A Phase 1 Double-Blind, Randomized Clinical Trial to Evaluate the Safety and Immunogenicity of a Recombinant Oligomeric gp145 Clade C Env Protein (gp145 C.6980) in Healthy, HIV-1-Uninfected Adult Participants in the US
Phase: PHASE1
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
PROTOCOL 
HVTN 122 
A phase 1 double-blind, randomized clinical trial to 
evaluate the safety and immunogenicity of a 
recombinant oligomeric gp145 clade C Env protein 
(gp145 C.6980) in healthy, HIV-1–uninfected adult 
participants in the US 
DAIDS DOCUMENT ID 12030 
BB IND [IND # OR DELETE] HELD BY DAIDS 
CLINICAL TRIAL SPONSORED BY 
Division of AIDS (DAIDS) 
National Institute of Allergy and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
Department of Health and Human Services (DHHS) 
Bethesda, Maryland, USA 
STUDY PRODUCTS PROVIDED BY 
Division of AIDS, NIAID, NIH 
Bethesda, Maryland, USA 
Vaccine Research Center 
Frederick, Maryland, USA 
September 27, 2017 
HVTN 122 
Version 1.0 

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Contents 
1 Ethical considerations ....................................................................................................4 
2 IRB/EC review considerations .......................................................................................6 
2.1 
Minimized risks to participants ......................................................................6 
2.2 
Reasonable risk/benefit balance .....................................................................6 
2.3 
Equitable participant selection .......................................................................7 
2.4 
Appropriate informed consent ........................................................................7 
2.5 
Adequate safety monitoring ...........................................................................7 
2.6 
Protect privacy/confidentiality .......................................................................7 
3 Overview ........................................................................................................................9 
3.1 
Protocol Team ..............................................................................................12 
4 Background ..................................................................................................................13 
4.1 
Vaccine product: gp145 C.6980 Env protein ...............................................13 
4.2 
Rationale for trial concept ............................................................................15 
4.3 
Rationale for trial design ..............................................................................15 
4.4 
Plans for future product development and testing ........................................16 
4.5 
Preclinical safety studies ..............................................................................16 
4.6 
Preclinical immunogenicity studies .............................................................17 
4.7 
Clinical studies .............................................................................................20 
4.8 
Potential risks of study products and administration ...................................21 
5 Objectives and endpoints .............................................................................................22 
5.1 
Primary objectives and endpoints ................................................................22 
5.2 
Secondary objectives and endpoints ............................................................22 
5.3 
Exploratory objectives ..................................................................................23 
6 Statistical considerations ..............................................................................................25 
6.1 
Accrual and sample size calculations ...........................................................25 
6.2 
Randomization .............................................................................................27 
6.3 
Blinding ........................................................................................................27 
6.4 
Statistical analyses ........................................................................................28 
7 Selection and withdrawal of participants .....................................................................34 
7.1 
Inclusion criteria ...........................................................................................34 
7.2 
Exclusion criteria ..........................................................................................36 
7.3 
Participant departure from vaccination schedule or withdrawal ..................40 
8 Study product preparation and administration .............................................................43 
8.1 
Vaccine regimen ...........................................................................................43 
8.2 
Study product formulation ...........................................................................43 
8.3 
Preparation of study products .......................................................................44 
8.4 
Administration ..............................................................................................46 
8.5 
Acquisition of study products ......................................................................46 
8.6 
Pharmacy records .........................................................................................46 
8.7 
Final disposition of study products ..............................................................46 
9 Clinical procedures ......................................................................................................48 
9.1 
Informed consent ..........................................................................................48 
9.2 
Pre-enrollment procedures ...........................................................................50 

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9.3 
Enrollment and vaccination visits ................................................................51 
9.4 
Follow-up visits ............................................................................................53 
9.5 
HIV counseling and testing ..........................................................................54 
9.6 
Contraception status .....................................................................................56 
9.7 
Urinalysis .....................................................................................................56 
9.8 
Assessments of reactogenicity .....................................................................56 
9.9 
Visit windows and missed visits ..................................................................58 
9.10 Early termination visit ..................................................................................58 
9.11 Pregnancy .....................................................................................................58 
10 Laboratory ....................................................................................................................59 
10.1 HVTN CRS laboratory procedures ..............................................................59 
10.2 Total blood volume ......................................................................................59 
10.3 Primary immunogenicity timepoints ............................................................59 
10.4 Endpoint assays: cellular ..............................................................................59 
10.5 Endpoint assays: humoral .............................................................................60 
10.6 Genotyping ...................................................................................................60 
10.7 Lab assay algorithm .....................................................................................60 
10.8 Exploratory studies .......................................................................................61 
10.9 Specimen storage and other use of specimens .............................................61 
10.10 Biohazard containment .................................................................................62 
11 Safety monitoring and safety review ...........................................................................63 
11.1 Safety monitoring and oversight ..................................................................63 
11.2 Safety reporting ............................................................................................64 
11.3 Initial safety evaluation ................................................................................66 
11.4 Safety pause and prompt PSRT AE review..................................................66 
11.5 Review of cumulative safety data ................................................................68 
11.6 Study termination .........................................................................................68 
12 Protocol conduct ..........................................................................................................69 
12.1 Social impacts ..............................................................................................70 
12.2 Emergency communication with study participants ....................................70 
13 Version history .............................................................................................................71 
14 Document references (other than literature citations) ..................................................72 
15 Acronyms and abbreviations........................................................................................74 
16 Literature cited .............................................................................................................77 
Appendix A Sample informed consent form ....................................................................81 
Appendix B Approved birth control methods (for sample informed consent form) ........98 
Appendix C Sample consent form for use of samples and information in other studies 100 
Appendix D Table of procedures (for sample informed consent form) ..........................104 
Appendix E Laboratory procedures ................................................................................105 
Appendix F Procedures at HVTN CRS ..........................................................................107 
Appendix G Protocol Signature Page .............................................................................109 

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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. 

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 The HVTN designs its research to minimize risk and maximize benefit to both 
study participants and their local communities. For example, HVTN protocols 
provide enhancement of participants’ knowledge of HIV and HIV prevention, 
as well as counseling, guidance, and assistance with any social impacts that 
may result from research participation. HVTN protocols also include careful 
medical review of each research participant’s health conditions and reactions 
to study products while in the study.  
 HVTN research aims to benefit local communities by directly addressing the 
health and HIV prevention needs of those communities and by strengthening 
the capacity of the communities through training, support, shared knowledge, 
and equipment. Researchers involved in HVTN trials are able to conduct other 
critical research in their local research settings. 
 The HVTN values the role of in-country Institutional Review Boards (IRBs), 
Ethics Committees (ECs), and other Regulatory Entities (REs) as custodians 
responsible for ensuring the ethical conduct of research in each setting. 

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

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2.3 
Equitable participant selection  
45 CFR 46.111 (a) 3 and 21 CFR 56.111 (a) 3: Subject selection is 
equitable 
This protocol has specific inclusion and exclusion criteria for investigators to 
follow in admitting participants into the protocol. Participants are selected 
because of these criteria and not because of positions of vulnerability or privilege. 
Investigators are required to maintain screening and enrollment logs to document 
volunteers who screened into and out of the protocol and for what reasons. 
2.4 
Appropriate informed consent 
45 CFR 46.111 (a) 4 & 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 10). Safety is 
monitored daily by HVTN Core and routinely by the HVTN 122 Protocol Safety 
Review Team (PSRT). In addition, the HVTN Safety Monitoring Board (SMB) 
periodically reviews study data. 
2.6 
Protect privacy/confidentiality 
45 CFR 46.111 (a) 7 and 21 CFR 56.111 (a) 7: There are adequate 
provisions to protect the privacy of subjects and maintain the 
confidentiality of data. 
Privacy refers to an individual’s right to be free from unauthorized or 
unreasonable intrusion into his/her private life and the right to control access to 
individually identifiable information about him/her. The term “privacy” concerns 
research participants or potential research participants as individuals whereas the 

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term “confidentiality” is used to refer to the treatment of information about those 
individuals. This protocol respects the privacy of participants by informing them 
about who will have access to their personal information and study data (see 
Appendix A). 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 double-blind, randomized clinical trial to evaluate the safety and 
immunogenicity of a recombinant oligomeric gp145 clade C Env protein (gp145 
C.6980) in healthy, HIV-1–uninfected adult participants in the US 
Primary objective(s) 
To evaluate the safety and tolerability of 1 injection of gp145 C.6980 at 2 dose 
levels with alum adjuvant in HIV-seronegative low risk adults 
Secondary objectives 
To evaluate the safety and tolerability of 3 injections of gp145 C.6980 at 2 dose 
levels with alum adjuvant in HIV-seronegative low risk adults 
To characterize the immunogenicity of 1 injection of gp145 C.6980 at 2 dose 
levels with alum adjuvant in HIV-seronegative low risk adults 
To characterize the immunogenicity of 3 injections of gp145 C.6980 at 2 dose 
levels with alum adjuvant in HIV-seronegative low risk adults 
Study products and routes of administration 
 gp145 C.6980: gp145 C.6980 is an HIV-1 subtype C recombinant gp145 Env 
protein produced in CHO (Chinese hamster ovary) cells and derived from an 
acute Tanzanian clade C Env (C06980.v0.c22). gp145 C.6980 will be given 
with aluminum hydroxide adjuvant, mixed together at the clinical site. 
300mcg (Group 1) and 100mcg (Group 2) of gp145 C.6980 will be admixed 
with aluminum hydroxide adjuvant containing ~600mcg ionic aluminum. 
The resulting vaccine/adjuvant mixtures will be given as single 1 mL 
intramuscular (IM) injections into the deltoid. 
 Placebo: Sodium Chloride for Injection, 0.9% delivered as a 1 mL IM 
injection 
Table 3-1 Schema 
Study arm Number 
Dose 
 
Month 0 
(Day 0) 
Month 2 
(Day 56) 
Month 6 
(Day 168) 
Group 1 
25 
300 mcg  
gp145 C.6980 
+ alum 
gp145 C.6980 
+ alum 
gp145 C.6980 
+ alum 
Group 2 
15 
100 mcg  
gp145 C.6980 
+ alum 
gp145 C.6980 
+ alum 
gp145 C.6980 
+ alum 
Group 3 
5 
NA 
 
placebo 
placebo 
placebo 
Total 
45 (40/5) 
 
 
 
 

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Note 
Enrollment will proceed in all study arms simultaneously and will be restricted to 
a maximum of 1 participant per group per day until 20% of participants (ie, the 
first 9 participants [5 in Group 1, 3 in Group 2, and 1 in Group 3]) have been 
enrolled. The PSRT will review the safety and reactogenicity data reported for the 
first 2 weeks following the first vaccination for each of these participants and will 
determine whether it is safe to proceed with full enrollment. 
Participants 
45 healthy, HIV-1–uninfected volunteers aged 18 to 50 years: 40 vaccinees, 5 
placebo recipients in the US 
Design 
Multicenter, randomized, placebo-controlled, double-blind trial 
Duration per participant 
12 months of scheduled clinic visits 
Estimated total study duration 
17 months (includes enrollment, planned safety hold, and follow-up) 
Investigational New Drug (IND) sponsor 
DAIDS, NIAID, NIH, DHHS (Bethesda, Maryland, USA) 
Study product providers 
 gp145 C.6980: Division of AIDS, NIAID, NIH (Bethesda, Maryland, USA) 
 Aluminum hydroxide adjuvant: Vaccine Research Center, NIAID, NIH 
(Frederick, Maryland, USA) 
Core operations 
HVTN Vaccine Leadership Group/Core Operations Center, Fred Hutchinson 
Cancer Research Center (FHCRC) (Seattle, Washington, USA) 
Statistical and data management center (SDMC) 
Statistical Center for HIV/AIDS Research and Prevention (SCHARP), FHCRC 
(Seattle, Washington, USA) 

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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 122 PSRT; HVTN Safety Monitoring Board (SMB) 

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3.1 
Protocol Team 
Protocol leadership 
Chair 
Katharine Bar 
University of Pennsylvania 
215-573-8497 
bark@upenn.edu 
Statistician 
Yunda Huang 
SCHARP, FHCRC 
206-667-5780 
yunda@scharp.org 
Cochair 
Hong Van Tieu 
New York Blood Center 
212-570-3081 
htieu@nybloodcenter.org 
Medical officers 
Maggie Brewinski Isaacs 
DAIDS, NIAID 
301-761-7009 
maggie.brewinskiisaacs@nih.gov 
Protocol Team 
leader 
Shelly Karuna 
HVTN Core, FHCRC 
206-667-4355 
mkaruna@fredhutch.org 
Laboratory lead 
Mingchao Shen 
HVTN Laboratory Program 
206-667-5360 
mshen@fredhutch.org 
 
 
 
 
Other contributors to the original protocol 
Core medical monitor 
Shelly Karuna 
HVTN Core, FHCRC 
Clinical safety specialist 
Megan Jones 
HVTN Core, FHCRC 
Vaccine developer 
representative 
Jane Halpern 
DAIDS, NIAID 
Clinical trials manager 
India Tindale 
HVTN Core, FHCRC 
Laboratory protocol 
operations manager 
On Ho 
HVTN Laboratory 
Program, FHCRC 
SDMC Associate director 
of lab science 
April Randhawa 
SCHARP, FHCRC 
Regulatory affairs 
Laurie Rinn 
HVTN Core, FHCRC 
SDMC Senior clinical 
data manager 
Gina Escamilla 
SCHARP, FHCRC 
Clinic coordinator 
Debbie Lucy 
New York Blood 
Center CRS 
DAIDS Project officer 
Michael Pensiero 
DAIDS, NIAID 
Community Advisory 
Board (CAB) member 
Aamina Morrison 
University of 
Pennsylvania CAB 
Protocol development 
managers 
Carter Bentley 
HVTN Core, FHCRC 
Ryan Jensen 
HVTN Core, FHCRC 
DAIDS protocol 
pharmacist 
Katherine Shin 
DAIDS, NIAID 
240-627-3047 
Community engagement 
unit representative 
Stephaun Wallace  
HVTN Core, FHCRC 
Statistical research 
associate 
Mengshu Shao 
SCHARP, FHCRC 
Community 
educator/recruiter 
Jermaine McCrossin 
New York Blood 
Center CRS 
Consultative 
investigator 
Merlin Robb 
MHRP 
Technical editor 
Erik Schwab 
HVTN Core, FHCRC 
 
 
 
 
 
 
 
 

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4 
Background 
4.1 
Vaccine product: gp145 C.6980 Env protein 
The gp145 C.6980 protein was derived from a clade C strain isolated from an 
acutely infected Tanzanian individual (CO6980.v0.c22) [4]. A clade C founder 
virus was deemed advantageous as clade C infections represent more than half the 
HIV-1 pandemic and are prevalent in highly impacted regions, including southern 
and eastern Africa but also in other parts of the world [5,6]. Relative to sera from 
persons infected with other clades of HIV-1, sera from clade C–infected 
individuals have been shown to be more broadly cross-reactive, neutralizing the 
greatest number of viruses in multiclade neutralization panels [7-9]. Further, the 
use of a primary virus isolate obtained in acute infection may better represent the 
properties of transmitted/founder viruses, which are the target of preventive 
vaccines [10,11].  
gp145 C.6980 is a novel immunogen constructed by modifying the gene for the 
CO6980.v0.c22 protein to terminate prior to the transmembrane region, thus 
retaining an intact membrane-proximal external region (MPER) without the 
carboxyl terminal cytoplasmic domain. Additional modifications to the gene were 
introduced to prevent cleavage at the gp120/gp41 cleavage site and to facilitate 
trimer assembly and antigen presentation. gp145 C.6980 is produced as a secreted 
protein from Chinese hamster ovary (CHO) cells and has been purified and tested 
in both in vitro and in vivo assays. The gp145 C.6980 immunogen was developed 
by the United States Military HIV Research Program (MHRP); the lot used in this 
study was manufactured by Avid Biosciences (Tustin, CA, USA). The study 
product for this trial is supplied by DAIDS. 
The expressed and purified gp145 C.6980 was shown to be assembled in multiple 
forms, with a significant fraction represented as Env trimers (Figure 4-1A). 
Cryoelectron microscopy of the gp145 trimers demonstrate the expected “fan-
blade” morphology (Figure 4-1B) [4].  

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Figure 4-1 A fraction of gp145 C.6980 is expressed as trimeric Env. (A) Blue Native-PAGE 
analysis demonstrates that purified gp145 C.6980 exists in multiple oligomeric forms, 
including trimers. (B) The majority of the trimer fraction (lane 3) appears as true trimeric 
Envs with “fan-blade” morphology by cryoelectron microscopy [4]. 
The primary virus CO6940.v0.c22 displays epitopes of and is neutralized by 
broadly neutralizing antibodies (bnAbs) targeting MPER (4E10), the CD4 binding 
site (VRC01) and V2 glycans (PG9/PG16, PGT121); the trimeric gp145 C.6980 
protein is similarly bound by each of these bnAbs and additional mAbs targeting 
V2 (697, 2158, 2297) [4]. Immunization of rabbits with each structural fraction 
was tested. All fractions of the gp145 C.6980 were immunogenic, with induced 
antibodies showing binding to clade C gp120 and gp140 Envs and cyclic V2 
peptides as well as neutralization of Tier 1, and some Tier 2, viruses (Figure 4-2). 
 
