2.5 mcg  
5 mcg 
Immune Design / Protein 
Sciences 
NCT01147068 
Pandemic influenza 
(recombinant protein) 
GLA-SE 
1.0 mcg 
Immune 
Design/Novavax 
NCT01596725 
Pandemic influenza (H5-
VLP) 
GLA-SE 
2.5 mcg 
Immune Design / 
Medicago 
NCT01991561 
Pandemic influenza (H5-
VLP) 
GLA-SE 
5 mcg 
Table 4-5. Ongoing clinical trials using IDRI GLA-SE adjuvant formulations in combination 
with other vaccines  

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European Vaccine 
Initiative (France) 
NCT01949909 
Malaria (p27A) 
GLA-SE 
2.5 mcg 
5 mcg 
European Vaccine 
Initiative (France) 
NCT02014727 
Malaria (AMA-1 DiCo) 
GLA-SE 
2.5 mcg 
IDRI (US) / NIAID 
NCT01751048 
Leishmaniasis (LEISH-F3) GLA-SE 
MPL-SE  
5 mcg 
IDRI (US) 
Leishmaniasis (LEISH-F3) SLA-SE 
10 mcg 
Aeras / IDRI (South 
Africa) 
NCT01927159 
TB (ID93) 
GLA-SE 
2 mcg 
5 mcg 
IDRI (South 
Africa) 
NCT02465216 
TB (ID93) 
GLA-SE 
2 mcg 
5 mcg 
4.9.3 
Clinical studies of the DNA Mosaic-Tre env vaccine 
The DNA Mosaic-Tre env vaccine, administered via Biojector, is currently being tested 
in HVTN 106 to evaluate the breadth of induced CD4 and CD8 T-cell responses 
compared to group M consensus Env CON-S and a wild-type transmitted/founder Env 
B.1059 with the same DNA backbone as the DNA Mosaic-Tre env. HVTN 106 enrolled 
105 participants randomized to receive 3 injections of DNA Mosaic-Tre env (previously 
known as DNA Mosaic env), DNA CON-S env, DNA WT env, or placebo, with 30 
participants in each active group and 15 participants in the control group. Participants 
randomized to active groups also received 2 doses of an MVA HIV vaccine boost. The 
final product administration was in May 2016. As of June 2016, study follow-up is 
ongoing and the study remains blinded. The vaccines have been well tolerated with the 
most frequent reactogenicity symptoms being local pain and/or tenderness at the injection 
site, with the majority being mild (see Table 4-6). There have been 6 AEs deemed related 
to product, none of which necessitated discontinuation of vaccinations, and no serious 
adverse events attributed to the vaccines. All 6 AEs related to any of the 3 DNAs or 
placebo were mild and all have resolved. They included 1 lymphadenopathy, 3 alanine 
aminotransferase increases, 1 aspartate aminotransferase increase, and 1 localized 
cutaneous erythema. The SAEs or AEs that required expedited reporting to the trial 
sponsor that were not related to vaccine were appendicitis, severe head injury from a fall, 
alcohol withdrawal, acute systemic allergic reaction, demyelinating disorder, hepatic 
mesenchymal hamartoma, and uterine leiomyosarcoma. 

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Table 4-6. Summary of local site injection pain and/or tenderness reactogenicity after 
injections with DNA or placebo in HVTN 106 
Deltoid pain and/or 
tenderness 
Vac 1 
N = 105 
n (%) 
Vac 2 
N = 101 
n (%) 
Vac 3 
N = 98 
n (%) 
None 
13 (12%) 
17 (17%) 
27 (28%) 
Mild 
68 (65%) 
73 (72%) 
55 (56%) 
Moderate 
24 (23%) 
11 (11%) 
16 (16%) 
Severe 
0 (0%) 
0 (0%) 
0 (0%) 
Potentially life-
threatening 
0 (0%) 
0 (0%) 
0 (0%) 
In addition, DNA vaccines with the same plasmid backbones and similar HIV inserts 
have been administered to over 2100 human subjects. The results of human clinical trials 
with VRC DNA vaccines have been published for HIV DNA vaccines [plasmid DNA 
vaccines developed by VRC/NIAID/NIH] [52-58]. Table 4-7 summarizes previous 
human experience with the same DNA plasmid backbone as used for the proposed 
clinical trial. 
Table 4-7. Clinical experience with same DNA plasmid backbone with different HIV gene 
inserts  
Protocol Number 
Clinical trials.gov NCT 
number 
Number of subjects 
received DNA product 
VRC 007 
NCT00089531 
15 
VRC 008 
NCT00109629 
40 
VRC 011 
NCT00321061 
60 
VRC 101 
NCT00270465 
12 
HVTN 204 
NCT00125970 
240 
RV 172 
NCT00123968 
138 
IAVI V001 
NCT00124007 
58 
HVTN 077 
NCT00801697 
130 
HVTN 096 
NCT00179954 
40 
HVTN 092 
NCT01783977 
143 
HVTN 505 
NCT00865566 
1252 
Total number of participants who have 
received DNA HIV product 
2128 
Similar to the clinical study results with the exact DNA construct being used in this 
study, data from these DNA products that have the same plasmid backbone and related 
HIV inserts indicate that these products have been well tolerated and the most frequently 
reported local reactogenicity and AEs have been injection site pain and/or tenderness. 
The most frequently reported systemic symptoms were headache and malaise/fatigue. To 
date, there have been no serious adverse events (SAEs) attributable to these DNA 
vaccines. 

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4.10 
Potential risks of study products and administration 
Table 4-8. 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, decreased appetite, 
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 including decreases 
in hemoglobin, WBC, and neutrophils 
 Injection site hematoma, bruising/ecchymosis, laceration, 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 Part A 
Primary objective 1: 
To evaluate the safety and tolerability of different doses of CH505TF Env gp120 in HIV-
uninfected healthy adults 
Primary endpoint 1: 
Local and systemic reactogenicity signs and symptoms, laboratory measures of safety, 
and AEs and SAEs 
Primary objective 2:  
To evaluate binding antibody responses elicited by different doses of the CH505TF 
gp120 vaccine 
Primary endpoint 2:  
HIV-specific binding Ab responses as assessed by binding Ab multiplex assay 2 weeks 
after the third vaccination with CH505TF gp120 
5.2 
Secondary objectives and endpoints Part A 
Secondary objective 1: 
To evaluate the ability of different doses of the vaccine regimen to elicit memory B cells 
that differentially bind CH505 wildtype gp120 TF Env vs the mutant CH505 Env IΔ371 
gp120 
Secondary endpoints 1: 
Differential binding to CH505 gp120 compared to CH505 I371 protein as assessed by 
flow cytometry analysis of the frequency of the differential binding memory B cells 2 
weeks after the third vaccination with CH505TF gp120 
Secondary objective 2: 
To evaluate the ability of different doses of the vaccine regimen to elicit HIV-specific 
nAbs 
Secondary endpoints 2: 
 
Magnitude and breadth of neutralizing antibody responses against autologous 
viral isolates as assessed by area under the magnitude-breadth curves 2 weeks 
after the third vaccination with CH505TF gp120 and at additional timepoints of 
interest following vaccination 

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 
Magnitude and breadth of neutralizing antibody responses against a cross-clade 
panel of isolates induced 2 weeks after the third vaccination with CH505TF and 
at additional timepoints of interest following vaccination 
Secondary objective 3: 
To evaluate HIV-specific T-cell responses induced by different doses of the CH505TF 
vaccine 
Secondary endpoint 3: 
Response rate and magnitude of CD4+ T-cell responses as assessed by intracellular 
cytokine staining assays (ICS) 2 weeks after the third vaccination with CH505TF and at 
additional timepoints of interest following vaccination 
Secondary objective 4: 
To isolate single B cells with desired specificities and determine lineage characteristics 
Secondary endpoint 4: 
Monoclonal antibodies may be evaluated for binding and neutralization including tier 2 
virus bnAb activity and CD4 binding site loop binding, neutralization of autologous TF 
or mutant CH505 viruses 
5.3 
Exploratory objectives Part A 
Exploratory objective 1: 
Based on the primary and secondary analyses, to further evaluate the immunogenicity of 
the different doses of CH505TF gp120 at additional timepoints of interest. 
Exploratory objective 2: 
To assess vaccine-induced follicular helper T cell (Tfh) responses 
5.4 
Primary objectives and endpoints Part B 
Primary objective 1: 
To evaluate the safety and tolerability of EnvSeq-1 vaccines administered with or without 
DNA Mosaic-Tre env in HIV-uninfected healthy adults 
Primary endpoint 1: 
Local and systemic reactogenicity signs and symptoms, laboratory measures of safety, 
and AEs and SAEs 
Primary objective 2: 

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To evaluate and compare vaccine-induced humoral responses elicited by EnvSeq-1 
vaccines administered in sequential and additive protein immunizations, with and without 
DNA 
Primary endpoints 2:  
 
Magnitude and breadth of neutralizing antibody response against autologous viral 
isolates 2 weeks after the fourth and sixth (final) vaccinations with and without 
DNA 
 
Magnitude and breadth of neutralizing antibody responses against a panel of 
heterologous isolates induced 2 weeks after the fourth and sixth (final) 
vaccinations with and without DNA 
5.5 
Secondary objectives and endpoints Part B 
Secondary objective 1: 
To evaluate and compare HIV-1 specific binding Ab responses elicited by EnvSeq-1 
vaccine administered in sequential and additive protein immunization, with and without 
DNA 
Secondary endpoints 1: 
 
HIV-specific binding Ab responses as assessed by binding Ab multiplex assay 2 
weeks after the fourth and sixth (final) vaccinations with and without DNA 
 
Differential binding to EnvSeq-1 gp120 compared to CH505 I371 protein 
Secondary objective 2: 
To evaluate HIV-specific T-cell responses induced by different doses of the EnvSeq-1 
vaccines 
Secondary endpoint 2: 
Response rate and magnitude of CD4+ T-cell responses as assessed by ICS assays 2 
weeks after the fourth and sixth (final) vaccinations with EnvSeq-1 vaccines with and 
without DNA 
Secondary objective 3: 
To isolate single B cells with desired specificities and determine lineage characteristics 
Secondary endpoint 3: 
Monoclonal antibodies may be evaluated for binding and neutralization including tier 2 
virus bnAb activity and CD4 binding site loop binding, neutralization of autologous TF 
or mutant CH505 viruses, and differential binding to CH505 gp120 compared to CH505 
I371 protein. 

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5.6 
Exploratory objectives Part B 
Exploratory objective 1: 
To further evaluate the immunogenicity of the vaccine regimens at different timepoints 
Exploratory objective 2: 
To determine the B cell repertoire of HIV-specific B cells 
Exploratory objective 3: 
To assess vaccine-induced follicular helper T cell (Tfh) responses 
Exploratory objective 4: 
To correlate vaccine-induced B-cell and Tfh responses to EnvSeq-1 gp120s with 
responses to the gut microbiome using optionally-provided stool specimens 
Exploratory objective 5: 
To compare immune responses in groups 6 and 8 with DNA to groups 5 and 7 without 
DNA 
Exploratory objective 6: 
To further evaluate immunogenicity of each vaccine regimen, additional immunogenicity 
assays may be performed, including on samples from other timepoints, based on the 
HVTN Laboratory Assay Algorithm. 
Exploratory objective 7: 
To conduct analyses related to furthering the understanding of HIV, immunology, 
vaccines, and clinical trial conduct. 

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6 
Statistical considerations 
6.1 
Accrual and sample size calculations 
Recruitment into Part A will target 42, and recruitment into Part B will target 90, healthy, 
HIV-uninfected adults aged 18 to 50 years old at low risk of HIV infection in regions 
where clade B is the predominant clade. Since enrollment is concurrent with receiving the 
first study vaccination, all participants will provide some safety data. However, for 
immunogenicity analyses, it is possible that data may be missing for various reasons, 
such as participants terminating from the study early, problems in shipping specimens, 
low cell viability of processed peripheral blood mononuclear cells (PBMCs) or high 
background. Immunogenicity data from 17 phase 1 and 2 phase 2a HVTN vaccine trials, 
which began enrolling after June 2005 (data as of September 2014), indicate that 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% of enrolled participants having missing data 
for the primary immunogenicity endpoint. 
6.1.1 
Sample size calculations for safety 
The ability of the study to identify SAEs can be expressed by the true event rate above 
which at least 1 event would likely be observed and the true event rate below which no 
events would likely be observed. Specifically, in each vaccine arm of Part A of the study 
(n = 12), there is a 90% chance of observing at least 1 event if the true rate of such an 
event is 17.5% or more; and there is a 90% chance of observing no events if the true rate 
is 0.8% or less. In all vaccine arms of the Part A of the study combined (n = 36), there is 
a 90% chance of observing at least 1 event if the true rate of such an event is 6.2% or 
more; and there is a 90% chance of observing no events if the true rate is 0.2% or less. In 
each vaccine arm of Part B of the study (n = 20), there is a 90% chance of observing at 
least 1 event if the true rate of such an event is 10.9% or more; and there is a 90% chance 
of observing no events if the true rate is 0.5% or less. In all vaccine arms of the Part B of 
the study combined (n = 80), there is a 90% chance of observing at least 1 event if the 
true rate of such an event is 2.9% or more; and there is a 90% chance of observing no 
events if the true rate is 0.1% or less. 
Probabilities of observing 0, 1 or more, and 2 or more events among arms of size 12 and 
20 are presented in Table 6-1 for a range of possible true adverse event rates. These 
calculations provide a more complete picture of the sensitivity of this study design to 
identify potential safety problems with the vaccine. 
Table 6-1 Probability of observing 0 events, 1 or more events, and 2 or more events, among 
arms of size 12 and 20, for different true event rates 
True event rate (%) 
Pr(0/12) 
Pr(1+/12) 
Pr(2+/12) 
Pr(0/20) 
Pr(1+/20) 
Pr(2+/20) 
1 
88.6 
11.4 
0.6 
88.8 
18.2 
1.7 
4 
61.3 
38.7 
8.1 
44.2 
55.8 
19.2 
10 
28.2 
71.8 
34.1 
12.2 
87.8 
60.8 
20 
6.9 
93.1 
72.5 
1.2 
98.8 
93.1 
30 
1.4 
98.6 
91.5 
0.1 
99.1 
<0.1 
40 
0.2 
99.8 
98.0 
<0.1 
>99.9 
<0.1 

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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 [59]. If none of the 36 participants receiving a vaccine regimen in Part A 
experience a safety event, the 95% 2-sided upper confidence bound for the true rate of 
such events in the total vaccinated population is 9.6%. For each individual Part A vaccine 
arm (n = 12), the 2-sided upper confidence bound for this rate is 24.2%. If none of the 80 
participants receiving a vaccine regimen in Part B experience a safety event, the 95% 2-
sided upper confidence bound for the true rate of such events in the total vaccinated 
population is 4.6%. For each individual Part B vaccine arm (n = 20), the 2-sided upper 
confidence bound for this rate is 16.1%. 
Table 6-2 Two-sided 95% confidence intervals based on observing a particular rate of safety 
endpoints for arms of size 12 and 20 
Observed event rate 
95% Confidence interval (%) 
0/12 
[0, 24.2] 
1/12 
[1.5, 35.4] 
2/12 
[4.7, 44.8] 
 
 
0/36 
[0, 9.6] 
1/36 
[0.5, 14.2] 
2/36 
[1.5, 18.1] 
 
 
0/20 
[0, 16.1] 
1/20 
[0.9, 23.6] 
2/20 
[2.8, 30.1] 
 
 
0/80 
[0, 4.6] 
1/80 
[0.2, 6.7] 
2/80 
[0.7, 8.7] 
6.1.2 
Sample size calculations for immunogenicity 
To address the humoral immunogenicity endpoints, the analysis will compare the area 
under the magnitude-breadth curve of the IgG Env binding Ab response, and will 
compare the frequency of memory B cells that bound to gp120CH505 TF but not to 
gp120CH505 TF I∆371, 2 weeks after the third (Part A) or fourth and sixth (Part B) 
vaccinations with CH505TF gp120. To estimate power, binding magnitude-breadth data 
were simulated assuming that the proportion of non-zero responses was 0.94 in both 
comparison groups. This is based on pilot data for the IgG binding Ab response in HVTN 
088. For these calculations, non-zero responses, modeled on the log10 scale, were drawn 
from a normal distribution. The mean non-zero response in group 1 was set to 4.06. This 
was the mean non-zero response in the HVTN 088 vaccine arm T2 (the treatment arm for 
vaccine naïve participants). The standard deviation (SD) of the non-zero response was set 
to 0.391 for both groups; this was the SD of the non-zero response in the HVTN 088 
vaccine arm.  

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The differential binding rate is the fraction of class memory B cells that have the property 
of binding the two protein hooks in a differential manner (defined by flow gating).  In the 
assay, two measurements are made simultaneously: binding to the transmitted founder 
CH505 virus, and binding to the IΔ371 variant.  Each of these yields a measurement of 
the proportion of memory B cells that bind to a target virus.  While the primary interest is 
in the differential binding to these two viruses, which is the difference of these 
proportions, we will also evaluate each measure separately to further describe and 
explore the relationship between these measures under the scenarios represented by the 
arms of this trial. 
Power for this is high if we can pool the cells across participants, which would be 
possible under an assumption of a homogeneous rate of differential binders across 
participants within a treatment group.  Our prior expectation is that this is at least 
approximately correct, though we will evaluate the homogeneity and if we find evidence 
for different rates across participants, we will revert to the more conservative approach of 
treating participant rates of differential binders as varying across participants around a 
common group mean. In case pooling is not justified, power is the same (on the per-SD 
scale) to that calculated for binding Abs, since preliminary data indicate that the log-
transformed rates of differential binding are consistent with the normal distribution. 
However, interpretation of these SDs differs between the differential binding rate power 
calculations and the power calculations for the primary antibody endpoints. In the case of 
binding Abs, the SDs are on the scale of log-transformed binding Ab response values 
(which are areas under the magnitude-breadth curve), so it is reasonable to describe these 
in terms of "fold changes".  However for differential binding Abs, the values and SDs are 
fractions. So for instance, if the SD is .001 (equivalently, 0.1%) that means that there is 
90% power to detect a 0.2% difference between the differential binding rates in the two 
arms. In the text below we provide example interpretations of the SDs for the context of 
the primary Ab binding endpoints only. 
To address antibody endpoints in Part A, the analysis will descriptively summarize 
binding response positivity call rates, and test superiority of the frequency of differential 
memory B cell binding (to wild type vs mutant IΔ371 CH505) and of the magnitude and 
breadth of the IgG binding Ab response to a panel of gp120 proteins for each of 2 
comparisons (Group 1 vs 2, and Group 2 vs 3), using a two- sided Wilcoxon rank sum 
test with 5%/2 type-I error rate per comparison. The sample size of 12 vaccinees per 
group will give 80% power to detect a true difference of 1.81 standard deviations (SDs) 
between the mean responses and 90% power to detect a true difference of 2.04 SDs. 
Using the mean and SD values from the HVTN 088 trial, the difference of 1.81 SDs 
translates to a difference of 0.708 units of log10 binding magnitude; if 1 of the comparison 
groups has the same mean as was seen among non-negative values among vaccine 
recipients in the HVTN 088 trial (4.06 units), then after incorporating the expected 6% 
zero-valued (negative responder) measures, this corresponds to observing an increase or 
decrease in the overall mean from 3.691 in group 1 to 4.336 in group 2. These 
calculations assume a 10% loss-to-follow-up rate and the (94%) response rate observed in 
the HVTN 088 vaccine recipients. The same approach will be used to test superiority of 
the magnitude of the IgG binding Ab response to each individual gp120 antigen in the 
panel. 
To address antibody endpoints in Part B, the analysis will descriptively summarize 
binding and neutralization response positivity call rates and test superiority of the of the 
frequency of differential memory B cell binding and of magnitude and breadth of the IgG 

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binding Ab response to a panel of gp120 proteins and of the neutralization of tier 1 and 
tier 2 panels of HIV-1 viruses. Each analysis will be conducted separately for each of 2 
pooled comparisons (additive vs sequential, pooling over groups with and without mosaic 
DNA: Groups 5 and 6 combined vs Groups 7 and 8 combined; effect of mosaic DNA, 
pooling over groups receiving additive and sequential proteins: Groups 5 and 7 combined 
vs Groups 6 and 8 combined), and for each of 6 pairwise comparisons among these 
groups using a two- sided Wilcoxon rank sum test with 5% type-I error rate per pooled 
comparison and a 5%/6 type-I error rate per pairwise comparison. The sample size of 20 
vaccinees per group will give 80% power to detect a true difference of 1.63 standard 
deviations (SDs) between the mean non-zero responses and 90% power to detect a true 
difference of 1.81 SDs for the pairwise comparisons. Using the mean and SD values from 
the HVTN 088 trial, the difference of 1.63 SDs translates to a difference of 0.637 units of 
log10 binding magnitude; if 1 of the comparison groups has the same mean as was seen 
among non-negative values among vaccine recipients in the HVTN 088 trial (4.06 units), 
then after incorporating the expected 6% zero-valued (negative responder) measures, this 
corresponds to observing an increase or decrease in the overall mean from 3.609 in group 
1 to 4.175 in group 2. The sample size of 40 vaccinees per pooled group will give 80% 
power to detect a true difference of 0.80 standard deviations (SDs) between the mean 
non-zero responses and 90% power to detect a true difference of 0.90 SDs (these 2 are 
each conducted at a 5% alpha level). Using the mean and SD values from the HVTN 088 
trial, the difference of 0.80 SDs translates to a difference of 0.313 units of log10 binding 
magnitude; if 1 of the comparison groups has the same mean as was seen among non-
negative values among vaccine recipients in the HVTN 088 trial (4.06 units), then after 
incorporating the expected 6% zero-valued (negative responder) measures, this 
corresponds to observing an increase or decrease in the overall mean from 3.722 in group 
1 to 4.007 in group 2. These calculations assume a 10% loss-to-follow-up rate and the 
(94%) response rate observed in the HVTN 088 vaccine recipients. The same approach 
will be used to test superiority of the magnitude of the IgG binding Ab response to each 
individual gp120 antigen in the binding panel. 
6.2 
Randomization 
The randomization sequence will be obtained by computer-generated random numbers 
and provided to each HVTN CRS through a Web-based randomization system. The 
randomization will be done in blocks to ensure balance across arms. At each institution, 
the pharmacist with primary responsibility for dispensing study products is charged with 
maintaining security of the treatment assignments (except in emergency situations as 
specified in the HVTN MOP). 
6.3 
Blinding 
Participants and site staff (except for site pharmacists) will be blinded as to participant 
treatment arm/group assignments (eg, vaccine or control). Study product assignments are 
accessible to those HVTN CRS pharmacists, DAIDS protocol pharmacists and contract 
monitors, and SDMC staff who are required to know this information in order to ensure 
proper trial conduct. Any discussion of study product assignment between pharmacy staff 
and any other HVTN CRS staff is prohibited. The HVTN SMB members also are 
unblinded to treatment assignment in order to conduct review of trial safety.  