Figure 4-2 gp145 C.6980 is immunogenic in rabbits. Mean ID50 values for sera from rabbits 
vaccinated with gp145 fractions (unfractionated, dimers, trimers, higher order multimers) 
against clade B and C viruses in TZM-bl assay (A) or PBMC inhibition assay (B) [4]. 
Aluminum hydroxide (alum) will be used as an adjuvant, which will be co-
administered with gp145 C.6980. When compared to 3 liposomal adjuvant 
formulations for immunogenicity in rabbits, alum was shown to generate 
comparable binding and neutralizing antibody titers [4].  
For the study protocol, gp145 C.6980 produced in CHO cells will be given with 
alum as an adjuvant mixed together at the clinical site. Vaccinees will receive 
either 300 mcg (Group 1) or 100 mcg (Group 2) of gp145 C.6980 admixed with 
alum adjuvant containing ~600 mcg ionic aluminum. The resulting 
vaccine/adjuvant mixtures will be given as a single 1 mL IM injection in the 
A 
B 

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deltoid. Placebo recipients will receive sodium chloride 0.9% delivered as a 1 mL 
IM injection. 
4.2 
Rationale for trial concept 
The development of a vaccine against HIV-1 infection remains a significant 
global health challenge. Based on the RV144 phase 3 HIV vaccine trial results, 
which provided the first clinical trial evidence that a vaccine combination could 
demonstrate modest efficacy in preventing HIV infection [12,13], an effective 
HIV vaccine is expected to require, as 1 component, an antigen that stimulates the 
production of an effective antibody response. This could consist of bnAbs that are 
capable of preventing HIV-1 entry into its target cells and blocking virus 
transmission [14,15] and/or non-neutralizing antibodies with effector functions 
[16]. Such an antigen is likely to be an Env glycoprotein, since this is the only 
protein expressed on the surface of the HIV virus particle that could serve as a 
target for vaccine-induced antibodies. 
Vaccine candidates tested to date in humans have not yet successfully generated 
strong bnAb responses against a wide spectrum of viruses. However, the RV144 
trial did demonstrate modest protection that was associated with antibody 
responses [17]. In RV144, a 31% decrease in risk of HIV infection was observed 
in participants who received ALVAC canarypox vector expressing Env, Gag, and 
Pro at 0, 1, 3, and 6 months and were boosted with a monomeric gp120 protein, 
AIDSVAX B/E, at 3 and 6 months, compared to those who received placebo. 
Subsequent analyses of immune responses have demonstrated that antibodies to 
the V1V2 region of HIV Env were inversely correlated with the risk of HIV-1 
infection in vaccine recipients [18-20]. 
While the Env protein in AIDSVAX was a gp120 monomer, several lines of 
evidence suggest that a trimeric Env antigen may better expose quaternary 
epitopes and lead to an improved protective immune response against HIV-1 
relative to monomeric protein [21-23]. In preclinical studies, the gp145 C.6980 
protein has been demonstrated to elicit neutralizing antibodies to certain viruses 
or pseudoviruses in rabbits [4] (Section 4.6).  
Hence, the goal of this trial is to evaluate the safety and immunogenicity of 2 dose 
levels of gp145 C.6980, a novel oligomeric Env antigen, in healthy, HIV-1–
uninfected adult participants in the US and, if it is demonstrated to be safe and 
immunogenic, to qualify it for further clinical testing, most likely as 1 component 
in a combination vaccine prime-boost strategy. 
4.3 
Rationale for trial design  
4.3.1 
Dose (amount and number) 
This study will test 2 doses: 300 mcg gp145 C.6980 with alum (n = 25) and 100 
mcg gp145 C.6980 with alum (n = 15) compared to placebo (n = 5). The 300 mcg 

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HVTN122_v1.0_FINAL / Page 16 of 109 
dose is based on dosing of Env proteins used in RV144 [12]; the 100 mcg dose is 
being tested to explore immunogenicity of a lower dose regimen. The 2 doses are 
projected to be used in combination vaccine trials that may occur subsequently.  
4.3.2 
Schedule 
All groups will receive the vaccine or placebo at Months 0, 2, and 6.  
Enrollment will proceed in all groups simultaneously and will be restricted to a 
maximum of 1 participant per group per day until the initial 20%, or 9 participants 
(5 in Group 1, 3 in Group 2, and 1 in Group 3) have been enrolled and observed 
for 2 weeks. The PSRT will review safety data reported for the first 2 weeks 
following the first vaccination for each of these participants and will determine 
whether it is safe to proceed with full enrollment. 
4.3.3 
Choice of control 
Placebo will be Sodium Chloride for Injection, 0.9% delivered as a 1 mL 
injection. 
4.4 
Plans for future product development and testing 
This trial is a phase 1 double-blind, placebo-controlled randomized clinical trial to 
evaluate the safety and immunogenicity of a recombinant gp145 clade C Env 
protein in healthy, HIV-1–uninfected adult participants in the US. If the trial 
demonstrates that gp145 C.6980 is safe, tolerable, and immunogenic, it will be 
considered as an Env immunogen in subsequent combination vaccine trials. In 
particular, the developers of gp145 C.6980 have been in discussion with 
representatives from the China Centers for Disease Control regarding the prospect 
of evaluating this protein as a boost component in a regimen that includes a DNA 
prime and a recombinant Tiantan strain vaccinia vector boost [24,25]. 
4.5 
Preclinical safety studies 
gp145 C.6980 has not previously been tested in humans. The immunogenicity 
studies performed to date with the gp145 C.6980, as well as its physiochemical 
characterization, suggest that the protein retains the intended conformation 
predicted to be immunogenic and is not associated with any unexpected properties 
that would raise potential safety concerns. The safety of other HIV Env proteins 
administered with alum has been extensively studied in clinical trials and 
preclinical studies. The extensive clinical experience with these HIV Envs as 
vaccine antigens is described briefly below (Section 4.6.3). 

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4.6 
Preclinical immunogenicity studies 
Table 4-1 Summary of preclinical immunogenicity studies 
Study 
number 
Test Article 
Adjuvant and 
Formulation 
Animal 
N 
Dose 
Route 
Schedule 
Assay 
1 
Unfractionated 
gp145 C.6980 
Unfractionated 
gp145 C.6980 
Unfractionated 
gp145 C.6980 
Unfractionated 
gp145 C.6980 
None 
Al(OH)3 + gp145 
C.6980  
L(DMPG/MPLA) 
+ gp145 C.6980  
L(DMPG/MPLA + 
gp145 C.6980) 
L(PIP/MPLA + 
gp145 C.6980) 
L(DMPG/MPLA) 
Rabbits 
4 
25mcg 
protein  
(+600 
mcg 
alum) 
IM 
Week 0, 
4, 8 
Binding 
ELISA 
Neutralization 
by TZM-bl 
and PBMC 
2 
Unfractionated 
gp145 C.6980 
gp145 C.6980 
dimer 
gp145 C.6980 
trimer 
gp145 C.6980 
multimer 
None 
Al(OH)3 + gp145 
C.6980 
Al(OH)3 + gp145 
C.6980 
Al(OH)3 + gp145 
C.6980 
Al(OH)3 + gp145 
C.6980 
Al(OH)3 
Rabbits 
4 
25mcg 
protein  
(+600 
mcg 
alum) 
IM 
Week 0, 
4, 8 
Binding 
ELISA 
Neutralization 
by TZM-bl 
and PBMC 
4.6.1 
Immunogenicity of gp145 C.6980 in rabbits, study #1 
The gp145 C.6980 protein has been evaluated in 2 rabbit studies testing the ability 
of the vaccine to stimulate a neutralizing antibody response (Table 4-1). Study 1 
tested the ability of unfractionated gp145 C.6980 to stimulate binding and 
neutralizing antibody responses in rabbits. Unfractionated gp145 C.6980 with 
alum was tested against unfractionated gp145 C.6980 and liposomal adjuvants 
that were prepared to encapsulate (Groups 3 and 4) or mix with (Group 2) the test 
article. Animals were immunized at weeks 0, 4, and 8 via IM injection. Blood was 
collected at Weeks -2, 0, 4, 8, 10, and 12. 
4.6.1.1 
Binding antibody responses 
Sera were collected 2 weeks after the last vaccination (Week 10) and tested for 
binding activity to homologous and heterologous Envs. Weak titers were seen in 
some animals to gp41 proteins, whereas there was a positive response against 
each of the clade C gp120 and gp140 proteins (Figure 4-3).  
 

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Figure 4-3 Fractionated and unfractionated gp145 C.6980 induced binding antibody 
responses in rabbits. Binding antibody titers elicited by vaccination with gp145 C.6980. 
Binding to various Env constructs by unfractionated gp145 C.6980–vaccinated rabbit sera in 
Study 1 (A). Binding of vaccinated animals’ sera to V1V2 (B) and V3 (C) peptides. Binding 
responses were similar for unfractionated gp145 C.6980 and fractionated gp145 C.6980 
(dimers, trimers, higher order oligomers) in Study 2 (D) [4]. 
4.6.1.2 
Neutralizing antibody responses 
Elicitation of neutralizing antibody responses was tested using the TZM-bl assay 
[26,27] and PBMC assay [28,29]. The TZM-bl assay provides a well-validated, 
high-throughput assessment of plasma inhibition of entry into a laboratory cell 
line. The PBMC neutralization provides a dose-response measure of plasma 
antibody inhibition of infectious molecular clones expressing luciferase reporters 
in a 72 hour culture of stimulated primary blood mononuclear cells. In the TZM-
bl assay, sera from vaccinated rabbits neutralized 3 of 6 viruses, reflecting a 
predominantly Tier 1 (easy to neutralize) response. There was no neutralizing 
activity against the homologous CO6980 pseudovirus (Tier 2) or heterologous 
Tier 2 CRF01_AE viruses (Figure 4-4 A, C). In the PBMC assay, neutralization 
was seen against 5 tested viruses, including the homologous CO6980 strain 
(Figure 4-4 B, D). 
4.6.2 
Immunogenicity of gp145 C.6980 in rabbits, study #2: fractionated 
protein 
In Study 2, rabbits were immunized with either unfractionated gp145 C.6980 or 
preparations enriched for dimers, trimers, or other higher order fractions based on 
size-exclusion chromatography (see Figure 4-1A). Sera were tested for binding 
and neutralizing antibody responses. 

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4.6.2.1 
Binding antibody responses 
Sera were collected 2 weeks after the last vaccination (week 10) and tested for 
binding activity to homologous and heterologous Envs (clade C gp120, subtype C 
gp140, and cyclic V2 peptides of the homologous CO6980.v0.c22 strain). 
Responses in sera from animals vaccinated with unfractionated gp145 C.6980 
were similar to the responses seen in Study 1. Sera from animals vaccinated with 
purified fractions displayed similar profiles as the unfractionated animals in Study 
1 and 2. 
4.6.2.2 
Neutralizing antibody responses 
As in Study 1, elicitation of neutralizing antibody responses was tested in the 
TZM-bl assay and PBMC assay. Sera from vaccinated rabbits were tested against 
the 3 heterologous pseudoviruses that were neutralized in Study 1 and the 
homologous C.6980 pseudovirus. Neutralization activity was seen for the 3 
heterologous Tier 1 viruses and was not different between the unfractionated and 
purified proteins. As in Study 1, neutralizing activity was seen against all 4 
viruses in the PBMC assay. Thus, unfractionated and each oligomeric formulation 
elicited Tier 1 neutralizing antibody responses. 
 
Figure 4-4 Fractionated and unfractionated gp145 C.6980 induce heterologous Tier 1 
neutralizing antibody responses. Neutralizing antibody responses detected by TZM-bl (A 
and C) and PBMC assays (B and D). In Study 1, neutralization in TZM-bl assay is seen 
against Tier 1 viruses only in the TZM-bl assay (A) and more widely in the PBMC assay (B). 
In Study 2, similar titers are seen with fractionated and unfractionated gp145 C.6980 against 
Tier 1 viruses (C and D). 
4.6.3 
Preclinical study of gp145 C.6980 in non-human primates 
gp145 C.6980 was administered to 16 Indian-origin rhesus macaques three times 
over a period of nine months in conjunction with recombinant live attenuated 
modified vaccinia Ankara (MVA) vector encoding HIV-1 GagPol/Env derived 
from subtypes A, C, and E.  Animals received MVA at month 0, followed by 

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concurrent MVA and gp145 at months 3, 6, and 12. gp145 C.6980 immunizations 
consisted of 100 mcg of protein adjuvanted with aluminum hydroxide 
(Alhydrogel, Brenntag) delivered IM. The protein was safely administered and 
well-tolerated with no adverse events. Animal body weights and temperatures 
remained stable following each immunization.gp145 C.6980 was immunogenic in 
all animals, eliciting binding antibody responses with a median titer of 105 to 
gp140 (subtype C CN54) and 103.7 to cyclic V2 peptide (gp145). Tier 1 
neutralizing antibodies were also consistently observed, showing a median ID50-1 
of 103 to both MW965 and TH023 (subtype C and E, respectively). gp120-
specific CD4+ T cells were observed in most animals, ranging from 0.1-0.5% of 
the memory compartment, while CD8+ T-cell responses were observed in only a 
subset of animals at 0.6-3% of memory cells. In sum, gp145 C.6980 showed 
consistent and robust immunogenicity with no safety concerns in nonhuman 
primates. 
4.7 
Clinical studies 
Though gp145 C.6980 has not previously been evaluated in humans, the safety of 
other HIV Env proteins administered with alum has been extensively studied in 
clinical and preclinical studies. The extensive clinical experience with these HIV 
Envs as vaccine antigens is described briefly here. 
Multiple monomeric Env proteins (gp120, gp140, gp145, gp160) have been 
administered in many clinical trials as the sole vaccine component or as a part of a 
prime boost regimen. The majority of proteins were produced in CHO cells (as is 
gp145 C.6980). Overall, vaccines consisting of or expressing HIV Env variants 
were well tolerated. The long-term safety data from NIAID-sponsored clinical 
trials conducted between 1987 and 2001 was analyzed by Gilbert and colleagues 
[30]. This report included 51 phase 1 and 2 trials, including data on 3189 
uninfected participants; the majority of studies included an Env protein as an 
immunogen [30]. The published analysis concluded that 1 vaccine containing a 
C4-V3 polypeptide vaccine emulsified in incomplete Freund’s adjuvant caused 
serious toxicity, but otherwise no serious safety problems were identified for any 
of the vaccines or adjuvants studied.  
The largest clinical safety dataset for Env proteins is from the VAX003, VAX004, 
and RV144 studies, in which more than 12,000 participants received either 
AIDSVAX B/E or AIDSVAX B/B (each a mixture of 2 CHO-derived gp120 
proteins totaling 600mcg [300mcg of each protein] in alum adjuvant). Safety data 
showed that these vaccines appeared safe and well tolerated [31]. In the RV144 
trial, the frequency of reactions in AIDSVAX B/E recipients was 54.6% vs. 
46.3% in placebo recipients. Pain and tenderness were the most frequent local 
reactions observed, and all reactions were generally mild and resolved within 3 
days. Systemic reactogenicity was also observed more frequently in the combined 
vaccine group (77.2%) than the placebo group (59.8%). Systemic reactions 
following the third and fourth vaccination could not be attributed to a specific 
vaccine (ie, AIDSVAX or ALVAC). 

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Recent clinical experience with other oligomeric Env antigens is also available 
from a smaller number of studies. Oligomeric forms of gp140 clade C and clade B 
Env proteins manufactured by Novartis Vaccines and Diagnostics have been 
evaluated in 3 IND studies (clade C gp140 strain TV1 with MF59 and clade B 
gp140 strain SF162 with MF59) [32,33]. An oligomeric gp160 Env protein was 
administered to 45 participants in RV132, a phase 1-2 prime-boost study in 
Thailand [34]. More than 100 participants received the oligomeric subtype C 
product in a recent HVTN study (HVTN 086) [35]. The safety profile of these 
products was similar to that observed for the AIDSVAX products. The vaccines 
were generally well tolerated without vaccine-related serious adverse events. 
4.8 
Potential risks of study products and administration 
Table 4-2 Summary of potential risks of study products and administration 
Common 
 
Mild to moderate injection site pain, tenderness, erythema, or 
swelling/induration/edema 
 
Malaise/fatigue, myalgia, or headache in the first few days following 
injection 
 
A vaccine-induced positive HIV antibody test result 
Less common 
 
Severe injection site pain or tenderness 
 
Fever, chills, flu-like syndrome, arthralgia, rash, nausea, or dizziness in the 
first few days following injection  
 
Vasovagal reaction/lightheadedness/dizziness related to the injection 
procedure 
 
Transient changes in clinical laboratory values 
 
Injection site hematoma, bruising/ecchymosis, other transient lesions, 
itching, or bleeding related to the injection procedure 
Uncommon or rare 
 
Severe localized injection site reaction, such as sterile abscess or secondary 
bacterial infection  
 
Allergic reaction, including rash, urticaria, angioedema, bronchospasm, or 
anaphylaxis 
 
Muscle damage at the injection site 
Theoretical risks 
 
Autoimmune disease  
 
Effects on a participant’s response to an approved HIV vaccine 
administered in the future 
 
Effects on susceptibility to HIV, if the participant is exposed to HIV  
 
Effects on the course of HIV infection/disease, if the participant is infected 
with HIV 
 
Effects on the fetus and on pregnancy 

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5 
Objectives and endpoints 
5.1 
Primary objectives and endpoints 
Primary objective 1:  
To evaluate the safety and tolerability of 1 injection of gp145 C.6980 at 2 dose 
levels with alum adjuvant in HIV-seronegative low risk adults 
Primary endpoints 1:  
Frequency of severe local and systemic reactogenicity signs and symptoms: pain, 
tenderness, maximum severity of pain and/or tenderness, erythema, induration, 
fever, malaise/fatigue, myalgia, headache, nausea, vomiting, chills, arthralgia, 
maximum severity of systemic symptoms (graded using the Division of AIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events. Corrected 
Version 2.1, dated July 2017) 
Frequency of AEs by treatment arm, by body system, Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term, severity, and assessed 
relationship to study products (graded using the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events. Corrected Version 
2.1, dated July 2017) 
Serious adverse events (SAEs) throughout the active surveillance period 
Laboratory measures of safety: white blood cells (WBC), neutrophils, 
lymphocytes, hemoglobin, platelets, ALT, and creatinine at baseline and 
following vaccinations, by treatment arm (graded using the Division of AIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events. Corrected 
Version 2.1, dated July 2017)  
5.2 
Secondary objectives and endpoints 
Secondary objective 1: 
To evaluate the safety and tolerability of 3 injections of gp145 C.6980 at 2 dose 
levels with alum adjuvant in HIV-seronegative low risk adults 
Secondary endpoints 1: 
Frequency of severe local and systemic reactogenicity signs and symptoms: pain, 
tenderness, maximum severity of pain and/or tenderness, erythema, induration, 
fever, malaise/fatigue, myalgia, headache, nausea, vomiting, chills, arthralgia, 
maximum severity of systemic symptoms (graded using the Division of AIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events. Corrected 
Version 2.1, dated July 2017) 

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Frequency of AEs by treatment arm, by body system, Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term, severity, and assessed 
relationship to study products (graded using the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events. Corrected Version 
2.1, dated July 2017) 
SAEs throughout the active surveillance period 
Laboratory measures of safety: white blood cells (WBC), neutrophils, 
lymphocytes, hemoglobin, platelets, ALT, and creatinine at baseline and 
following vaccinations, by treatment arm (graded using the Division of AIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events. Corrected 
Version 2.1, dated July 2017) 
Secondary objective 2: 
To characterize the immunogenicity of 1 injection of gp145 C.6980 at 2 dose 
levels with alum adjuvant in HIV-seronegative low risk adults 
Secondary endpoints 2: 
Response rates and levels of vaccine-induced binding antibodies to HIV proteins 
measured by the binding antibody multiplex assay (BAMA) at 2 weeks following 
the first vaccination 
Secondary objective 3 
To characterize the immunogenicity of 3 injections of gp145 C.6980 at 2 dose 
levels with alum adjuvant in HIV-seronegative low risk adults 
Secondary endpoints 3: 
Response rates and levels of vaccine-induced binding antibodies to HIV proteins 
measured by the BAMA at 2 weeks following the third vaccination 
Response rates and levels of CD4+ and CD8+ T cells measured by intracellular 
cytokine staining (ICS) at 2 weeks following the third vaccination 
Response rates and levels of neutralizing antibody responses against HIV-1 
isolates at 2 weeks following the third vaccination 
5.3 
Exploratory objectives 
Exploratory objective 1: 
To describe participants’ baseline characteristics (eg, previous exposure to 
vaccinia) and their impact on vaccine-induced immune responses  

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Exploratory objective 2: 
To determine the frequency of circulating Tfh, Tfr, and plasmablasts in response 
to each vaccination regimen 
Exploratory objective 3: 
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 4: 
To conduct analyses related to furthering the understanding of HIV, immunology, 
vaccines, and clinical trial conduct. 

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6 
Statistical considerations 
6.1 
Accrual and sample size calculations 
Recruitment will target enrolling 45 healthy, HIV-uninfected adult participants 
aged 18 to 50 years, at low risk for HIV infection: 40 vaccine and 5 placebo 
recipients. Each participant will be randomly assigned to receive 1 of 2 doses of 
the vaccine regimen or placebo in a 5:3:1 ratio with 25, 15, and 5 participants in 
the 300 mcg dose (Group 1), 100 mcg dose (Group 2) and placebo (Group 3) 
arms, respectively. Since the 300 mcg dose level will be considered in future 
China CDC/NIAID/HVTN collaborative trials, the sample size of Group 1 
accounts for the minimal sample size requirement (≥ 20) by China FDA to 
generate safety data for exporting the vaccine to China. The placebo arm provides 
a control group for assay quality assurance and blinding. 
To ensure that both men and women will be adequately represented in the trial, 
the trial will enroll at least approximately 40% of each sex assigned at birth 
overall. Hence, when approximately 18 participants of 1 sex are enrolled, sites 
will be notified to stop further recruitment of persons of that sex assigned at birth. 
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 PBMCs, or high assay background levels. 
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 at days 14 and 182. For this 
reason, the sample size calculations in Section 6.1.2 account for 4 enrolled 
participants having missing data for the primary immunogenicity endpoint. 
6.1.1 
Sample size calculations for safety 
The goal of the safety evaluation for this study is to identify safety concerns 
associated with product administration. The ability of the study to detect SAEs 
can be expressed by the true event rate above which at least 1 SAE would likely 
be observed and the true event rate below which no events would likely be 
observed. Specifically, for each vaccine arm of the study (n = 15, 25), there is a 
90% chance of observing at least 1 event if the true rate of such an event is 14.3% 
or 8.9% or more, respectively; and there is a 90% chance of observing no events 
if the true rate is 0.4% or 0.7% less, respectively. For vaccine arms combined (n = 
40), there is a 90% chance of observing at least 1 event if the true rate of such an 
event is 5.6% or more; and there is a 90% chance of observing no events if the 
true rate is 0.26% or less. As a reference, in previous AVEG HIV vaccine trials, 
3.5% of control participants experienced an SAE; in HVTN vaccine trials from 
December 2000 through April 2014, about 4% of participants who received 
placebos experienced an SAE.  

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Probabilities of observing 0 and 2 or more events among 15, 25, or 40 vaccine 
recipients are presented in Table 6-1 below for a range of possible true AE rates. 
These calculations provide a complete picture of the sensitivity of this study 
design to identify potential safety problems with the vaccine. For example, we see 
that if the true rate of AEs is 1%, there is an 86%, 78%, or 67% chance that no 
events will be observed in the vaccine arm of 15, 25, or 40 participants, 
respectively.  
Table 6-1 Probability of observing 0 events, 1 or more events, and 2 or more events, among 
n=15, 25 or 40 vaccine recipients, for different true event rates 
True event 
rate (%) 
Pr(0/15) 
Pr(2+/15) 
Pr(0/25) 
Pr(2+/25) 
Pr(0/40) 
Pr(2+/40) 
1 
0.860 
0.010 
0.778 
0.026 
0.669 
0.061 
3.5 
0.586 
0.095 
0.410 
0.218 
0.240 
0.411 
5 
0.463 
0.171 
0.277 
0.358 
0.129 
0.601 
10 
0.206 
0.451 
0.072 
0.729 
0.015 
0.920 
20 
0.035 
0.833 
0.004 
0.973 
<0.001 
0.999 
30 
0.005 
0.965 
<0.001 
0.998 
<0.001 
>0.999 
40 
<0.001 
0.995 
<0.001 
>0.999 
<0.001 
<0.999 
An alternative way of describing the statistical properties of the study design is in 
terms of the 95% confidence interval (CI) for the true rate of an AE based on the 
observed data. Table 6-2 shows the 2-sided 95% CIs for the probability of an 
event based on a particular observed rate. Calculations are done using the score 
test method [36]. If none of the 15, 25 or 40 vaccine recipients experience a safety 
event, the 95% 2-sided upper confidence bound for the true rate of such events is 
21.8%, 13.7% or 8.81%, respectively. 
Table 6-2 Two-sided 95% confidence intervals based on observing a particular rate of safety 
endpoints for arms of size n1 and n2 
Observed 
event rate 
CI (%) 
0/15 
(0.00, 21.8) 
1/15 
(0.17, 31.9) 
2/15 
(1.66, 40.5) 
0/25 
(0.00, 13.7) 
1/25 
(0.10, 20.4) 
2/25 
(0.98, 26.0) 
0/40 
(0.00, 8.81) 
1/40 
(0.06, 13.2) 
2/40 
(0.61, 16.9) 
6.1.2 
Sample size calculations for immunogenicity 
The main goals of this trial regarding immunogenicity outcomes involve a 
preliminary estimation of response rates based on data from the BAMA, ICS, and 
nAb assays among vaccinees at 2 weeks following vaccination. No adjustment for 
multiple comparisons will be made for the use of multiple assays. The precision 
with which the true response rate can be estimated from the observed data 
depends on the true underlying response rate and the sample size. Two-sided 95% 

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confidence intervals for the response rate based on observing a particular rate of 
responses in the vaccinees is shown in Table 6-3. Calculations are done using the 
score test method [36]. The n = 13, 22, 36 assumes a 10% rate of missing 
immunogenicity data. 
Table 6-3 Two-sided 95% confidence intervals for the true response rate based on observing 
a particular rate of responses in the vaccinees (n = 13, 22, 36) 
No. of responses 
Observed response rate (%) 
CI 
 
n = 13 
 
3/13 
23.1 
[8.2, 50.2] 
5/13 
38.5 
[17.7, 64.5] 
7/13 
53.8 
[29.1, 76.8] 
11/13 
84.6 
[57.8, 95.7] 
12/13 
92.3 
[66.7, 98.6] 
 
n = 22 
 
3/22 
13.6 
[4.8, 33.3] 
5/22 
22.7 
[10.1, 43.4] 
7/22 
31.8 
[16.4, 52.7] 
11/22 
50.0 
[30.7, 69.3] 
15/22 
68.2 
[47.3, 83.6] 
19/22 
86.4 
[66.7, 95.3] 
20/22 
90.9 
[72.2, 97.5] 
 
n = 36 
 
3/36 
8.3 
[2.9, 21.8] 
5/36 
13.9 
[6.1, 28.7] 
7/36 
19.4 
[9.8, 35] 
11/36 
30.6 
[18, 46.9] 
15/36 
41.7 
[27.1, 57.8] 
19/36 
52.8 
[37, 68] 
23/36 
63.9 
[47.6, 77.5] 
27/36 
75 
[58.9, 86.2] 
33/36 
91.7 
[78.2, 97.1] 
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 Manual of Operations 
(MOP). 
6.3 
Blinding 
Participants and site staff (except for site pharmacists) will be blinded as to 
participant treatment arm assignments (eg, vaccine or 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 

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this information in order to ensure proper trial conduct. Any discussion of study 
product assignment between pharmacy staff and any other HVTN CRS staff is 
prohibited. The HVTN SMB members also are unblinded to treatment assignment 
in order to conduct review of trial safety.  
When a participant leaves the trial prior to study completion, the participant will 
be told he or she must wait until all participants are unblinded to learn his or her 
treatment assignment.  
Emergency unblinding decisions will be made by the site investigator. If time 
permits, the HVTN 122 PSRT should be consulted before emergency unblinding 
occurs. See the HVTN MOP for more information. 
6.4 
Statistical analyses 
This section describes the final study analyses, unblinded as to treatment arm 
assignment. All data from enrolled participants will be analyzed according to the 
initial randomization assignment regardless of how many vaccinations they 
received. In the rare instance that a participant receives the wrong treatment at a 
specific vaccination time, the Statistical Analysis Plan (SAP) will address how to 
analyze the participant’s safety data. Analyses are modified intent-to-treat in that 
individuals who are randomized but not enrolled do not contribute data and hence 
are excluded. Because of blinding and the brief length of time between 
randomization and enrollment—typically no more than 4 working days—very 
few such individuals are expected. 
Analyses for primary endpoints will be performed using SAS and R. All other 
descriptive and inferential statistical analyses will be performed using SAS, 
StatXact, or R statistical software. 
No formal multiple comparison adjustments will be employed for multiple safety 
endpoints, multiple primary immunogenicity endpoints, or secondary endpoints. 
However, multiplicity adjustments will be made for certain immunogenicity 
assays, as discussed below, when the assay endpoint is viewed as a collection of 
hypotheses (eg, testing multiple peptide pools to determine a positive response). 
6.4.1 
Analysis variables 
The analysis variables consist of baseline participant characteristics, safety, and 
immunogenicity for primary- and secondary-objective analyses. 
6.4.2 
Baseline comparability 
Treatment arms will be compared for baseline participant characteristics using 
descriptive statistics. 

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6.4.3 
Safety/tolerability analysis 
Since enrollment is concurrent with receiving the first vaccination, all participants 
will have received at least 1 vaccination and therefore will provide some safety 
data. 
6.4.3.1 
Reactogenicity 
The number and percentage of participants experiencing each type of 
reactogenicity sign or symptom will be tabulated by severity and treatment arm 
and the percentages displayed graphically by arm. For a given sign or symptom, 
each participant’s reactogenicity will be counted once under the maximum 
severity for all injection visits. In addition to the individual types of events, the 
maximum severity of local pain or tenderness, induration or erythema, and of 
systemic symptoms will be calculated. 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 9.8) 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. 

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6.4.3.4 
Reasons for vaccination discontinuation and early study termination 
The number and percentage of participants who discontinue vaccination and who 
terminate the study early will be tabulated by reason and treatment arm. 
6.4.4 
Immunogenicity analysis 
6.4.4.1 
General approach 
For the statistical analysis of immunogenicity endpoints, data from enrolled 
participants will be used according to the initial randomization assignment 
regardless of how many injections they received. Additional analyses may be 
performed, limited to participants who received all scheduled injections per 
protocol. Assay results that are unreliable, from specimens collected outside of 
the visit window, or from HIV-infected participants postinfection are excluded. 
Since the exact date of HIV infection is unknown, any assay data from blood 
draws 4 weeks prior to an infected participant’s last seronegative sample and 
thereafter may be excluded. If an HIV-infected participant does not have a 
seronegative sample postenrollment, then all data from that participant may be 
excluded from the analysis. 
Discrete categorical assay endpoints (eg, response rates) will be analyzed by 
tabulating the frequency of positive response for each assay by antigen and 
treatment arm at each timepoint for which an assessment is performed. Crude 
response rates will be presented with their corresponding 95% confidence interval 
estimates calculated using the score test method [36]. 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. Barnard or Fisher’s exact 
tests, as specified in the SAP, will be used to compare the response rates of the 2 
vaccine arms, with a significant difference declared if the 2-sided p-value is ≤ 
0.05. In general Barnard’s is preferred since under most circumstances it is more 
powerful than Fisher’s [37].  
For quantitative assay data (eg, IgG binding Ab response from the multiplex assay 
or CD4+/CD8+ T cell response 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 control arm separately.  
The difference between arms at a specific timepoint may be tested with a 
nonparametric Wilcoxon rank sum test if the data are not normally distributed and 
with a 2-sample t-test if the data appear to be normally distributed. An appropriate 
data transformation (eg, log10 transformation) may be applied to better satisfy 
assumptions of symmetry and homoscedasticity (constant variance).  

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6.4.4.2 
Multivariate display of immunogenicity endpoints 
Data visualization techniques may be used to explore the relationship among 
immunogenicity readouts. The set of readouts may be based on 1 of the primary 
endpoints (eg, ICS), on the set of primary endpoints, or on immunogenicity 
endpoints that also include secondary or exploratory endpoints. To understand the 
relationship between pairs of readouts, scatter plots may be used when the number 
of readouts is small or for a larger number of readouts, a heat map showing the 
degree of correlation between any 2 pairs. Principal component analysis (PCA) 
and associated “biplots” of the scores and loadings are particularly useful to 
understand associations between readouts, especially when readouts are correlated 
[38]. PCA is a method to reduce the dimensionality of the number of readouts to a 
smaller set of values (principal components) that are normalized linear 
combinations of the readouts in such a way that the first principal component 
accounts for the most variability in the data and subsequent components, while 
maximizing variability, are uncorrelated with each other. A ‘biplot’ displays the 
first and second principal component scores and principal component loadings. 
The x-axis is the value from the first principal component and the y-axis is the 
second principal component, where each axis label includes the percentage of 
variation in the total set of readouts captured by the principal component. The top 
axis is the first principal component loadings and the right axis is the second 
principal component loadings. An arrow is drawn for each immunogenicity 
readout (eg, Env-specific CD4+ T cell polyfunctionality score, Env-specific 
CD8+ T cell total magnitude) from the origin to the point defined by its first 2 
principal component loadings. The length of the arrow represents the amount of 
total variation of the set of readouts captured by the given readout. The direction 
of an arrow conveys the extent to which the variation of a readout is in the 
direction of the first or second principal component. The angle between 2 arrows 
conveys information about the correlation of the 2 readouts, with a 0 degree angle 
denoting perfect correlation and a 90 degree angle denoting no correlation. Each 
arrow on the biplot is labeled by the immunogenicity readout it represents. A 
biplot is annotated with key meta-information such as the treatment arm (most 
common application) or a demographic category. Depending on the application, 
K-means clustering and hierarchical clustering may also be applied for 
multivariate graphical display of immunogenicity readouts. 
6.4.4.3 
Secondary analysis of binding antibody data as measured by the BAMA 
assay 
When a small panel of antigens (eg, ≤ 5) is being assessed in a multiplexed 
immunoassay, the response magnitudes and rates at 2 weeks following the first 
and third vaccinations will be evaluated for each antigen. When a larger panel is 
being assessed, in addition to assessing each antigen separately, a summary 
measure across a group of similar antigens will be calculated, for example, a 
weighted-average may be constructed to account for the correlations between 
antigens as an integrated magnitude of responses to multiple antigens. Then this 
summary measure may be used as the outcome variable to assess if this overall 
response measure differs by arms. 