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When a participant leaves the trial prior to study completion, the participant will be told 
he or she must wait until all participants are unblinded to learn his or her treatment 
assignment.  
Emergency unblinding decisions will be made by the site investigator. If time permits, 
the HVTN 115 PSRT should be consulted before emergency unblinding occurs. 
6.4 
Statistical analyses 
This section describes the final study analyses, unblinded as to treatment arm/group 
assignment. All data from enrolled participants will be analyzed according to the initial 
randomization assignment regardless of how many vaccinations they received. In the rare 
instance that a participant receives the wrong treatment at a specific vaccination time, the 
Statistical Analysis Plan (SAP) will address how to analyze the participant’s safety data. 
Analyses are modified intent-to-treat in that individuals who are randomized but not 
enrolled do not contribute data and hence are excluded. Because of blinding and the brief 
length of time between randomization and enrollment—typically no more than 4 working 
days—very few such individuals are expected. 
Analyses for primary endpoints will be performed using SAS and R. All other descriptive 
and inferential statistical analyses will be performed using SAS, StatXact, or R statistical 
software. 
No formal multiple comparison adjustments will be employed for multiple safety 
endpoints, multiple primary immunogenicity endpoints, or secondary endpoints. 
However, multiplicity adjustments will be made for certain immunogenicity assays, as 
discussed below, when the assay endpoint is viewed as a collection of hypotheses (eg, 
testing multiple peptide pools to determine a positive response). 
6.4.1 
Analysis variables 
The analysis variables consist of baseline participant characteristics, safety, and 
immunogenicity for primary- and secondary-objective analyses. 
6.4.2 
Baseline comparability 
Treatment arms will be compared for baseline participant characteristics using descriptive 
statistics. 
6.4.3 
Safety/tolerability analysis 
Since enrollment is concurrent with receiving the first vaccination, all participants will 
have received at least 1 vaccination and therefore will provide some safety data. 
6.4.3.1 
Reactogenicity 
The number and percentage of participants experiencing each type of reactogenicity sign 
or symptom will be tabulated by severity and treatment arm and the percentages 
displayed graphically by arm. For a given sign or symptom, each participant’s 
reactogenicity will be counted once under the maximum severity for all injection visits. 
In addition, to the individual types of events, the maximum severity of local pain or 

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tenderness, induration or erythema, and of 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 postenrollment values. In addition, 
the number (percentage) of participants with local laboratory values recorded as meeting 
Grade 1 AE criteria or above as specified in the Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events (Section 9.10) 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 
Discrete categorical assay endpoints (eg, response rates) will be analyzed by tabulating 
the frequency of positive response for each assay by antigen and treatment arm at each 
timepoint for which an assessment is performed. Crude response rates will be presented 
with their corresponding 95% confidence interval estimates calculated using the score 
test method [59]. Because of the small numbers of control participants, no adjustment 
will be made to the vaccine arm estimates for the false positive rates in the control arms. 
To address the aims of Part B, Barnard or Fisher’s exact tests, as specified in the SAP, 
will be used to compare the response rates of any 2 vaccine arms and of pooled groups as 
described in Section 4.1.2, with a significant difference declared if the 2-sided p-value is 

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≤ 0.05. In general, Barnard’s is preferred since under most circumstances it is more 
powerful than Fisher’s [60]. 
In addition to response rate estimates for each timepoint, the probability of observing at 
least 1 positive response by a given timepoint and the probability of observing more than 
1 positive response by a given timepoint will be estimated, with corresponding 
confidence intervals, for each vaccine arm using maximum likelihood-based methods 
[61]. 
For quantitative assay data (eg, magnitudes and magnitude-breadth AUCs from the 
neutralizing antibody multiplex assay or percentage of positive cells from the ICS assay), 
graphical and tabular summaries of the distributions by antigen, treatment arm, and 
timepoint will be made. For all primary and secondary immunogenicity endpoints, box 
plots and plots of estimated reverse cumulative distribution curves will be used for 
graphical display of all of the study arms. Typically the results will be shown for each 
vaccine arm and for the set of control arms pooled into 1 group. 
To test for differences among the vaccine arms in Part A and separately in Part B, first a 
Kruskal-Wallis rank test or an F-test (depending on the normality assumption) will be 
used to test for overall differences. Secondly, if the overall test is significant at the 2-
sided 0.05 level, then individual tests comparing the 2 adjacent pairs of vaccine arms 
(Part A) and all 6 pairs of 4 vaccine arms (Part B) will be done unless pre-specified. If 
rank-based tests are used then the tests will be inverted to construct Hodges-Lehmann 
point estimates and 2-sided (1-0.05/k) × 100% CIs about the differences in location 
centers of the k = 2 (Part A) or k = 6 (Part B) pair-wise comparisons of vaccine arms. If 
actual-value tests are used then the Dunnett’s procedure will be used to construct 
simultaneous confidence intervals about the pairs of mean differences for the many-to-
one comparisons [62] when multiple vaccine arms are each compared with 1 common 
control arm. When all pair-wise comparisons between the multiple vaccine arms are of 
interest, the Tukey procedure [63] will be used. If only specific comparisons between 
pairs of the multiple vaccine arms are of interest, the Holm-Bonferroni procedure will be 
used. An appropriate data transformation (eg, log10 transformation) may be applied to 
better satisfy assumptions of symmetry and homoscedasticity (constant variance). 
Significance of the differences between pairs will be evaluated using 2 procedures, first 
based on whether the simultaneous 95% CIs exclude zero and secondly based on whether 
the nominal (unadjusted) 95% CIs exclude zero.  
Some immunologic assays have underlying continuous or count-type readout that are 
dichotomized into responder/nonresponder categories (eg, nAb multiplex assay 
positivity). If treatment arm differences for these assays are best summarized by a 
mixture model, then Lachenbruch’s test statistic [64] or an alternative two-part test [65] 
(as defined in the SAP) will be used to evaluate the composite null hypothesis of equal 
response rates in the 2 arms and equal response distributions. Lachenbruch’s test statistic 
equals the square of a binomial Z-statistic for comparing the response rates plus the 
square of a Wilcoxon statistic for comparing the response distributions in the subgroup of 
responders. A permutation procedure is used to obtain a 2-sided p-value. For estimation, 
differences in response rates between arms will be estimated using the methods described 
above, and in the subgroup of positive responders, differences in location parameters 
between arms will be estimated using the methods described above. 
Based upon previous HVTN trials, missing 10% of immunogenicity results for a specific 
assay is common due to study participants terminating from the study early, problems in 

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shipping specimens, or low cell viability of processed peripheral blood mononuclear cells 
(PBMCs). To achieve unbiased statistical estimation and inferences with standard 
methods applied in a complete-case manner (only including participants with observed 
data in the analysis), missing data need to be missing completely at random (MCAR). 
Following the most commonly used definition, MCAR assumes that the probability of an 
observation being missing does not depend on any participant characteristics (observed or 
unobserved). When missing data are minimal (specifically if no more than 20% of 
participants are missing any values), then standard complete-case methods will be used, 
because violations of the MCAR assumption will have little impact on the estimates and 
hypothesis tests.  
If a substantial amount of immunogenicity data are missing for an endpoint (at least 1 
value missing from more than 20% of participants), then using the methods that require 
the MCAR assumption may give misleading results. In this situation, analyses of the 
immunogenicity endpoints at a specific timepoint will be performed using parametric 
generalized linear models fit by maximum likelihood. These methods provide unbiased 
estimation and inferences under the parametric modeling assumptions and the assumption 
that the missing data are missing at random (MAR). MAR assumes that the probability of 
an observation being missing may depend upon the observed responses and upon 
observed covariates, but not upon any unobserved factors. Generalized linear models for 
response rates will use a binomial error distribution and for quantitative endpoints, a 
normal error distribution. For assessing repeated immunogenicity measurement, linear 
mixed effects models will be used. If the immunological outcomes are left- and/or right- 
censored, then the linear mixed effects models of Hughes [66] will be used, because they 
accommodate the censoring. In addition, secondary analyses of repeated immunogenicity 
measurements may be done using weighted GEE [67] methods, which are valid under 
MAR. All of the models described above in this paragraph will include as covariates all 
available baseline predictors of the missing outcomes. 
Some “resource-intensive” immunogenicity endpoints are only measured in subset of 
participants, eg, immunogenicity endpoints based on mucosal samples. For such 
endpoints, exploratory analyses will be conducted to assess the correlation of participant 
characteristics measured in (nearly) all subjects with the resource-intensive endpoints. 
For example, if the same assay is performed on blood and mucosal samples, then a 
scatterplot and Spearman rank correlation coefficient (r) will be used to assess the 
correlation of responses. If at least moderate correlations exist (eg, r ≥ 0.3), then the 
semiparametric efficient analysis method of Rotnitzky and Robins [68] will be used 
(described in Gilbert, Sato et al. for application to vaccine studies [69]) to estimate the 
mean of the resource-intensive endpoint for each group and to compare means between 
groups. 
6.4.4.2 
Primary analyses of neutralization magnitude-breadth curves 
Tier 1 Screen of Vaccine Regimens versus Placebo  
The area-under-the-magnitude-breadth curve (AUC-MB) to the tier 1 panel of 3 isolates 
will be computed for each participant with evaluable neutralization data, as described in 
[70]. Dunnett’s procedure will be applied with 2-sided alpha = 0.05 to determine which 
of the k = 3 (Part A) or k = 4 (Part B) vaccine groups have a significantly higher mean 
AUC-MB than that of the pooled placebo groups, as described in [71] (see their formula 
(1.1)). This procedure will be applied to construct 95% CIs about the k differences in 
mean AUC-MB for each vaccine regimen versus the pooled placebo groups (vaccine – 

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placebo), which simultaneously have at least 95% coverage probability. The rule for a 
vaccine regimen passing the tier 1 screen is that the lower confidence limit about the 
mean difference is above zero. The vaccine regimens passing the tier 1 screen will be 
advanced to tier 2 evaluation, and regimens failing the tier 1 screen are not planned to 
undergo evaluation for neutralization of the tier 2 isolates. 
Tier 2 screen of vaccine regimens versus placebo 
For the set of vaccine regimens passing the tier 1 screen, the same Dunnett’s procedure as 
described above, using the AUC-MB endpoint for the tier 2 isolates, will be used to 
determine the set of vaccine regimens that pass the tier 2 screen. 
6.4.4.3 
Secondary analyses of neutralization magnitude-breadth curves 
Superiority comparisons of vaccine regimens passing the tier 2 screen 
For the set of vaccine regimens that passed the tier 2 screen, an F-test will be performed 
for whether any of the mean AUC-MBs differ. If this test is not significant (p-value 
> 0.05), then the conclusion will be that there were no significant differences in mean 
AUC-MBs among the advanced vaccine regimens. If the F-test is significant, then 
simultaneous 95% CIs about the mean-differences in AUC-MBs will be reported. These 
CIs are computed as the estimated mean-difference plus or minus tN-m,025 multiplied by 
the square-root of S2 (1/ni + 1/nj), where tN-m,025 is the 97.5th percentile of a t-distribution 
with N – m degrees of freedom, where N is the total number of vaccine recipients 
evaluated (summing over the advanced vaccine regimens) and m is the number of 
advanced vaccine regimens. In addition, S2 is an estimate of the common sample 
variance of the AUC-MB, whereas ni and nj are the sample sizes of evaluable 
participants for vaccine regimens i and j being compared. Following Fisher’s least 
significant difference procedure, the pairs of vaccine regimens with this CI excluding 
zero are deemed to have a significant difference. Nominal (unadjusted) 95% CIs about 
pairs of vaccine arms will also be reported. 
Omnibus comparison of magnitude-breadth distributions 
The analyses of magnitude-breadth described above are based on the endpoint area-
under-the-curve, which is interpreted as the average log10 IC50 to the set of isolates in the 
test panel. Use of this endpoint is maximally statistically powerful if 1 vaccine arm has 
greater magnitude and breadth than the comparator vaccine arm, but may miss an effect 
wherein 1 vaccine arm has greater magnitude and the comparator vaccine arm has greater 
breadth. Therefore, a secondary analysis may compare the distribution of magnitude-
breadth curves among vaccine arms using the test statistic max|BdG| from Huang, et al 
[70] (see page 85), which is designed to detect general differences in magnitude-breadth 
curve distributions.  
Selecting the best vaccine regimen among those passing the tier 2 screen 
For each vaccine regimen that passes the tier 2 screen, the best vaccine regimen will be 
deemed as that with the greatest value of the max|BdG| test statistic comparing its 
distribution of magnitude-breadth curves versus the pooled placebo group. 

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Superiority comparisons of vaccine regimens passing the tier 2 screen 
Similarly, the max|BdG| test statistic will be used to compare the distribution of 
magnitude-breadth curves between each pair of advanced vaccine regimens. The Holm-
Bonferroni procedure will be applied to determine the pairs of regimens with significant 
differences in distribution controlling the family-wise false positive error rate at no more 
than 0.05. Nominal (unadjusted) 95% CIs about pairs of vaccine arms will also be 
reported. 
6.4.4.4 
Analysis of CD4+ T-cell response as measured by the ICS assay  
The analysis of CD4+ 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 [72] and/or the Fisher’s exact test-based 
positivity criteria will be used. Details of the positivity criteria will be discussed in the 
SAP. The magnitude of marginal response will be analyzed as described for quantitative 
data in the general approach section. For each T-cell subset, graphs will be used to 
display the background-subtracted magnitudes for each participant by protein, treatment 
arm and timepoint. When 3 or more cytokines are being measured by the ICS assay, the 
polyfunctionality of ICS responses may also be analyzed as an exploratory endpoint. 
Besides descriptive plots of the magnitude of polyfunctional responses, the COMPASS 
(Combinatorial Polyfunctionality analysis of Antigen-Specific T-cell Subsets) statistical 
framework 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, 2 
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 of 
neutralizing antibodies is defined as the average of the log10 NAb titer over the panel of 
isolates, where titers that are below the limit-of-detection are set to half of that limit. 
Response breadth of binding antibodies is similarly defined as the average of the 
response over the panel of antigens. Two choices are to compare the M-B curves among 
vaccine arms, as follows: a non-parametric Wilcoxon rank sum test on the subject-
specific area-under-the M-B curve (AUC M-B) or a Kolmogorov-Smirnov type test on 
the 2 group-average M-B curves. Simulations can be used to obtain 2-sided p-values for 
the latter test. Second, a weighted-average score-like variable may be constructed to 
account for the correlations between analytes as an integrate magnitude of responses to 
multiple analytes. Similar group comparison methods described in the first approach may 
be adopted. Details of either approach will be described in the SAP. 
6.4.5 
Analyses prior to end of scheduled follow-up visits 
Any analyses conducted prior to the end of the scheduled follow-up visits should not 
compromise the integrity of the trial in terms of participant retention or safety or 

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immunogenicity endpoint assessments. In particular, early unblinded analyses by 
treatment assignment require careful consideration and should be made available on a 
need to know basis only. 
6.4.5.1 
Safety 
During the course of the trial, unblinded analyses of safety data will be prepared 
approximately every 4 months for review by the SMB. Ad hoc safety reports may also be 
prepared for SMB review at the request of the HVTN 115 PSRT. The HVTN leadership 
must approve any other requests for unblinded safety data prior to the end of the 
scheduled follow-up visits. 
6.4.5.2 
Immunogenicity 
An unblinded statistical analysis by treatment assignment of a primary immunogenicity 
endpoint may be performed when all participants have completed the 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 1 
of the primary immunogenicity endpoints of the same class (humoral, cell-mediated, 
innate or mucosal) or, if no primary endpoint of the same class, at least 1 of the primary 
immunogenicity endpoints reaches the aforementioned threshold. The Laboratory 
Program will review the analysis report prior to distribution to the protocol chairs, 
DAIDS, vaccine developer, and other key HVTN members and investigators. 
Distribution of reports will be limited to those with a need to know for the purpose of 
informing future trial-related decisions. The HVTN leadership must approve any other 
requests for HVTN immunogenicity analyses prior to the end of the scheduled follow-up 
visits. 

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7 
Selection and withdrawal of participants 
Participants will be healthy, HIV-uninfected (seronegative) adults who comprehend the 
purpose of the study and have provided written informed consent. Volunteers will be 
recruited and screened; those determined to be eligible, based on the inclusion and 
exclusion criteria, will be enrolled in the study. Final eligibility determination will 
depend on results of laboratory tests, medical history, physical examinations, and answers 
to self-administered and/or interview questions.  
Investigators should always use good clinical judgment in considering a volunteer’s 
overall fitness for trial participation. Some volunteers may not be appropriate for 
enrollment even if they meet all inclusion/exclusion criteria. Medical, psychiatric, 
occupational, or other conditions may make evaluation of safety and/or immunogenicity 
difficult, and some volunteers may be poor candidates for retention. 
Determination of eligibility, taking into account all inclusion and exclusion criteria, must 
be made within 56 days prior to enrollment unless otherwise noted in Sections 7.1 and 
7.2. 
7.1 
Inclusion criteria 
General and Demographic Criteria 
1. Age of 18 to 50 years 
2. Access to a participating HVTN CRS and willingness to be followed for the planned 
duration of the study 
3. Ability and willingness to provide informed consent 
4. Assessment of understanding: volunteer demonstrates understanding of this study 
completes a questionnaire prior to first vaccination with verbal demonstration of 
understanding of all questionnaire items answered incorrectly 
5. Agrees not to enroll in another study of an investigational research agent before the last 
required protocol clinic visit 
6. Willing to be contacted by phone, text message, or e-mail 6 months after completion of 
the scheduled clinic visits 
7. Good general health as shown by medical history, physical exam, and screening 
laboratory tests 
HIV-Related Criteria: 
8. Willingness to receive HIV test results 
9. Willingness to discuss HIV infection risks and amenable to HIV risk reduction 
counseling.  

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10. Assessed by the clinic staff as being at “low risk” for HIV infection and committed to 
maintaining behavior consistent with low risk of HIV exposure through the last required 
protocol clinic visit. 
Laboratory Inclusion Values 
Hemogram/CBC 
11. Hemoglobin ≥ 11.5 g/dL for volunteers who were born female, ≥ 13.0 g/dL for 
volunteers who were born male 
12. White blood cell count = 3,300 to 12,000 cells/mm3 
13. Total lymphocyte count ≥ 800 cells/mm3 
14. Remaining differential either within institutional normal range or with site physician 
approval 
15. Platelets = 125,000 to 550,000/mm3 
Chemistry 
16. Chemistry panel: ALT, AST, and alkaline phosphatase < 1.25 times the institutional 
upper limit of normal; creatinine ≤ institutional upper limit of normal. 
Virology 
17. Negative HIV-1 and -2 blood test: Volunteers must have a negative FDA-approved 
enzyme immunoassay (EIA). 
18. Negative Hepatitis B surface antigen (HBsAg)  
19. Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV polymerase 
chain reaction (PCR) if the anti-HCV is positive 
Urine 
20. Normal urine: 
 
Negative urine glucose, and 
 
Negative or trace urine protein, and 
 
Negative or trace urine hemoglobin (if trace hemoglobin is present on dipstick, a 
microscopic urinalysis with red blood cells levels within institutional normal range). 
Reproductive Status 
21. Volunteers who were born female: negative serum or urine beta human chorionic 
gonadotropin (β-HCG) pregnancy test performed prior to vaccination on the day of initial 
vaccination. Persons who are NOT of reproductive potential due to having undergone 

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total hysterectomy or bilateral oophorectomy (verified by medical records), are not 
required to undergo pregnancy testing. 
22. Reproductive status: A volunteer who was born female must: 
 
Agree to consistently use effective contraception (see Appendix C) for sexual activity 
that could lead to pregnancy from at least 21 days prior to enrollment through the last 
required protocol clinic visit. Effective contraception is defined as using the 
following methods: 
 
Condoms (male or female) with or without a spermicide, 
 
Diaphragm or cervical cap with spermicide, 
 
Intrauterine device (IUD), 
 
Hormonal contraception, or 
 
Any other contraceptive method approved by the HVTN 115 PSRT 
 
Successful vasectomy in the male partner (considered successful if a volunteer 
reports that a male partner has [1] documentation of azoospermia by microscopy, 
or [2] a vasectomy more than 2 years ago with no resultant pregnancy despite 
sexual activity postvasectomy); 
 
Or not be of reproductive potential, such as having reached menopause (no menses 
for 1 year) or having undergone hysterectomy, bilateral oophorectomy, or tubal 
ligation; 
 
Or be sexually abstinent. 
23. Volunteers who were born female must also agree not to seek pregnancy through 
alternative methods, such as artificial insemination or in vitro fertilization until after the 
last required protocol clinic visit 
7.2 
Exclusion criteria 
General 
1. Blood products received within 120 days before first vaccination  
2. Investigational research agents received within 30 days before first vaccination 
3. Body mass index (BMI) ≥ 40; or BMI ≥ 35 with 2 or more of the following: age > 45, 
systolic blood pressure > 140 mm Hg, diastolic blood pressure > 90 mm Hg, current 
smoker, known hyperlipidemia  
4. Intent to participate in another study of an investigational research agent or any other 
study that requires non-HVTN HIV antibody testing during the planned duration of the 
HVTN 115 study  
5. Pregnant or breastfeeding 

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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 115 PSRT will determine eligibility 
on a case-by-case basis. 
8. Non-HIV experimental vaccine(s) received within the last 5 years in a prior vaccine 
trial. Exceptions may be made for vaccines that have subsequently undergone licensure 
by the FDA or by the national regulatory authority where the volunteer is enrolling. For 
volunteers who have received control/placebo in an experimental vaccine trial, the HVTN 
115 PSRT will determine eligibility on a case-by-case basis. For volunteers who have 
received an experimental vaccine(s) greater than 5 years ago, eligibility for enrollment 
will be determined by the HVTN 115 PSRT on a case-by-case basis. 
9. Live attenuated vaccines other than influenza vaccine received within 30 days before 
first vaccination or scheduled within 14 days after injection (eg, measles, mumps, and 
rubella [MMR]; oral polio vaccine [OPV]; varicella; yellow fever) 
10. Influenza vaccine or any vaccines that are not live attenuated vaccines and were 
received within 14 days prior to first vaccination (eg, tetanus, pneumococcal, Hepatitis A 
or B) 
11. Allergy treatment with antigen injections within 30 days before first vaccination or 
that are scheduled within 14 days after first vaccination  
Immune System  
12. Immunosuppressive medications received within 168 days before first vaccination. 
(Not exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical 
corticosteroids for mild, uncomplicated dermatitis; or [4] a single course of 
oral/parenteral corticosteroids at doses < 2 mg/kg/day and length of therapy < 11 days 
with completion at least 30 days prior to enrollment.) 
13. Serious adverse reactions to vaccines or to vaccine components including history of 
anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, 
and/or abdominal pain. (Not excluded from participation: a volunteer who had a 
nonanaphylactic adverse reaction to pertussis vaccine as a child.)  
14. Immunoglobulin received within 60 days before first vaccination 
15. Autoimmune disease  
16. Immunodeficiency 
Clinically significant medical conditions  
17. Untreated or incompletely treated syphilis infection 
18. Clinically significant medical condition, physical examination findings, clinically 
significant abnormal laboratory results, or past medical history with clinically significant 

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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. 
19. Any medical, psychiatric, occupational, or other condition that, in the judgment of the 
investigator, would interfere with, or serve as a contraindication to, protocol adherence, 
assessment of safety or reactogenicity, or a volunteer’s ability to give informed consent 
20. Psychiatric condition that precludes compliance with the protocol. Specifically 
excluded are persons with psychoses within the past 3 years, ongoing risk for suicide, or 
history of suicide attempt or gesture within the past 3 years. 
21. Current anti-tuberculosis (TB) prophylaxis or therapy 
22. Asthma exclusion criteria: 
Asthma other than mild, well-controlled asthma. (Symptoms of asthma severity as 
defined in the most recent National Asthma Education and Prevention Program (NAEPP) 
Expert Panel report). 
Exclude a volunteer who: 
 
Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or 
 
Uses moderate/high dose inhaled corticosteroids, or 
 
In the past year has either of the following: 
 
Greater than 1 exacerbation of symptoms treated with oral/parenteral 
corticosteroids; 
 
Needed emergency care, urgent care, hospitalization, or intubation for asthma. 
23. Diabetes mellitus type 1 or type 2, including cases controlled with diet alone. (Not 
excluded: history of isolated gestational diabetes.) 
24. Thyroidectomy, or thyroid disease requiring medication during the last 12 months 
25. Hypertension: 

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 
If a person has been found to have elevated blood pressure or hypertension during 
screening or previously, exclude for blood pressure that is not well controlled. Well-
controlled blood pressure is defined as consistently ≤ 140 mm Hg systolic and ≤ 90 
mm Hg diastolic, with or without medication, with only isolated, brief instances of 
higher readings, which must be ≤ 150 mm Hg systolic and ≤ 100 mm Hg diastolic. 
For these volunteers, blood pressure must be ≤ 140 mm Hg systolic and ≤ 90 mm Hg 
diastolic at enrollment. 
 
If a person has NOT been found to have elevated blood pressure or hypertension 
during screening or previously, exclude for systolic blood pressure ≥ 150 mm Hg at 
enrollment or diastolic blood pressure ≥ 100 mm Hg at enrollment. 
26. Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or platelet 
disorder requiring special precautions) 
27. Malignancy (Not excluded from participation: Volunteer who has had malignancy 
excised surgically and who, in the investigator’s estimation, has a reasonable assurance of 
sustained cure, or who is unlikely to experience recurrence of malignancy during the 
period of the study) 
28. Seizure disorder: History of seizure(s) within past 3 years. Also exclude if volunteer has 
used medications in order to prevent or treat seizure(s) at any time within the past 3 
years. 
29. Asplenia: any condition resulting in the absence of a functional spleen 
30. History of hereditary angioedema, acquired angioedema, or idiopathic angioedema. 
7.3 
Participant departure from vaccination schedule or withdrawal 
This section concerns an individual participant’s departure from the vaccination schedule. 
Pause rules for the trial as a whole are described in Section 11.4. 
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 other than influenza vaccine  
 
Receipt of allergy treatment with antigen injections 
 
Within 14 days prior to any study injection 
 
Receipt of influenza vaccine or any vaccines that are not live attenuated vaccines 
(eg, pneumococcal)  

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 
Pre-vaccination abnormal vital signs or clinical symptoms that may mask assessment 
of vaccine reaction. 
Vaccinations should not be administered outside the visit window period specified in the 
HVTN 115 Study Specific Procedures. 
In order to avoid vaccination delays and missed vaccinations, participants who plan to 
receive licensed vaccines or allergy treatments should be counseled to schedule receipt of 
these substances, when possible, outside the intervals indicated above. The effects of 
these substances on safety and immunogenicity assessments and their interactions with 
study vaccines are unknown. Therefore, if circumstances allow, these substances should 
also be avoided in the 2 week interval between a study vaccination and completion of the 
2 week postvaccination follow-up visit. 
7.3.2 
Participant departure from vaccination schedule 
Every effort should be made to follow the vaccination schedule per the protocol. If a 
participant misses a vaccination and the visit window period for the vaccination has 
passed, that vaccination cannot be given. The participant should be asked to continue 
study visits. The participant should resume the vaccination schedule with the next 
vaccination unless there are circumstances that require further delay or permanent 
discontinuation of vaccination (see Sections 7.3.1 and 7.3.3).  
7.3.3 
Discontinuing vaccination for a participant 
Under certain circumstances, an individual participant’s vaccinations will be permanently 
discontinued. Specific events that will result in stopping a participant’s vaccination 
schedule include: 
 
Co-enrollment in a study with an investigational research agent (rare exceptions 
allowing for the continuation of vaccinations may be granted with the unanimous 
consent of the HVTN 115 PSRT). 
 
Clinically significant condition (ie, a condition that affects the immune system or for 
which continued vaccinations and/or blood draws may pose additional risk), 
including but not limited to the following: 
 
Pregnancy (regardless of outcome); 
 
Any grade 4 local or systemic reactogenicity symptom, lab abnormality, or AE 
that is subsequently considered to be related to vaccination; 
 
Any grade 3 lab abnormality or other clinical AE (exception: fever or vomiting 
and subjective local and systemic symptoms) that is subsequently considered to 
be related to vaccination; or 
 
Clinically significant type 1 hypersensitivity reaction associated with study 
vaccination. Consultation with the HVTN 115 PSRT is required prior to 
subsequent vaccinations following any type 1 hypersensitivity reaction associated 
with study vaccination; or 
 
Investigator determination in consultation with Protocol Team leadership (eg, for 
repeated nonadherence to study staff instructions). 

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 
Participant misses more than 3 vaccinations(s) (see Section 7.3.2). 
Such participants should be counseled on the importance of continuing with the study and 
strongly encouraged to participate in follow-up visits and protocol-related procedures per 
the protocol for the remainder of the trial, unless medically contraindicated. 
In addition, vaccinations will be stopped for participants diagnosed with HIV infection. 
HIV-infected participants will not continue in the trial (see Sections 7.3.4 and 9.7.1). 
7.3.4 
Participant termination from the study 
Under certain circumstances, an individual participant may be terminated from 
participation in this study. Specific events that will result in early termination include: 
 
Participant refuses further participation, 
 
Participant relocates and remote follow-up or transfer to another HVTN CRS is not 
possible, 
 
HVTN CRS determines that the participant is lost to follow-up,  
 
Participant becomes HIV infected, 
 
Investigator decides, in consultation with Protocol Team leadership, to terminate 
participation (eg, if participant exhibits inappropriate behavior toward clinic staff), or 
 
Any condition where termination from the study is required by applicable 
regulations. 
 

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8 
Study product preparation and administration 
CRS pharmacists should consult the Pharmacy Guidelines and Instructions for DAIDS 
Clinical Trials Networks for standard pharmacy operations. The protocol schema is 
shown in Table 3-1. Study products are listed in Section 3, Overview, sub-section Study 
products and routes of administration. See the Investigator’s Brochures for further 
information about study products. 
8.1 
Vaccine regimen 
The schedule of vaccination is shown in Section 3 and additional information is given 
below. 
Part A 
Group 1 
Treatment 1 (T1): 20 mcg CH505TF gp120 admixed with 10 mcg GLA-SE, to be 
administered as a 1mL IM injection into either thigh at months 0, 2, 4, 8 and 12. 
Group 2 
Treatment 2 (T2): 100 mcg CH505TF gp120 admixed with 10 mcg GLA-SE, to be 
administered as a 1mL IM injection into either thigh at months 0, 2, 4, 8 and 12 
Group 3 
Treatment 3 (T3): 400 mcg CH505TF gp120 admixed with 10 mcg GLA-SE, to be 
administered as a 1mL IM injection into either thigh at months 0, 2, 4, 8 and 12. 
Group 4 
Control 4 (C4): Placebo for CH505TF/GLA-SE (labeled as Sodium Chloride for 
Injection, 0.9% USP) to be administered as a 1mL (IM) injection, into either thigh at 
months 0, 2, 4, 8 and 12. 
Part B 
Group 5 
Treatment 5 (T5): TBD mcg CH505TF gp120 admixed with 10 mcg GLA-SE, to be 
administered as a 1mL IM injection, into either thigh at month 0. 
AND 
Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL IM by Biojector 2000® into the same thigh at month 0. 
Then 

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TBD CH505w53 gp120 admixed with 10 mcg GLA-SE, to be administered as a 1mL IM 
injection, into either thigh at month 2. 
AND 
Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL IM by Biojector 2000® into the same thigh at month 2. 
Then 
TBD mcg CH505w78 gp120 admixed with 10 mcg GLA-SE, to be administered as a 
1mL IM injection, into either thigh at month 4. 
AND 
Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL IM by Biojector 2000® into the same thigh at month 4. 
Then 
TBD mcg CH505w100 gp120 admixed with 10 mcg GLA-SE, to be administered as a 
1mL IM injection, into either thigh at month 8. 
AND 
Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL IM by Biojector 2000® into the same thigh at month 8. 
Then 
TBD mcg CH505w100 gp120 admixed with 10 mcg GLA-SE, to be administered as a 
1mL IM injection, into either thigh at month 12. 
AND 
Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL IM by Biojector 2000® into the same thigh at month 12. 
Then 
TBD CH505w100 gp120 admixed with 10 mcg GLA-SE, to be administered as a 1mL 
IM injection, into either thigh at month 16. 
AND 
Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL IM by Biojector 2000® into the same thigh at month 16. 
Group 6 
Treatment 6 (T6): TBD mcg CH505TF gp120 admixed with 10 mcg GLA-SE, to be 
administered as a 1mL IM injection, into either thigh at month 0. 

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AND 
4 mg DNA Mosaic-Tre env (labeled as HV13284 + HV13285 + HV13286) 1mL IM by 
Biojector 2000® into the same thigh at month 0. 
Then 
TBD mcg CH505w53 gp120 admixed with 10 mcg GLA-SE, to be administered as a 
1mL IM injection, into either thigh at month 2. 
AND 
4 mg DNA Mosaic-Tre env (labeled as HV13284 + HV13285 + HV13286) 1mL IM by 
Biojector 2000® into the same thigh at month 2. 
Then 
TBD mcg CH505w78 gp120 admixed with 10 mcg GLA-SE, to be administered as a 
1mL IM injection, into either thigh at month 4. 
AND 
4 mg DNA Mosaic-Tre env (labeled as HV13284 + HV13285 +HV13286) 1mL IM by 
Biojector 2000® into the same thigh at month 4. 
Then 
TBD mcg CH505w100 gp120 admixed with 10 mcg GLA-SE, to be administered as a 
1mL IM injection, into either thigh at month 8. 
AND 
4 mg DNA Mosaic-Tre env (labeled as HV13284 + HV13285 + HV13286) 1mL IM by 
Biojector 2000® into the same thigh at month 8. 
Then 
TBD mcg CH505w100 gp120 admixed with 10 mcg GLA-SE, to be administered as a 
1mL IM injection, into either thigh at month 12. 
AND 
4 mg DNA Mosaic-Tre env (labeled as HV13284 + HV13285 + HV13286) 1mL IM by 
Biojector 2000® into the same thigh at month 12. 
Then 
TBD mcg CH505w100 gp120 admixed with 10 mcg GLA-SE, to be administered as a 
1mL IM injection, into either thigh at month 16. 
AND 

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4 mg DNA Mosaic-Tre env (labeled as HV13284 + HV13285 + HV13286) 1mL IM by 
Biojector 2000® into the same thigh at month 16. 
Group 7 
Treatment 7 (T7): TBD CH505TF gp120 admixed with 10 mcg GLA-SE, to be 
administered as a 1 mL IM injection into either thigh at month 0. 
AND 
Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL IM by Biojector 2000® into the same thigh at month 0. 
Then 
TBD mcg CH505TF gp120 + TBD mcg CH505w53 gp120 admixed with 10 mcg GLA-
SE, to be administered as a 1 mL IM injection into either thigh at month 2. 
AND 
Placebo for DNA-Tre Mosaic env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL IM by Biojector 2000® into the same thigh at month 2. 
Then 
TBD mcg CH505TF gp120 + TBD CH505w53 gp120 + TBD mcg CH505w78 gp120 
admixed with 10 mcg GLA-SE, to be administered as a 1 mL IM injection into either 
thigh at month 4. 
AND 
Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL IM by Biojector 2000® into the same thigh at month 4. 
Then 
TBD mcg CH505w53 gp120 + TBD mcg CH505w78 + TBD mcg CH505w100 gp120 
admixed with 10 mcg GLA-SE, to be administered as a 1 mL IM injection into either 
thigh at month 8. 
AND 
Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL IM by Biojector 2000® into the same thigh at month 8. 
Then 
TBD mcg CH505w78 gp120 + TBD mcg CH505w100 gp120 admixed with 10 mcg 
GLA-SE, to be administered as a 1 mL IM injection into either thigh at month 12. 
AND 

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Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL IM by Biojector 2000® into the same thigh at month 12. 
Then 
TBD mcg CH505w100 gp120 admixed with 10 mcg GLA-SE, to be administered as a 1 
mL IM injection into either thigh at month 16. 
AND 
Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL IM by Biojector 2000® into the same thigh at month 16. 
Group 8 
Treatment 8 (T8): TBD mcg CH505TF gp120 admixed with 10 mcg GLA-SE, to be 
administered as a 1 mL IM injection into either thigh at month 0. 
AND 
4 mg DNA Mosaic-Tre env (labeled as HV13284 + HV13285 + HV13286) 1mL IM by 
Biojector 2000® into the same thigh at month 0. 
Then 
TBD mcg CH505TF gp120 + TBD mcg CH505w53 gp120 admixed with 10 mcg GLA-
SE, to be administered as a 1 mL IM injection into either thigh at month 2. 
AND 
4 mg DNA Mosaic-Tre env (labeled as HV13284 + HV13285 +HV13286) 1mL IM by 
Biojector 2000® into the same thigh at month 2. 
Then 
TBD mcg CH505TF gp120 + TBD mcg CH505w53 gp120 + TBD mcg CH505w78 
gp120 admixed with 10 mcg GLA-SE, to be administered as a 1 mL IM injection into 
either thigh at month 4. 
AND 
4 mg DNA Mosaic-Tre env (labeled as HV13284 + HV13285 + HV13286) 1mL IM by 
Biojector 2000® into the same thigh at month 4. 
Then 
TBD mcg CH505w53 gp120 + TBD mcg CH505w78 gp120 + TBD mcg CH505w100 
gp120 admixed with 10 mcg GLA-SE, to be administered as a 1 mL IM injection into 
either thigh at month 8. 
AND 

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4 mg DNA Mosaic-Tre env (labeled as HV13284 + HV13285 + HV13286) 1mL IM by 
Biojector 2000® into the same thigh at month 8. 
Then 
TBD mcg CH505w78 gp120 + TBD mcg CH505w100 gp120 admixed with 10 mg GLA-
SE, to be administered as a 1 mL IM injection into either thigh at month 12. 
AND 
4 mg DNA Mosaic-Tre env (labeled as HV13284 + HV13285 + HV13286) 1mL IM by 
Biojector 2000® into the same thigh at month 12. 
Then 
TBD mcg CH505w100 gp120 admixed with 10 mcg GLA-SE, to be administered as a 1 
mL IM injection into either thigh at month 16. 
AND 
4 mg DNA Mosaic-Tre env (labeled as HV13284 + HV13285 + HV13286) 1mL IM by 
Biojector 2000® into the same thigh at month 16. 
Group 9 
Placebo for CH505TF gp120/GLA-SE (labeled as Sodium Chloride for injection, 0.9% 
USP) to be administered as a 1mL IM injection to either thigh at month 0. 
AND 
Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL by Biojector 2000® into the same thigh at month 0. 
Then 
Placebo for CH505TF or CH505w53 gp120/GLA-SE (labeled as Sodium Chloride for 
injection, 0.9% USP) to be administered as a 1mL IM injection to either thigh at month 2. 
AND 
Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL by Biojector 2000® into the same thigh at month 2. 
Then 
Sodium Chloride for injection, 0.9% USP for CH505TF or CH505w78 or CH505w100 or 
CH505w53, 78, or CH505w53,78,100 or CH505w78,100, to be administered as a 1mL 
IM injection to either thigh at months 4, 8 and 12. 
AND 

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Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL by Biojector 2000® into the same thigh at months 4, 8 and 12. 
Then  
Placebo for CH505w100 gp120/GLA-SE (labeled as Sodium Chloride for injection, 0.9% 
USP) to be administered as a 1mL IM injection to either thigh at month 16. 
AND 
Placebo for DNA Mosaic-Tre env (labeled as Sodium Chloride for injection, 0.9% USP) 
1mL by Biojector 2000® into the same thigh at month 16. 
8.2 
Study product formulation  
8.2.1 
CH505TF gp120 
The CH505TF gp120 vaccine will be provided as a 0.8 mg/mL vial. Each sterile, single 
use vial contains 0.75 mL of product. Product should be stored at ≤ -65°C (+/-10°C). The 
study products are described in further detail within the Investigator’s Brochure (IB). 
8.2.2 
CH505w53 gp120 
More information will be provided prior to the implementation of Part B. 
8.2.3 
CH505w78 gp120 
More information will be provided prior to the implementation of Part B. 
8.2.4 
CH505w100 gp120 
More information will be provided prior to the implementation of Part B. 
8.2.5 
DNA Mosaic-Tre env (labeled as HV13284 + HV13285 + HV13286) 
The DNA Mosaic-Tre env vaccine will be provided as a 4 mg/mL (3.9 mg/mL ± 0.2 
mg/mL) vial. The product is a clear, colorless solution. Each sterile, single-use vial 
contains 1.33 mL of product. The product must be stored at -20°C +/- 5°C. The study 
products are described in further detail in the IB. 
8.2.6 
GLA-SE (glucopyranosyl lipid adjuvant-stable emulsion) 
The GLA-SE adjuvant will be provided as vials containing 20 µg/mL GLA in a 4% oil-
in-water emulsion. Each sterile, single use vial contains 0.6 mL of product. Product 
appears as a milky-white liquid. GLA-SE must be stored at 2-8°C and must not be frozen. 
The study product is described in further detail within the IB. 
8.2.7 
Placebo for DNA Mosaic-Tre env 
Sodium Chloride for injection, 0.9% USP will be used as the placebo. It must be stored as 
recommended by the manufacturer. 

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8.2.8 
Placebo for CH505TF, w53, w78, w100 gp120 
Sodium Chloride for injection, 0.9% USP will be used as the placebo. It must be stored as 
recommended by the manufacturer. 
8.3 
Preparation of study products  
Part A: 
8.3.1 
Group 1: 20 mcg CH505TF gp120 + 10 mcg GLA-SE 
One vial of CH505TF gp120 0.8 mg/mL and one vial of GLA-SE (20 mcg/mL) will be 
needed to prepare the dose.  
Prior to admixture, the pharmacist will remove a vial of CH505TF gp120 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 a vial of GLA-SE 
from the refrigerator and allow to equilibrate to room temperature. 
Using aseptic technique, the pharmacist will add 0.6 mL of CH505TF gp120 and 1.8 mL 
of Sodium Chloride for injection, 0.9% USP to an empty vial. Mix the contents of this 
vial thoroughly using a vortexer machine at high speed for 3 seconds. The final 
concentration of CH505TF gp120 will be 200 mcg/mL. 
Next, using aseptic technique, withdraw 0.5 mL from the diluted 200 mcg/mL vial of 
CH505TF gp120 and place into an empty vial. Add 2 mL of Sodium Chloride for 
injection, 0.9% USP to this vial for further dilution and mix the contents of this vial 
thoroughly using a vortexer machine at high speed for 3 seconds. The final concentration 
of CH505TF gp120 will be 40 mcg/mL. 
Next, using aseptic technique, withdraw 0.6 mL of the diluted 40 mcg/mL CH505TF 
gp120 admixture and add to a vial of 20 mcg/mL GLA-SE and mix thoroughly using a 
vortexer machine at high speed for 3 seconds, yielding a concentration of 20 mcg/mL 
CH505TF gp120 and 10 mcg/mL GLA-SE.  
Finally, using aseptic technique, withdraw 1 mL from the vial containing 20 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 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. 
8.3.2 
Group 2: 100 mcg CH505TF gp120 + 10 mcg GLA-SE 
One vial of CH505TF gp120 0.8 mg/mL and one vial of GLA-SE (20 mcg/mL) will be 
needed to prepare the dose. 

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Prior to admixture, the pharmacist will remove a vial of CH505TF gp120 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 a vial of GLA-SE 
from the refrigerator and allow to equilibrate to room temperature. 
Using aseptic technique, the pharmacist will add 0.6 mL of CH505TF gp120 and 1.8 mL 
of Sodium Chloride for injection, 0.9% USP to an empty vial. Mix the contents of this 
vial thoroughly using a vortexer machine at high speed for 3 seconds. The final 
concentration of CH505TF gp120 is 200 mcg/mL. 
Next, using aseptic technique, withdraw 0.6 mL of the diluted 200 mg/mL CH505TF 
gp120 admixture and add to a vial of GLA-SE 20 mcg/mL and mix thoroughly using a 
vortexer machine at high speed for 3 seconds, yielding a concentration of 100 mcg/mL 
CH505TF gp120 and 10 mcg/mL GLA-SE.  
Finally, using aseptic technique, withdraw 1 mL from the vial containing 100 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 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. 
8.3.3 
Group 3: 400 mcg CH505TF gp120 + 10 mcg GLA-SE 
One vial of CH505TF gp120 0.8 mg/mL and one vial of GLA-SE (20 mcg/mL) will be 
needed to prepare the dose.  
Prior to admixture, the pharmacist will remove a vial of CH505TF gp120 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 a vial of GLA-SE 
from the refrigerator and allow to equilibrate to room temperature. 
Using aseptic technique, the pharmacist will add 0.6 mL of CH505TF gp120 to a vial 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. 
Finally, using aseptic technique, 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 thigh, with an expiration date and time of 8 hours following the last mixing 
procedure. 

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Any unused portion of vials or expired prefilled syringes should be disposed of in 
accordance with institutional or pharmacy policy. 
8.3.4 
Group 4: Placebo for CH505TF gp120/GLA-SE 
The pharmacist using aseptic technique will withdraw 1 mL of Sodium Chloride for 
Injection, 0.9% USP 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 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. 
Part B: 
More information will be provided prior to the implementation of part B regarding 
CH505TF, w53, 78 and 100 gp120. 
8.3.5 
Placebo for CH505 Proteins- Groups 5-9 
The pharmacist using aseptic technique will withdraw 1 mL of Sodium Chloride for 
Injection, 0.9% USP 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 
“CH505 Protein/GLA-SE or placebo”. The syringe must also be labeled for IM 
administration into 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. 
8.3.6 
Placebo for DNA Mosaic-Tre env  
The pharmacist using aseptic technique will withdraw 1 mL of Sodium Chloride for 
Injection, 0.9% USP into the Biojector 2000® syringe and cap the syringe.  
The syringe should be labeled as “DNA Mosaic env 4 mg or Placebo”. The syringe must 
also be labeled for IM administration into thigh. The study product should be 
administered as soon as possible after preparation.  
Any unused portion of vials or expired prefilled syringes should be disposed of in 
accordance with institutional or pharmacy policy. 
8.3.7 
DNA Mosaic-Tre env (labeled as HV13284 + HV13285+ HV13286) 
One vial of HV13284 + HV13285 + HV13286, 4 mg/mL will be needed to prepare the 
dose. Prior to dispensing, the pharmacist will remove the study product from the freezer 
and allow it to thaw at room temperature.  

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Once thawed, the pharmacist will gently swirl the contents of the vial and then, using 
aseptic technique, will withdraw 1 mL from the vial into the Biojector 2000® syringe and 
cap the syringe.  
The syringe should be labeled as “DNA Mosaic env 4 mg or Placebo”. The syringe must 
also be labeled for IM administration into thigh, with a preparation date and time. The 
study product should be administered as soon as possible after preparation.  
Any unused portion of vials or expired prefilled syringes should be disposed of in 
accordance with institutional or pharmacy policy. 
8.4 
Administration 
All injections should be administered in the thigh of either leg.  
At sites where registered pharmacists are legally authorized to administer drug, the 
HVTN CRS may choose to have the HVTN CRS pharmacist administer the injections. 
When preparing a dose in a syringe and administering the dose, consideration should be 
given to the volume of solution in the needle before and after the dose is administered. 
Particularly, if the needle used to withdraw the product is replaced prior to vaccine 
administration, consideration should be given to conserving the full dose of product. The 
pharmacy and clinic staff members are encouraged to work together to administer the 
dose specified in the protocol.  
8.4.1 
DNA Mosaic-Tre env vaccine or placebo 
DNA vaccine or placebo will be administered IM as a 1 mL injection, using the Biojector 
2000® at Months 0, 2, 4, 8, 12 and 16, to participants randomized into groups 5, 6, 7, 8 
and 9. 
The Biojector 2000® will be used as directed by Bioject Inc. Neither the material being 
injected nor injection site skin preparation require deviation from standard procedures. 
The injection site is disinfected and the area allowed to dry completely. The skin around 
the injection site is held firmly while the syringe is placed against the injection site at a 
90° angle. The actuator is pressed and the material is released into the muscle and held 
firmly for 3 seconds. After the injection, the site is covered with a sterile covering and 
pressure applied with 3 fingers for 1 minute. Biojector 2000® utilizes sterile, single-use 
syringes for variable dose, up to 1mL, medication administration. The study product is 
delivered under pressure by a compressed CO2 gas cartridge that is stored inside the 
Biojector 2000®. When the Biojector 2000®’s actuator is depressed, CO2 is released, 
causing the plunger to push the study product out of the sterile syringe through the skin 
and into the underlying tissue. The study product is expelled through a micro-orifice at 
high velocity in a fraction of a second to pierce the skin. The CO2 does not come in 
contact with the injectate and the syringe design prevents any back splatter or 
contamination of the device by tissue from the subject. 
8.4.2 
CH505 gp120 proteins or placebo 
Part A: 

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CH505TF gp120 protein admixed with GLA-SE adjuvant or placebo are to be given as a 
1 mL IM injection, using a 3 mL or 5 mL syringe, at months 0, 2, 4, 8 and 12. 
Part B:  
CH505 gp120 proteins admixed with GLA-SE adjuvant or placebo are to be given as a 1 
mL IM injection, using a 3 mL or 5 mL syringe, at months 0, 2, 4, 8, 12, and 16. 
When preparing a dose in a syringe and administering the dose, consideration should be 
given to the volume of solution in the needle before and after the dose is administered. 
Particularly, if the needle used to withdraw the product is replaced prior to vaccine 
administration, consideration should be given to conserving the full dose of product. The 
pharmacy and clinic staff members are encouraged to work together to administer the 
dose specified in the protocol. 
8.5 
Acquisition of study products 
DNA and EnvSeq-1 vaccines will be provided by DAIDS. GLA-SE adjuvant will be 
provided by Infectious Disease Research Institute (IDRI). Placebo for DNA and Placebo 
for EnvSeq-1 proteins will not be provided through the protocol and must be obtained by 
the site. 
Once an HVTN CRS is protocol registered, the pharmacist can obtain study products 
from the NIAID Clinical Research Products Management Center (CRPMC) by following 
the ordering procedures given in Pharmacy Guidelines and Instructions for DAIDS 
Clinical Trials Networks. 
8.6 
Pharmacy records 
The HVTN CRS pharmacist is required to maintain complete records of all study 
products. The pharmacist of record is responsible for maintaining randomization codes 
and randomization confirmation notices for each participant in a secure manner. 
8.7 
Final disposition of study products 
All unused study products must be returned to the CRPMC after the study is completed 
or terminated unless otherwise instructed by the CRPMC. The procedures and relevant 
form are included in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks.  

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9 
Clinical procedures 
The schedule of clinical procedures for Part A is shown in Appendix K. The schedule of 
clinical procedures for Part B is shown in Appendix L. 
9.1 
Informed consent 
Informed consent is the process of working with participants so that they fully understand 
what will and may happen to them while participating in a research study. The HVTN 
informed consent form documents that a participant (1) has been informed about the 
potential risks, benefits, and alternatives to participation, and (2) is willing to participate 
in an HVTN study. Informed consent encompasses all written or verbal study information 
HVTN CRS staff provide to the participant, before and during the trial. HVTN CRS staff 
will obtain informed consent of participants according to HVTN policies and procedures. 
The informed consent process continues throughout the study. Key study concepts should 
be reviewed periodically with the participant and the review should be documented. At 
each study visit, HVTN CRS staff should consider reviewing the procedures and 
requirements for that visit and for the remaining visits. Additionally, if any new 
information is learned that might affect the participants’ decisions to stay in the trial, this 
information will be shared with trial participants. If necessary, participants will be asked 
to sign revised informed consent forms. 
An HVTN CRS may employ recruitment efforts prior to the participant consenting. For 
example, some HVTN CRSs use a telephone script to prescreen people before they come 
to the clinic for a full screening visit. Participants must sign a screening or protocol-
specific consent before any procedures are performed to determine eligibility. HVTN 
CRSs must submit recruitment and prescreening materials to their IRB/EC and any 
applicable RE for human subjects protection review and approval. 
Note: As defined in the DAIDS Protocol Registration Manual, an RE is “Any group other 
than the local IRB/EC responsible for reviewing and/or approving a clinical research 
protocol and site-specific ICFs [informed consent forms] prior to implementation at a 
site.” CRSs are responsible for knowing the requirements of their applicable REs. 
9.1.1 
Screening consent form 
Without a general screening consent, screening for a specific study cannot take place 
until the site receives protocol registration from the DAIDS RSC Protocol Registration 
Office. 
Some HVTN CRSs have approval from their IRB/EC and any applicable RE to use a 
general screening consent form that allows screening for an unspecified HIV vaccine 
trial. In this way, HVTN CRS staff can continually screen potential participants and, 
when needed, proceed quickly to obtain protocol-specific enrollment consent. Sites 
conducting general screening or prescreening approved by their IRB/EC and any 
applicable RE may use the results from this screening to determine eligibility for this 
protocol, provided the tests are conducted within the time periods specified in the 
eligibility criteria.  