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6.4.4.4 
Secondary analysis of CD4+ and CD8+ T-cell response as measured by 
the ICS assay  
The analysis of CD4+ and CD8+ T-cell response rates as measured by the ICS 
assay will be evaluated and compared as described under the general approach. 
For each T-cell subset, the positivity call for each peptide pool will include a 
multiple comparison adjustment for the number of peptide pools used in the 
assay. In general, the Mixture Models for Single-cell Assays (MIMOSA) 
statistical framework [39] 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 Combinatorial Polyfunctionality analysis of Antigen-Specific T-
cell Subsets () statistical framework [40] 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.  
6.4.5 
Analyses prior to end of scheduled follow-up visits 
Any analyses conducted prior to the end of the scheduled follow-up visits should 
not compromise the integrity of the trial in terms of participant retention or safety 
or immunogenicity endpoint assessments. In particular, early unblinded analyses 
by treatment assignment require careful consideration and should be made 
available on a need to know basis only. 
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 122 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 

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least 1 of the primary immunogenicity endpoints of the same class (humoral or 
cell-mediated) 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 information available at the time of 
enrollment including results of screening laboratory tests, medical history, 
physical examinations, and answers to self-administered and/or interview 
questions.  
Investigators should always use good clinical judgment in considering a 
volunteer’s overall fitness for trial participation. Some volunteers may not be 
appropriate for enrollment even if they meet all inclusion/exclusion criteria. 
Medical, psychiatric, occupational, or other conditions may make evaluation of 
safety and/or immunogenicity difficult, and some volunteers may be poor 
candidates for retention. 
Determination of eligibility, taking into account all inclusion and exclusion 
criteria, must be made within 56 days prior to enrollment unless otherwise noted 
in Sections 7.1 and 7.2. 
7.1 
Inclusion criteria 
General and Demographic Criteria 
1. Age of 18 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 and completes a questionnaire prior to first vaccination with verbal 
demonstration of understanding of all questionnaire items initially answered 
incorrectly 
5. Agrees not to enroll in another study of an investigational research agent before 
the last scheduled protocol clinic visit 
6. Good general health as shown by medical history, physical exam, and screening 
laboratory tests 
HIV-Related Criteria: 
7. Willingness to receive HIV test results 

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8. Willingness to discuss HIV infection risks and amenable to HIV risk reduction 
counseling.  
9. Assessed by the clinic staff as being at “low risk” for HIV infection and 
committed to maintaining behavior consistent with low risk of HIV exposure 
through the last required protocol clinic visit. Low risk guidelines are found on 
the protocol web page under Study Materials on the HVTN Members' site 
(https://members.hvtn.org/protocols/hvtn122).  
Laboratory Inclusion Values 
Hemogram/CBC 
10. Hemoglobin ≥ 11.0 g/dL for volunteers who were born female, ≥ 13.0 g/dL for 
volunteers who were born male 
11. White blood cell count = 3,300 to 12,000 cells/mm3 
12. Total lymphocyte count ≥ 800 cells/mm3 
13. Remaining differential either within institutional normal range or with site 
physician approval 
14. Platelets = 125,000 to 550,000/mm3 
Chemistry 
15. Chemistry panel: ALT, AST, and alkaline phosphatase < 1.25 times the 
institutional upper limit of normal; creatinine ≤ institutional upper limit of normal. 
Virology 
16. Negative HIV-1 and -2 blood test: US volunteers must have a negative FDA-
approved enzyme immunoassay (EIA).  
17. Negative Hepatitis B surface antigen (HBsAg)  
18. Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV 
polymerase chain reaction (PCR) if the anti-HCV is positive 
Urine 
19. Normal urine: 
 Negative urine glucose, and 
 Negative or trace urine protein, and 

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 Negative or trace urine hemoglobin (if trace hemoglobin is present on 
dipstick, a microscopic urinalysis with red blood cells levels within 
institutional normal range). 
Reproductive Status 
20. Volunteers who were born female: negative serum or urine beta human 
chorionic gonadotropin (β-HCG) pregnancy test performed prior to vaccination 
on the day of initial vaccination. Persons who are NOT of reproductive potential 
due to having undergone total hysterectomy or bilateral oophorectomy (verified 
by medical records), are not required to undergo pregnancy testing. 
21. Reproductive status: A volunteer who was born female must: 
 Agree to consistently use effective contraception (see Appendix A) for sexual 
activity that could lead to pregnancy from at least 21 days prior to enrollment 
until after the last required protocol clinic visit. Effective contraception is 
defined as using the following methods: 
 Condoms (male or female) with or without a spermicide, 
 Diaphragm or cervical cap with spermicide, 
 Intrauterine device (IUD), 
 Hormonal contraception, or 
 Any other contraceptive method approved by the HVTN 122 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. 
22. Volunteers who were born female must also agree not to seek pregnancy 
through alternative methods, such as artificial insemination or in vitro 
fertilization until after the last required protocol clinic visit 
7.2 
Exclusion criteria 
General 
1. Blood products received within 120 days before first vaccination  

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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 122 study  
5. Pregnant or breastfeeding 
6.  Active duty and reserve US military personnel 
Vaccines and other Injections 
7. HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have 
received control/placebo in an HIV vaccine trial, the HVTN 122 PSRT will 
determine eligibility on a case-by-case basis. 
8. Non-HIV experimental vaccine(s) received within the last 5 years in a prior 
vaccine trial. Exceptions may be made by the HVTN 122 PSRT for vaccines that 
have subsequently undergone licensure by the FDA. For volunteers who have 
received control/placebo in an experimental vaccine trial, the HVTN 122 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 122 PSRT on a case-by-case basis. 
9. Live attenuated vaccines other than influenza vaccine received within 30 days 
before or scheduled and intended to be received within 14 days after the first 
vaccination (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 and intended to be received 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 prednisone or equivalent at doses < 60 mg/day and length of 
therapy < 11 days with completion at least 30 days prior to enrollment.) 

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13. Serious adverse reactions to vaccines or to vaccine components, including 
history of anaphylaxis and related symptoms such as hives, respiratory difficulty, 
angioedema, and/or abdominal pain. (Not excluded from participation: a 
volunteer who had a nonanaphylactic adverse reaction to pertussis vaccine as a 
child.)  
14. Immunoglobulin received within 60 days before first vaccination 
15. Autoimmune disease  
16. Immunodeficiency 
Clinically significant medical conditions  
17. Untreated or incompletely treated syphilis infection 
18. Clinically significant medical condition, physical examination findings, 
clinically significant abnormal laboratory results, or past medical history with 
clinically significant implications for current health. A clinically significant 
condition or process includes but is not limited to: 
 A process that would affect the immune response, 
 A process that would require medication that affects the immune response, 
 Any contraindication to repeated injections or blood draws, 
 A condition that requires active medical intervention or monitoring to avert 
grave danger to the volunteer’s health or well-being during the study period, 
 A condition or process for which signs or symptoms could be confused with 
reactions to vaccine, or 
 Any condition specifically listed among the exclusion criteria below. 
19. Any medical, psychiatric, occupational, or other condition that, in the 
judgment of the investigator, would interfere with, or serve as a contraindication 
to, protocol adherence, assessment of safety or reactogenicity, or a volunteer’s 
ability to give informed consent 
20. Psychiatric condition that precludes compliance with the protocol. 
Specifically excluded are persons with psychoses within the past 3 years, ongoing 
risk for suicide, or history of suicide attempt or gesture within the past 3 years. 
21. Current anti-tuberculosis (TB) prophylaxis or therapy 
22. Asthma other than mild, well-controlled asthma. (Symptoms of asthma severity 
as defined in the most recent National Asthma Education and Prevention Program 
(NAEPP) Expert Panel report).  

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Exclude a volunteer who: 
 Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or 
 Uses moderate/high dose inhaled corticosteroids, or 
 In the past year has either of the following: 
 Greater than 1 exacerbation of symptoms treated with oral/parenteral 
corticosteroids; 
  Needed emergency care, urgent care, hospitalization, or intubation for 
asthma. 
23. Diabetes mellitus type 1 or type 2, including cases controlled with diet alone. 
(Not excluded: history of isolated gestational diabetes.) 
24. Thyroidectomy, or thyroid disease requiring medication during the last 12 
months 
25. Hypertension: 
 If a person has been found to have elevated blood pressure or hypertension 
during screening or previously, exclude for blood pressure that is not well 
controlled. Well-controlled blood pressure is defined as consistently ≤ 140 
mm Hg systolic and ≤ 90 mm Hg diastolic, with or without medication, with 
only isolated, brief instances of higher readings, which must be ≤ 150 mm Hg 
systolic and ≤ 100 mm Hg diastolic. For these volunteers, blood pressure must 
be ≤ 140 mm Hg systolic and ≤ 90 mm Hg diastolic at enrollment. 
 If a person has NOT been found to have elevated blood pressure or 
hypertension during screening or previously, exclude for systolic blood 
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 

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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)  
 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 122 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 

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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 122 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; upon review, the 
HVTN 122 PSRT may allow continuation of vaccination if a participant 
had grade 3 erythema and/or induration 
 SAE that is subsequently considered to be related to vaccination 
 Clinically significant type 1 hypersensitivity reaction associated with 
study vaccination. Consultation with the HVTN 122 PSRT is required 
prior to subsequent vaccinations following any type 1 hypersensitivity 
reaction associated with study vaccination 
 Investigator determination in consultation with Protocol Team leadership (eg, 
for repeated nonadherence to study staff instructions). 
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 9.5.1). 

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7.3.4 
Participant termination from the study 
Under certain circumstances, an individual participant may be terminated from 
participation in this study. Specific events that will result in early termination 
include: 
 Participant 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. See the Investigator’s Brochures (IB) for further 
information about study products. 
8.1 
Vaccine regimen 
The schedule of vaccination is shown in Section 3 and additional information is 
given below.  
Group 1 
Treatment 1 (T1): gp145 C.6980, 300 mcg, admixed with Aluminum Hydroxide 
Suspension to be administered as 1 mL IM in the deltoid at Months 0, 2, and 6 
Group 2 
Treatment 2 (T2): gp145 C.6980, 100 mcg, admixed with Aluminum Hydroxide 
Suspension to be administered as 1 mL IM in the deltoid at Months 0, 2, and 6 
Group 3 
Placebo 3 (P3): Placebo for gp145 C.6980 (Sodium Chloride for Injection, 0.9%) 
to be administered as 1 mL IM in the deltoid at months 0, 2, and 6 
8.2 
Study product formulation  
gp145 C.6980 [labeled as HIV Env gp145 C.6980]:  
The gp145 C.6980 protein will be provided as 600 mcg per mL clear colorless to 
slightly yellow solution when thawed. Each single-use vial contains 0.5 mL (300 
mcg) of product. The vials will have a nominal fill volume sufficient to allow 
withdrawal of 0.5 mL. The product must be stored frozen at -65°C or colder.  
The study product is described in further detail in the Investigator’s Brochure 
(IB). 
Placebo for gp145 C.6980 (Sodium Chloride for Injection, 0.9%):  
Sodium Chloride for Injection, 0.9% will be used as the placebo for gp145 
C.6980. The product must be stored as directed by the manufacturer. 
Aluminum Hydroxide Suspension [labeled as Aluminum Hydroxide 
Suspension]:  

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The Aluminum Hydroxide Suspension appears as an opaque, white gelatinous 
precipitate in aqueous suspension. The product is provided in 3 mL size vial 
containing 0.7 mL (3.5 mg of aluminum) per vial. The Aluminum Hydroxide 
Suspension was vialed by Leidos Biomedical Research, Inc., Frederick, 
Maryland, for the NIH Vaccine Research Center, utilizing Alhydrogel ‘85’ 2%, an 
aluminum hydroxide wet gel suspension from Brenntag Biosector (Denmark), a 
well-known source for quality GMP materials, diluted to a concentration of 5 
mg/mL aluminum content with water for injection and vialed under aseptic 
conditions compliant with cGMP regulations. The product must be stored 
refrigerated at 2° to 8° C. 
8.3 
Preparation of study products 
Pharmacists should refer to USP 38 General Chapter Physical Tests/ <797> 
Pharmaceutical Compounding – Sterile, and should follow the requirements of 
their country, their institution, and their pharmacy regulatory authority regarding 
these procedures. At minimum, study products must be prepared in a biological 
safety cabinet or an isolator by appropriately trained and qualified pharmacy 
personnel using aseptic technique. 
8.3.1 
gp145 C.6980, 300 mcg, admixed with Aluminum Hydroxide 
Suspension (Group 1) 
One vial of gp145 C.6980, 1 vial of Aluminum Hydroxide Suspension, 1 
vial/ampule of Sterile Water for Injection, and 1 empty sterilized vial will be 
needed to prepare the dose.  
Prior to dispensing, the pharmacist will retrieve the gp145 C.6980 vial from the 
freezer and allow to thaw at room temperature. The pharmacist will also retrieve 
the Aluminum Hydroxide Suspension vial from the refrigerator. The pharmacist 
will retrieve Sterile Water for Injection vial and empty sterilize vial from storage.  
Using aseptic technique, the pharmacist will gently swirl the contents of the vial 
containing aluminum hydroxide, withdraw 0.12 mL of the aluminum hydroxide 
and inject it into the empty sterilize vial (mixing vial). The pharmacist will then 
add 0.38 mL of Sterile Water for Injection to the mixing vial which contains 0.12 
mL of aluminum hydroxide. The mixing vial should be gently swirled and 
inverted (do not shake). Next, the pharmacist will then gently swirl the vial 
containing gp145 C.6980 after which, using aseptic technique, the pharmacist will 
withdraw 0.5 mL (300 mcg) of gp145 C.6980 from the correct vial and inject it 
into the mixing vial (which contains aluminum hydroxide mixed with Sterile 
Water for Injection). After gentle swirling and inversion (do not shake vigorously) 
the pharmacist, using aseptic technique, will withdraw 1 mL of the mixed 
preparation for dosing into a 2, 3, or 5 mL size syringe. The pharmacist will apply 
an overlay to the syringe. 
The syringe should be labeled as “HVTN 122 study product”. The syringe must 
also be labeled for administration in the deltoid and “Gently roll the syringe prior 

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to administration”. This study product should be administered as soon as possible 
after preparation.  
8.3.2 
gp145 C.6980, 100 mcg, admixed with Aluminum Hydroxide 
Suspension (Group 2) 
One vial of gp145 C.6980, 1 vial of Aluminum Hydroxide Suspension, 1 
vial/ampule of Sterile Water for Injection, and 1 empty sterilized vial will be 
needed to prepare the dose.  
Prior to dispensing, the pharmacist will retrieve the gp145 C.6980 vial from the 
freezer and allow to thaw at room temperature. The pharmacist will also retrieve 
the Aluminum Hydroxide Suspension vial from the refrigerator. The pharmacist 
will retrieve Sterile Water for Injection vial and empty sterilize vial from storage.  
Using aseptic technique, the pharmacist will gently swirl the contents of the vial 
containing aluminum hydroxide, withdraw 0.12 mL of the aluminum hydroxide 
and inject it into the empty sterilize vial (mixing vial). The pharmacist will then 
add 0.71 mL of Sterile Water for Injection to the mixing vial which contains 0.12 
mL of aluminum hydroxide. The mixing vial should be gently swirled and 
inverted (do not shake). Next, the pharmacist will then gently swirl the vial 
containing gp145 C.6980 after which, using aseptic technique, the pharmacist will 
withdraw 0.17 mL (100 mcg) of gp145 C.6980 from the correct vial and inject it 
into the mixing vial (which contains aluminum hydroxide mixed with Sterile 
Water for Injection). After gentle swirling and inversion (do not shake vigorously) 
the pharmacist, using aseptic technique, will withdraw 1 mL of the mixed 
preparation for dosing into a 2, 3, or 5 mL size syringe. The pharmacist will apply 
an overlay to the syringe. 
The syringe should be labeled as “HVTN 122 study product”. The syringe must 
also be labeled for administration in the deltoid and “Gently roll the syringe prior 
to administration”. This study product should be administered as soon as possible 
after preparation. 
8.3.3 
Placebo for gp145 C.6980 (Sodium Chloride for Injection, 0.9%) 
(Group 3) 
Using aseptic technique, the pharmacist will withdraw 1 mL of Sodium Chloride 
for Injection, 0.9% into a 2, 3, or 5 mL size syringe. The pharmacist will apply an 
overlay to the syringe. 
The syringe should be labeled as “HVTN 122 study product”. The syringe must 
also be labeled for administration in the deltoid and “Gently roll the syringe prior 
to administration”. In order to maintain the blind, the study product should be 
administered as soon as possible after preparation. 
Any unused portion of vials or expired prefilled syringes is disposed of in 
accordance with institutional or pharmacy policy. 

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8.4 
Administration 
All injections are to be given IM in the deltoid.  
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. 
The person administering the injection should gently roll the syringe prior to 
administration of the study product. These syringes will be labeled as “HVTN 122 
study product”. 
Any administrator of study product will be blinded to the individual participant’s 
treatment assignment. At sites where registered pharmacists are legally authorized 
to administer injections, the HVTN CRS may choose to have a blinded 
pharmacist administer vaccinations. 
8.5 
Acquisition of study products 
gp145 C.6980 will be provided by the Division of AIDS, NIAID, NIH. 
Aluminum Hydroxide Suspension will be provided by the Vaccine Research 
Center, NIAID, NIH. 
Sodium Chloride for Injection, 0.9% will not be provided through the protocol 
and must be obtained by the site. 
Once an HVTN CRS is protocol registered, 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 

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procedures and relevant form are included in the Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks.  

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

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enrollment consent. Sites conducting general screening or prescreening approved 
by their IRB/EC and any applicable RE may use the results from this screening to 
determine eligibility for this protocol, provided the tests are conducted within the 
time periods specified in the eligibility criteria.  
9.1.2 
Protocol-specific consent forms 
The protocol-specific consent forms describe the study products to be used and all 
aspects of protocol participation, including screening and enrollment procedures. 
A sample protocol-specific consent form for the main study is located in 
Appendix A. A separate sample consent form for other uses of specimens is 
located in Appendix C. 
Each HVTN CRS is responsible for developing a protocol-specific consent 
form(s) for local use, based on the sample protocol-specific consent forms in 
Appendix A and Appendix C. The consent form(s) must be developed in 
accordance with requirements of the following: 
 CRS’s IRB/EC and any applicable REs, 
 CRS’s institution, and 
 Elements of informed consent as described in Title 45, CFR Part 46 and Title 
21 CFR, Part 50, and in the International Conference on Harmonisation (ICH) 
E6, Good Clinical Practice: Consolidated Guidance 4.8.  
Study sites are strongly encouraged to have their local CABs review their sites-
specific consent forms. This review should include, but should not be limited to, 
issues of cultural competence, local language considerations, and the level of 
understandability. 
The sample informed consent form includes instructions throughout the document 
for developing specific content. 
Sites should follow the instructions in the Protocol-specific Official Memo 
distributed along with this protocol regarding when they may begin using their 
site-specific protocol consent forms. 
Regarding protocol registration, sites should follow procedures outlined in the 
current version of the DAIDS Protocol Registration Manual. 
9.1.3 
Assessment of Understanding 
Study staff are responsible for ensuring that participants fully understand the 
study before enrolling them. This process involves reviewing the informed 
consent form with the participant, allowing time for the participant to reflect on 
the procedures and issues presented, and answering all questions completely.  

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An Assessment of Understanding is used to document the participant’s 
understanding of key concepts in this HIV vaccine trial. The participant must 
complete the Assessment of Understanding before enrollment. Staff may provide 
assistance in reading and understanding the questions and responses, if necessary. 
Participants must verbalize understanding of all questions answered incorrectly. 
This process and the participant’s understanding of the key concepts should be 
recorded in source documentation at the site. 
IRB/EC and any applicable RE may require that a participant has signed either a 
screening or protocol-specific consent document prior to administering the 
Assessment of Understanding. The consent process (including the use of the 
Assessment of Understanding) should be explained thoroughly to the IRB/EC and 
any applicable RE, whose recommendations should be followed. 
9.2 
Pre-enrollment procedures 
Screening may occur over the course of several contacts/visits, up to and 
including before vaccination on day 0. All inclusion and exclusion criteria must 
be assessed within 56 days before enrollment, unless otherwise specified in the 
eligibility criteria (or below in this section). 
After the appropriate informed consent has been obtained and before enrollment, 
the following procedures are performed: 
 Medical history, documented in the case history record; 
 Assessment of whether the volunteer is at low risk for HIV infection; 
 Complete physical examination, including height, weight, vital signs, and 
clinical assessments of head, ears, eyes, nose, and throat; neck; lymph nodes; 
heart; chest; abdomen; extremities; neurological function; and skin; 
 Assessment of concomitant medications the volunteer is taking, including 
prescription and nonprescription drugs, vitamins, topical products, 
alternative/complementary medicines (eg, herbal and health food 
supplements), recreational drugs, vaccinations, and allergy shots; 
 Laboratory tests as defined in the inclusion and exclusion criteria, including: 
  Screening HIV test 
 CBC with differential and platelet count 
 Chemistry panel (ALT, AST, ALP, and creatinine) 
 Urine dipstick (urinalysis if indicated, see Section 9.7) 
 HBsAg 
 Anti-HCV Ab 

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 Syphilis test 
 Urine or serum pregnancy test (volunteers 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. 
 Administration of behavioral risk assessment questionnaire; 
 Obtaining of volunteer demographics in compliance with the NIH Policy on 
Reporting Race and Ethnicity Data: Subjects in Clinical Research, Aug. 8, 
2001 (available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-
053.html); 
 Counseling on HIV testing and risk reduction, performed in compliance with 
the US Centers for Disease Control and Prevention (CDC)’s current 
guidelines or other local guidelines for HIV counseling, testing, and referral as 
described in Section 9.5; 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 HVTN CRS requests the 
randomization assignment via a Web-based randomization system. In general, the 
time interval between randomization and enrollment should not exceed 4 working 
days. However, circumstances may require a participant’s enrollment visit to be 
changed. This may exceed the 4-day randomization time limit. 
At all vaccination visits, the following procedures are performed before 
vaccination: 

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 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). 
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 9.8). 
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 9.5);  
 Pregnancy prevention assessment (as described in Section 9.2 and 9.6); 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 F:  
 Confirm that participants received HIV test results from previous visit. If not, 
provide test results and post-test counseling as appropriate; 
 Assess for clinical evidence of vaccinia scarification; and 
 Specimen collection (should be completed prior to vaccination). 

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9.4 
Follow-up visits 
The following procedures are performed at all scheduled follow-up visits: 
 Risk reduction counseling (as described in Section 9.5);  
 Pregnancy prevention assessment (as described in Section 9.2 and 9.6); and 
 Assessment of new or unresolved social impacts (site staff will ask participant 
about the status of any unresolved social impacts and if s/he has experienced 
any new social impacts as a result of the trial participation); 
 Assessment of new or continuing concomitant medications (as described in 
Section 9.2); and 
 Assessment of new or unresolved AEs/intercurrent illnesses. 
Additional procedures will be performed at scheduled follow-up visits as 
specified in Appendix F:  
 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; 
 Clinical laboratory tests including: 
 CBC with differential, 

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 Chemistry panel (see Section 9.2), and 
 Urine dipstick (urinalysis if appropriate; see Section 9.7); 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. 
9.5 
HIV counseling and testing 
HIV counseling will be performed in compliance with the CDC’s guidelines or 
other local guidelines for HIV counseling and referral. HIV testing will be 
performed in accordance with the current HVTN HIV testing algorithm following 
enrollment. 
Participants will be counseled routinely during the trial on the avoidance of HIV 
infection and on the potential negative social impacts of testing antibody positive 
due to the vaccine. They will also be counseled on the risks of HIV antibody 
testing outside of the HVTN CRSs and will be discouraged from doing so during 
study participation and/or during any period of vaccine-induced positive serology. 
Study staff will take particular care to inform study participants of the likelihood 
of routine HIV testing being offered or performed outside the study CRS at 
emergency rooms, clinics, and medical offices. Such testing has become more 
likely due to the CDC’s revised guidelines for HIV counseling and testing, as well 
as policy changes in many countries to make HIV testing more frequent and 
routine. CRS staff should inform participants of their right to opt out of HIV 
testing outside the study site. CRS staff should inform study participants if local 
and/or state policies and regulations permit medical providers to perform HIV 
testing without first informing patients. If this is the case, then CRS staff should 
advise study participants that they may decline testing preemptively. CRS staff 
should also inform participants if positive results must be reported to local public 
health authorities. CRS staff should also inform participants of the need to 
maintain study blinding by getting HIV testing only at the study CRS. CRS staff 
should provide participants with CRS contact information and should encourage 
participants to ask medical providers to contact the CRS. The CRS can verify that 
the participant is in an HIV vaccine clinical trial and should only be tested at the 
study CRS. 
Potential participants identified as being HIV infected during screening are not 
enrolled. All participants who become HIV infected during the study will be 
terminated from this study. Potential and enrolled participants identified as HIV 
infected will be referred for medical treatment, counseling, and management of 
the HIV infection. These individuals may also be referred to appropriate ongoing 
clinical trials or observational studies. 

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9.5.1 
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 F. 
Signs or symptoms of an acute HIV infection syndrome, an intercurrent illness 
consistent with HIV-1 infection, or probable HIV exposure would prompt a 
diagnostic workup per the HVTN algorithm for Recent Exposure/Acute 
Infection Testing to determine HIV infection. 
 HIV testing will be performed at multiple timepoints throughout the study 
(see Appendix F). The Laboratory Program (or approved diagnostic 
laboratory) will follow the HVTN HIV testing algorithm (see Study Specific 
Procedures [SSP]), which is able to distinguish vaccine-induced antibody 
responses from actual HIV infections.  
 All participants can receive HIV-1 diagnostic testing from the site following 
their last scheduled visit until they are told that they did not receive an HIV 
vaccine or that they do not have vaccine-induced seropositivity. 
 All participants who received vaccine product and who have vaccine-induced 
positive or indeterminate HIV-1 serology (as measured by the standard anti-
HIV antibody screening tests) at or after the study is unblinded will be offered 
poststudy HIV-1 diagnostic testing (per the HVTN poststudy HIV-1 testing 
algorithm) periodically and free of charge as medically/socially indicated 
(approximately every 6 months) unless or until HIV Ab testing is no longer 
the standard test in clinical settings.  
9.5.2 
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 9.5.1). 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. 

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9.6 
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. 
9.7 
Urinalysis 
Dipstick testing may be performed in the clinic or the lab, as long as the required 
elements (glucose, protein, and hemoglobin) are tested. The examination is 
performed on urine obtained by clean catch. 
If the screening dipstick is transiently abnormal due to menses or infection, 
document this issue in the participant’s source documentation. For infection, 
provide appropriate treatment and/or referral. Following resolution, repeat the 
dipstick and, if within the eligibility limits specified in the protocol, the 
participant may be enrolled. 
Follow-up urinalysis should be deferred if a participant is menstruating, but 
should be performed as soon as possible. If a follow-up dipstick is abnormal due 
to a participant’s menstrual period, document in the comment section of the case 
report form (CRF) and repeat the dipstick once the participant is no longer 
menstruating. A micro-urinalysis is not required. 
9.8 
Assessments of reactogenicity 
For all participants, baseline assessments are performed before and reactogenicity 
assessments are performed after each vaccination. All reactogenicity symptoms 
are followed until resolution and graded according to the Division of AIDS Table 
for Grading the Severity of Adult and Pediatric Adverse Events, Corrected 
Version 2.1, dated July 2017, except as noted in Section 11.2.2 . 
The reactogenicity assessment period is 7 full days following each vaccination per 
the assessment schedule shown in Table 9-1. Participants are instructed to record 
symptoms using a postvaccination memory tool. Contact between the participant 
and the CRS staff should take place at least once within the 3 days following 

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vaccination. 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 event 
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 
1-7b 
Between 12:00am and 11:59pm on each of days 1-7 
HVTN CRS staff or participant 
a Day of vaccination 
b New or unresolved reactogenicity symptoms present on day 7 are followed until resolution 
9.8.1 
Assessment of systemic and local symptoms 
Systemic symptoms include increased body temperature, malaise and/or fatigue, 
myalgia, headache, chills, arthralgia, nausea, and vomiting. Local symptoms 
include pain and/or tenderness at the injection site. The daily maximum severity 
reached for each symptom during the assessment period is reported.  
Body temperature is measured by oral or infrared thermometry and reported in 
degrees Celsius. If temperature is measured in Fahrenheit, the conversion to 
Celsius should be documented in the participant’s chart note. A measurement is 
taken once daily during the assessment period and should be repeated if 
participant is feeling feverish. 
9.8.2 
Assessment of injection site 
Typical injection site reactions are erythema/redness and induration/swelling. The 
maximum horizontal and maximum vertical measurements for all injection site 
reactions are recorded. 
All injection site reactions are monitored until resolution. Areas greater than 25 
cm2 are followed daily; otherwise, the frequency of follow-up is based on 
clinician judgment. 

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9.8.3 
Assessment of lymph nodes 
This assessment is required only when reactogenicity assessments are performed 
by HVTN CRS staff, not by the participant. 
Only the proximally draining lymph nodes are assessed (eg, axillary nodes on the 
same side of the body for injections given in the deltoid). Lymph nodes are first 
evaluated for enlargement and tenderness. If they are found to be enlarged, 
measurements are taken to determine the size (widest diameter) of the enlarged 
node(s). 
9.9 
Visit windows and missed visits 
Visit windows are defined in HVTN 122 Study Specific Procedures. For a visit 
not performed within the window period, a Missed Visit form is completed. If the 
missed visit is one that required safety assessments or local safety labs, HVTN 
CRS staff should attempt to bring the participant in for an interim visit as soon as 
possible. 
Procedures performed at an interim visit are usually toxicity/safety assessments 
(including local safety labs) and HIV testing. With the exception of HIV testing, 
these procedures are performed only if they were required at the missed visit or if 
clinically indicated. HIV testing may be performed as deemed appropriate by the 
study staff. Blood samples for immunogenicity assays are not typically collected 
at interim visits. 
If a missed visit required vaccination, please refer to Section 7.3.2 and Section 
7.3.3 for resolution. 
9.10 
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. 
9.11 
Pregnancy 
If a participant becomes pregnant during the course of the study, no more 
injections of study product will be given, but remaining visits and study 
procedures should be completed unless medically contraindicated or applicable 
regulations require termination from the study. If the participant terminates from 
the study prior to the pregnancy outcome, the site should make every effort to 
keep in touch with the participant in order to ascertain the pregnancy outcome. 
Pregnancies and pregnancy outcomes will be reported. 

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10 
Laboratory 
10.1 
HVTN CRS laboratory procedures 
The HVTN 122 Site Lab Instructions and SSP provide further guidelines for 
operational issues concerning the clinical and processing laboratories. This 
document 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 E. 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 E. 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 
The primary immunogenicity timepoints in this study occur 2 weeks after the first 
and third vaccinations. 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 E. 
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. ICS parameters will include cytokines such 
as IFN-γ, interleukin (IL)-2, and tumor necrosis factor (TNF)-α, and may include 
other cytokines (such as cytokines relevant to Th2 and Th17 responses) to identify 
T cells of specific functionality. Markers of cytotoxic potential (eg, Granzyme B) 

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and of Tfh functionality (eg, CXCR5 and PD-1) may also be included. Data will 
be reported as percentages of CD4+ or CD8+ T cells responding to a specific 
peptide pool. Additional cell surface markers, cytokines, or functional markers 
may also be analyzed. 
10.5 
Endpoint assays: humoral 
10.5.1 
Binding antibody multiplex assay  
HIV-specific IgG antibodies will be assessed on plasma/serum samples from 
study participants taken at the primary immunogenicity timepoints and baseline. 
IgG subclass and IgA assays may also be performed. Specimens from other 
timepoints may also be assayed based on the results of the initial assay. 
10.5.2 
Neutralizing antibody assay 
HIV-1–specific nAb assays will be performed on serum samples from study 
participants taken at the primary immunogenicity timepoints. Specimens from the 
baseline and other timepoints may also be analyzed at the discretion of the HVTN 
Laboratory Program, which may be contingent on the results of the primary 
immunogenicity timepoints. The TZM-bl assay will test neutralization of the 
vaccine strain (CO6980) and a single highly neutralization-sensitive Tier 1 virus 
as a positive control (MW965.26). The global panel and/or clade-specific panels 
may be used to assess Tier 2 neutralization [41,42]. 
10.6 
Genotyping 
Molecular human leukocyte antigen (HLA) typing may be performed on enrolled 
participants using cryopreserved PBMC collected at baseline, initially on 
specimens from participants who demonstrate vaccine-induced T-cell responses at 
postvaccination timepoints. Other participants (including control recipients) may 
be HLA-typed to support future studies of immunological interest at the discretion 
of the HVTN Laboratory Program. Other markers, such as genes associated with 
immune responses or HIV-1disease progression may also be assessed.  
10.7 
Lab assay algorithm 
The Lab Assay Algorithm lists assays to characterize cellular, humoral, and innate 
immune responses as well as host genetics that may be conducted to determine 
endpoints in HVTN vaccine trials. The type of assay(s) employed will be 
dependent on the response obtained by the primary immunogenicity assays at 
relevant timepoints. Please note that the Lab Assay Algorithm will be updated 
periodically to include new assays. 

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10.8 
Exploratory studies 
Samples may be used for other testing and research related to furthering the 
understanding of HIV immunology or vaccines. In addition, cryopreserved 
samples may be used to perform additional assays to support standardization and 
validation of existing or newly developed methods.  
10.8.1 
Tfh phenotyping 
Flow cytometry may be used to identify peripheral blood follicular helper T 
(pTfh) cells and peripheral T follicular regulatory (pTfr) cells. Phenotyping of 
pTfh and pTfr cells will be based on expression of CXCR5, PD-1, CD127, and 
CD25 on CD4+ T cells, and may include additional markers. For example, if flow 
cytometry panels are successfully developed to assess CD69, OX40, IL-21, and 
CD154 expression as a functional read-out, vaccine-specific Tfh cells may be 
assessed and isolated for further analysis. 
10.8.2 
B cell plasmablasts 
Flow cytometry may be used to identify the early precursors for antibody-
secreting B cells, called B cell plasmablasts, in the peripheral blood.  Plasmablasts 
will be mainly characterized by CD19+ CD20- and high expression of CD27 and 
CD38. The flow cytometry panels might also include additional markers and 
assessment of antigen specificity. 
10.8.3 
Vaccinia neutralizing antibody assay 
Neutralizing antibody assays may be performed on serum samples collected at 
baseline to assess participant exposure to vaccinia. 
10.9 
Specimen storage and other use of specimens 
The HVTN stores specimens from all study participants indefinitely, unless a 
participant requests that specimens be destroyed or if required by IRB/EC, or RE. 
Other use of specimens is defined as studies not covered by the protocol or the 
informed consent form for the main study (Appendix A). 
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 CRS’s 
informed consent form, or as otherwise authorized under applicable law. Other 
testing on specimens (“other use”) will occur only after review and approval by 
the HVTN, the IRB/EC of the researcher requesting the specimens, and the CRS’s 
IRBs/ECs/REs if required. 
As part of consenting for the study, participants document their initial decision to 
allow or not allow their specimens to be used in other research, and they may 

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change their decision at any time. The participant’s initial decision about other 
use of their specimens, and any later change to that decision, is recorded by their 
CRS in a Web-based tool that documents their current decisions for other use of 
their specimens. The HVTN will only allow other research to be done on 
specimens from participants who allow such use.   
CRSs must notify HVTN Regulatory Affairs if institutional or local governmental 
requirements pose a conflict with or impose restrictions on specimen storage or 
other use of specimens. 
10.10 
Biohazard containment 
As the transmission of HIV and other blood-borne pathogens can occur through 
contact with contaminated needles, blood, and blood products, appropriate 
precautions will be employed by all personnel in the drawing of blood and 
shipping and handling of all specimens for this study, as currently recommended 
by the CDC and the NIH or other applicable agencies. 
All dangerous goods materials, including Biological Substances, Category A or 
Category B, must be transported according to instructions detailed in the 
International Air Transport Association Dangerous Goods Regulations. 