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9.1.2 
Protocol-specific consent forms 
The protocol-specific consent forms describe the study products to be used and all 
aspects of protocol participation, including screening and enrollment procedures. A 
sample protocol-specific consent form for Part A is located in Appendix A. A sample 
protocol-specific consent form for Part B is located in Appendix B. A separate sample 
consent form for other uses of specimens is located in Appendix D. 
Each HVTN CRS is responsible for developing a protocol-specific consent form(s) for 
local use, based on the sample protocol-specific consent forms in Appendix A, Appendix 
B, and Appendix D. The consent form(s) must be developed in accordance with 
requirements of the following: 
 
CRS’s IRB/EC and any applicable REs, 
 
CRS’s institution, and 
 
Elements of informed consent as described in Title 45, CFR Part 46 and Title 21 
CFR, Part 50, and in the International Conference on Harmonisation (ICH) E6, 
Good Clinical Practice: Consolidated Guidance 4.8.  
Study sites are strongly encouraged to have their local CABs review their site-specific 
consent forms. This review should include, but should not be limited to, issues of cultural 
competence, local language considerations, and the level of understandability. 
The sample informed consent form includes instructions throughout the document for 
developing specific content. 
Sites should follow the instructions in the Protocol-specific Official Memo distributed 
along with this protocol regarding when they may begin using their site-specific protocol 
consent forms. 
Regarding protocol registration, sites should follow procedures outlined in the current 
version of the DAIDS Protocol Registration Manual. 
9.1.3 
Assessment of Understanding 
Study staff are responsible for ensuring that participants fully understand the study before 
enrolling them. This process involves reviewing the informed consent form with the 
participant, allowing time for the participant to reflect on the procedures and issues 
presented, and answering all questions completely.  
An Assessment of Understanding is used to document the participant’s understanding of 
key concepts in this HIV vaccine trial. The participant must complete the Assessment of 
Understanding before enrollment. Staff may provide assistance in reading and 
understanding the questions and responses, if necessary. Participants must verbalize 
understanding of all questions answered incorrectly. This process and the participant’s 
understanding of the key concepts should be recorded in source documentation at the site. 
IRB/EC and any applicable RE may require that a participant has signed either a 
screening or protocol-specific consent document prior to administering the Assessment of 
Understanding. The consent process (including the use of the Assessment of 

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Understanding) should be explained thoroughly to the IRB/EC and any applicable RE, 
whose recommendations should be followed. 
9.2 
Pre-enrollment procedures for Parts A and B 
Screening may occur over the course of several contacts/visits, up to and including before 
vaccination on day 0. All inclusion and exclusion criteria must be assessed within 56 
days before enrollment, unless otherwise specified in the eligibility criteria (or below in 
this section). 
After the appropriate informed consent has been obtained and before enrollment, the 
following procedures are performed: 
 
Medical history, documented in the case history record; 
 
Assessment of whether the volunteer is at low risk for HIV infection; 
 
Complete physical examination, including height, weight, vital signs, and clinical 
assessments of head, ears, eyes, nose, and throat; neck; lymph nodes; heart; chest; 
abdomen; extremities; neurological function; and skin; 
 
Assessment of concomitant medications the volunteer is taking, including 
prescription and nonprescription drugs, vitamins, topical products, 
alternative/complementary medicines (eg, herbal and health food supplements), 
recreational drugs, vaccinations, and allergy shots (record the complete generic name 
for all medications); 
 
HIV infection assessment including pretest counseling (see Section 9.7); 
 
Laboratory tests as defined in the inclusion and exclusion criteria, including: 
 
Screening HIV test, 
 
HBsAg, 
 
Anti-HCV antibodies, 
 
Syphilis test, 
 
CBC with differential and platelets, 
 
Chemistry panel (ALT, AST, alkaline phosphatase, and creatinine), 
 
Urine dipstick (as described in Section 9.9), and 
 
Urine or serum pregnancy test (participants who were born female) 
 
Administration of behavioral risk assessment questionnaire; 
 
Obtaining of volunteer demographics in compliance with the NIH Policy on 
Reporting Race and Ethnicity Data: Subjects in Clinical Research, Aug. 8, 2001 
(available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-053.html); 

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 
Counseling on HIV testing and risk reduction, performed in compliance with the US 
Centers for Disease Control and Prevention (CDC)’s current guidelines or other local 
guidelines for HIV counseling, testing, and referral as described in Section 9.7; and 
 
Discussion of pregnancy prevention. A pregnant or breastfeeding person may not be 
enrolled in this trial. Specific criteria and assessment of contraception and pregnancy 
status are described in study inclusion criteria. Discussion of pregnancy prevention 
includes advising a participant who was born female and who reports no current 
sexual activity that could lead to that participant becoming pregnant to have a plan to 
begin adequate birth control. This plan would be put to use if, during the study, the 
participant becomes sexually active in a way that could lead to that participant 
becoming pregnant.  
9.2.1 
Use of screening results from another HVTN study 
If a participant screens for an HVTN study at the same HVTN CRS but then does not join 
that study, screening results from that effort may be applied to the screening for this 
protocol, as long as the screening was done under participant consent, the participant has 
signed a consent form to begin screening for this study, and the tests were conducted 
within the time periods specified in the eligibility criteria (see Sections 7.1 and 7.2). 
9.3 
Enrollment and vaccination visits 
Enrollment is simultaneous with first vaccination. The time interval between 
randomization and enrollment should not exceed 4 working days. The HVTN CRS 
registers the participant by scheduling the day 0 visit (enrollment) via the Web-based 
randomization system, and requests the randomization assignment. Circumstances may 
require a participant’s enrollment visit to be changed. This may exceed the 4-day 
randomization time limit. 
At all vaccination visits, the following procedures are performed before vaccination: 
 
Abbreviated physical examination, including weight, vital signs, and a symptom-
directed evaluation by history and/or appropriate physical exam based on participant 
self-reported symptoms or complaints; 
 
Assessment of baseline reactogenicity parameters; 
 
Assessment of concomitant medications (as described in Section 9.2); 
 
Assessment of any new or unresolved AEs/intercurrent illnesses; and 
 
Urine or serum pregnancy test (for participants who were born female). Persons who 
are NOT of reproductive potential due to having undergone total hysterectomy or 
bilateral oophorectomy (verified by medical records), are not required to undergo 
pregnancy testing. 
Following completion of all procedures in the preceding list, and if results indicate that 
vaccination may proceed, vaccination is prepared and administered (see Sections 8.3 and 
8.4). 

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Administration of all injections during a vaccination visit must be accomplished within 1 
calendar day. 
Immediately following vaccination, the participant remains in the clinic for observation. 
An initial reactogenicity assessment is made at a target of 30 minutes after injection, with 
an acceptable range of 25-60 minutes. Before leaving the clinic, the participant is given 
the postvaccination memory tool and is instructed on how to complete it. The site will 
make arrangements to be in contact with the participant during the reactogenicity period 
(as described in Section 9.10). 
The following procedures will be performed at all vaccination visits. These procedures 
may be performed prior to or following vaccination:  
 
Risk reduction counseling (as described in Section 9.7);  
 
Pregnancy prevention assessment (as described in Section 9.2 and 9.8); and 
 
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 K 
and Appendix L:  
 
Administration of the social impact assessment questionnaire (types of impacts 
assessed involve personal relationships, health insurance, life insurance, educational 
or employment opportunities, housing, immigration, or travel); 
 
Administration of behavioral risk assessment questionnaire; 
 
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); and 
 
In Part B, optional stool specimen collection (should be completed prior to 
vaccination) (see Appendix L). Collect dietary, antibiotic use, and gastrointestinal 
symptom information from participants providing stool specimen.  
9.4 
Follow-up visits 
The following procedures are performed at all scheduled follow-up visits: 
 
Risk reduction counseling (as described in Section 9.7);  
 
Pregnancy prevention assessment (as described in Section 9.2 and 9.8); and 
 
Assessment of new or unresolved social impacts (site staff will ask participant about 
the status of any unresolved social impacts and if s/he has experienced any new 
social impacts as a result of the trial participation); 

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 
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 K and Appendix L:  
 
Administration of the social impact assessment questionnaire (types of impacts 
assessed involve personal relationships, health insurance, life insurance, educational 
or employment opportunities, housing, immigration, or travel); 
 
Administration of a questionnaire that asks the participant about any HIV testing he 
or she may have received outside of the study. Participants will also be asked whether 
they believe they received the active vaccine or the control; 
 
HIV infection assessment including pre-test counseling. A subsequent follow-up 
contact is conducted to provide post-test counseling and to report results to 
participant; 
 
Confirm that participants received HIV test results from previous visit. If not, provide 
test results and post-test counseling as appropriate; 
 
Abbreviated physical examination including weight, vital signs, and a symptom-
directed evaluation by history and/or appropriate physical exam based on participant 
self-reported symptoms or complaints; 
 
Complete physical examination, including weight, vital signs, and clinical 
assessments of head, ears, eyes, nose, and throat; neck; lymph nodes; heart; chest; 
abdomen; extremities; neurological function; and skin; 
 
Specimen collection; 
 
In Part B, specimen collection includes optional stool sample (see Appendix L). 
Collect dietary, antibiotic use, and gastrointestinal symptom information from 
participants providing stool specimen. 
 
Clinical laboratory tests including: 
 
CBC with differential, 
 
Chemistry panel (see Section 9.2), and 
 
Urine dipstick (urinalysis if appropriate; see Section 9.9); and 
 
Urine or serum pregnancy test (for participants who were born female). Persons who 
are NOT of reproductive potential due to having undergone total hysterectomy or 
bilateral oophorectomy (verified by medical records), are not required to undergo 
pregnancy testing. 

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9.5 
Contact at 6 months after last scheduled visit 
CRS staff will contact study participants at 6 months after the last scheduled visit to 
collect the information listed below. This contact may be accomplished by phone, text 
message, or email. If indicated, the participant may be asked to come in for a clinical 
assessment which may also include referrals for AESI assessment. AESIs are described 
further in Appendix M. 
 
Confirmation of vital status; if deceased, attempt to learn cause and date of death 
 
If participant is alive, record the participant’s responses to the following: 
 
Assessment of new or unresolved AEs/intercurrent illnesses: 
o Life threatening adverse experiences; 
o Persistent or significant disability/incapacity; 
o Hospitalizations and reasons; 
o Other important medical events that may jeopardize the participant or may 
require intervention to prevent 1 of the other outcomes listed above; 
o New chronic conditions requiring more than 30 days of medical intervention 
or medication; 
o AESI (Section 11.2.2. A sample list of AESI is provided in Appendix M); 
o New diagnosis of HIV infection; and 
o 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.  
9.5.1 
Interim contacts 
CRSs may report safety information obtained at a contact other than scheduled contacts. 
These contacts are reported as interim visits. 
9.6 
Stool sample collection in Part B 
Three stool samples will be collected from the study participants in Part B who agree to 
this procedure: 1 prior to enrollment (before the injection of the vaccine), 1 at the Month 
8.5 timepoint, and 1 at the Month 16.5 timepoint. These samples will be collected using 
swabs, either via rectal swabs or by taking swabs from stool. If bulk stool is provided, a 
portion may be kept for further analysis. 

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9.7 
HIV counseling and testing 
HIV counseling will be performed in compliance with the CDC’s guidelines or other 
local guidelines for HIV counseling and referral. HIV testing will be performed in 
accordance with the current HVTN HIV testing algorithm following enrollment. 
Participants will be counseled routinely during the trial on the avoidance of HIV infection 
and on the potential negative social impacts of testing antibody positive due to the 
vaccine. They will also be counseled on the risks of HIV antibody testing outside of the 
HVTN CRSs and will be discouraged from doing so during study participation and/or 
during any period of vaccine-induced positive serology. 
Study staff will take particular care to inform study participants of the likelihood of 
routine HIV testing being offered or performed outside the study CRS at emergency 
rooms, clinics, and medical offices. Such testing has become more likely due to the 
CDC’s revised guidelines for HIV counseling and testing, as well as policy changes in 
many countries to make HIV testing more frequent and routine. CRS staff should inform 
participants of their right to opt out of HIV testing outside the study site. CRS staff 
should inform study participants if local and/or state policies and regulations permit 
medical providers to perform HIV testing without first informing patients. If this is the 
case, then CRS staff should advise study participants that they may decline testing 
preemptively. CRS staff should also inform participants if positive results must be 
reported to local public health authorities. CRS staff should also inform participants of 
the need to maintain study blinding by getting HIV testing only at the study CRS. CRS 
staff should provide participants with CRS contact information and should encourage 
participants to ask medical providers to contact the CRS. The CRS can verify that the 
participant is in an HIV vaccine clinical trial and should only be tested at the study CRS. 
Potential participants identified as being HIV infected during screening are not enrolled. 
All participants who become HIV infected during the study will be terminated from this 
study. Potential and enrolled participants identified as HIV infected will be referred for 
medical treatment, counseling, and management of the HIV infection. These individuals 
may also be referred to appropriate ongoing clinical trials or observational studies. 
9.7.1 
Distinguishing intercurrent HIV infection from vaccine-induced positive serology 
The study product may elicit an antibody response to HIV proteins. Therefore, vaccine-
induced positive serology may occur in this study. Several precautionary measures will 
be taken to distinguish intercurrent HIV infection from vaccine-induced positive 
serology. These precautionary measures include: 
 
Participants will have physical examinations at visits specified in Appendix K and 
Appendix L. Signs or symptoms of an acute HIV infection syndrome, an intercurrent 
illness consistent with HIV-1 infection, or probable HIV exposure would prompt a 
diagnostic workup per the HVTN algorithm for Recent Exposure/Acute Infection 
Testing to determine HIV infection. 
 
HIV testing will be performed at multiple timepoints throughout the study (Appendix 
K and Appendix L). The Laboratory Program (or approved diagnostic laboratory) 
will follow the HVTN HIV testing algorithm (as described in the HVTN Laboratory 
Manual of Operations), which is able to distinguish vaccine-induced antibody 
responses from actual HIV infections.  

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 
All participants can receive HIV-1 diagnostic testing from the site following their last 
scheduled visit until they are told that they did not receive an HIV vaccine or that 
they do not have vaccine-induced seropositivity. 
 
All participants who received vaccine product and who have vaccine-induced 
positive or indeterminate HIV-1 serology (as measured by the standard anti-HIV 
antibody screening tests) at or after the study is unblinded will be offered poststudy 
HIV-1 diagnostic testing (per the HVTN poststudy HIV-1 testing algorithm) 
periodically and free of charge as medically/socially indicated (approximately every 
6 months) unless or until HIV Ab testing is no longer the standard test in clinical 
settings.  
9.7.2 
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 9.7.1). In order to provide poststudy HIV testing to 
distinguish between VISP and HIV infection, and to mitigate potential social harms 
resulting from VISP in HIV vaccine recipients who are not infected with HIV, the HVTN 
has created a VISP registry. Following study unblinding, the registry will allow trained 
staff to verify that an individual has received an HIV vaccine, and therefore has the 
potential for VISP. Information in the VISP registry will not be used for research. Rather, 
the registry exists to support provision of poststudy testing and counseling services to 
HIV vaccine recipients. The registry contains the names of all study participants, unless 
they request that their names be removed. 
9.8 
Contraception status 
Contraception status is assessed and documented at every scheduled clinic visit for a 
participant who was born female and who is sexually active in a way that could cause that 
participant to become pregnant. Prior to enrollment and throughout the study, staff will 
ask participants to verbally confirm their use of adequate contraceptive methods. A 
participant who was born female and is sexually active in a way that could cause that 
participant to become pregnant should be reminded at all scheduled clinic visits of the 
importance of using contraception and should be referred to specific counseling, 
information, and advice as needed. (Specific contraception requirements are listed in 
Section 7.1). This reminder should be documented in the participant’s study record. 
Self-reported infertility—including having reached menopause (no menses for 1 year) or 
having undergone hysterectomy, bilateral oophorectomy, or tubal ligation—must be 
documented in the participant’s study record. 
9.9 
Urinalysis 
Dipstick testing may be performed in the clinic or the lab, as long as the required 
elements (glucose, protein, and hemoglobin) are tested. The examination is performed on 
urine obtained by clean catch. 
If the screening dipstick is transiently abnormal due to menses or infection, document this 
issue in the participant’s source documentation. For infection, provide appropriate 

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treatment and/or referral. Following resolution, repeat the dipstick and, if within the 
eligibility limits specified in the protocol, the participant may be enrolled. 
Follow-up urinalysis should be deferred if a participant is menstruating, but should be 
performed as soon as possible. If a follow-up dipstick is abnormal due to a participant’s 
menstrual period, document in the comment section of the case report form (CRF) and 
repeat the dipstick once the participant is no longer menstruating. A micro-urinalysis is 
not required. 
9.10 
Assessments of reactogenicity 
For all participants, baseline assessments are performed before and reactogenicity 
assessments are performed after each vaccination. All reactogenicity symptoms are 
graded according to the Division of AIDS Table for Grading the Severity of Adult and 
Pediatric AdverseEvents, Version 2.0, November 2014, except as noted in Section 11.2.2. 
The reactogenicity assessment period is 7 full days following each vaccination per the 
assessment schedule shown in Table 9-1. Participants are instructed to record symptoms 
using a postvaccination memory tool. Contact between the participant and the site staff 
should take place at least once within 72 hours/3 days postvaccination. Clinic staff will 
follow new or unresolved reactogenicity symptoms present at day 7 to resolution. 
Participants are instructed to contact the clinic for events that arise during the period 
between vaccination and the next scheduled visit. In general, a participant who self-
reports any postvaccination reaction greater than mild is seen by a clinician within 48 
hours after onset, unless the reaction is improving and/or has completely resolved.  
Reactogenicity events are reported using CRFs that correspond to the time of assessment 
in Table 9-1. Reactogenicity assessments include assessments of systemic and local 
symptoms, vaccine-related lesions, and lymph nodes. Events not listed on a CRF, or with 
an onset after the reactogenicity assessment period (day of vaccination and 7 full days 
after), or those meeting SAE/adverse events requiring expedited reporting to DAIDS 
criteria, are recorded on an adverse experience log form.  
Table 9-1 Schedule of reactogenicity assessments 
Day 
Time 
Performed by 
0a 
Baseline: before vaccination 
HVTN CRS staff 
 
Early: 25-60 minutes after vaccination 
HVTN CRS staff 
 
Between early assessment and 11:59pm 
day 0 
HVTN CRS staff or participant 
1 
Between 12:00am and 11:59pm day 1 
HVTN CRS staff or participant 
2 
Between 12:00am and 11:59pm day 2 
HVTN CRS staff or participant 
3 
Between 12:00am and 11:59pm day 3 
HVTN CRS staff or participant 
4 
Between 12:00am and 11:59pm day 4 
HVTN CRS staff or participant 
5 
Between 12:00am and 11:59pm day 5 
HVTN CRS staff or participant 
6 
Between 12:00am and 11:59pm day 6 
HVTN CRS staff or participant 
7 b 
Between 12:00am and 11:59pm day 7 
HVTN CRS staff or participant 
a Day of vaccination 
b New or unresolved reactogenicity symptoms present on day 7 are followed until resolution 

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9.10.1 
Assessment of systemic and local symptoms 
Systemic symptoms include increased body temperature, malaise and/or fatigue, myalgia, 
headache, chills, arthralgia, nausea, and vomiting. Local symptoms include pain and/or 
tenderness proximal to the injection site. The daily maximum severity reached for each 
symptom during the assessment period is reported.  
Body temperature is measured by oral or infrared thermometry and reported in degrees 
Celsius. If temperature is measured in Fahrenheit, the conversion to Celsius should be 
documented in the participant’s chart note. A measurement is taken once daily during the 
assessment period and should be repeated if participant is feeling feverish. 
9.10.2 
Assessment of injection site 
Typical injection site reactions are erythema/redness and induration/swelling. The 
maximum horizontal and maximum vertical measurements for all injection site reactions 
are recorded. 
All injection site reactions are monitored until resolution. Areas greater than 25 cm2 are 
followed daily; otherwise, the frequency of follow-up is based on clinician judgment. 
9.10.3 
Assessment of lymph nodes 
This assessment is required only when reactogenicity assessments are performed by 
HVTN CRS staff, not by the participant. 
Only the proximally draining lymph nodes are assessed (eg, inguinal nodes on the same 
side of the body for injections given in the vastus lateralis). Lymph nodes are first 
evaluated for enlargement and tenderness. If they are found to be enlarged, measurements 
are taken to determine the size (widest diameter) of the enlarged node(s). 
9.11 
Visit windows and missed visits 
Visit windows are defined in HVTN 115 Study Specific Procedures. For a visit not 
performed within the window period, a Missed Visit form is completed. If the missed 
visit is one that required safety assessments or local safety labs, HVTN CRS staff should 
attempt to bring the participant in for an interim visit as soon as possible. 
Procedures performed at an interim visit are usually toxicity/safety assessments 
(including local safety labs) and HIV testing. With the exception of HIV testing, these 
procedures are performed only if they were required at the missed visit or if clinically 
indicated. HIV testing may be performed as deemed appropriate by the study staff. Blood 
samples for immunogenicity assays are not typically collected at interim visits. 
If a missed visit required vaccination, please refer to Section 7.3.2 and Section 7.3.3 for 
resolution. 

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9.12 
Early termination visit 
In the event of early participant termination, site staff should consider if the following 
assessments are appropriate: a final physical examination, clinical laboratory tests 
(including urine dipstick, CBC with differential, and chemistry panel), pregnancy testing, 
social impact assessment, and HIV test. 
9.13 
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. In case of required termination, enrollment in an observational study 
should be offered to the participant. If the participant terminates from the study prior to 
the pregnancy outcome, the site should make every effort to keep in touch with the 
participant in order to ascertain the pregnancy outcome. Pregnancies and pregnancy 
outcomes will be reported. 

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10 
Laboratory 
10.1 
HVTN CRS laboratory procedures 
The HVTN Site Lab Reference Manual provides further guidelines for operational issues 
concerning the clinical and processing laboratories. The manual includes guidelines for 
general specimen collection, special considerations for phlebotomy, specimen labeling, 
whole blood processing, HIV screening/diagnostic testing, and general screening and 
safety testing. 
Tube types for blood collection are specified in Appendix I and Appendix J. For tests 
performed locally, the local lab may assign appropriate tube types. 
In specific situations, the blood collection tubes may be redirected to another laboratory 
or may require study-specific processing techniques. In these cases, laboratory special 
instructions will be posted on the protocol-specific section of the HVTN website. 
10.2 
Total blood volume 
Required blood volumes per visit are shown in Appendix I and Appendix J. Not shown is 
any additional blood volume that would be required if a safety lab needs to be repeated, 
or if a serum pregnancy test needs to be performed. The additional blood volume would 
likely be minimal. The total blood volume drawn for each participant will not exceed 500 
mL in any 56-day (8-week) period. 
10.3 
Primary immunogenicity timepoints 
Part A 
The primary immunogenicity timepoint in Part A is at visit 8 (day 126) (ie, 2 weeks after 
the third vaccination visit). Endpoint assays for humoral and cellular responses are 
performed on participants at the primary immunogenicity timepoint and may be 
performed at baseline. Depending on the number of responders observed, assays for 
humoral and cellular responses may be performed on participants at other timepoints; the 
schedule is shown in Appendix I. 
Part B 
The primary immunogenicity timepoints in in Part B are at visit 10 (day 238) (ie, 2 weeks 
after the fourth vaccination visit) and visit 15 (day 500) (2 weeks after the sixth 
vaccination visit). Endpoint assays for humoral and cellular responses are performed on 
participants at the primary immunogenicity timepoints and may be performed at baseline. 
Depending on the number of responders observed, assays for humoral and cellular 
responses may be performed on participants at other timepoints; the schedule is shown in 
Appendix J. 

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10.4 
Endpoint assays: cellular 
10.4.1 
Flow cytometry 
Flow cytometry will be used to examine vaccine-specific CD4+ and CD8+ T-cell 
responses following stimulation of PBMCs with synthetic HIV peptides that span the 
proteins encoded by the vaccine construct. ICS parameters will include cytokines such as 
IFN-γ, IL-2, and TNF-α, and may include other cytokines to identify T cells of specific 
functionality (such as Th2 and Th17). Markers of cytotoxic potential (Granzyme B, 
perforin and CD57) may also be included. Data will be reported as percentages of CD4+ 
or CD8+ T cells responding to a specific peptide pool. Additional cell surface markers, 
cytokines, or functional markers may also be analyzed. 
Flow cytometry will also be used to phenotypically characterize peripheral follicular 
helper T cells (pTfh). Identification of pTfh will be based on expression of CXCR5 and 
PD-1 on CD4+ T cells, and may include additional markers. 
10.5 
Endpoint assays: humoral 
10.5.1 
Binding antibody assays 
HIV-1 Env binding IgG and IgA antibodies to the vaccine immunogens (EnvSeq-1 gp120 
TF, 53, 78, 100) will be assessed on plasma/serum samples from study participants taken 
at the primary immunogenicity timepoints and baseline. Conformational epitopes (ie 
CD4BS specificities using differential binding to EnvSeq-1 gp120 compared to CH505 
I371 protein and sCD4 blocking) will be determined. Specimens from other timepoints 
as well as other HIV antigens (ie other conformational epitopes and linear epitopes and 
profiling the antibody subclasses (IgG1, IgG2, IgG3, IgG4) may also be assayed based on 
the results of the initial assay.  
10.5.2 
Neutralizing antibody assay 
HIV-1–specific neutralizing antibody assays will be performed on serum samples from 
all study participants taken at the primary immunogenicity timepoints. Specimens from 
the baseline and other timepoints may also be analyzed at the discretion of the HVTN 
Laboratory Program, which may be contingent on the results of the primary 
immunogenicity timepoints. Assays will be performed with the 4 EnvSeq-1 vaccine 
isolates (CH0505.TF, CH0505.w53.e16, CH0505.w78.33, CH0505.w100.B6) and a tier 1 
variant of the TF strain, CH0505.wk4.3. Additional assays will test neutralization of 
heterologous tier 1 and tier 2 isolates [73]. 
10.5.3 
B-cell lineage and repertoire analysis 
Single memory B cells or plasmablasts will be single cell sorted. For plasmablasts, VH 
and VL genes will be amplified and cloned into an IgG1 backbone for expression and 
determination of binding and neutralization. For memory B cells, Env reactive memory B 
cells will be sorted using CH505 Env hooks, and then single cell sorted into individual 
wells of 96 well plates. VH and VL genes will be amplified and cloned into an IgG1 
backbone and tested for Env binding and HIV neutralization. In some cases, memory B 
cells will be cultured in limiting dilution cultures and screened for binding and 
neutralization before PCR and VH and VL rescue. Finally, next generation sequencing 

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for all VH and VL families will be performed on memory B cells or plasmablasts for VH 
and VL genes.  
10.6 
Lab assay algorithm 
The Lab Assay Algorithm lists assays to characterize cellular, humoral, and innate 
immune responses as well as host genetics that may be conducted to determine endpoints 
in HVTN vaccine trials. The type of assay(s) employed will be dependent on the response 
obtained by the primary immunogenicity assays at relevant timepoints. Please note that 
the Lab Assay Algorithm will be updated periodically to include new assays. 
10.7 
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. 
10.7.1 
Fc-Mediated Antibody Effector Function 
Additional assays to measure the induction of antibody Fc-mediated antibody functions 
(ie antibody dependent cellular cytotoxicity, phagocytosis, FcR binding, glycan 
modifications, recognition of virus particles and infected cells, etc.) may be performed on 
select samples and timepoints based on the primary analysis. 
10.7.2 
Microbiome analysis 
Swabs of stool and/or bulk stool samples will be shipped to a central laboratory. Stool 
samples will be subjected to culture to obtain bacteria samples that are processed to yield 
a homogeneous stool flora lysate of each culture type. These lysates are then available to 
use to assess antibody binding by Western blot, ELISA, or other methods. In addition, 
stool samples will be subjected to chaotropic lysis and bead beating to liberate bacterial 
DNA, followed by DNA extraction. Purified DNA will be subjected to quality control 
qPCR assays to measure total bacterial load and assess for PCR inhibitors. Broad-range 
16S rRNA PCR will be performed. Bacterial community composition will be assessed 
using taxonomic assignment of reads to a custom reference set of 16S rRNA gene 
sequences from the human gut. Some samples may be analyzed by shotgun 
metagenomics to create protein expression libraries to analyze the effect of stool 
composition on vaccine response. Finally, bulk stool samples will have antibodies 
extracted for analysis of the presence of mucosal antibodies elicited by the vaccine. 
10.8 
Other use of stored specimens 
The HVTN stores specimens from all study participants indefinitely, unless a participant 
requests that specimens be destroyed or if required by IRB/EC, or RE. 
Other use of specimens is defined as studies not covered by the protocol or the informed 
consent form for the main study (Appendix A). 

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This research may relate to HIV, vaccines, the immune system, and other diseases. This 
could include limited genetic testing and, potentially, genome-wide studies. This research 
is done only to the extent authorized in each study site’s informed consent form, or as 
otherwise authorized under applicable law. Other testing on specimens will occur only 
after review and approval by the HVTN, the IRB/EC of the researcher requesting the 
specimens, and the CRS’s IRBs/ECs/REs if required. 
The protocol sample informed consent form is written so that the participant either 
explicitly allows or does not allow their samples to be used in other research when they 
sign the form. Participants who initially agree to other use of their samples may rescind 
their approval once they enter the study; such participants will remain in this study and 
their samples will only be used for the studies described in this protocol. If a participant 
decides against allowing other research using his or her samples, or at any time rescinds 
prior approval for such other use, the study site investigator or designee must notify 
HVTN Regulatory Affairs in writing. In either case, HVTN Regulatory Affairs directs the 
HVTN Lab Program not to use samples from these participants for such other uses.  
CRSs must notify HVTN Regulatory Affairs if institutional or local governmental 
requirements pose a conflict with or impose restrictions on other use of specimens. 
10.9 
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 115 PSRT 
The HVTN 115 PSRT is composed of the following members: 
 
DAIDS medical officer representative, 
 
Protocol chair and cochair, 
 
Protocol Team leader, 
 
Core medical monitor, and 
 
 Clinical safety specialist. 
The clinician members of HVTN 115 PSRT are responsible for decisions related to 
participant safety. 
The Protocol Team clinic coordinator, project manager, vaccine developer representative, 
clinical trial manager, and others may also be included in HVTN 115 PSRT meetings. 
11.1.2 
HVTN SMB 
The SMB is a multidisciplinary group consisting of biostatisticians, clinicians, and 
experts in HIV vaccine research that, collectively, has experience in the conduct and 
monitoring of vaccine trials. Members of the SMB are not directly affiliated with the 
protocols under review.  
The SMB reviews safety data, unblinded as to treatment arm, approximately every 4 
months. The reviews consist of evaluation of cumulative reactogenicity events, AE, 
laboratory safety data, and individual reports of adverse events requiring expedited 
reporting to DAIDS. To increase the sensitivity for detecting potential safety problems, 
the SMB will review safety data aggregated across multiple protocols that use the same 
or similar vaccine candidates. The SMB conducts additional special reviews at the 
request of the HVTN 115 PSRT.  
Study sites will receive SMB summary minutes and are responsible for forwarding them 
to their IRB/EC and any applicable RE. 
11.1.3 
SDMC roles and responsibilities in safety monitoring  
The roles and responsibilities of the SDMC in relation to safety monitoring include: 
 
Maintaining a central database management system for HVTN clinical data; 
 
Providing reports of clinical data to appropriate groups such as the HVTN 115 PSRT 
and HVTN SMB (see Section 11.1.2); 

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11.1.4 
HVTN Core roles and responsibilities in safety monitoring 
 
Daily monitoring of clinical data for events that meet the safety pause and HVTN 
115 PSRT AE review criteria (see Section 11.4); 
 
Notifying HVTN CRSs and other groups when safety pauses or planned holds are 
instituted and lifted (see Section 11.4); 
 
Querying HVTN CRSs for additional information regarding reported clinical data; 
and 
 
Providing support to the HVTN 115 PSRT. 
11.2 
Safety reporting 
11.2.1 
Submission of safety forms to SDMC 
Sites must submit all safety forms (eg, reactogenicity, adverse experience, urinalysis, 
local lab results, concomitant medications) before the end of the next business day after 
receiving the information. The forms should not be held in anticipation of additional 
information at a later date. If additional information is received at a later date, the forms 
should be updated and resubmitted before the end of the next business day after receiving 
the new information. 
11.2.2 
AE reporting 
An AE is any untoward medical occurrence in a clinical investigation participant 
administered a study product/procedure(s) and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational study product/procedure(s), whether or not 
related to the investigational study product/procedure(s). All AEs are graded according to 
the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.0, November 2014, available on the RSC website at 
http://rsc.tech-res.com/safetyandpharmacovigilance/gradingtables.aspx, except: 
 
Weight loss is required to be reported as an AE only if it is considered to be 
deleterious to the participant’s health (see HVTN 115 Study Specific Procedures); 
 
Injection Site Erythema or Redness and Injection Site Induration or Swelling will not 
consider interference with usual social and functional activities such that: 
 
Grade 1 is: 2.5 to < 5 cm in diameter OR 6.25 to < 25 cm2 surface area; 
 
Grade 2 is: ≥ 5 to < 10 cm in diameter OR ≥ 25 to < 100 cm2 surface area; 
 
Grade 3 is: ≥ 10 cm in diameter OR ≥ 100 cm2 surface area OR Ulceration OR 
Secondary infection OR Phlebitis OR Sterile abscess OR Drainage; 
 
Grade 4 is: Potentially life-threatening consequences (eg, abscess, exfoliative 
dermatitis, necrosis involving dermis or deeper tissue); 

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 
The grading of Insomnia events will consider the criteria within the Insomnia 
parameter as well as the general AE functional table such that: 
 
Grade 1 Insomnia is defined as: Mild difficulty falling asleep, staying asleep, or 
waking up early causing no or minimal interference with usual social and 
functional activities with intervention not indicated; 
 
Grade 2 Insomnia is defined as: Moderate difficulty falling asleep, staying 
asleep, or waking up early, causing greater than minimal interference with usual 
social and functional activities with intervention indicated; 
 
Grade 3 Insomnia is defined as: Severe difficulty falling asleep, staying asleep, or 
waking up early, causing inability to perform usual social and functional 
activities with intervention or hospitalization indicated. 
If a definition of insomnia falls between 2 grades, the final grading will be selected 
based on the degree of interference with usual social and functional activities caused 
by the symptoms. 
All AEs are reported to the SDMC on the appropriate CRF. Clinic staff should evaluate 
every AE to determine if (1) the AE meets the requirements for expedited reporting to 
DAIDS (Section 11.2.3), (2) if the AE meets the criteria for a safety pause/prompt AE 
review (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 M. 
Sites are expected to notify the CSS of any serious safety concern requiring their 
attention (see Table 11-1). Telephone numbers and email addresses are listed in the Key 
Resource Guide of the HVTN 115 Study Specific Procedures. Telephone numbers and 
email addresses are found on the protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/hvtn115). Concerns requiring immediate attention 
should be communicated by calling the clinical safety phone. 
In the case of email notification, the CSS will reply during working hours (US Pacific 
Time) to confirm that the email has been received and reviewed. If email service is not 
available, the HVTN CRS should notify the CSS of the event by telephone, then submit 
CRFs. 
In addition, site investigators are required to submit AE information in accordance with 
IRB/EC and any applicable RE requirements. 
11.2.3 
Expedited reporting of adverse events to DAIDS 
Requirements, definitions and methods for expedited reporting of AEs are outlined in 
Version 2.0 (January 2010) of the Manual for Expedited Reporting of Adverse Events to 
DAIDS (DAIDS EAE Manual), which is available on the RSC website at http://rsc.tech-
res.com/safetyandpharmacovigilance/. The SAE Reporting Category will be used for this 
study.  
The internet-based DAIDS Adverse Experience Reporting System (DAERS) must be 
used for expedited AE reporting to DAIDS. In the event of system outages or technical 
difficulties, expedited AE reports may be submitted via the DAIDS EAE Form. For 

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questions about DAERS, please contact CRMSsupport@niaid.nih.gov or from within the 
DAERS application itself.  
Sites where DAERS has not been implemented will submit expedited AE reports by 
documenting the information on the current DAIDS EAE Form. This form is available on 
the RSC website: http://rsc.tech-res.com/safetyandpharmacovigilance/. For questions 
about expedited AE reporting, please contact the RSC (DAIDSRSCSafetyOffice@tech-
res.com).  
The study products for which expedited reporting are required are  
 
CH505TF HIV gp120 with GLA-SE or placebo  
 
CH505w53 HIV gp120 with GLA-SE or placebo 
 
CH505w78 HIV gp120 with GLA-SE or placebo 
 
CH505w100 HIV gp120 with GLA-SE or placebo 
 
DNA Mosaic-Tre env or placebo 
While the participant is in the main study reporting period (See Section 3), the SAE 
Reporting Category will be used.  
After the protocol-defined AE reporting period for the study, unless otherwise noted, only 
Suspected, Unexpected Serious Adverse Reactions as defined in Version 2.0 of the 
DAIDS EAE Manual must be reported to DAIDS, if the study staff become aware of the 
events.  
The NIAID/DAIDS will report all unexpected SAEs related to the study products 
observed in this clinical trial to the FDA in accordance with 21 CFR 312.32 (IND Safety 
Reports). However, because safety is a primary study endpoint, the Sponsor Medical 
Officer will not routinely be unblinded to study treatment assignment when there is an 
assessment of relatedness of the SAE with the study product(s); and the safety report will 
be sent to the FDA based on the blinded attribution assessment. 
If the PSRT or sponsor believes unblinding of the site PI to treatment assignment will 
assist with the clinical management of the SAE, the PSRT will consult the independent 
HVTN SMB for a recommendation. In the event the HVTN SMB determines that 
unblinding is indicated, the SMB will inform the site physician of the participant’s 
treatment assignment in such a manner as to maintain the study blind of the PSRT and 
study team. For additional impact and management of SAEs on the study, refer to Section 
11.4. 
11.3 
Safety reviews 
11.3.1 
Initial safety evaluation 
Enrollment across all participating HVTN CRSs will be restricted to a maximum of 1 
participant per day and restricted to US sites until 10 participants have been enrolled. All 

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groups in Part A will enroll simultaneously. The HVTN 115 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 10 participants, and will 
determine whether it is safe to proceed with full enrollment in Part A. 
11.3.2 
Safety evaluation for moving from Part A to Part B 
In addition to monitoring participant safety throughout the study period, the HVTN 115 
PSRT will review all cumulative safety data available from groups 1 through 4 up to and 
including the 2-week visit after the third vaccination. Based on the assessment of this 
safety data, the HVTN 115 PSRT will make a decision regarding the appropriateness of 
moving to Part B from a safety perspective. The HVTN SMB may perform an additional 
unblinded review of this safety data to make the final determination based on safety for 
proceeding to part B. 
11.4 
Safety pause and prompt PSRT AE review 
When a trial is placed on safety pause, all enrollment and vaccination with the product 
related to the event that triggered the pause will be held until further notice. The AEs that 
will lead to a safety pause or prompt HVTN 115 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 115 
PSRT, participant safety may be threatened. Criteria for an individual participant’s 
departure from the schedule of vaccinations are listed in Section 7.3. 
Table 11-1 AE notification and safety pause/AE review rules 
Event and 
relationship to study 
products 
Severity 
HVTN CRS actiona 
HVTN Core action 
SAE, related 
Grade 5 or 
Grade 4 
Phone immediately, email 
and submit forms 
immediately 
Immediate pause 
SAE, not related 
Grade 5 
Phone immediately, email 
and submit forms 
immediately 
Immediate HVTN 115 
PSRT notification 
SAE, related 
Grade 3 
Email and submit forms 
immediately 
Prompt HVTN 115 PSRT 
AE review to consider 
pause 
AEb, related 
Grade 4 or 
3 
Email and submit forms 
immediately 
Prompt HVTN 115 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/hvtn115). 
b Does not include subjective reactogenicity symptoms (injection site pain, tenderness, fatigue/malaise, myalgia, arthralgia, chills, headache, 
nausea). 
For all safety pauses, HVTN Core notifies the HVTN 115 PSRT, HVTN Regulatory 
Affairs, DAIDS Pharmaceutical Affairs Branch (PAB), DAIDS Regulatory Affairs 
Branch (RAB), DAIDS Safety and Pharmacovigilance Team (SPT), and participating 
HVTN CRSs. When an immediate safety pause is triggered, HVTN Core notifies the 
SMB.  

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Once a trial is paused, the HVTN 115 PSRT reviews safety data and decides whether the 
pause can be lifted or permanent discontinuation of vaccination is appropriate, consulting 
the SMB if necessary. HVTN Core notifies the participating HVTN CRSs, HVTN 
Regulatory Affairs, DAIDS PAB, DAIDS RAB, and DAIDS SPT of the decision 
regarding resumption or discontinuation of study vaccinations. Based on the HVTN 115 
PSRT assessment, DAIDS RAB notifies the FDA as needed. 
If an immediate HVTN 115 PSRT notification or prompt HVTN 115 PSRT AE review is 
triggered, HVTN Core notifies the HVTN 115 PSRT as soon as possible during working 
hours (US Pacific Time)—or, if the information was received during off hours, by the 
morning of the next work day. If a prompt HVTN 115 PSRT AE review cannot be 
completed within 72 hours of notification (excluding weekends and US federal holidays), 
an automatic safety pause occurs. 
The HVTN requires that each CRS submit to its IRB/EC and any applicable RE protocol-
related safety information (such as IND safety reports, notification of vaccine holds due 
to the pause rules, and notification of other unplanned safety pauses). CRSs must also 
follow all applicable RE reporting requirements. 
In addition, all other AEs are reviewed routinely by the HVTN 115 PSRT (see Section 
11.5.2). 
11.5 
Review of cumulative safety data 
Routine safety review occurs at the start of enrollment and then throughout the study. 
Reviews proceed from a standardized set of protocol-specific safety data reports. These 
reports are produced by the SDMC and include queries to the HVTN CRSs. Events are 
tracked by internal reports until resolution.  
11.5.1 
Daily review 
Blinded daily safety reviews are routinely conducted by HVTN Core for events requiring 
expedited reporting to DAIDS, and events that meet safety pause criteria or prompt 
HVTN 115 PSRT AE review criteria. 
11.5.2 
Weekly review 
During the injection phase of the trial, the HVTN 115 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 115 PSRT. HVTN Core 
reviews reports of clinical and laboratory AEs. Events identified during the review that 
are considered questionable, inconsistent, or unexplained are referred to the HVTN CRS 
clinic coordinator for verification. 
11.6 
Study termination 
This study may be terminated early by the determination of the HVTN 115 PSRT, a 
pertinent national regulatory authority, NIH, FDA, Office for Human Research 

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Protections (OHRP), or vaccine developer(s). In addition, the conduct of this study at an 
individual HVTN CRS may be terminated by the determination of the IRB/EC and any 
applicable RE. 

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12 
Protocol conduct 
This protocol and all actions and activities connected with it will be conducted in 
compliance with the principles of GCP (ICHe6), and according to DAIDS and HVTN 
policies and procedures as specified in the HVTN Manual of Operations, DAIDS Clinical 
Research Policies and Standard Procedures Documents including procedures for the 
following: 
 
Protocol registration, activation, and implementation; 
 
Informed consent, screening, and enrollment; 
 
Study participant reimbursement; 
 
Clinical and safety assessments; 
 
Safety monitoring and reporting; 
 
Data collection, documentation, transfer, and storage; 
 
Participant confidentiality; 
 
Study follow-up and close-out; 
 
Unblinding of staff and participants; 
 
Quality control; 
 
Protocol monitoring and compliance; 
 
Advocacy and assistance to participants regarding negative social impacts associated 
with the vaccine trial; 
 
Risk reduction counseling;  
 
Specimen collection, processing, and analysis;  
 
Ancillary studies, and 
 
Destruction of specimens. 
Any policies or procedures that vary from DAIDS and HVTN standards or require 
additional instructions (eg, instructions for randomization specific to this study) will be 
described in the HVTN 115 Study Specific Procedures.  
12.1 
Social impacts 
Participants in this study risk experiencing discrimination or other personal problems, 
resulting from the study participation itself or from the development of VISP. The HVTN 

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CRS is obliged to provide advocacy for and assistance to participants regarding these 
negative social impacts associated with the vaccine trial. If HVTN CRS staff have 
questions regarding ways to assist a participant dealing with a social impact, a designated 
NIAID or HVTN Core representative can be contacted.  
Social harms are tabulated by the SDMC and are subjected to descriptive analysis. The 
goal is to reduce their incidence and enhance the ability of study staff to mitigate them 
when possible. 
Summary tables of social impact events will be generated weekly, and made available for 
review by the protocol chairs, protocol team leader, and the designated NIAID 
representative. 
12.2 
Compliance with NIH guidelines for research involving products 
containing recombinant or synthetic Nucleic Acid Molecules 
Because this study is evaluating products containing recombinant or synthetic DNA, it 
must comply with regulations set forth in the NIH’s Guidelines for Research Involving 
Recombinant or Synthetic Nucleic Acid Molecules (April 2016). Information about the 
study must be submitted to site Institutional Biosafety Committees (IBCs). Investigators 
at each site are responsible for obtaining IBC approval per NIH guideline section IV-B7-
a-(1). IBC review and approval must be documented by the investigator and submitted as 
part of DAIDS initial protocol registration for this trial before participants are enrolled at 
the site. If this protocol is amended, investigators should follow the requirements of their 
IBC. 
12.3 
Emergency communication with study participants 
As in all clinical research, this study may generate a need to reach participants quickly to 
avoid imminent harm, or to report study findings that may otherwise concern their health 
or welfare.  
When such communication is needed, the CRS will request that its IRB/EC and any 
applicable RE expedite review of the message. If this review cannot be completed in a 
timeframe consistent with the urgency of the required communication, the site should 
contact the participant first, and then notify the IRB/EC and any applicable RE of the 
matter as soon as possible. 

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13 
Version history 
The Protocol Team may modify the original version of the protocol. Modifications are 
made to HVTN protocols via clarification memos, letters of amendment, or full protocol 
amendments.  
The version history of, and modifications to, Protocol HVTN 115 are described below. 
Protocol history and modifications 
Date: May 2, 2017 
Protocol version: 1.0 
Original protocol 

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14 
Document references (other than literature 
citations) 
Other documents referred to in this protocol, and containing information relevant to the 
conduct of this study, include: 
 
Assessment of Understanding. Accessible through the HVTN protocol-specific 
website. 
 
Current CDC Guidelines. Revised Recommendations for HIV Testing of Adults, 
Adolescents, and Pregnant Women in Health-Care Settings. Available at 
http://www.cdc.gov/mmwr/PDF/rr/rr5514.pdf.  
 
Division of AIDS (DAIDS) Clinical Research Policies and Standard Procedures 
Documents. Available at https://www.niaid.nih.gov/research/daids-clinical-research-
policies-standard-procedures  
 
Division of AIDS Protocol Registration Manual. Available at 
https://www.niaid.nih.gov/sites/default/files/documents/prmanual.pdf  
 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events. Version 2.0, November 2014. Available at http://rsc.tech-
res.com/docs/default-
source/safety/daids_ae_grading_table_v2_nov2014.pdf?sfvrsn=8  
 
The Manual for Expedited Reporting of Adverse Events to DAIDS. Version 2.0, 
January 2010. Available at http://rsc.tech-res.com/clinical-research-sites/safety-
reporting/manual  
 
HVTN Certificate of Confidentiality. Accessible through the HVTN website. 
 
HVTN 115 Special Instructions. Accessible through the HVTN protocol-specific 
website. 
 
HVTN 115 Study Specific Procedures. Accessible through the HVTN protocol-
specific website. 
 
HVTN Laboratory Manual of Operations. Accessible through the HVTN website. 
 
HVTN Manual of Operations. Accessible through the HVTN website. 
 
Dangerous Goods Regulations (updated annually), International Air Transport 
Association. Available for purchase at 
http://www.iata.org/publications/dgr/Pagesindex.aspx  
 
Lab assay algorithm 
 
HVTN algorithm for diagnosis of HIV infections. Part of the HVTN Laboratory 
Manual of Operations (see above). 

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 
International Conference on Harmonisation (ICH) E6 (R1), Guideline for Good 
Clinical Practice: Section 4.8, Informed consent of trial subjects. Available at 
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html 
 
Participants’ Bill of Rights and Responsibilities. Accessible through the HVTN 
website. 
 
NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid 
Molecules. Available at 
http://osp.od.nih.gov/sites/default/files/resources/NIH_Guidelines.pdf . 
 
NIH Policy on Reporting Race and Ethnicity Data: Subjects in Clinical Research. 
Available at http://grants1.nih.gov/grants/guide/notice-files/NOT-OD-01-053.html. 
 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks, July 
2008. 
 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials. Available at https://www.niaid.nih.gov/research/daids-clinical-site-
implementation-operations 
 
Title 21, Code of Federal Regulations, Part 50. Available at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=5
0 
 
Title 45, Code of Federal Regulations, Part 46. Available at 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html 
See Section 16 for literature cited in the background and statistics sections of this 
protocol. 

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15 
Acronyms and abbreviations 
Ab 
antibody 
Ad 
adenovirus 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC-MB area-under-the-magnitude-breadth curve 
β-HCG 
beta human chorionic gonadotropin 
BMI 
body mass index 
bnAb 
broadly neutralizing antibody 
bs 
binding site 
CAB 
Community Advisory Board 
CBC 
complete blood count 
CDC 
US Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CHAVI-ID Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen 
Discovery 
CIOMS 
Council for International Organizations of Medical Sciences 
CI 
confidence intervals 
CRF 
case report form 
CRPMC 
NIAID Clinical Research Products Management Center 
CRS* 
clinical research site 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS (US NIH) 
DHHS 
US Department of Health and Human Services 
EAE 
adverse events requiring expedited reporting to DAIDS 
EC 
Ethics Committee 
EIA 
enzyme immunoassay 
ELISA 
enzyme-linked immunosorbent assay 
FDA 
US Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equation 
HCV 
hepatitis C virus 
HVTN 
HIV Vaccine Trials Network 
IB 
Investigator’s Brochure 
IBC 
Institutional Biosafety Committee 
ICH 
International Conference on Harmonisation 
ICS 
intracellular cytokine staining 
IFN-γ 
interferon gamma 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 

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IUD 
intrauterine device 
MAR 
missing at random 
MCAR 
missing completely at random 
MMR 
measles, mumps, and rubella 
nAb 
neutralizing antibody 
NHP 
nonhuman primate 
NIAID 
National Institute of Allergy and Infectious Diseases (US NIH) 
NICD 
National Institute for Communicable Diseases (Johannesburg, South Africa) 
NIH 
US National Institutes of Health 
OHRP 
US Office for Human Research Protections 
OPV 
oral polio vaccine 
PAB 
DAIDS Pharmaceutical Affairs Branch 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PI 
Principal Investigator 
PSRT 
Protocol Safety Review Team 
RAB 
DAIDS Regulatory Affairs Branch 
RE 
regulatory entity 
RSC 
DAIDS Regulatory Support Center 
SAE 
serious adverse event 
SCHARP Statistical Center for HIV/AIDS Research and Prevention 
SDMC 
statistical and data management center 
SIV 
simian immunodeficiency virus 
SMB 
Safety Monitoring Board 
SPT 
DAIDS Safety and Pharmacovigilance Team 
TB 
tuberculosis 
TF 
transmitter/founder 
Tfh 
T follicular helper T cells 
UCA 
unmutated common ancestor 
UW-VSL University of Washington Virology Specialty Laboratory 
VISP 
Vaccine induced seropositivity 
VRC 
Vaccine Research Center (NIAID) 
* CRSs were formerly referred to as HIV Vaccine Trial Units (HVTUs). Conversion to 
use of the term CRS is in process, and some HVTN documents may still refer to HVTUs. 

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Korber B, Montefiori D, Mascola J. Tiered Categorization of a Diverse Panel of HIV-1 
Env Pseudoviruses for Assessment of Neutralizing Antibodies. J Virol 2010;84:1439-52. 
 