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11 
Safety monitoring and safety review 
11.1 
Safety monitoring and oversight 
11.1.1 
HVTN 122 PSRT 
The HVTN 122 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 122 PSRT are responsible for decisions related 
to participant safety. 
The Protocol Team clinic coordinator, clinical data manager, vaccine developer 
representative, clinical trial manager, and others may also be included in HVTN 
122 PSRT meetings. 
11.1.2 
HVTN SMB 
The SMB is a multidisciplinary group consisting of biostatisticians, clinicians, 
and experts in HIV vaccine research that, collectively, has experience in the 
conduct and monitoring of vaccine trials. Members of the SMB are not directly 
affiliated with the protocols under review.  
The SMB reviews safety data, unblinded as to treatment arm, approximately 
every 4 months. The reviews consist of evaluation of cumulative reactogenicity 
events, AE, laboratory safety data, and individual reports of adverse events 
requiring expedited reporting to DAIDS. The SMB conducts additional special 
reviews at the request of the HVTN 122 PSRT. 
Study sites will receive SMB summary minutes and are responsible for 
forwarding them to their IRB/EC and any applicable RE. 
11.1.3 
SDMC roles and responsibilities in safety monitoring  
The roles and responsibilities of the SDMC in relation to safety monitoring 
include: 

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 Maintaining a central database management system for HVTN clinical data; 
and 
 Providing reports of clinical data to appropriate groups such as the HVTN 122 
PSRT and HVTN SMB (see Section 11.1.2). 
11.1.4 
HVTN Core roles and responsibilities in safety monitoring 
 Daily monitoring of clinical data for events that meet the safety pause and 
HVTN 122 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 122 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, Corrected 
Version 2.1, dated July 2017, available on the RSC website at http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids-grading-tables, except: 
 Unintentional weight loss is required to be reported as an AE only if it is 
considered to be potentially deleterious to the participant’s health (see HVTN 
122 Study Specific Procedures); 

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 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); 
During the study period, 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) and (2) if the AE 
meets the criteria for a safety pause/prompt AE review (Section 11.4). 
Sites are expected to notify HVTN clinical safety staff of any serious safety 
concern requiring their attention (see Table 11-1). Telephone numbers and email 
addresses are found on the protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/hvtn122). 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/clinical-research-sites/safety-reporting/manual. 
The SAE Reporting Category will be used for this study.  
The internet-based DAIDS Adverse Experience Reporting System (DAERS) must 
be used for expedited AE reporting to DAIDS. In the event of system outages or 
technical difficulties, expedited AE reports may be submitted via the DAIDS EAE 
Form. For questions about DAERS, please contact CRMSsupport@niaid.nih.gov 
or from within the DAERS application itself.  
The study products for which expedited reporting are required are:  
 gp145 C.6980 with aluminum hydroxide adjuvant  

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 placebo (Sodium Chloride for Injection, 0.9%)  
The expedited reporting period for this study comprises the entire study period for 
each individual participant (from study enrolment until study completion or 
discontinuation from the study). During this period the SAE Reporting Category 
will be used.  
After the protocol-defined AE reporting period for the study, unless otherwise 
noted, only Suspected, Unexpected Serious Adverse Reactions as defined in 
Version 2.0 of the DAIDS EAE Manual must be reported to DAIDS, if the study 
staff become aware of the events.  
The NIAID/DAIDS will report all unexpected SAEs related to the study products 
observed in this clinical trial to the FDA in accordance with 21 CFR 312.32 (IND 
Safety Reports). However, because safety is a primary study endpoint, the 
Sponsor Medical Officer will not routinely be unblinded to study treatment 
assignment when there is an assessment of relatedness of the SAE with the study 
product(s); and the safety report will be sent to the FDA based on the blinded 
attribution assessment. 
If the PSRT believes unblinding is appropriate (eg, if unblinding to treatment 
assignment will assist with the clinical management of the SAE), the PSRT will 
consult the independent HVTN SMB for a recommendation. In the event the 
HVTN SMB determines that unblinding is indicated, the SMB will inform the 
individual (eg, site physician) of the participant’s treatment assignment in such a 
manner as to maintain the study blind of the PSRT and study team. For additional 
impact and management of SAEs on the study, see Section 11.4. 
11.3 
Initial safety evaluation 
Enrollment will proceed in all groups simultaneously and will be restricted to a 
maximum of 1 participant per day until 5 participants in Group 1, 3 participants in 
Group 2 and 1 placebo recipient in Group 3 have been enrolled. The HVTN 122 
PSRT will review the cumulative safety data through 2 weeks postvaccination on 
each of these participants and will determine whether it is safe to proceed with 
full enrollment. 
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 122 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 122 PSRT, participant safety may be threatened. 
Criteria for an individual participant’s departure from the schedule of vaccinations 
are listed in Section 7.3. 

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Table 11-1 AE notification and safety pause/AE review rules 
Event and 
relationship to study 
products 
Severity 
HVTN CRS actiona 
HVTN Core action 
SAE, related 
Grade 5 or 
Grade 4 
Phone immediately, email 
and submit forms 
immediately 
Immediate pause 
SAE, not related 
Grade 5 
Phone immediately, email 
and submit forms 
immediately 
Immediate HVTN 122 PSRT 
notification 
SAE, related 
Grade 3 
Email and submit forms 
immediately 
Immediate HVTN 122 PSRT 
notification and prompt HVTN 122 
PSRT AE review to consider pause 
AEb, related 
Grade 3 or 
Grade 4 
Email and submit forms 
immediately 
Immediate HVTN 122 PSRT 
notification and prompt HVTN 122 
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/hvtn###). 
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 122 PSRT, HVTN 
Regulatory Affairs, DAIDS Pharmaceutical Affairs Branch (PAB), DAIDS 
Regulatory Affairs Branch (RAB), DAIDS Safety and Pharmacovigilance Team 
(SPT), and participating HVTN CRSs. When an immediate safety pause is 
triggered, HVTN Core notifies the SMB.  
Once a trial is paused, the HVTN 122 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 122 PSRT assessment, DAIDS RAB 
notifies the FDA as needed. 
If an immediate HVTN 122 PSRT notification or prompt HVTN 122 PSRT AE 
review is triggered, HVTN Core notifies the HVTN 122 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 122 
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 122 PSRT (see 
Section 11.5.2). 

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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 122 PSRT AE review criteria. 
11.5.2 
Weekly review 
During the injection phase of the trial, the HVTN 122 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 122 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 122 PSRT, 
the US FDA, NIH, Office for Human Research Protections (OHRP), or vaccine 
developer(s). In addition, the conduct of this study at an individual HVTN CRS 
may be terminated by the determination of the IRB/EC and any applicable RE. 

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12 
Protocol conduct 
This protocol and all actions and activities connected with it will be conducted in 
compliance with the principles of GCP (ICHe6), and according to DAIDS and 
HVTN policies and procedures as specified in the HVTN Manual of Operations, 
DAIDS Clinical Research Policies and Standard Procedures Documents including 
procedures for the following: 
 Protocol registration, activation, and implementation; 
 Informed consent, screening, and enrollment; 
 Study participant reimbursement; 
 Clinical and safety assessments; 
 Safety monitoring and reporting; 
 Data collection, documentation, transfer, and storage; 
 Participant confidentiality; 
 Study follow-up and close-out; 
 Unblinding of staff and participants; 
 Quality control; 
 Protocol monitoring and compliance; 
 Advocacy and assistance to participants regarding negative social impacts 
associated with the vaccine trial; 
 Risk reduction counseling;  
 Specimen collection, processing, and analysis;  
 Ancillary studies, and 
 Destruction of specimens. 
Any policies or procedures that vary from DAIDS and HVTN standards or require 
additional instructions (eg, instructions for randomization specific to this study) 
will be described in the HVTN 122 Study Specific Procedures.  

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12.1 
Social impacts 
Participants in this study risk experiencing discrimination or other personal 
problems, resulting from the study participation itself or from the development of 
VISP. The HVTN CRS is obliged to provide advocacy for and assistance to 
participants regarding these negative social impacts associated with the vaccine 
trial. If HVTN CRS staff have questions regarding ways to assist a participant 
dealing with a social impact, a designated NIAID or HVTN Core representative 
can be contacted.  
Social harms are tabulated by the SDMC and are subjected to descriptive analysis. 
The goal is to reduce their incidence and enhance the ability of study staff to 
mitigate them when possible. 
Summary tables of social impact events will be generated weekly, and made 
available for review by the protocol chairs, protocol team leader, and the 
designated NIAID representative. 
12.2 
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 122 are described 
below. 
Protocol history and modifications 
Date: September 27, 2017 
Protocol version: Version 1.0 
Protocol modification: Original protocol 
 
 

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14 
Document references (other than literature 
citations) 
Other documents referred to in this protocol, and containing information relevant 
to the conduct of this study, include: 
 Assessment of Understanding. Accessible through the HVTN protocol-
specific website. 
 Current CDC Guidelines. Revised Recommendations for HIV Testing of 
Adults, Adolescents, and Pregnant Women in Health-Care Settings. Available 
at http://www.cdc.gov/mmwr/PDF/rr/rr5514.pdf  
 Division of AIDS (DAIDS) Clinical Research Policies and Standard 
Procedures Documents. Available at 
https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-
procedures  
 Division of AIDS Protocol Registration Manual. Available at 
https://www.niaid.nih.gov/sites/default/files/prmanual.pdf  
 Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events. Corrected Version 2.1, dated July 2017. Available at 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-
tables  
 The Manual for Expedited Reporting of Adverse Events to DAIDS. Version 
2.0, January 2010. Available at http://rsc.tech-res.com/clinical-research-
sites/safety-reporting/manual  
 HVTN Certificate of Confidentiality. Accessible through the HVTN website. 
 HVTN 122 Special Instructions. Accessible through the HVTN protocol-
specific website. 
 HVTN 122 Study Specific Procedures. Accessible through the HVTN 
protocol-specific website. 
 HVTN 122 Site Lab Instructions. Accessible through the HVTN protocol-
specific website. 
 HVTN Manual of Operations. Accessible through the HVTN website. 
 Dangerous Goods Regulations (updated annually), International Air Transport 
Association. Available for purchase at 
http://www.iata.org/ps/publications/dgr/Pages/index.aspx  

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 Lab assay algorithm (available upon request) 
 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 Policy on Reporting Race and Ethnicity Data: Subjects in Clinical 
Research. Available at http://grants1.nih.gov/grants/guide/notice-files/NOT-
OD-01-053.html  
 Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks, 
July 2008. 
 Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials. Available at 
https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf  
 Title 21, Code of Federal Regulations, Part 50. Available at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFR
Part=50  
 Title 45, Code of Federal Regulations, Part 46. Available at 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html  
See Section 16 for literature cited in the background and statistics sections of this 
protocol. 

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15 
Acronyms and abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AVEG 
AIDS Vaccine Evaluation Group 
BAMA 
binding antibody multiplex assay 
β-HCG 
beta human chorionic gonadotropin 
BMI 
body mass index 
bnAb 
broadly neutralizing antibody 
CAB 
Community Advisory Board 
CBC 
complete blood count 
CDC 
US Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary 
CI 
confidence interval 
COMPASS 
Combinatorial Polyfunctionality analysis of Antigen-Specific 
T-cell Subsets 
CRF 
case report form 
CRPMC 
NIAID Clinical Research Products Management Center 
CRS 
clinical research site 
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 
FS 
functionality score 
GCP 
Good Clinical Practice 
HBsAG 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HVTN 
HIV Vaccine Trials Network 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 

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ICS 
intracellular cytokine staining 
IFN-γ 
interferon gamma 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IL-2 
interleukin 2 
IM 
intramuscular 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
MedDRA Medical Dictionary for Regulatory Activities 
MHRP 
(US) Military HIV Research Program 
MIMOSA Mixture Models for Single-cell Assays 
MMR 
measles, mumps, and rubella 
MPER 
membrane-proximal external region 
MVA 
modified vaccinia Ankara 
nAb 
neutralizing antibody 
NIAID 
National Institute of Allergy and Infectious Diseases (US NIH) 
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 
PCA 
principal component analysis 
PCR 
polymerase chain reaction 
PFS 
polyfunctionality score 
PI 
Principal Investigator 
PSRT 
Protocol Safety Review Team 
pTfh 
peripheral T follicular helper (cells) 
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 
SMB 
Safety Monitoring Board 
SPT 
DAIDS Safety and Pharmacovigilance Team 
TB 
tuberculosis 
Tfh 
T follicular helper (cells) 
Tfr 
T follicular regulatory (cells) 
TNF-α 
tumor necrosis factor - alpha 

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UW-VSL University of Washington Virology Specialty Laboratory 
VISP 
Vaccine induced seropositivity 
VRC 
Vaccine Research Center (NIAID) 
WBC 
white blood cell 

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16 
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4. Wieczorek L, Krebs SJ, Kalyanaraman V, et al. Comparable Antigenicity and 
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5. Hemelaar J, Gouws E, Ghys PD, Osmanov S. Global and regional 
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6. Buonaguro L, Tornesello ML, Buonaguro FM. Human immunodeficiency 
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8. Rademeyer C, Moore PL, Taylor N, et al. Genetic characteristics of HIV-1 
subtype C envelopes inducing cross-neutralizing antibodies. Virology 
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9. Gray ES, Moore PL, Choge IA, et al. Neutralizing antibody responses in 
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13. Haynes BF, Gilbert PB, McElrath MJ, et al. Immune-correlates analysis of an 
HIV-1 vaccine efficacy trial. N Engl J Med 2012;366:1275-86. 
14. Mascola JR, Haynes BF. HIV-1 neutralizing antibodies: understanding 
nature's pathways. Immunol Rev 2013;254:225-44. 
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Opin HIV AIDS 2013;8:326-32. 
16. Lewis GK. Role of Fc-mediated antibody function in protective immunity 
against HIV-1. Immunology 2014;142:46-57. 
17. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with 
ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. The New 
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18. Haynes BF, Gilbert PB, McElrath MJ, et al. Immune-correlates analysis of an 
HIV-1 vaccine efficacy trial. The New England journal of medicine 
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19. Chung AW, Ghebremichael M, Robinson H, et al. Polyfunctional Fc-Effector 
Profiles Mediated by IgG Subclass Selection Distinguish RV144 and 
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vaccination. Sci Transl Med 2014;6:228ra39. 
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potent neutralizing antibody responses than monomeric gp120. Proceedings 
of the National Academy of Sciences of the United States of America 
2012;109:12111-6. 
22. Earl PL, Sugiura W, Montefiori DC, et al. Immunogenicity and protective 
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23. Sanders RW, van Gils MJ, Derking R, et al. HIV-1 VACCINES. HIV-1 
neutralizing antibodies induced by native-like envelope trimers. Science 
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24. Liu Q, Li Y, Luo Z, et al. HIV-1 vaccines based on replication-competent 
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infection. AIDS 2015;29:649-58. 
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J; Zhao, K; Shao, Y. Development of HIV-1 vaccines based on replication 
competent Tiantan vaccinia vector in China. Lancet 2015;386:1. 

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26. Montefiori DC. Measuring HIV neutralization in a luciferase reporter gene 
assay. Methods Mol Biol 2009;485:395-405. 
27. Montefiori DC. Evaluating neutralizing antibodies against HIV, SIV, and 
SHIV in luciferase reporter gene assays. Curr Protoc Immunol 2005;Chapter 
12:Unit 12 1. 
28. Matyas GR, Wieczorek L, Beck Z, et al. Neutralizing antibodies induced by 
liposomal HIV-1 glycoprotein 41 peptide simultaneously bind to both the 
2F5 or 4E10 epitope and lipid epitopes. AIDS 2009;23:2069-77. 
29. Edmonds TG, Ding H, Yuan X, et al. Replication competent molecular 
clones of HIV-1 expressing Renilla luciferase facilitate the analysis of 
antibody inhibition in PBMC. Virology 2010;408:1-13. 
30. Gilbert PB, Chiu YL, Allen M, et al. Long-term safety analysis of preventive 
HIV-1 vaccines evaluated in AIDS vaccine evaluation group NIAID-
sponsored Phase I and II clinical trials. Vaccine 2003;21:2933-47. 
31. Pitisuttithum P, Rerks-Ngarm S, Bussaratid V, et al. Safety and 
reactogenicity of canarypox ALVAC-HIV (vCP1521) and HIV-1 gp120 
AIDSVAX B/E vaccination in an efficacy trial in Thailand. PloS one 
2011;6:e27837. 
32. Spearman P, Lally MA, Elizaga M, et al. A trimeric, V2-deleted HIV-1 
envelope glycoprotein vaccine elicits potent neutralizing antibodies but 
limited breadth of neutralization in human volunteers. J Infect Dis 
2011;203:1165-73. 
33. Gray GE, Mayer KH, Elizaga ML, et al. Subtype C gp140 Vaccine Boosts 
Immune Responses Primed by the South African AIDS Vaccine Initiative 
DNA-C2 and MVA-C HIV Vaccines after More than a 2-Year Gap. Clin 
Vaccine Immunol 2016;23:496-506. 
34. Thongcharoen P, Suriyanon V, Paris RM, et al. A phase 1/2 comparative 
vaccine trial of the safety and immunogenicity of a CRF01_AE (subtype E) 
candidate vaccine: ALVAC-HIV (vCP1521) prime with oligomeric gp160 
(92TH023/LAI-DID) or bivalent gp120 (CM235/SF2) boost. J Acquir 
Immune Defic Syndr 2007;46:48-55. 
35. Churchyard G, Mlisana K, Karuna S, et al. Sequential Immunization with 
gp140 Boosts Immune Responses Primed by Modified Vaccinia Ankara or 
DNA in HIV-Uninfected South African Participants. PLoS One 
2016;11:e0161753. 
36. Agresti A, Coull BA. Approximate is better than "exact" for interval 
estimation of binomial proportions. Am Stat 1998;52:119-26. 