 

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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 EnvSeq-1 
Envs adjuvanted with GLA-SE, administered alone or with DNA Mosaic-Tre env, in 
healthy, HIV-uninfected adult participants 
HVTN protocol number: HVTN 115 
Site: [Insert site name] 
Thank you for your interest in our research study. Please read this consent form or ask 
someone to read it to you. If you decide to join the study, we will ask you to sign or make 
your mark on this form. We will offer you a copy to keep. We will ask you questions to 
see if we have explained everything clearly. You can also ask us questions about the 
study.  
Research is not the same as treatment or medical care. The purpose of a research study is 
to answer scientific questions. 
About the study 
The HIV Vaccine Trials Network (HVTN) and [Insert site name] are doing a study to test 
HIV vaccines. HIV is the virus that causes AIDS. 
Up to 132 people will take part in this study at multiple sites in the U.S. 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 2 parts, part A and part B. Forty-two (42) people will take part 
in part A of this study. After we see the results from part A, we will decide what amount 
of vaccine will be used for part B of the study. If we decide to do part B, 90 more people 
will join. Part B will look at different combinations of vaccines. 
You are being invited to join part A of the study.  
1. We are doing this study to answer several questions. 
 
Are the study vaccines safe to give to people? 
 
Are people able to take the study vaccines without becoming too uncomfortable? 
 
How do people’s immune systems respond to the study vaccines? (Your immune 
system protects you from disease.) 
2. The study vaccines cannot give you HIV. 
The study vaccines are not made from actual HIV. It is impossible for the study vaccines 
to give you HIV. Also, they cannot cause you to give HIV to someone else. 

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3. We do not know if the study vaccines will decrease, increase, or not change your 
risk of becoming infected with HIV if you are exposed to the virus. 
Sites: Any change to the language in this section requires approval from HVTN 
Regulatory Affairs. 
Several studies have tested whether HIV vaccines can reduce the risk of getting HIV 
from another person. In some studies, people who got the vaccine seemed to have the 
same risk of getting HIV as people who did not get the vaccine. In one study, people who 
got the vaccine seemed to have a lower risk of getting HIV than people who did not get 
the vaccine. In studies with a different vaccine, some people who got the vaccine had a 
higher risk of getting HIV than people who did not get the vaccine.  
This study differs from the studies in which people who got the vaccine had a higher or 
lower risk of getting HIV. The study staff can tell you about the differences.  
We do not know whether the vaccines in this study will affect your risk of getting HIV 
from another person. The risk could be higher, lower, or unchanged. It’s very important 
to avoid exposure to HIV during and after the study. We will tell you how to avoid HIV. 
4. These study vaccines are experimental. 
The study vaccine in part A is called CH505TF gp120. The study vaccines in part B are 
CH505TF gp120, CH505w53 gp120, CH505w78 gp120, CH505w100 gp120, and DNA 
Mosaic-Tre env. From here on, we will call them the study vaccines. They are 
experimental HIV vaccines. That means we do not know whether the vaccines will be 
safe to use in people, or whether they will work to prevent HIV infection. These vaccines 
are used only in research studies. 
The vaccines were developed by the Division of AIDS (DAIDS) at the National Institutes 
of Health (NIH). The EnvSeq-1 vaccines have man-made pieces of protein that look like 
part of the protein found in HIV. Your body’s immune system might learn to recognize 
these proteins and prepare itself to fight HIV. This is called an immune response. 
The CH505 vaccines are 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).  
In part A of the study, we are looking to see what amount of vaccine will create the best 
immune response.  
The study vaccine in part A has not been given to people before. The vaccine has been 
tested in animals and appears safe. Even if something looks like it is safe or works in 
animals, it may not be true for people. 
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 experience side effects that limit their normal activities or make them go 
to the doctor. 

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Rarely, a vaccine can cause an allergic reaction, including a rash, hives, or difficulty 
breathing. Allergic reactions can be life-threatening. You should tell us if you have ever 
had a bad reaction to any injection or vaccine. 
Very rarely, a vaccine causes an autoimmune disease in a person, or makes an 
autoimmune disease worse. An autoimmune disease happens when your immune system 
attacks your own body, instead of attacking an infection. 
Risks of the study vaccines: 
This section lists the side effects we know about. There may be others that we don’t yet 
know about, even serious ones. We will tell you if we learn about any new side effects. 
The EnvSeq-1 vaccine has not been given to people before, but similar vaccines have 
been used in other studies. The most common complaints were pain or tenderness at the 
injection site.  
The adjuvant, GLA-SE, has been tested in humans with vaccines for other diseases. The 
most common complaints were pain and tenderness at the injection site and feeling tired. 
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. 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) 

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We will also do blood and urine tests. These tests tell us about some aspects of your 
health, such as how healthy your kidneys, liver, and immune system are. We will also test 
you for Hepatitis B, Hepatitis C, and syphilis. We will ask you about medications you are 
taking. We will ask you about behaviors that might put you at risk for getting HIV. If you 
were born female, we will test you for pregnancy.  
We will review the screening results with you. The screening results may show you are 
not eligible to join the study, even if you want to.  
Sites: adapt the following section so it is applicable to the care available at your site 
7. If we find that you have a health problem during screening or during the study, we 
will tell you about the care that we can give here for free. 
For the care that we cannot give, we will explain how we will help you get care 
elsewhere. For health problems that are unrelated to the study, we will not pay for care. 
8. If you were born female and are sexually active in a way that could lead you to get 
pregnant, you must agree to use effective 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 6 months after your last study injection. We 
will talk to you about effective birth control methods. They are listed on a handout that we 
will give to you  
Being in the study 
If you meet the study requirements and want to join, here is what will happen: 
9. You will come to the clinic for scheduled visits about [#] times over 18 months. 
Site: Insert number of visits and range of visit lengths. (There is site-specific variation in 
screening protocols and in the number of possible follow-up visits between protocol-
mandated visits.) 
Visits can last from [#] to [#] hours. 
You may have to come for more visits if you have a lab or health issue. 
We may contact you after the main study ends (for example, to tell you about the study 
results). 
10. We will give you [Site: Insert compensation] for each study visit you complete. 
This amount is to cover the costs of [Site: Insert text] 

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Site: Insert any costs to participants (eg, birth control costs for female participants who 
could become pregnant). 
Payments you receive for being in the study may be taxable. We may need to ask you for 
your Social Security number for tax reasons. 
You do not have to pay anything to be in this study. 
11. We will give you either the study vaccines or a placebo. 
Not everyone in this study will get the study vaccines. Some people will get a placebo, a 
substance that does not contain vaccine. We will compare the results from people who 
got the placebo with results from people who got the study vaccines. In this study, the 
placebo is sterile salt water. 
You have a 1-in-7 chance of getting the placebo, which means you have a 6-in-7 chance 
of receiving the study vaccine. 
Site: Modify the randomization metaphor in the next sentence as appropriate to your 
local culture. Whether you get the study vaccines or the placebo is completely random, 
like flipping a coin.  
We have no say in whether you get the study vaccines or the placebo. We will not know 
which one you are getting, and neither will you. Only the pharmacist at this clinic will 
have this information while the study is going on.  
You will have to wait until everyone completes their final study visits to find out whether 
you got the study vaccines or the placebo. This could be several years. But, if you have a 
serious medical problem and need to know what you got before the end of the study, we 
can tell you. 
12. We will give you the study products on a schedule. 
You will be in 1 of 4 groups. You will not know which group you will be assigned to. 
You will get 1 injection with needle and syringe into the upper thigh at each of 5 separate 
visits.  
Site: If a picture version of the injection schedule has been provided in a separate 
protocol appendix, you may insert it below in place of (or in addition to) the text version 
or give it as a separate document to volunteers if you believe it will be helpful to them. 
You are not required to do either. 

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Injection Schedule 
 
Group 
Vaccine 
dose 
First 
injection 
2 months 
later 
4 months 
later 
8 months 
later 
12 months 
later 
 
 
 
 
 
 
 
 
Part A 
1 
Low 
EnvSeq-1 TF 
EnvSeq-1 
TF 
EnvSeq-1 
TF 
EnvSeq-1 
TF 
EnvSeq-1 TF 
 
2 
Medium 
EnvSeq-1 TF 
EnvSeq-1 
TF 
EnvSeq-1 
TF 
EnvSeq-1 
TF 
EnvSeq-1 TF 
 
3 
High 
EnvSeq-1 TF 
EnvSeq-1 
TF 
EnvSeq-1 
TF 
EnvSeq-1 
TF 
EnvSeq-1 TF 
 
4 
None 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
You will have to wait in the clinic for about a half hour after each injection to see if there 
are any problems. Then for that night and for 7 more days, you will need to keep track of 
how you are feeling and if you have any symptoms. To help you do this, we will give you 
tools and show you how to use them. 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 born female;  
 
Ask questions about your health, including medications you may be taking; 
 
Ask questions about any personal problems or benefits you may have from being in 
the study; and 
 
Take urine and blood samples. 
When we take blood, the amount will depend on the lab tests we need to do. It will be 
some amount between 10 mL and 210 mL (2 teaspoons to about 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 I, 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.  

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14. We will counsel you on avoiding HIV infection. 
We will ask you personal questions about your HIV risk factors such as sexual behavior, 
alcohol, and drug use. We will talk with you about ways to keep your risk of getting HIV 
low.  
15. We will test your samples for this study 
We will send your samples (without your name) to labs approved by the HVTN for this 
study, which are located in the United States. Researchers at these labs will test your 
samples to see how your immune system responds to the study products. In rare cases, 
some of your samples may be sent to labs approved by the HVTN in other countries for 
research related to this study. 
Researchers may also do genetic testing related to this study on your samples. Your genes 
are passed to you from your birth parents. They affect how you look and how your body 
works. The differences in people’s genes can help explain why some people get a disease 
while others do not. These types of genetic tests involve some of your genes, not all of 
your genes (your genome). The researchers will study the genes related to the immune 
system and HIV and those that affect how people get HIV. 
If you become HIV infected, the researchers may look at all of the genes of the virus 
found in your samples. The researchers will use this information to learn more about HIV 
and the study product(s). 
In some cases, researchers may take cells from your samples and grow more of them over 
time, so that they can continue to contribute to this study. 
Tests done on your samples are for research purposes only. The labs will not give the 
results to you or this clinic, and the results will not become part of your study record. 
When your samples are no longer needed for this study, the HVTN will continue to store 
them. 
16. After your clinic visits end, we will contact you about 6 months later. 
We will contact you by phone, email, or text message [Site: Modify mode of contact as 
appropriate; consult IRB/EC if necessary] after your study visits to ask questions about 
your health. If you prefer to answer these questions in person, you can come to the clinic 
to do this. 
If we have any concerns about your health, we may need to have more contact with you. 
You are also welcome to contact us at any time if you have concerns about your health 
related to being in the study. 
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 are infected with HIV, we will ask 
you to come back to the clinic for another HIV test. We will draw about 15 mL ( about 1 
tablespoon) of blood. We may ask you to come back more than once for this testing. 

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Because we will want to contact you, please tell us if your contact information changes, if 
you are moving away, or if you do not want us to contact you anymore. 
Site: Delete next section if using separate consent for use of samples and information in 
other studies 
17. When samples are no longer needed for this study, the HVTN wants to keep them 
for use in other studies by HVTN or other researchers. We will call these “extra 
samples.” 
This section gives you information so you can decide if you want your extra samples and 
information used in other studies. You will mark your decision at the end of the form. If 
you have any questions, please ask.  
Do I have to agree? No. You are free to say yes or no, or to change your mind after you 
sign this form. At your request, we will destroy all extra samples that we have. Your 
decision will not affect your being in this study or have any negative consequences here.  
Where are the samples stored? Extra samples are stored in a secure central place called a 
repository. [Site: insert specific information if your regulatory authority requires it.] 
Your samples will be stored in the HVTN repository in the United States. 
How long will the samples be stored? There is no limit on how long your extra samples 
will be stored. [Site: insert limits if your regulatory authority imposes them.] 
Will I be paid for the use of my samples? No. Also, a researcher may make a new 
scientific discovery or product based on the use of your samples. If this happens, there is 
no plan to share any money with you. The researcher is not likely to ever know who you 
are. 
Will I benefit from allowing my samples to be used in other studies? Probably not. 
Results from these other studies are not given to you, this clinic, or your doctor. They are 
not part of your medical record. The studies are only being done for research purposes. 
Will the HVTN sell my samples and information? No, but the HVTN may share your 
samples with other researchers. Once we share your samples and information, we will not 
be able to get them back. 
How do other researchers get my samples and information? When a researcher wants to 
use your samples and/or information, their research plan must be approved by the HVTN. 
Also, the researcher’s institutional review board (IRB) or ethics committee (EC) will 
review their plan. [Site: 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 other researchers? The samples and limited information 
will be labeled with a code number. Your name will not be part of the information. 
However, some information that we share may be personal, such as your race, ethnicity, 
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.  

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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. 
If you become HIV infected, the researchers may look at all of the genes of the virus 
found in your samples. The researchers will use this information to learn more about HIV 
and the study product(s). 
In some cases, researchers may take cells from your samples and grow more of them over 
time, so that they can continue to contribute to this study. 
If you agree, your samples could also be used for genome wide studies. In these studies, 
researchers will look at all of your genes (your genome). The researchers compare the 
genomes of many people, looking for common patterns of genes that could help them 
understand diseases. The researchers may put the information from the genome-wide 
studies into a protected database so that other researchers can access it. Usually, no one 
would be able to look at your genome and link it to you as a person. However, if another 
database exists that also has information on your genome and your name, someone might 
be able to compare the databases and identify you. If others found out, it could lead to 
discrimination or other problems. The risk of this is very small. 
Who will have access to my information in studies using my extra samples?  
People who may see your information are: 
 
Researchers who use your stored samples and limited information for other research 
 
Government agencies that fund or monitor the research using your samples or 
information 
 
The researcher’s Institutional Review Board or Ethics Committee 
 
The people who work with the researcher  
All of these people will do their best to protect your information. The results of any new 
studies that use your extra samples or information may be published. No publication will 
use your name or identify you personally. 
18. We will do our best to protect your private information. 
Sites: Check HIPAA authorization for conflicts with this section. 
Your study records and samples will be kept in a secure location. We will label all of 
your samples and most of your records with a code number, not your name or other 
personal information. However, it is possible to identify you, if necessary. We will not 
share your name with the lab that does the tests on your samples, or with anyone else who 
does not need to know your name. 
Sites: Any change to the following boxed text requires approval from HVTN Regulatory 
Affairs.  

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We do need to share your name with the HVTN in case you need proof in the future that 
you participated in an HIV vaccine study. The HVTN will keep your name in a secure 
file with these items:  
 The name of your study  
 Your age or date of birth  
 Your study ID number  
 What study product(s) you received  
There are no HIV test results kept in this file. The HVTN will not share any information 
that could identify you without your agreement. The HVTN will remove your name from 
the file if you do not want it there. 
Clinic staff will have access to your study records. Your records may also be reviewed by 
groups who watch over this study to see that we are protecting your rights, keeping you 
safe, and following the study plan. These groups include: 
 
The US National Institutes of Health and its study monitors, 
 
The US Food and Drug Administration, 
 
[Insert name of local IBC], 
 
[Insert name of local IRB/EC] , 
 
[Insert name of local and/or national regulatory authority as appropriate], 
 
IDRI and people who work for them,  
 
The HVTN and people who work for them,  
 
The HVTN Safety Monitoring Board, and 
 
The US Office for Human Research Protections. 
All reviewers will take steps to keep your records private. 
We cannot guarantee absolute privacy. At this clinic, we have to report the following 
information:  
Site: Include any public health or legal reporting requirements. Bulleted examples should 
include all appropriate cases (reportable communicable disease, risk of harm to self or 
others, etc.). 
 
[Item 1] 
 
[Item 2] 

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 
[Item 3] 
We have a Certificate of Confidentiality from the US government, to help protect your 
privacy. With the certificate, we do not have to release information about you to someone 
who is not connected to the study, such as the courts or police. Sometimes we can’t use 
the certificate. Since the US government funds this research, we cannot withhold 
information from it. Also, you can still release information about yourself and your study 
participation to others. 
The results of this study may be published. No publication will use your name or identify 
you personally. 
We may share information from the study with other researchers. We will not share your 
name or information that can identify you. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This 
website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time. 
19. We may stop your injections or take you out of the study at any time. We may do 
this even if you want to stay in the study and even if you were scheduled for more 
injections.  
This may happen if: 
 
you do not follow instructions, 
 
we think that staying in the study might harm you, 
 
you get HIV, 
 
you enroll in a different research study where you get another study product, or 
 
the study is stopped for any reason. 
If we stop your injections, we may ask you to stay in the study to complete other study 
procedures. 
20. We will stop your injections if you become pregnant during the study. 
We will encourage you to stay in the study if you choose. We will discuss your study 
options with you. 
If you leave the study while you are still pregnant, we will contact you after your due date 
to ask some questions about your pregnancy and delivery. 
21. If you get infected with HIV during the study, we will help you get care and support. 
You will not be able to stay in this study. We will counsel you about your HIV infection 
and about telling your partner(s). We will tell you where you can get support and medical 
care, and if there are other studies you may want to join. Site: Modify the following 
sentence as appropriate. We will not provide or pay for any of your HIV care directly.  

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Other Risks 
22. There are other risks to being in this study. 
This section describes the other risks and restrictions we know about. There may also be 
unknown risks, even serious ones. We will tell you if we learn anything new that may 
affect your willingness to stay in the study. 
Risks of routine medical procedures:  
In this study, we will do some routine medical procedures. These are taking blood and 
giving injections. These procedures can cause bruising, pain, fainting, soreness, redness, 
swelling, itching, a sore, bleeding, and (rarely) muscle damage or infection where you got 
the injection. Taking blood can cause a low blood cell count (anemia), making you feel 
tired. 
Personal problems/discrimination/testing HIV antibody positive: 
About 10 to 20% of people who join HVTN studies report personal problems or 
discrimination because of joining an HIV vaccine study. Family or friends may worry, 
get upset or angry, or assume that you are infected with HIV or at high risk and treat you 
unfairly as a result. Rarely, a person has lost a job because the study took too much time 
away from work, or because their employer thought they had HIV.  
The body makes antibodies to fight or prevent infection. Most vaccines cause the body to 
make antibodies as a way of preventing infection. Your body may make antibodies to 
HIV because you received HIV study vaccines. The study vaccines may cause you to test 
positive on some types of HIV antibody tests, even if you are not infected with HIV. This 
is called vaccine-induced seropositivity (VISP). VISP means that after you get the study 
vaccines, a routine HIV test done outside this clinic may say you have HIV, even if you 
don’t. For this reason, you should plan to get HIV tests only at this clinic during the 
study. Our tests can tell the difference between true HIV infection and a positive result 
that is caused by the study vaccines. 
If you have a positive test result caused by the study vaccines at any time, we can arrange 
free HIV testing for as long as you need it. If this happens, we do not know how long you 
will test positive due to the study vaccines. If you receive a positive HIV test result and 
we determine it is because you have HIV, we will refer you for follow-up care. 
It is unlikely, but you could test negative at the end of the study and positive some time 
later, even though you don’t have HIV. This could happen if different HIV tests come 
into use. We will give you a phone number to call for more information.  
Site: Modify the following paragraph if applicable. If someone believes you are infected 
with HIV even if you are not, you could face discrimination and other problems. For 
example, in some countries, you could be denied medical or dental care, employment, 
insurance, a visa, or entry into the military. If you do have a positive HIV antibody test 
caused by the study vaccines, you will not be able to donate blood or organs. Your family 
and friends may treat you differently. We will give you a brochure that tells you more 
about testing HIV positive because of an HIV vaccine, and how you can avoid some of 
these problems. 

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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 6 
months. 
You should always tell the delivery staff if you have VISP. However, you may still be 
tested for HIV using the antibody test when you deliver your baby. If your test is positive 
and the delivery staff believes you have an HIV infection, your baby may be started on 
antiretroviral treatment when it is not needed. If this happens, we can arrange for you and 
the baby to have a test that can tell the difference between true HIV infection and a VISP 
result. If you or the baby continue to have VISP, we can arrange this testing for free for 
as long as it is needed. 
Embarrassment/anxiety: 
You may feel embarrassed when we ask about your HIV risks, such as having sex and 
using drugs. Also, waiting for your HIV test results or other health test results could 
make you feel anxious. You could feel worried if your test results show that you are 
infected with HIV. If you feel embarrassed or anxious, please tell us and we will try to 
help you. 
Risks of disclosure of your personal information: 
We will take several steps to protect your personal information. Although the risk is very 
low, it is possible that your personal information could be given to someone who should 
not have it. If that happened, you could face discrimination, stress, and embarrassment. 
We can tell you more about how we will protect your personal information if you would 
like it.  
Risks of genetic testing: 
The genetic testing could show you may be at risk for certain diseases. If others found 
out, it could lead to discrimination or other problems. However, it is almost impossible 
for you or others to know your test results from the genetic testing. The results are not 
part of your study records and are not given to you.  
In the very unlikely event that your genetic information becomes linked to your name, a 
federal law called the Genetic Information Nondiscrimination Act (GINA) helps protect 
you. GINA keeps health insurance companies and employers from seeing results of 
genetic testing when deciding about giving you health insurance or offering you work. 
GINA does not help or protect you against discrimination by companies that sell life, 
disability or long-term care insurance. 
Unknown risks: 
We do not know if the study vaccines will increase, decrease, or not change your risk of 
becoming infected with HIV if exposed. If you get infected with HIV, we do not know 
how the study vaccines might affect your HIV infection or how long it takes to develop 
AIDS. 

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We do not know if getting these study vaccines will affect how you respond to any future 
approved HIV vaccine. It could be that a future HIV vaccine may not work as well for 
you because you got the study vaccines. Currently, no HIV vaccine has been approved 
for use.  
We do not know how the study vaccines will affect a pregnant participant or a developing 
baby.  
Benefits 
23. The study may not benefit you. 
We do not know whether getting the study vaccines might benefit you in any way. 
However, being in the study might still help you in some ways. The counseling that you 
get as part of the study may help you avoid getting HIV. The lab tests and physical exams 
that you get while in this study might detect health problems you don’t yet know about.  
This study may help in the search for a vaccine to prevent HIV. However, if the study 
vaccines later become approved and sold, there are no plans to share any money with 
you.  
Your rights and responsibilities 
24. If you join the study, you have rights and responsibilities. 
You have many rights that we will respect. You also have responsibilities. We list these 
in the Participant’s Bill of Rights and Responsibilities. We will give you a copy of it. 
Leaving the study 
25. Tell us if you decide to leave the study. 
You are free to leave the study at any time and for any reason. Your care at this clinic and 
your legal rights will not be affected, but it is important for you to let us know.  
We will ask you to come back to the clinic one last time for a physical exam, and we may 
ask to take some blood and urine samples. We will also ask about any personal problems 
or benefits you have experienced from being in the study. We believe these steps are 
important to protecting your health, but it is up to you whether to complete them. 
Injuries 
Sites: Do not make changes to the following section without obtaining approval from 
HVTN Regulatory Affairs at vtn.core.reg@hvtn.org. 
26. If you get sick or injured during the study, contact us immediately. 
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. 

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If you become sick or injured in this study, there is a process to decide if it is related to 
the study products and/or procedures. If it is, we call it a study-related injury. There are 
funds to pay for treatment of study-related injuries if certain conditions are met.  
The HVTN has limited funds to pay medical costs that it determines are reasonable. 
(Sites: insert locale- appropriate medical insurance language in the following sentence) 
If the injury is not study related, then you and your health insurance will be responsible 
for treatment costs.  
Some injuries are not physical. For example, you might be harmed emotionally by being 
in an HIV vaccine study. Or you might lose wages because you cannot go to work. 
However, there are no funds to pay for these kinds of injuries, even if they are study 
related. 
You may disagree with the decision about whether your injury is study related. If you 
wish, the HVTN will ask independent experts to review the decision. You always have 
the right to use the court system if you are not satisfied. 
Questions  
27. If you have questions or problems at any time during your participation in this 
study, use the following important contacts. 
If you have questions about this study, contact 
[name and telephone number of the investigator or other study staff]. 
If you have any symptoms that you think may be related to this study, contact 
[name and telephone number of the investigator or other study staff]. 
If you have questions about your rights as a research participant, or problems or concerns 
about how you are being treated in this study, contact 
[name/title/phone of person on IRB or other appropriate organization]. 
If you want to leave this study, contact 
[name and telephone number of the investigator or other study staff]. 
Your permissions and signature  
Site: Delete this section if using a separate consent for use of samples and information in 
other studies 
28. In Section 17 of this form, we told you about possible other uses of your extra 
samples and limited information, outside this study. Please choose only one of the 
options below and write your initials or make your mark in the box next to it. 
Whatever you choose, the HVTN keeps track of your decision about how your 
samples and information can be used. 
 

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

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Appendix B 
Sample informed consent form for Part B 
Title: A phase 1 clinical trial to evaluate the safety and immunogenicity of EnvSeq-1 
Envs adjuvanted with GLA-SE, administered alone or with DNA Mosaic-Tre env, in 
healthy, HIV-uninfected adult participants 
HVTN protocol number: HVTN 115 
Site: [Insert site name] 
Thank you for your interest in our research study. Please read this consent form or ask 
someone to read it to you. If you decide to join the study, we will ask you to sign or make 
your mark on this form. We will offer you a copy to keep. We will ask you questions to 
see if we have explained everything clearly. You can also ask us questions about the 
study.  
Research is not the same as treatment or medical care. The purpose of a research study is 
to answer scientific questions. 
About the study 
The HIV Vaccine Trials Network (HVTN) and [Insert site name] are doing a study to test 
HIV vaccines. HIV is the virus that causes AIDS. 
Up to 132 people will take part in this study at multiple sites in the U.S. 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 2 parts, part A and part B. Forty-two (42) people joined part A 
of this study. You are being invited to join part B of the study. Up to 90 people will join 
part B. 
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 different combinations of study 
vaccines? (Your immune system protects you from disease.) 
2. The study vaccines cannot give you HIV. 
The study vaccines are not made from actual HIV. It is impossible for the study vaccines 
to give you HIV. Also, they cannot cause you to give HIV to someone else. 
3. We do not know if the study vaccines will decrease, increase, or not change your 
risk of becoming infected with HIV if you are exposed to the virus. 
Sites: Any change to the language in this section requires approval from HVTN 
Regulatory Affairs. 

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Several studies have tested whether HIV vaccines can reduce the risk of getting HIV 
from another person. In some studies, people who got the vaccine seemed to have the 
same risk of getting HIV as people who did not get the vaccine. In one study, people who 
got the vaccine seemed to have a lower risk of getting HIV than people who did not get 
the vaccine. In studies with a different vaccine, some people who got the vaccine had a 
higher risk of getting HIV than people who did not get the vaccine.  
This study differs from the studies in which people who got the vaccine had a higher or 
lower risk of getting HIV. The study staff can tell you about the differences.  
We do not know whether the vaccines in this study will affect your risk of getting HIV 
from another person. The risk could be higher, lower, or unchanged. It’s very important 
to avoid exposure to HIV during and after the study. We will tell you how to avoid HIV. 
4. These study vaccines are experimental. 
The study vaccines are called CH505TF gp120, CH505w53 gp120, CH505w78 gp120, 
CH505w100 gp120, and DNA Mosaic-Tre env. From here on, we will call them the study 
vaccines. They are experimental HIV vaccines. That means we do not know whether the 
vaccines will be safe to use in people, or whether they will work to prevent HIV 
infection. These vaccines are used only in research studies. 
The vaccines were developed by the Division of AIDS (DAIDS) at the National Institutes 
of Health (NIH). The CH505 vaccines have man-made pieces of protein that look like 
part of the protein found in HIV. Your body’s immune system might learn to recognize 
these proteins and prepare itself to fight HIV. This is called an immune response. By 
giving many injections of the CH505 vaccines, we hope the immune system develops 
antibody responses that can fight against many strains of HIV. The CH505 vaccines are 
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 DNA in the study vaccine will tell the body to make small amounts of proteins that 
look like the ones found in HIV. 
The CH505TF gp120 vaccine was given to people in part A and was found to be safe. 
The other CH505 gp120 vaccines are very similar to the CH505TF gp120 vaccine, but 
have not been given to people. The DNA vaccine has been given to people in another 
study. The CH505TF gp120 and DNA 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. 
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 experience side effects that limit their normal activities or make them go 
to the doctor. 

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Rarely, a vaccine can cause an allergic reaction, including a rash, hives, or difficulty 
breathing. Allergic reactions can be life-threatening. You should tell us if you have ever 
had a bad reaction to any injection or vaccine. 
Very rarely, a vaccine causes an autoimmune disease in a person, or makes an 
autoimmune disease worse. An autoimmune disease happens when your immune 
system attacks your own body, instead of attacking an infection. 
Risks of the study vaccines: 
This section lists the side effects we know about. There may be others that we don’t yet 
know about, even serious ones. We will tell you if we learn about any new side effects. 
The CH505TF gp120 vaccine has been given to people before. The most common 
complaints were pain or tenderness where people were injected. 
The adjuvant, GLA-SE, has been tested in humans with vaccines for other diseases. The 
most common complaints were pain and tenderness and feeling tired. 
The DNA vaccine has been tested in 30 people. The most common complaints were pain 
and tenderness where people were injected. Similar DNA vaccines have been given to 
more than 1,000 people in other studies. In studies with similar DNA vaccines, the most 
common complaints were pain or itching at the injection site, headache, and feeling tired. 
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. 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 

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 
Listening to your heart and lungs 
 
Feeling your abdomen (stomach and liver) 
We will also do blood and urine tests. These tests tell us about some aspects of your 
health, such as how healthy your kidneys, liver, and immune system are. We will also test 
you for: Hepatitis B, Hepatitis C, and syphilis. We will ask you about medications you 
are taking. We will ask you about behaviors that might put you at risk for getting HIV. If 
you were born female, we will test you for pregnancy.  
We will review the screening results with you. The screening results may show you are 
not eligible to join the study, even if you want to.  
Sites: adapt the following section so it is applicable to the care available at your site 
7. If we find that you have a health problem during screening or during the study, we 
will tell you about the care that we can give here for free. 
For the care that we cannot give, we will explain how we will help you get care 
elsewhere. For health problems that are unrelated to the study, we will not pay for care. 
8. If you were born female and are sexually active in a way that could lead you to get 
pregnant, you must agree to use effective 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 6 months after your last study injection. We 
will talk to you about effective birth control methods. They are listed on a handout that 
we will give to you.  
Being in the study 
If you meet the study requirements and want to join, here is what will happen: 
9. You will come to the clinic for scheduled visits about [#] times over 22 months. 
Site: Insert number of visits and range of visit lengths. (There is site-specific variation in 
screening protocols and in the number of possible follow-up visits between protocol-
mandated visits.) 
Visits can last from [#] to [#] hours. 
You may have to come for more visits if you have a lab or health issue. 
We may contact you after the main study ends (for example, to tell you about the study 
results). 

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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). 
Payments you receive for being in the study may be taxable. We may need to ask you for 
your Social Security number for tax reasons. 
You do not have to pay anything to be in this study. 
11. We will give you either the study vaccines or a placebo. 
Not everyone in this study will get the study vaccines. Some people will get a placebo, a 
substance that does not contain vaccine. We will compare the results from people who 
got the placebo with results from people who got the study vaccines. In this study, the 
placebo is sterile salt water. 
You have a 1-in-9 chance of getting the placebo, which means you have an 8-in-9 chance 
of receiving the study vaccines. 
Site: Modify the randomization metaphor in the next sentence as appropriate to your 
local culture. Whether you get the study vaccines or the placebo is completely random, 
like flipping a coin.  
We have no say in whether you get the study vaccines or the placebo. We will not know 
which one you are getting, and neither will you. Only the pharmacist at this clinic will 
have this information while the study is going on.  
You will have to wait until everyone completes their final study visits to find out whether 
you got the study vaccines or the placebo. This could be several years. But, if you have a 
serious medical problem and need to know what you got before the end of the study, we 
can tell you. 
12. We will give you the study products on a schedule. 
You will be in 1 of 5 groups. You will not know which group you will be assigned to. 
You will get 2 injections at each of 6 separate visits. The EnvSeq-1 injections will be 
given with needle and syringe into the muscle of your upper thigh. The DNA injections 
will be given by a device called a Biojector 2000 into the muscle of your upper thigh. The 
Biojector 2000 delivers the vaccine or placebo through the skin without using a needle. 
The FDA has approved it for delivering injections into muscles. The placebo will be 
given either with a needle and syringe or Biojector 2000. 
Site: If a picture version of the injection schedule has been provided in a separate 
protocol appendix, you may insert it below in place of (or in addition to) the text version 
or give it as a separate document to volunteers if you believe it will be helpful to them. 
You are not required to do either. 

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Injection Schedule 
 
Group 
First 
injection 
2 months later 
4 months later 
8 months later 
12 months 
later 
16 months 
later 
Part B 
5 
EnvSeq-1 TF 
+  
placebo 
EnvSeq-1 53 
+  
placebo 
EnvSeq-1 78 
+  
placebo 
EnvSeq-1 100 
+  
placebo 
EnvSeq-1 
100 
+  
placebo 
EnvSeq-1 100 
+  
placebo 
 
6 
EnvSeq-1 TF 
+  
mosaic DNA 
EnvSeq-1 53 
+  
mosaic DNA 
EnvSeq-1 78 
+  
mosaic DNA 
EnvSeq-1 100 
+  
mosaic DNA 
EnvSeq-1 
100 
+  
mosaic DNA 
EnvSeq-1 100 
+  
mosaic DNA 
 
7 
EnvSeq-1 TF 
+  
placebo 
EnvSeq-1 TF, 
53 
+  
placebo 
EnvSeq-1 TF, 
53, 78  
+  
placebo 
EnvSeq-1 53, 
78, 100 
+  
placebo 
EnvSeq-1 
78, 100 
+  
placebo 
EnvSeq-1 100 
+  
placebo 
 
8 
EnvSeq-1 TF 
+  
mosaic DNA 
EnvSeq-1 TF, 
53 
+  
mosaic DNA 
EnvSeq-1 TF, 
53. 78 
+  
mosaic DNA 
EnvSeq-1 53, 
78, 100 
+  
mosaic DNA 
EnvSeq-1 
78, 100 
+  
mosaic DNA 
EnvSeq-1 100 
+  
mosaic DNA 
 
9 
Placebo 
+ placebo 
Placebo 
+ placebo 
Placebo 
+ placebo 
Placebo 
+ placebo 
Placebo 
+ placebo 
Placebo 
+ placebo 
You will have to wait in the clinic for about a half hour after each injection to see if there 
are any problems. Then for that night and for 7 more days, you will need to keep track of 
how you are feeling and if you have any symptoms. To help you do this, we will give you 
tools and show you how to use them. 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 born female;  
 
Ask questions about your health, including medications you may be taking; 
 
Ask questions about any personal problems or benefits you may have from being in 
the study; and 
 
Take urine and blood samples. 
When we take blood, the amount will depend on the lab tests we need to do. It will be 
some amount between 10 mL and 210 mL (2 teaspoons to about 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 

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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 J, Table of procedures (for informed consent form) in this section 
or distribute it as a separate sheet if it is helpful to your study participants. You are not 
required to do either. 
We will be looking for side effects. We will review the results of these procedures and 
tests with you at your next visit, or sooner if necessary. If any of the results are important 
to your health, we will tell you.  
14. If you agree, we will also collect stool samples. 
At the end of this form we will ask if you allow us to collect stool samples. You can 
decide not to give these samples and still be in the study. 
We would like to collect a small sample of your stool to look at the bacteria living in your 
stomach. We want to learn if your immune response to the study vaccines is influenced 
by these bacteria. We will ask you to do this 3 times during this study. You may provide 
a stool sample at home or at the clinic by pooping into a cup we will give you. The clinic 
must receive the stool sample within 4 hours after it is collected. Another option is that 
we can collect a stool sample by doing rectal swabs. If that is what you choose, we will 
briefly insert a sterile swab into your rectum. We will do this up to 4 times. 
15. We will counsel you on avoiding HIV infection. 
We will ask you personal questions about your HIV risk factors such as sexual behavior, 
alcohol, and drug use. We will talk with you about ways to keep your risk of getting HIV 
low. 
16. We will test your samples for this study 
We will send your samples (without your name) to labs approved by the HVTN for this 
study, which are located in the United States. Researchers at these labs will test your 
samples to see how your immune system responds to the study products. In rare cases, 
some of your samples may be sent to labs approved by the HVTN in other countries for 
research related to this study. 
Researchers may also do genetic testing related to this study on your samples. Your genes 
are passed to you from your birth parents. They affect how you look and how your body 
works. The differences in people’s genes can help explain why some people get a disease 
while others do not. These types of genetic tests involve some of your genes, not all of 
your genes (your genome). The researchers will study the genes related to the immune 
system and HIV and those that affect how people get HIV. 
If you become HIV infected, the researchers may look at all of the genes of the virus 
found in your samples. The researchers will use this information to learn more about HIV 
and the study product(s). 
In some cases, researchers may take cells from your samples and grow more of them over 
time, so that they can continue to contribute to this study. 

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Tests done on your samples are for research purposes only. The labs will not give the 
results to you or this clinic, and the results will not become part of your study record. 
When your samples are no longer needed for this study, the HVTN will continue to store 
them. 
17. After your clinic visits end, we will contact you about 6 months later. 
We will contact you by phone, email, or text message [Site: Modify mode of contact as 
appropriate; consult IRB/EC if necessary] after your study visits to ask questions about 
your health. If you prefer to answer these questions in person, you can come to the clinic 
to do this. 
If we have any concerns about your health, we may need to have more contact with you. 
You are also welcome to contact us at any time if you have concerns about your health 
related to being in the study. 
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 are infected with HIV, we will ask 
you to come back to the clinic for another HIV test. We will draw about 15 mL (about 1 
tablespoon) of blood. We may ask you to come back more than once for this testing. 
Because we will want to contact you, please tell us if your contact information changes, if 
you are moving away, or if you do not want us to contact you anymore. 
Site: Delete next section if using separate consent for use of samples and information in 
other studies. 
18. When samples are no longer needed for this study, the HVTN wants to keep them 
for use in other studies by HVTN or other researchers. We will call these “extra 
samples.” 
This section gives you information so you can decide if you want your extra samples and 
information used in other studies. You will mark your decision at the end of the form. If 
you have any questions, please ask.  
Do I have to agree? No. You are free to say yes or no, or to change your mind after you 
sign this form. At your request, we will destroy all extra samples that we have. Your 
decision will not affect your being in this study or have any negative consequences here.  
Where are the samples stored? Extra samples are stored in a secure central place called a 
repository.Your samples will be stored in the HVTN repository in the United States.  
How long will the samples be stored? There is no limit on how long your extra samples 
will be stored. [Site: insert limits if your regulatory authority imposes them.] 
Will I be paid for the use of my samples? No. Also, a researcher may make a new 
scientific discovery or product based on the use of your samples. If this happens, there is 
no plan to share any money with you. The researcher is not likely to ever know who you 
are. 

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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 other researchers. Once we share your samples and information, we will not 
be able to get them back. 
How do other researchers get my samples and information? When a researcher wants to 
use your samples and/or information, their research plan must be approved by the HVTN. 
Also, the researcher’s institutional review board (IRB) or ethics committee (EC) will 
review their plan. [Site: 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 other researchers? The samples and limited information 
will be labeled with a code number. Your name will not be part of the information. 
However, some information that we share may be personal, such as your race, ethnicity, 
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.  
If you become HIV infected, the researchers may look at all of the genes of the virus 
found in your samples. The researchers will use this information to learn more about HIV 
and the study product(s).  
In some cases, researchers may take cells from your samples and grow more of them over 
time, so that they can continue to contribute to this study.  
If you agree, your samples could also be used for genome wide studies. In these studies, 
researchers will look at all of your genes (your genome). The researchers compare the 
genomes of many people, looking for common patterns of genes that could help them 
understand diseases. The researchers may put the information from the genome-wide 
studies into a protected database so that other researchers can access it. Usually, no one 
would be able to look at your genome and link it to you as a person. However, if another 
database exists that also has information on your genome and your name, someone might 
be able to compare the databases and identify you. If others found out, it could lead to 
discrimination or other problems. The risk of this is very small. 
Who will have access to my information in studies using my extra samples?  
People who may see your information are: 
 
Researchers who use your stored samples and limited information for other research 
 
Government agencies that fund or monitor the research using your samples or 
information 

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

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 
IDRI and people who work for them,  
 
The HVTN and people who work for them,  
 
The HVTN Safety Monitoring Board, and 
 
The US Office for Human Research Protections. 
All reviewers will take steps to keep your records private. 
We cannot guarantee absolute privacy. At this clinic, we have to report the following 
information:  
Site: Include any public health or legal reporting requirements. Bulleted examples should 
include all appropriate cases (reportable communicable disease, risk of harm to self or 
others, etc.). 
 
[Item 1] 
 
[Item 2] 
 
[Item 3] 
We have a Certificate of Confidentiality from the US government, to help protect your 
privacy. With the certificate, we do not have to release information about you to someone 
who is not connected to the study, such as the courts or police. Sometimes we can’t use 
the certificate. Since the US government funds this research, we cannot withhold 
information from it. Also, you can still release information about yourself and your study 
participation to others. 
The results of this study may be published. No publication will use your name or identify 
you personally. 
We may share information from the study with other researchers. We will not share your 
name or information that can identify you. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This 
website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time. 
20. We may stop your injections or take you out of the study at any time. We may do 
this even if you want to stay in the study and even if you were scheduled for more 
injections.  
This may happen if: 
 
you do not follow instructions, 
 
we think that staying in the study might harm you, 
 
you get HIV, 

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 
you enroll in a different research study where you get another study product, or 
 
the study is stopped for any reason. 
If we stop your injections, we may ask you to stay in the study to complete other study 
procedures. 
21. We will stop your injections if you become pregnant during the study. 
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. 
22. If you get infected with HIV during the study, we will help you get care and support. 
You will not be able to stay in this study. We will counsel you about your HIV infection 
and about telling your partner(s). We will tell you where you can get support and medical 
care, and if there are other studies you may want to join. Site: Modify the following 
sentence as appropriate. We will not provide or pay for any of your HIV care directly.  
Other Risks 
23. There are other risks to being in this study. 
This section describes the other risks and restrictions we know about. There may also be 
unknown risks, even serious ones. We will tell you if we learn anything new that may 
affect your willingness to stay in the study. 
Risks of routine medical procedures:  
In this study, we will do some routine medical procedures. These are taking blood and 
giving injections. These procedures can cause bruising, pain, fainting, soreness, redness, 
swelling, itching, a sore, bleeding, and (rarely) muscle damage or infection where you got 
the injection. Taking blood can cause a low blood cell count (anemia), making you feel 
tired. 
Risks of Biojector: 
Injection of the DNA vaccine with the Biojector 2000® device may cause a small red 
bump and then a scab on the thigh. This usually goes away within a few days. Tell the 
study nurse or doctor if you have a bump or scab. 
Risks of rectal swab: 
If you choose to provide a stool sample by rectal swabbing, you may feel pressure as the 
swab is inserted into your rectum, but it is usually not painful. Some people might have a 
little bit of bleeding. 
Personal problems/discrimination/testing HIV antibody positive: 

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About 10 to 20% of people who join HVTN studies report personal problems or 
discrimination because of joining an HIV vaccine study. Family or friends may worry, 
get upset or angry, or assume that you are infected with HIV or at high risk and treat you 
unfairly as a result. Rarely, a person has lost a job because the study took too much time 
away from work, or because their employer thought they had HIV.  
The body makes antibodies to fight or prevent infection. Most vaccines cause the body to 
make antibodies as a way of preventing infection. Your body may make antibodies to 
HIV because you received HIV study vaccines. The study vaccines may cause you to test 
positive on some types of HIV antibody tests, even if you are not infected with HIV. This 
is called vaccine-induced seropositivity (VISP). VISP means that after you get the study 
vaccines, a routine HIV test done outside this clinic may say you have HIV, even if you 
don’t. For this reason, you should plan to get HIV tests only at this clinic during the 
study. Our tests can tell the difference between true HIV infection and a positive result 
that is caused by the study vaccines. 
If you have a positive test result caused by the study vaccines at any time, we can arrange 
free HIV testing for as long as you need it. If this happens, we do not know how long you 
will test positive due to the study vaccines. If you receive a positive HIV test result and 
we determine it is because you have HIV, we will refer you for follow-up care. 
It is unlikely, but you could test negative at the end of the study and positive some time 
later, even though you don’t have HIV. This could happen if different HIV tests come 
into use. We will give you a phone number to call for more information.  
Site: Modify the following paragraph if applicable. If someone believes you are infected 
with HIV even if you are not, you could face discrimination and other problems. For 
example, in some countries, you could be denied medical or dental care, employment, 
insurance, a visa, or entry into the military. If you do have a positive HIV antibody test 
caused by the study vaccines, you will not be able to donate blood or organs. Your family 
and friends may treat you differently. We will give you a brochure that tells you more 
about testing HIV positive because of an HIV vaccine, and how you can avoid some of 
these problems. 
If you become pregnant during or after the study and have VISP, we don't know if the 
antibodies could be passed to your baby. We know that this happens with other vaccines, 
like tetanus vaccine. These antibodies from the mother are not a danger to the baby, and 
they go away over time. For most babies antibodies from the mother last for about 6 
months. 
You should always tell the delivery staff if you have VISP. However, you may still be 
tested for HIV using the antibody test when you deliver your baby. If your test is positive 
and the delivery staff believes you have an HIV infection, your baby may be started on 
antiretroviral treatment when it is not needed. If this happens, we can arrange for you and 
the baby to have a test that can tell the difference between true HIV infection and a VISP 
result. If you or the baby continue to have VISP, we can arrange this testing for free for 
as long as it is needed. 
Embarrassment/anxiety:  
You may feel embarrassed when we ask about your HIV risks, such as having sex and 
using drugs. Also, waiting for your HIV test results or other health test results could 

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make you feel anxious. You could feel worried if your test results show that you are 
infected with HIV. If you feel embarrassed or anxious, please tell us and we will try to 
help you. 
Risks of disclosure of your personal information: 
We will take several steps to protect your personal information. Although the risk is very 
low, it is possible that your personal information could be given to someone who should 
not have it. If that happened, you could face discrimination, stress, and embarrassment. 
We can tell you more about how we will protect your personal information if you would 
like it.  
Risks of genetic testing: 
The genetic testing could show you may be at risk for certain diseases. If others found 
out, it could lead to discrimination or other problems. However, it is almost impossible 
for you or others to know your test results from the genetic testing. The results are not 
part of your study records and are not given to you.  
In the very unlikely event that your genetic information becomes linked to your name, a 
federal law called the Genetic Information Nondiscrimination Act (GINA) helps protect 
you. GINA keeps health insurance companies and employers from seeing results of 
genetic testing when deciding about giving you health insurance or offering you work. 
GINA does not help or protect you against discrimination by companies that sell life, 
disability or long-term care insurance. 
Unknown risks:  
We do not know if the study vaccines will increase, decrease, or not change your risk of 
becoming infected with HIV if exposed. If you get infected with HIV, we do not know 
how the study vaccines might affect your HIV infection or how long it takes to develop 
AIDS. 
We do not know if getting these study vaccines will affect how you respond to any future 
approved HIV vaccine. It could be that a future HIV vaccine may not work as well for 
you because you got the study vaccines. Currently, no HIV vaccine has been approved 
for use.  
We do not know how the study vaccines will affect a pregnant participant or a developing 
baby.  
Benefits 
24. The study may not benefit you. 
We do not know whether getting the study vaccines might benefit you in any way. 
However, being in the study might still help you in some ways. The counseling that you 
get as part of the study may help you avoid getting HIV. The lab tests and physical exams 
that you get while in this study might detect health problems you don’t yet know about.  

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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 
25. If you join the study, you have rights and responsibilities. 
You have many rights that we will respect. You also have responsibilities. We list these 
in the Participant’s Bill of Rights and Responsibilities. We will give you a copy of it. 
Leaving the study 
26. Tell us if you decide to leave the study.  
You are free to leave the study at any time and for any reason. Your care at this clinic and 
your legal rights will not be affected, but it is important for you to let us know.  
We will ask you to come back to the clinic one last time for a physical exam, and we may 
ask to take some blood and urine samples. We will also ask about any personal problems 
or benefits you have experienced from being in the study. We believe these steps are 
important to protecting your health, but it is up to you whether to complete them. 
Injuries 
Sites: Do not make changes to the following section without obtaining approval from 
HVTN Regulatory Affairs at vtn.core.reg@hvtn.org. 
27. 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, there is a process to decide if it is related to 
the study products and/or procedures. If it is, we call it a study-related injury. There are 
funds to pay for treatment of study-related injuries if certain conditions are met.  
The HVTN has limited funds to pay medical costs that it determines are reasonable. 
(Sites: insert locale- appropriate medical insurance language in the following sentence) 
If the injury is not study related, then you and your health insurance will be responsible 
for treatment costs.  
Some injuries are not physical. For example, you might be harmed emotionally by being 
in an HIV vaccine study. Or you might lose wages because you cannot go to work. 
However, there are no funds to pay for these kinds of injuries, even if they are study 
related. 
You may disagree with the decision about whether your injury is study related. If you 
wish, the HVTN will ask independent experts to review the decision. You always have 
the right to use the court system if you are not satisfied. 

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Questions  
28. If you have questions or problems at any time during your participation in this 
study, use the following important contacts. 
If you have questions about this study, contact 
[name and telephone number of the investigator or other study staff]. 
If you have any symptoms that you think may be related to this study, contact 
[name and telephone number of the investigator or other study staff]. 
If you have questions about your rights as a research participant, or problems or concerns 
about how you are being treated in this study, contact 
[name/title/phone of person on IRB or other appropriate organization]. 
If you want to leave this study, contact 
[name and telephone number of the investigator or other study staff]. 
Your permissions and signature  
Site: Delete this section if using a separate consent for use of samples and information in 
other studies 
29. In section 14 of this form, we told you about collecting stool samples. Please write 
your initials or make your mark in the box next to the options you choose. 
I agree to provide stool samples. 
I do not agree to provide stool samples. 
30. In Section 18 of this form, we told you about possible other uses of your extra 
samples and limited information, outside this study. Please choose only one of the 
options below and write your initials or make your mark in the box next to it. 
Whatever you choose, the HVTN keeps track of your decision about how your 
samples and information can be used. 
 