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37. Lydersen S, Fagerland MW, Laake P. Recommended tests for association in 
2 x 2 tables. Stat Med 2009;28:1159-75. 
38. James G, Witten D, Hastie T, Tibshirani R. An introduction to statistical 
learning with applications in R. New York: R. Springer, 2013. 
39. Finak G, McDavid A, Chattopadhyay P, et al. Mixture models for single-cell 
assays with applications to vaccine studies. Biostatistics 2014;15:87-101. 
40. Lin L, Finak G, Ushey K, et al. COMPASS identifies T-cell subsets 
correlated with clinical outcomes. Nat Biotechnol 2015;33:610-6. 
41. Seaman MS, Janes H, Hawkins N, et al. Tiered categorization of a diverse 
panel of HIV-1 Env pseudoviruses for assessment of neutralizing antibodies. 
J Virol 2010;84:1439-52. 
42. DeCamp A, Hraber P, Bailer RT, et al. Global panel of HIV-1 Env reference 
strains for standardized assessments of vaccine-elicited neutralizing 
antibodies. J Virol 2014;88:2489-507. 
 
 

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Appendix A 
Sample informed consent form 
Title: A phase 1 double-blind, randomized clinical trial to evaluate the safety and 
immunogenicity of a recombinant oligomeric gp145 clade C Env protein (gp145 
C.6980) in healthy, HIV-1–uninfected adult participants in the US 
HVTN protocol number: HVTN 122 
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 an HIV vaccine. HIV is the virus that causes AIDS. 
About 45 people will take part in this study at multiple sites. The researcher in 
charge of this study at this clinic is [Insert name of site PI]. The US National 
Institutes of Health (NIH) is paying for the study.  
1. We are doing this study to answer several questions. 
 Is the study vaccine safe to give to people? 
 Are people able to take the study vaccine without becoming too 
uncomfortable? 
 How do people’s immune systems respond to the study vaccine? (Your 
immune system protects you from disease.) 
2. The study vaccine cannot give you HIV. 
The study vaccine is not made from actual HIV. It is impossible for the study 
vaccine to give you HIV. Also, it cannot cause you to give HIV to someone else. 
3. We do not know if the study vaccine will decrease, increase, or not change 
your risk of becoming infected with HIV if you are exposed to the virus. 
Site: Any change to the following boxed text requires approval from HVTN 
Regulatory Affairs at vtn.core.reg@hvtn.org. 

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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.  
We do not know whether the vaccine 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. This study vaccine is experimental. 
The study vaccine is called gp145 C.6980. From here on, we will call it gp145 or 
the study vaccine. It is an experimental HIV vaccine. That means we do not know 
if the vaccine will be safe to use in people, or if it will work to prevent HIV 
infection. This vaccine is used only in research studies. 
The vaccine was developed by the US Military HIV Research Program and is 
being supplied for this study by the Division of AIDS at the US National 
Institutes of Health.  
This protein vaccine is a man-made copy of a piece of a protein found on the 
outside of HIV. This protein has been changed in order to strengthen the immune 
response made by the body’s immune system. This protein is mixed with an 
adjuvant called alum. An adjuvant is something added to the vaccine to help the 
immune system respond better. Alum is the most widely used vaccine adjuvant. It 
has been used in licensed vaccines given to hundreds of millions of people all 
over the world. 
This study vaccine has not been given to people before. In one study it was tested 
in monkeys in combination with another vaccine without causing health problems 
(no changes in weight or temperature). Similar HIV protein vaccines mixed with 
alum adjuvant have been given to more than 12,000 people in clinical trials 
without causing any serious health problems. 
General risks of vaccines: 
All vaccines can cause fever, chills, rash, aches and pains, nausea, headache, 
dizziness, and feeling tired. Vaccines can also cause pain, redness, swelling, or 
itching where you got the injection. Most people can still do their planned 
activities after getting a vaccine. Rarely, people have side effects that limit their 
normal activities or make them go to the doctor. 

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Rarely, a vaccine can cause an allergic reaction, including a rash, hives, or trouble 
breathing. Allergic reactions can be life-threatening. You should tell us if you 
have ever had a bad reaction to any injection or vaccine. 
Very rarely, a vaccine causes an autoimmune disease in a person, or makes an 
autoimmune disease worse. An autoimmune disease happens when your immune 
system attacks your own body, instead of attacking an infection. 
Joining the study 
5. It is completely up to you whether or not to join the study.  
Take your time in deciding. If it helps, talk to people you trust, such as your 
doctor, friends or family. If you decide not to join this study, or if you leave it 
after you have joined, your other care at this clinic and the benefits or rights you 
would normally have will not be affected. 
If you join this study, you may not be allowed to join other HIV vaccine or HIV 
prevention studies now or in the future. You cannot be in this study while you are 
in another study where you get a study product. Being in more than one study 
may not be safe. Also during the study, you should not donate blood or tissue. 
If you choose not to join this study, you may be able to join another study. 
Site: Remove item 6 if you use a separate screening consent that covers these 
procedures. 
6. If you want to join the study, we will screen you to see if you are eligible. 
Screening involves a physical exam, HIV test and health history. A physical exam 
may include, but is not limited to: 
 Checking your weight, temperature and blood pressure 
 Looking in your mouth and throat 
 Listening to your heart and lungs 
 Feeling your abdomen (stomach and liver) 
We will also do blood and urine tests. These tests tell us about some aspects of 
your health, such as how healthy your kidneys, liver, and immune system are. We 
will also test you for Hepatitis B, Hepatitis C, and syphilis. We will ask you about 
medications you are taking. We will ask you about behaviors that might put you 
at risk for getting HIV. If you were born female, we will test you for pregnancy.  
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.  

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(Site: adapt the following section so it is applicable to the care available at your site) 
7. If we find that you have a health problem during screening or during the 
study, we will tell you about the care that we can give here for free. 
For the care that we cannot give, we will explain how we will help you get care 
elsewhere. For health problems that are unrelated to the study, we will not pay for 
care. 
8. If you were born female and could become pregnant, you must agree to use 
birth control to join this study. 
Site: If you want to include Appendix B, 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 vaccine 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 
[Insert period of time]. 
Site: Insert number of visits and range of visit lengths. (There is site-specific variation 
in screening protocols and in the number of possible follow-up visits between 
protocol-mandated visits.) 
Visits can last from [#] to [#] hours. 
You may have to come for more visits if you have a lab or health issue. 
We may contact you after the main study ends (for example, to tell you about the 
study results). 
10. We will give you [Site: Insert compensation] for each study visit you 
complete. 
This amount is to cover the costs of [Site: Insert text] 
Site: Insert any costs to participants (eg, birth control costs for female participants 
who could become pregnant). 

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Payments you receive for being in the study may be taxable. We may need to ask 
you for your Social Security number for tax reasons. 
You do not have to pay anything to be in this study. 
11. We will give you either the study vaccine or a placebo.  
Not everyone in this study will get the study vaccine. 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 
vaccine. In this study, the placebo is sterile salt water. 
You have a 8-in-9 chance of getting the study vaccine. Site: Modify the 
randomization metaphor in the next sentence as appropriate to your local culture. 
Whether you get the study vaccine or the placebo is completely random, like 
flipping a coin.  
We have no say in whether you get the study vaccine or the placebo. We will not 
know which one you are getting, and neither will you. Only the pharmacist at this 
clinic will have this information while the study is going on.  
You will have to wait until everyone completes their final study visits to find out 
whether you got the study vaccine 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 vaccine on a schedule. 
You will be in one of 3 groups. You will get injections of the study vaccine or 
placebo into the upper arm. This will happen 3 times during the study. 
 
 
 
Injection Schedule 
 
Number 
First injection 
2 months later 
6 months later 
Group 1 
25 
High dose gp145 
+ alum 
High dose gp145 
+ alum 
High dose gp145 
+ alum 
Group 2 
15 
Low dose gp145 
+ alum 
Low dose gp145 
+ alum 
Low dose gp145 + 
alum 
Group 3 
5 
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 that night and for 7 more days, you will need to 
keep track of how you are feeling and if you have any symptoms. Within 3 days 
of your injections, we will also ask you how you are doing. You should always 
contact us 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. 

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13. In addition to giving you the study vaccine, 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;  
 Test your body’s response to some vaccines you may have gotten previously; 
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 17 mL and 180 mL (a little more than 1 tablespoon 
to ¾ cup). Your body will make new blood to replace the blood we take out.  
Site: You may want to add a sentence to the end of the previous paragraph 
contextualizing the blood volumes described (eg, “To compare, people who donate 
blood in the US can give a total of about 500 mL in an 8-week period.”). Modify the 
example for cultural relevance and alter blood volumes as necessary. 
Site: Insert Appendix D, Table of procedures (for informed consent form) in this 
section or distribute it as a separate sheet if it is helpful to your study participants. 
You are not required to do either. 
We will be looking for side effects. We will review the results of these procedures 
and tests with you at your next visit, or sooner if necessary. If any of the results 
are important to your health, we will tell you.  
14. We will counsel you on avoiding HIV infection. 
We will ask you personal questions about your HIV risk factors such as sexual 
behavior, alcohol, and drug use. We will talk with you about ways to keep your 
risk of getting HIV low.  
15. The HVTN will test your samples to see how your immune system responds 
to the study products. 
We will send your samples (without your name) to labs approved by the HVTN 
for this study. 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. 

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Researchers may also do genetic testing related to this study on your samples. 
Your genes are passed to you from your birth parents. They affect how you look 
and how your body works. The differences in people’s genes can help explain 
why some people get a disease while others do not. The genetic testing will only 
involve some of your genes, not all of your genes (your genome). The researchers 
will study only the genes related to the immune system and HIV and those that 
affect how people get HIV.  
If you become HIV infected, the researchers may look at all of the genes of the 
virus found in your samples. The researchers will use this information to learn 
more about HIV and the study product(s).  
In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to contribute to this study.  
These tests done on your samples are for research purposes only, not to check 
your health. The labs will not give the results to you or this clinic because these 
tests are not approved for use in making healthcare decisions. These labs are only 
approved to do research tests. 
When your samples are no longer needed for this study, the HVTN will continue 
to store them. 
Site: Delete next section if using separate consent for use of samples and information 
in other studies 
16. When samples are no longer needed for this study, the HVTN wants to keep 
them for use in other studies and share them with other researchers.  
The HVTN calls these samples “extra samples”. The HVTN will only allow your 
extra samples to be used in others studies if you agree to this. You will mark your 
decision at the end of this form. If you have any questions, please ask. 
Do I have to agree? No. You are free to say yes or no, or to change your mind 
after you sign this form. At your request, we will destroy all extra samples that we 
have. Your decision will not affect your being in this study or have any negative 
consequences here.  
Where are the samples stored? Extra samples are stored in a secure central place 
called a repository. Your samples will be stored in the HVTN repository in the 
United States. 
How long will the samples be stored? There is no limit on how long your extra 
samples will be stored. [Site: Revise the previous sentence to insert limits if your 
regulatory authority imposes them.] 
Will I be paid for the use of my samples? No. Also, a researcher may make a new 
scientific discovery or product based on the use of your samples. If this happens, 

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there is no plan to share any money with you. The researcher is not likely to ever 
know who you are. 
Will I benefit from allowing my samples to be used in other studies? Probably not. 
Results from these other studies are not given to you, this clinic, or your doctor. 
They are not part of your medical record. The studies are only being done for 
research purposes. 
Will the HVTN sell my samples and information? No, but the HVTN may share 
your samples with HVTN or other researchers. Once we share your samples and 
information, we may not be able to get them back. 
How do other researchers get my samples and information? When a researcher 
wants to use your samples and information, their research plan must be approved 
by the HVTN. Also, the researcher’s institutional review board (IRB) or ethics 
committee (EC) will review their plan. [Site: If review by your institution’s 
IRB/EC/RE is also required, insert a sentence stating this.] IRBs/ECs protect the 
rights and well-being of people in research. If the research plan is approved, the 
HVTN will send your samples to the researcher’s location.  
What information is shared with HVTN or other researchers? The samples and 
information will be labeled with a code number. Your name will not be part of the 
information. However, some information that we share may be personal, such as 
your race, ethnicity, sex, health information from the study, and HIV status. We 
may share information about the study product you received and how your body 
responded to the study product.  
What kind of studies might be done with my extra samples and information? The 
studies will be related to HIV, vaccines, the immune system and other diseases.  
Researchers may also do genetic testing on your samples.  
In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to contribute to this study.  
If you agree, your samples could also be used for genome wide studies. In these 
studies, researchers will look at all of your genes (your genome). The researchers 
compare the genomes of many people, looking for common patterns of genes that 
could help them understand diseases. The researchers may put the information 
from the genome-wide studies into a protected database so that other researchers 
can access it. Usually, no one would be able to look at your genome and link it to 
you as a person. However, if another database exists that also has information on 
your genome and your name, someone might be able to compare the databases 
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: 

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

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

HVTN 122 Version 1.0 / September 27, 2017 
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18. We may stop your injections or take you out of the study at any time. We 
may do this even if you want to stay in the study and even if you were 
scheduled for more injections.  
This may happen if: 
 you do not follow instructions, 
 we think that staying in the study might harm you, 
 you get HIV, 
 you enroll in a different research study where you get another study product, 
or 
 the study is stopped for any reason. 
If we stop your injections, we may ask you to stay in the study to complete other 
study procedures. 
19. We will stop your injections if you become pregnant 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. 
20. If you get infected with HIV during the study, we will help you get care and 
support. 
You will not be able to stay in this study. We will counsel you about your HIV 
infection and about telling your partner(s). We will tell you where you can get 
support and medical care. Site: Modify the following sentence as appropriate. We 
will not provide or pay for any of your HIV care directly.  
Other Risks 
21. There are other risks to being in this study. 
This section describes the other risks and restrictions we know about. There may 
also be unknown risks, even serious ones. We will tell you if we learn anything 
new that may affect your willingness to stay in the study. 
Risks of routine medical procedures:  
In this study, we will do some routine medical procedures. These are taking blood 
and giving injections. These procedures can cause bruising, pain, fainting, 
soreness, redness, swelling, itching, a sore, bleeding, and (rarely) muscle damage 

HVTN 122 Version 1.0 / September 27, 2017 
HVTN122_v1.0_FINAL / Page 92 of 109 
or infection where you got the injection. Taking blood can cause a low blood cell 
count (anemia), making you feel tired. 
Personal problems/discrimination/testing HIV antibody positive: 
About 10 to 20% of people who join HVTN studies report personal problems or 
discrimination because of joining an HIV vaccine study. Family or friends may 
worry, get upset or angry, or assume that you are infected with HIV or at high risk 
and treat you unfairly as a result. Rarely, a person has lost a job because the study 
took too much time away from work, or because their employer thought they had 
HIV.  
The body makes antibodies to fight or prevent infection. Most vaccines cause the 
body to make antibodies as a way of preventing infection. Your body may make 
antibodies to HIV because you received an HIV study vaccine. The study vaccine 
may cause you to test positive on some types of HIV antibody tests, even if you 
are not infected with HIV. This is called vaccine-induced seropositivity (VISP). 
VISP means that after you get the study vaccine, a routine HIV test done outside 
this clinic may say you have HIV, even if you don’t. For this reason, you should 
plan to get HIV tests only at this clinic during the study. Our tests can tell the 
difference between true HIV infection and a positive result that is caused by the 
study vaccine. 
If you have a positive test result caused by the study vaccine at any time, we can 
arrange free HIV testing for as long as you need it. If this happens, we do not 
know how long you will test positive due to the study vaccine. If you receive a 
positive HIV test result and we determine it is because you have HIV, we will 
refer you for follow-up care. 
It is unlikely, but you could test negative at the end of the study and positive some 
time later, even though you don’t have HIV. This could happen if different HIV 
tests come into use. We will give you a phone number to call for more 
information.  
Site: Modify the following paragraph if applicable. If someone believes you are 
infected with HIV even if you are not, you could face discrimination and other 
problems. For example, in some countries, you could be denied medical or dental 
care, employment, insurance, a visa, or entry into the military. If you do have a 
positive HIV antibody test caused by the study vaccine, you will not be able to 
donate blood or organs. Your family and friends may treat you differently. We 
will give you a brochure that tells you more about testing HIV positive because of 
an HIV vaccine, and how you can avoid some of these problems. 
If you become pregnant during or after the study and have VISP, we don't know if 
the antibodies could be passed to your baby. We know that this happens with 
other vaccines, like tetanus vaccine. These antibodies from the mother are not a 
danger to the baby, and they go away over time. For most babies antibodies from 
the mother last for about 6 months. 