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

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Appendix C 
Approved birth control methods (for sample 
informed consent form) 
You should not become pregnant during the study because we do not know how the study 
vaccines could affect the developing baby. 
You must agree to use effective birth control from 21 days before your first injection until 
6 months after your last study injection.  
Effective birth control means using any of the following methods every time you have 
sex: 
 
Birth control drugs that prevent pregnancy—given by pills, shots, patches, vaginal 
rings, or inserts under the skin; 
 
Male or female condoms, with or without a cream or gel that kills sperm; 
 
Diaphragm or cervical cap with a cream or gel that kills sperm; 
 
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 1 year; 
 
You have had a hysterectomy (your uterus removed); 
 
You have had your ovaries removed; 
 
You have a tubal ligation (your “tubes tied”) or confirmed successful placement of a 
product that blocks the fallopian tubes; 
 
You are having sex only with a female partner or partners; 
 
You only have oral sex; or, 
 
You are sexually abstinent (no sex at all). 
Remember: If you are having sex, you need to use male or female condoms to protect 
yourself from HIV infection. 
If you join the study, we will test you for pregnancy at some visits, including before each 
study injection 

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Appendix D 
Sample consent form for use of samples and 
information in other studies 
Title: A phase 1 clinical trial to evaluate the safety and immunogenicity of EnvSeq-1 
Envs adjuvanted with GLA-SE, administered alone or with DNA Mosaic-Tre env, in 
healthy, HIV-uninfected adult participants 
HVTN protocol number: HVTN 115 
Site: [Insert site name] 
When samples are no longer needed for this study, the HVTN wants to keep them for use 
in other studies. We will call these “extra samples.” 
This form gives you information so you can decide if you want your extra samples and 
information used in other studies. You will mark your decision at the end of the form. If 
you have any questions, please ask.  
1. Do I have to agree?  
No. You are free to say yes or no, or to change your mind after you sign this form. At 
your request, we will destroy all extra samples that we have. Your decision will not affect 
your being in this study or have any negative consequences here.  
2. Where are the samples stored?  
Extra samples are stored in a secure central place called a repository. Your samples will 
be stored in the HVTN repository in the United States.  
3. How long will the samples be stored?  
There is no limit on how long your extra samples will be stored. [Site: insert limits if your 
regulatory authority imposes them.] 
4. Will I be paid for the use of my samples?  
No. Also, a researcher may make a new scientific discovery or product based on the use 
of your samples. If this happens, there is no plan to share any money with you. The 
researcher is not likely to ever know who you are. 
5. Will I benefit from allowing my samples to be used in other studies?  
Probably not. Results from these other studies are not given to you, this clinic, or your 
doctor. They are not part of your medical record. The studies are only being done for 
research purposes. 
6. Will the HVTN sell my samples and information?  
No, but the HVTN may share your samples with other researchers. Once we share your 
samples and information, we will not be able to get them back. 

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7. How do other researchers get my samples and information?  
When a researcher wants to use your samples and/or information, their research plan 
must be approved by the HVTN. Also, the researcher’s institutional review board (IRB) 
or ethics committee (EC) will review their plan. [Site: 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 other researchers?  
The samples and limited information will be labeled with a code number. Your name will 
not be part of the information. However, some information that we share may be 
personal, such as your race, ethnicity, gender, health information from the study, and HIV 
status. We may share information about the study product you received and how your 
body responded to the study product.  
9. What kind of studies might be done with my extra samples and information?  
 
The studies will be related to HIV, vaccines, the immune system and other 
diseases.  
Researchers may also do genetic testing on your samples. 
If you become HIV infected, the researchers may look at all of the genes of the virus 
found in your samples. The researchers will use this information to learn more about HIV 
and the study product(s).  
In some cases, researchers may take cells from your samples and grow more of them over 
time, so that they can continue to contribute to this study. 
If you agree, your samples could also be used for genome wide studies. In these studies, 
researchers will look at all of your genes (your genome). The researchers compare the 
genomes of many people, looking for common patterns of genes that could help them 
understand diseases. The researchers may put the information from the genome-wide 
studies into a protected database so that other researchers can access it. Usually, no one 
would be able to look at your genome and link it to you as a person. However, if another 
database exists that also has information on your genome and your name, someone might 
be able to compare the databases and identify you. If others found out, it could lead to 
discrimination or other problems. The risk of this is very small. 
10. What are the risks of genetic testing?  
The genetic testing could show you may be at risk for certain diseases. If others found 
out, it could lead to discrimination or other problems. However, it is almost impossible 
for you or others to know your test results from the genetic testing. The results are not 
part of your study records and are not given to you.  
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. 

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GINA does not help or protect you against discrimination by companies that sell life, 
disability or long-term care insurance.  
11. Who will have access to my information in studies using my extra samples? 
People who may see your information are: 
 
Researchers who use your stored samples and limited information for other research 
 
Government agencies that fund or monitor the research using your samples or 
information 
 
The researcher’s Institutional Review Board or Ethics Committee 
 
The people who work with the researcher  
All of these people will do their best to protect your information. The results of any new 
studies that use your extra samples or information may be published. No publication will 
use your name or identify you personally. 
Questions  
12. If you have questions or problems about allowing your samples and information to 
be used in other studies, use the following important contacts. 
If you have questions about the use of your samples or information or if you want to 
change your mind about their use, contact 
[name and telephone number of the investigator or other study staff]. 
If you think you may have been harmed because of studies using your samples or 
information, contact [name and telephone number of the investigator or other study staff]. 
If you have questions about your rights as a research participant, contact 
[name/title/phone of person on IRB or other appropriate organization]. 

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

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Appendix E 
Injection schedule for part A sample 
informed consent form 
 

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Appendix F 
Injection schedule for part B sample 
informed consent form 
 

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Appendix G 
Table of procedures for Part A (for sample informed consent form) 
 
 
 
Time after first injection visit (in months) 
 
Procedure 
Screening 
visit(s) 
First 
injection 
visit  
0.25 
0.5 
2 
2.5 
4 
4.5 
8 
8.5 
12 
12.25 
12.5 
15 
18 
24 
Injection 
 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
 
Brief physical 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Urine test 
√ 
 
 
√ 
 
 
 
 
 
 
 
 
√ 
 
 
 
Blood drawn 
√ 
√ 
√ 
√ 
 
√ 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
 
Pregnancy test 
(participants born 
female)* 
√ 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
√ 
 
 
HIV testing & pretest 
counseling 
√ 
 
 
 
 
√ 
 
√ 
 
√ 
√ 
 
 
√ 
√ 
 
Risk reduction 
counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Interview/questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Health contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
Not shown in this table is a time after all study participants have completed their last scheduled visit when you can find out what products you received.  
* Persons who had a complete hysterectomy (removal of the uterus and ovaries, verified by medical records), are not required to have a pregnancy test.

HVTN 115, Version 1.0 / May 2, 2017 
HVTN115_v1.0_FINAL.docx / Page 155 of 163 
Appendix H 
Table of procedures for Part B (for sample informed consent form) 
 
 
 
Time after first injection visit (in months) 
 
Procedure 
Part B  
Eligibility  
visit(s) 
First 
injection 
visit 
0.25 
0.5 
2 
2.5 
4 
4.5 
8 
8.5 
12 
12.5 
16 
16.25 
16.5 
19 
22 
28 
Injection 
 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
 
Brief physical 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Urine test 
√ 
 
 
√ 
 
 
 
 
 
 
 
 
 
 
√ 
 
 
 
Blood drawn 
√ 
√ 
√ 
√ 
 
√ 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Pregnancy test 
(participants born 
female)* 
√ 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
√ 
 
 
HIV testing & pretest 
counseling 
√ 
 
 
 
 
√ 
 
√ 
 
√ 
√ 
 
√ 
 
 
√ 
√ 
 
Risk reduction 
counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Interview/questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Stool sample (optional) 
 
√ 
 
 
 
 
 
 
 
√ 
 
 
 
 
√ 
 
 
 
Health contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
Not shown in this table is a time after all study participants have completed their last scheduled visit when you can find out what products you received.  
* Persons who had a complete hysterectomy (removal of the uterus and ovaries, verified by medical records), are not required to have a pregnancy test.

HVTN 115, Version 1.0 / May 2, 2017 
HVTN115_v1.0_FINAL.docx / Page 156 of 163 
Appendix I 
Laboratory procedures for Part A 
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
169
Day:
D0
D7
D14
D56
D70
D112
D126
D224
D238
D364
D371
D378
D455
D546
D728
Week:
W0
W1
W2
W8
W10
W16
W18
W32
W34
W52
W53
W54
W65
W78
W104
Month:
M0
M0.25
M0.5
M2
M2.5
M4
M4.5
M8
M8.5
M12
M12.25
M12.5
M15
M18
M24
VAC1
VAC2
VAC3
VAC4
VAC5
Procedure
Ship to1, 2
Tube4
Tube size (vol. 
capacity)4
BLOOD COLLECTION
Screening or diagnostic assays
     Screening HIV test
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     HBsAg/anti-HCV
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     Syphilis
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     HIV diagnostics8
UW-VSL
UW-VSL
EDTA
10mL
—
—
—
—
—
10
—
10
—
10
10
—
—
10
20
—
70
Safety labs
     CBC/ Diff/ platelets
Local lab
Local lab
EDTA
5mL
5
—
—
5
—
5
—
5
—
5
—
—
5
5
—
—
35
     Chemistry panel5
Local lab
Local lab
SST
5mL
5
—
—
5
—
5
—
5
—
5
—
—
5
5
—
—
35
Immunogenicity assays6
     Cellular assays
          ICS
CSR
FHCRC
ACD
8.5mL
—
42.5
—
42.5
—
42.5
—
42.5
—
42.5
—
—
42.5
—
42.5
—
297.5
          Phenotyping (pTfh)
CSR
FHCRC
ACD
8.5mL
—
—
17
—
—
—
—
—
—
—
—
17
—
—
—
—
34
     Humoral assays
          Binding Ab
CSR
Duke
SST
8.5mL
—
8.5
—
8.5
—
8.5
—
8.5
—
8.5
—
—
8.5
—
8.5
—
59.5
          Neutralizing Ab
CSR
Duke
SST
8.5mL
—
8.5
—
8.5
—
8.5
—
8.5
—
8.5
—
—
8.5
—
8.5
—
59.5
          B-cell lineage 
CSR
Duke
ACD
8.5mL
—
34
34
34
—
34
—
34
—
34
—
34
68
—
34
—
340
Specimen storage
     PBMC
CSR
ACD
8.5mL
—
42.5
—
42.5
—
42.5
—
42.5
—
42.5
—
—
42.5
—
68
—
323
     Plasma
CSR
ACD
8.5mL
—
z
z
z
—
z
—
z
—
z
—
z
z
—
z
—
0
     Serum
CSR
SST
8.5mL
—
25.5
—
17
—
17
—
17
—
17
—
—
17
—
17
—
127.5
Visit total
25
161.5
51
163
0
173
0
173
0
173
10
51
197
20
198.5
0
1396
56-Day total
25
186.5
237.5
400.5
400.5
336
173
346
0
173
10
61
258
20
198.5
0
URINE COLLECTION
      Urinalysis
Local lab
Local lab
X
—
—
X
—
—
—
—
—
—
—
—
X
—
—
—
      Pregnancy test7
Local lab
Local lab
X
X
—
—
X
—
X
—
X
—
X
—
—
X
—
—
Screening 
visit3
Assay Location2
Total
Tube volume (mL)
 
1CSR = central specimen repository 
2HVTN Laboratory Program includes laboratories at UW-VSL, FHCRC, and Duke. UW-VSL = University of Washington Virology Specialty Laboratory (Seattle, Washington, USA); FHCRC = Fred Hutchinson Cancer Research Center (Seattle, 
Washington, USA); Duke = Duke University Medical Center (Durham, North Carolina, USA). 
3Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination.  
4Local labs may assign appropriate alternative tube types for locally performed tests. 
5Chemistry panels are defined in Section 9.2 (pre-enrollment) and Section 9.4 (follow-up visits). 
6Immunogenicity assays will be performed at M0 (for binding Ab assay) and M4.5. Based on the number of responders observed at these timepoints, lab assays may be performed on participants for humoral and cellular responses at other timepoints 
7For a participant who was born female (ie, assigned female sex at birth), pregnancy test must be performed on urine or blood specimens on the day of vaccination with negative results received prior to vaccination. Persons who have undergone total 
hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing. 
8At an early termination visit for a withdrawn or terminated participant (Section 9.12), blood should be drawn for HIV diagnostic testing, as shown for visit 15 above. 
9Visit 16 is a health contact visit. Clinic visits are not required unless a participant indicates symptoms that require further assessment. See Section 9.5. 
z = 5 x 1mL aliquots of ACD plasma will be harvested for storage during PBMC processing; no separate blood draw is needed. 

HVTN 115, Version 1.0 / May 2, 2017 
HVTN115_v1.0_FINAL.docx / Page 157 of 163 
Appendix J 
Laboratory procedures for Part B 
 
1CSR = central specimen repository 
2HVTN Laboratory Program includes laboratories at UW-VSL, FHCRC, and Duke. UW-VSL = University of Washington Virology Specialty Laboratory (Seattle, Washington, USA); FHCRC = Fred Hutchinson Cancer Research Center (Seattle, 
Washington, USA); Duke = Duke University Medical Center (Durham, North Carolina, USA). 
3Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination.  
4Local labs may assign appropriate alternative tube types for locally performed tests. 
5Chemistry panels are defined in Section 9.2 (pre-enrollment) and Section 9.4 (follow-up visits). 
6Immunogenicity assays will be performed at M0 (for binding Ab assay), M8.5 and M 16.5. Based on the number of responders observed at these timepoints, lab assays may be performed on participants for humoral and cellular responses at other timepoints 
7For a participant who was born female (ie, assigned female sex at birth), pregnancy test must be performed on urine or blood specimens on the day of vaccination with negative results received prior to vaccination. Persons who have undergone total 
hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing. 
8At an early termination visit for a withdrawn or terminated participant (see Section 9.12), blood should be drawn for HIV diagnostic testing, as shown for visit 17 above.  
9Optional stool specimens may be collected at or before enrollment and at visits 10 and 15 (2 weeks after the fourth and sixth vaccinations, respectively). 
10Visit 18 is a health contact visit. Clinic visits are not required unless a participant indicates symptoms that require further assessment. See Section 9.5. 
z = 5 x 1mL aliquots of ACD plasma will be harvested for storage during PBMC processing; no separate blood draw is needed. 
 
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1810
Day:
D0
D7
D14
D56
D70
D112
D126
D224
D238
D364
D378
D485
D493
D500
D576
D667
D849
Week:
W0
W1
W2
W8
W10
W16
W18
W32
W34
W52
W54
W69
W70
W71
W82
W95
W121
Month:
M0
M0.25
M0.5
M2
M2.5
M4
M4.5
M8
M8.5
M12
M12.5
M16
M16.25
M16.5
M19
M22
M28
VAC1
VAC2
VAC3
VAC4
VAC5
VAC6
Procedure
Ship to1, 2
Tube4
Tube size (vol. 
capacity)4
BLOOD COLLECTION
Screening or diagnostic assays
     Screening HIV test
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     HBsAg/anti-HCV
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     Syphilis
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     HIV diagnostics8
UW-VSL
UW-VSL
EDTA
10mL
—
—
—
—
—
10
—
10
—
10
10
—
10
—
—
10
20
—
80
Safety labs
—
—
     CBC/ Diff/ platelets
Local lab
Local lab
EDTA
5mL
5
—
—
5
—
5
—
5
—
5
—
5
—
—
5
5
—
—
40
     Chemistry panel5
Local lab
Local lab
SST
5mL
5
—
—
5
—
5
—
5
—
5
—
5
—
—
5
5
—
—
40
Immunogenicity assays6
—
—
     Cellular assays
—
—
          ICS
CSR
FHCRC
ACD
8.5mL
—
42.5
—
42.5
—
42.5
—
42.5
—
42.5
—
42.5
—
—
42.5
—
42.5
—
340
          Phenotyping (pTfh)
CSR
FHCRC
ACD
8.5mL
—
—
17
—
—
—
—
—
—
—
—
—
—
17
—
—
—
—
34
     Humoral assays
—
—
          Binding Ab
CSR
Duke
SST
8.5mL
—
8.5
—
8.5
—
8.5
—
8.5
—
8.5
—
8.5
—
—
8.5
—
8.5
—
68
          Neutralizing Ab
CSR
Duke
SST
8.5mL
—
8.5
—
8.5
—
8.5
—
8.5
—
8.5
—
8.5
—
—
8.5
—
8.5
—
68
          B-cell repertoire analysis 
CSR
Duke
ACD
8.5mL
—
34
34
34
—
34
—
34
—
34
—
34
—
34
68
—
34
—
374
Specimen storage
—
—
     PBMC
CSR
ACD
8.5mL
—
42.5
—
42.5
—
42.5
—
42.5
—
42.5
—
42.5
—
—
42.5
—
68
—
365.5
     Plasma
CSR
ACD
8.5mL
—
z
z
z
—
z
—
z
—
z
—
z
—
z
z
—
z
—
0
     Serum
CSR
SST
8.5mL
—
25.5
—
17
—
17
—
17
—
17
—
17
—
—
17
—
17
—
144.5
Visit total
25
161.5
51
163
0
173
0
173
0
173
10
163
10
51
197
20
198.5
0
1569
56-Day total
25
186.5
237.5
400.5
400.5
336
173
346
0
173
10
173
10
61
258
20
198.5
0
URINE COLLECTION
      Urinalysis
Local lab
Local lab
X
—
—
X
—
—
—
—
—
—
—
—
—
—
X
—
—
—
      Pregnancy test7
Local lab
Local lab
X
X
—
—
X
—
X
—
X
—
X
—
X
—
—
X
—
—
STOOL COLLECTION (OPTIONAL)9
     Stool
CSR
Duke
—
X
—
—
—
—
—
—
—
X
—
—
—
—
X
—
—
—
Total
Screening 
visit3
Assay Location2
Tube volume (mL)

HVTN 115, Version 1.0 / May 2, 2017 
HVTN115_v1.0_FINAL.docx / Page 158 of 163 
Appendix K 
Procedures at HVTN CRS for Part A 
Visit: 
01a  
02h 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
15 
16b 
Post 
Day: 
 
D0 
D7 
D14 
D58 
D70 
D112 
D126 
D224 
D238 
D364 
D371 
D378 
D455 
D546 
D728 
 
Month: 
 
M0 
M0.25 
M0.5 
M2 
M2.5 
M4 
M4.5 
M8 
M8.5 
M12 
M12.25 
M12.5 
M15 
M18 
M24 
 
Procedure 
Scr. 
VAC1 
 
 
VAC2 
 
VAC3 
 
VAC4 
 
VAC5 
 
 
 
 
AESIc 
 
Study proceduresd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed screening consent (if used) 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Assessment of understanding 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Signed protocol consent 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Medical history  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Complete physical exam 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
Abbreviated physical exam 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
— 
Risk reduction counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Pregnancy prevention assessmente 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Behavioral risk assessment 
X 
— 
— 
— 
— 
X 
— 
— 
— 
X 
— 
— 
— 
X 
— 
— 
— 
Confirm eligibility, obtain demographics, 
randomize  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Social impact assessment 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Social impact assessment questionnaire 
— 
— 
— 
— 
— 
X 
— 
— 
— 
X 
— 
— 
— 
— 
X 
— 
— 
Outside testing and belief questionnaire 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
— 
X 
— 
— 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Intercurrent illness/adverse experience 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
HIV infection assessmentf 
X 
— 
— 
— 
— 
X 
— 
X 
— 
X 
X 
— 
— 
X 
X 
— 
— 
Confirm HIV test results provided to 
participant 
— 
X 
— 
— 
— 
— 
X 
— 
X 
— 
X 
X 
— 
— 
X 
X 
X 
Local lab assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine dipstick 
X 
— 
— 
X 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
— 
Pregnancy (urine or serum HCG)g 
X 
X 
— 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
X 
— 
--- 
— 
CBC, differential 
X 
— 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
X 
X 
— 
--- 
— 
Chemistry panel (see Section 9.2 and 9.3)  
X 
— 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
X 
X 
— 
--- 
— 
 
a Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination. 
b Clinic visits are not required unless a participant indicates symptoms that require further assessment. See Section 9.5. 
c See Section 9.5. 
d For specimen collection requirements, see Appendix I. 
e Pregnancy prevention assessment is required only for participants who were born female and are capable of becoming pregnant. 
f Includes pre-test counseling. A subsequent follow-up contact is conducted to provide post-test counseling and to report results to participant. 
g For a participant who was born female (ie, assigned female sex at birth), pregnancy test must be performed on urine or blood specimens on the day of vaccination with negative results received prior to vaccination. Pregnancy test to determine eligibility 
may be performed at screening, but must also be done on Day 0 prior to vaccination. Persons who have undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing. 

HVTN 115, Version 1.0 / May 2, 2017 
HVTN115_v1.0_FINAL.docx / Page 159 of 163 
Appendix K, continued 
Visit: 
01a  
02d 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
15 
16 
Post 
Day: 
 
D0 
D7 
D14 
D58 
D70 
D112 
D126 
D224 
D238 
D364 
D371 
D378 
D455 
D546 
D728 
 
Month: 
 
M0 
M0.25 
M0.5 
M2 
M2.5 
M4 
M4.5 
M8 
M8.5 
M12 
M12.25 
M12.5 
M15 
M18 
M24 
 
Procedure 
Scr. 
VAC1 
 
 
VAC2 
 
VAC3 
 
VAC4 
 
VAC5 
 
 
 
 
AESI 
 
Syphilis, Hepatitis B, Hepatitis C 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Vaccination procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccinationb 
— 
X 
— 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
— 
— 
— 
— 
Reactogenicity assessmentsc 
— 
X 
— 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
— 
— 
— 
— 
Poststudy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblind participant 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
  
a Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination. 
b 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. 
c Reactogenicity assessments performed daily for at least 7 days postvaccination (see Section 9.10). 

HVTN 115, Version 1.0 / May 2, 2017 
HVTN115_v1.0_FINAL.docx / Page 160 of 163 
Appendix L 
Procedures at HVTN CRS for Part B 
Visit: 
01a  
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
15 
16 
17 
18b 
Post 
Day: 
 
D0 
D7 
D14 
D58 
D70 
D112 
D126 
D224 
D238 
D364 
D378 
D485 
D493 
D500 
D576 
D667 
D849 
 
Month: 
 
M0 
M0.25 
M0.5 
M2 
M2.5 
M4 
M4.5 
M8 
M8.5 
M12 
M12.5 
M16 
M16.25 
M16.5 
M19 
M22 
M28 
 
Procedure 
Scr. 
VAC1 
 
 
VAC2 
 
VAC3 
 
VAC4 
 
VAC5 
 
VAC6 
 
 
 
 
AESIc 
 
Study proceduresd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed screening consent (if 
used) 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Assessment of 
understanding 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Signed protocol consent 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Medical history  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Complete physical exam 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
Abbreviated physical exam 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
X 
— 
Stool collection (optional) e 
— 
X 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
— 
X 
— 
— 
— 
— 
Risk reduction counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Pregnancy prevention 
assessmentf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Behavioral risk assessment 
X 
— 
— 
— 
— 
X 
— 
— 
— 
X 
— 
— 
— 
X 
— 
— 
— 
— 
— 
Confirm eligibility, obtain 
demographics, randomize  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Social impact assessment 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Social impact assessment 
questionnaire 
— 
— 
— 
— 
— 
X 
— 
— 
— 
X 
— 
— 
— 
— 
— 
— 
X 
— 
— 
Outside testing and belief 
questionnaire 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
— 
X 
— 
— 
— 
— 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Intercurrent illness/adverse 
experience 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
HIV infection assessmentg 
X 
— 
— 
— 
— 
X 
— 
X 
— 
X 
X 
— 
X 
— 
— 
X 
X 
— 
— 
Confirm HIV test results 
provided to participant 
— 
X 
— 
— 
— 
— 
X 
— 
X 
— 
X 
X 
— 
X 
— 
— 
X 
X 
X 
Local lab assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine dipstick 
X 
— 
— 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
— 
 
a Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination. 
b Clinic visits are not required unless a participant indicates symptoms that require further assessment. See Section 9.5. 
c See Section 9.5. 
d For specimen collection requirements, see Appendix J. 
e Optional stool specimens must be collected prior to first vaccination. 
f Pregnancy prevention assessment is required only for participants who were born female and are capable of becoming pregnant. 
g Includes pre-test counseling. A subsequent follow-up contact is conducted to provide post-test counseling and to report results to participant. 

HVTN 115, Version 1.0 / May 2, 2017 
HVTN115_v1.0_FINAL.docx / Page 161 of 163 
Appendix L, continued 
Visit: 
01a  
02f 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Post 
Day: 
 
D0 
D7 
D14 
D58 
D70 
D112 
D126 
D224 
D238 
D364 
D378 
D485 
D493 
D500 
D576 
D667 
D849 
 
Month: 
 
M0 
M0.25 
M0.5 
M2 
M2.5 
M4 
M4.5 
M8 
M8.5 
M12 
M12.5 
M16 
M16.25 
M16.5 
M19 
M22 
M28 
 
Procedure 
Scr. 
VAC1 
 
 
VAC2 
 
VAC3 
 
VAC4 
 
VAC5 
 
VAC6 
 
 
 
 
AESI 
 
Study proceduresb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy (urine or serum 
HCG)c 
X 
X 
— 
— 
X 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
X 
— 
— 
— 
CBC, differential 
X 
— 
— 
X 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
X 
X 
 
— 
— 
Chemistry panel (see Section 
9.2 and 9.3)  
X 
— 
— 
X 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
X 
X 
— 
— 
— 
Syphilis, Hepatitis B,  
Hepatitis C 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Vaccination procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccinationd 
— 
X 
— 
— 
X 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
— 
— 
— 
— 
Reactogenicity assessmentse 
— 
X 
— 
— 
X 
— 
X 
— 
X 
— 
X 
— 
X 
— 
— 
— 
— 
— 
— 
Poststudy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
— 
 
Unblind participant 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
 
 
a Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination. 
b For specimen collection requirements, see Appendix J. 
c For a participant who was born female (ie, assigned female sex at birth), pregnancy test must be performed on urine or blood specimens on the day of vaccination with negative results received prior to vaccination. Pregnancy test to determine eligibility 
may be performed at screening, but must also be done on Day 0 prior to vaccination. Persons who have undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing. 
d 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. 
e Reactogenicity assessments performed daily for at least 7 days postvaccination (see Section 9.10).f 
 
 

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HVTN 115, Version 1.0 / May 2, 2017 
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Appendix M 
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 115 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