HVTN 122 Version 1.0 / September 27, 2017 
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You should always tell the delivery staff if you have VISP. However, you may 
still be tested for HIV using the antibody test when you deliver your baby. If your 
test is positive and the delivery staff believes you have an HIV infection, your 
baby may be started on antiretroviral treatment when it is not needed. If this 
happens, we can arrange for you and the baby to have a test that can tell the 
difference between true HIV infection and a VISP result. If you or the baby 
continue to have VISP, we can arrange this testing for free for as long as it is 
needed. 
Embarrassment/anxiety:  
You may feel embarrassed when we ask about your HIV risks, such as having sex 
and using drugs. Also, waiting for your HIV test results or other health test results 
could make you feel anxious. You could feel worried if your test results show that 
you are infected with HIV. If you feel embarrassed or anxious, please tell us and 
we will try to help you. 
Risks of disclosure of your personal information: 
We will take several steps to protect your personal information. Although the risk 
is very low, it is possible that your personal information could be given to 
someone who should not have it. If that happened, you could face discrimination, 
stress, and embarrassment. We can tell you more about how we will protect your 
personal information if you would like it.  
Risks of genetic testing: 
It is unlikely, but the genetic tests done on your samples could show you may be 
at risk for certain diseases. If others found out, it could lead to discrimination or 
other problems. However, it is almost impossible for you or others to know your 
test results from the genetic testing. The results are not part of your study records 
and are not given to you.  
In the very unlikely event that your genetic information becomes linked to your 
name, a federal law called the Genetic Information Nondiscrimination Act 
(GINA) helps protect you. GINA keeps health insurance companies and 
employers from seeing results of genetic testing when deciding about giving you 
health insurance or offering you work. GINA does not help or protect you against 
discrimination by companies that sell life, disability, or long-term care insurance. 
Unknown risks:  
We do not know if the study vaccine will increase, decrease, or not change your 
risk of becoming infected with HIV if exposed. If you get infected with HIV, we 
do not know how the study vaccine might affect your HIV infection or how long 
it takes to develop AIDS. 
We do not know if getting this study vaccine will affect how you respond to any 
future approved HIV vaccine. It could be that a future HIV vaccine may not work 

HVTN 122 Version 1.0 / September 27, 2017 
HVTN122_v1.0_FINAL / Page 94 of 109 
as well for you because you got the study vaccine. Currently, no HIV vaccine has 
been approved for use.  
We do not know how the study vaccine will affect a pregnant participant or a 
developing baby.  
Benefits 
22. The study may not benefit you. 
We do not know whether getting the study vaccine might benefit you in any way. 
However, being in the study might still help you in some ways. The counseling 
that you get as part of the study may help you avoid getting HIV. The lab tests 
and physical exams that you get while in this study might detect health problems 
you don’t yet know about.  
This study may help in the search for a vaccine to prevent HIV. However, if the 
study vaccine later become approved and sold, there are no plans to share any 
money with you.  
Your rights and responsibilities 
23. If you join the study, you have rights and responsibilities. 
You have many rights that we will respect. You also have responsibilities. We list 
these in the Participant’s Bill of Rights and Responsibilities. We will give you a 
copy of it. 
Leaving the study 
24. Tell us if you decide to leave the study.  
You are free to leave the study at any time and for any reason. Your care at this 
clinic and your legal rights will not be affected, but it is important for you to let us 
know.  
We will ask you to come back to the clinic one last time for a physical exam, and 
we may ask to take some blood and urine samples. We will also ask about any 
personal problems or benefits you have experienced from being in the study. We 
believe these steps are important to protecting your health, but it is up to you 
whether to complete them. 
Injuries 
Site: Approval from HVTN Regulatory Affairs (at vtn.core.reg@hvtn.org) is needed 
for any change (other than those that the instructions specifically request or those 
previously approved by HVTN Regulatory Affairs) to the boxed text. 

HVTN 122 Version 1.0 / September 27, 2017 
HVTN122_v1.0_FINAL / Page 95 of 109 
25. If you get sick or injured during the study, contact us immediately. 
Your health is important to us. (Site: adjust the following 2 sentences if applicable 
to the care available at your site) We will tell you about the care that we can give 
here. For the care that we cannot provide, we will explain how we will help you 
get care elsewhere. 
If you become sick or injured in this study, there is a process to decide if it is 
related to the study vaccine or the adjuvant 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. (Site: insert locale-appropriate medical insurance language in the 
following sentence) If the injury is not study related, then you and your health 
insurance will be responsible for treatment costs.  
Some injuries are not physical. For example, you might be harmed emotionally by 
being in an HIV vaccine study. Or you might lose wages because you cannot go 
to work. However, there are no funds to pay for these kinds of injuries, even if 
they are study related. 
You may disagree with the decision about whether your injury is study related. If 
you wish, the HVTN will ask independent experts to review the decision. You 
always have the right to use the court system if you are not satisfied. 
Questions  
26. If you have questions or problems at any time during your participation in 
this study, use the following important contacts. 
If you have questions about this study, contact 
[name or title and telephone number of the investigator or other study staff]. 
If you have any symptoms that you think may be related to this study, contact 
[name or title and telephone number of the investigator or other study staff]. 
This study has been reviewed and approved by a committee called the 
[name of local IRB/EC]. If you have questions about your rights as a research 
participant, or problems or concerns about how you are being treated in this study, 
contact 
[name or title and telephone number of person on IRB or other appropriate organization] 
at the committee. 
If you want to leave this study, contact 
[name or title and telephone number of the investigator or other study staff]. 

HVTN 122 Version 1.0 / September 27, 2017 
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 Your permissions and signature  
Site: Delete the following section if using a separate consent for use of samples and 
information in other studies 
27. In Section 16 of this form, we told you about possible other uses of your extra 
samples and information, outside this study. Please choose only one of the 
options below and write your initials or make your mark in the box next to it. 
Whatever you choose, the HVTN keeps track of your decision about how 
your samples and information can be used. 
 
 
I allow my extra samples and information to be used for other studies related to HIV, 
vaccines, the immune system, and other diseases. This may include genetic testing and 
keeping my cells growing over time.  
OR 
 
 
I agree to the option above and also to allow my extra samples and information to be 
used in genome wide studies. 
OR 
 
 
I do not allow my extra samples to be used in any other studies. This includes not 
allowing genetic testing, growing more of my cells, or genome wide studies.  
 
28. If you agree to join this study, you will need to sign or make your mark 
below. Before you sign or make your mark on this consent form, make sure 
of the following: 
 You have read this consent form, or someone has read it to you. 
 You feel that you understand what the study is about and what will happen to 
you if you join. You understand what the possible risks and benefits are. 
 You have had your questions answered and know that you can ask more. 
 You agree to join this study. 
You will not be giving up any of your rights by signing this consent form. 

HVTN 122 Version 1.0 / September 27, 2017 
HVTN122_v1.0_FINAL / Page 97 of 109 
 
 
 
 
 
 
 
Participant’s name (print) 
 
Participant’s signature or mark 
 
Date 
 
Time 
 
 
 
 
 
 
 
Clinic staff conducting consent 
discussion (print) 
 
Clinic staff signature 
 
Date 
 
Time 
For participants who are unable to read or write, a witness should complete the 
signature block below: 
 
 
 
 
 
 
 
Witness’s name (print) 
 
Witness’s signature  
 
Date 
 
Time 
*Witness is impartial and was present for the consent process. 
 
 

HVTN 122 Version 1.0 / September 27, 2017 
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Appendix B 
Approved birth control methods (for sample 
informed consent form) 
Site: Any change to the following boxed text requires approval from HVTN 
Regulatory Affairs at vtn.core.reg@hvtn.org. 
You should not become pregnant during the study because we do not know how 
the study vaccine 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 one year; 
 You have had a hysterectomy (your uterus removed); 
 You have had your ovaries removed; 
 You have a tubal ligation (your “tubes tied”) or confirmed successful 
placement of a product that blocks the fallopian tubes; 
 You are having sex only with a female partner or partners; 
 You only have oral sex; or, 
 You are sexually abstinent (no sex at all). 

HVTN 122 Version 1.0 / September 27, 2017 
HVTN122_v1.0_FINAL / Page 99 of 109 
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. 

HVTN 122 Version 1.0 / September 27, 2017 
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Appendix C 
Sample consent form for use of samples and 
information in other studies 
Title: A phase 1 double-blind, randomized clinical trial to evaluate the safety and 
immunogenicity of a recombinant oligomeric gp145 clade C Env protein (gp145 
C.6980) in healthy, HIV-1–uninfected adult participants in the US 
HVTN protocol number: HVTN 122 
Site: [Insert site name] 
When samples are no longer needed for this study, the HVTN wants to use them 
in other studies and share them with other researchers.  
The HVTN calls these samples extra samples”. The HVTN will only allow your 
extra samples to be used in other studies if you agree to this. You will mark your 
decision at the end of this form. If you have any questions, please ask.  
1. Do I have to agree?  
No. You are free to say yes or no, or to change your mind after you sign this form. 
At your request, we will destroy all extra samples that we have. Your decision 
will not affect your being in this study or have any negative consequences here.  
2. Where are the samples stored?  
Extra samples are stored in a secure central place called a repository. Your 
samples will be stored in the HVTN repository in the United States. 
3. How long will the samples be stored?  
There is no limit on how long your extra samples will be stored. [Site: Revise the 
previous sentence to insert limits if your regulatory authority imposes them.] 
4. Will I be paid for the use of my samples?  
No. Also, a researcher may make a new scientific discovery or product based on 
the use of your samples. If this happens, there is no plan to share any money with 
you. The researcher is not likely to ever know who you are. 
5. Will I benefit from allowing my samples to be used in other studies?  
Probably not. Results from these other studies are not given to you, this clinic, or 
your doctor. They are not part of your medical record. The studies are only being 
done for research purposes. 
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 may not be able to get them back. 

HVTN 122 Version 1.0 / September 27, 2017 
HVTN122_v1.0_FINAL / Page 101 of 109 
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 HVTN or other researchers?  
The samples and information will be labeled with a code number. Your name will 
not be part of the information. However, some information that we share may be 
personal, such as your race, ethnicity, gender, health information from the study, 
and HIV status. We may share information about the study product you received 
and how your body responded to the study product.  
9. What kind of studies might be done with my extra samples and information?  
The studies will be related to HIV, vaccines, the immune system and other 
diseases.  
Researchers may also do genetic testing on your samples.  
In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to contribute to this study. 
If you agree, your samples could also be used for genome wide studies. In these 
studies, researchers will look at all of your genes (your genome). The researchers 
compare the genomes of many people, looking for common patterns of genes that 
could help them understand diseases. The researchers may put the information 
from the genome-wide studies into a protected database so that other researchers 
can access it. Usually, no one would be able to look at your genome and link it to 
you as a person. However, if another database exists that also has information on 
your genome and your name, someone might be able to compare the databases 
and identify you. If others found out, it could lead to discrimination or other 
problems. The risk of this is very small. 
10. What are the risks of genetic testing?  
It is unlikely, but the genetic tests done on your samples could show you may be 
at risk for certain diseases. If others found out, it could lead to discrimination or 
other problems. However, it is almost impossible for you or others to know your 
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 

HVTN 122 Version 1.0 / September 27, 2017 
HVTN122_v1.0_FINAL / Page 102 of 109 
employers from seeing results of genetic testing when deciding about giving you 
health insurance or offering you work. GINA does not help or protect you against 
discrimination by companies that sell life, disability, or long-term care insurance.  
11. Who will have access to my information in studies using my extra samples? 
People who may see your information are: 
 Researchers who use your 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 or title and telephone number of the investigator or other study staff]. 
If you think you may have been harmed because of studies using your samples or 
information, contact 
[name or title and telephone number of the investigator or other study staff]. 
If you have questions about your rights as a research participant, contact 
[name or title and telephone of person on IRB or other appropriate organization]. 

HVTN 122 Version 1.0 / September 27, 2017 
HVTN122_v1.0_FINAL / Page 103 of 109 
13. Please choose only one of the options below and write your initials or make 
your mark in the box next to it. Whatever you choose, the HVTN keeps track 
of your choice about how your samples and information can be used. 
 
I allow my extra samples and information to be used for other studies related 
to HIV, vaccines, the immune system, and other diseases. This may include 
genetic testing and keeping my cells growing over time.  
OR 
 
 
I agree to the option above and also to allow my extra samples and 
information to be used in genome wide studies. 
OR 
 
 
I do not allow my extra samples to be used in any other studies. This includes 
not allowing genetic testing, growing more of my cells, or genome wide 
studies.  
 
 
 
 
 
 
 
 
 
Participant’s name (print) 
 
Participant’s signature or mark 
 
Date 
 
Time 
 
 
 
 
 
 
 
Clinic staff conducting consent 
discussion (print) 
 
Clinic staff signature 
 
Date 
 
Time 
For participants who are unable to read or write, a witness should complete the 
signature block below: 
 
 
 
 
 
 
 
 
Witness’s name (print) 
 
Witness’s signature  
 
Date 
 
Time 
*Witness is impartial and was present for the consent process.

HVTN 122 Version 1.0 / September 27, 2017 
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Appendix D 
Table of procedures (for sample informed consent form) 
 
 
 
Time after 1st injection visit 
Procedure 
Screening 
visit(s) 
First 
injection 
visit 
1 
week 
2 
weeks 
2 months 
(2nd injection 
visit) 
2½ 
months 
6 months 
(3rd injection 
visit) 
6 months 
+ 1 week 
6½ 
months 
9 
months 
12 
months 
Injection 
 
√ 
 
 
√ 
 
√ 
 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
 
 
 
Complete physical 
√ 
 
 
 
 
 
 
 
 
 
√ 
Brief physical 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Urine test 
√ 
 
 
√ 
 
 
 
 
√ 
 
 
Blood drawn 
√ 
√ 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
Pregnancy test 
(participants born 
female)* 
√ 
√ 
 
 
√ 
 
√ 
 
 
√ 
 
HIV testing & pretest 
counseling 
√ 
 
 
 
 
√ 
√ 
 
 
√ 
√ 
Risk reduction 
counseling 
√ 
√ 
 
√ 
√ 
√ 
√ 
 
√ 
√ 
√ 
Questions/questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Not shown in this table is a time after all study participants have completed their last scheduled visit when you can find out what product you received.  
* Persons who have had a total hysterectomy (removal of the uterus) or removal of both ovaries (verified by medical records), are not required to have a pregnancy test. 
 

HVTN 122 Version 1.0 / September 27, 2017 
HVTN122_v1.0_FINAL / Page 105 of 109 
Appendix E 
Laboratory procedures 
 
  
  
  
  
  
Tube volume (mL) 
Total 
  
Visit: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
  
Day: 
Screening 
visit3 
D0 
D7 
D14 
D56 
D70 
D168 
D175 
D182 
D273 
D364 
  
Week: 
W0 
W1 
W2 
W8 
W10 
W24 
W25 
W26 
W39 
W52 
  
Assay Location2 
Month: 
M0 
M0.25 
M0.5 
M2 
M2.5 
M6 
M6.25 
M6.5 
M9 
M12 
  
  
VAC1 
  
  
VAC2 
  
VAC3 
  
  
  
  
Procedure 
Ship to1 
Tube4 
Tube size 
(vol. capacity)4 
  
  
  
  
  
  
  
  
  
  
  
BLOOD COLLECTION 
  
Screening or diagnostic assays 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
     Screening HIV test 
Local Lab 
Local Lab 
SST 
5mL 
5 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
5 
     HBsAg/anti-HCV 
Local Lab 
Local Lab 
SST 
5mL 
5 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
5 
     Syphilis 
Local Lab 
Local Lab 
SST 
5mL 
5 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
5 
     HIV diagnostics9 
UW-VSL 
UW-VSL 
EDTA 
10mL 
— 
— 
— 
— 
— 
10 
10 
— 
— 
10 
209 
50 
Safety labs 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
     CBC/ Diff/ platelets 
Local lab 
Local lab 
EDTA 
5mL 
5 
— 
— 
5 
— 
5 
— 
— 
5 
5 
— 
25 
     Chemistry panel5 
Local lab 
Local lab 
SST 
5mL 
5 
— 
— 
5 
— 
5 
— 
— 
5 
5 
— 
25 
Immunogenicity assays6 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
     Host genetics7 
CSR 
HVTN Labs 
ACD 
8.5mL 
— 
17 
— 
— 
— 
— 
— 
— 
— 
— 
— 
17 
     Cellular assays 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
          ICS 
CSR 
HVTN Labs 
ACD 
8.5mL 
— 
42.5 
— 
42.5 
— 
42.5 
— 
— 
42.5 
— 
42.5 
212.5 
          pTfh, pTfr, and plasmablasts 
CSR 
HVTN Labs 
ACD 
8.5mL 
— 
z 
42.5 
— 
— 
— 
42.5 
42.5 
— 
— 
— 
127.5 
     Humoral assays 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
          Binding Ab 
CSR 
HVTN Labs 
SST 
8.5mL 
— 
8.5 
— 
8.5 
— 
8.5 
— 
— 
8.5 
— 
8.5 
42.5 
          Neutralizing Ab 
CSR 
HVTN Labs 
SST 
8.5mL 
— 
8.5 
— 
8.5 
— 
8.5 
— 
— 
8.5 
— 
8.5 
42.5 
Vaccinia neutralizing Ab 
CSR 
HVTN Labs 
SST 
8.5mL 
— 
y 
— 
— 
— 
— 
— 
— 
— 
— 
— 
0 
Specimen storage 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
     PBMC 
CSR 
  
ACD 
8.5mL 
— 
42.5 
— 
42.5 
— 
42.5 
— 
— 
42.5 
— 
68 
238 
     Serum 
CSR 
  
SST 
8.5mL 
— 
17 
— 
17 
— 
17 
— 
— 
17 
— 
17 
85 
Visit total 
  
  
  
  
25 
136 
42.5 
129 
0 
139 
52.5 
42.5 
129 
20 
164.5 
880 
56-Day total 
  
  
  
  
25 
161 
203.5 
332.5 
332.5 
268 
52.5 
95 
224 
20 
164.5 
  
URINE COLLECTION 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
      Urine dipstick10 
Local lab 
Local lab 
  
  
X 
— 
— 
X 
— 
— 
— 
— 
X 
— 
— 
  
      Pregnancy test8 
Local lab 
Local lab 
  
  
X 
X 
— 
— 
X 
— 
X 
— 
— 
X 
— 
  
 

HVTN 122 Version 1.0 / September 27, 2017 
HVTN122_v1.0_FINAL / Page 106 of 109 
1 CSR = Central Specimen Repository; UW-VSL = University of Washington Virology Specialty Laboratory (Seattle, Washington, USA) 
2 HVTN Laboratories include: Fred Hutchinson Cancer Research Center (Seattle, Washington, USA); Duke University Medical Center (Durham, North Carolina, USA) 
3 Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination.  
4 Local labs may assign appropriate alternative tube types for locally performed tests. 
5 Chemistry panels are defined in Section 9.2 (pre-enrollment) and Section 9.3 (postenrollment). 
 
6 Immunogenicity assays will be performed at M0 and M0.5 (for binding Ab assay) and M6.5. Based on the number of responders observed at these timepoints, lab assays may be 
performed on participants for humoral and cellular responses at other timepoints 
7 Genotyping may be performed on enrolled participants using cryopreserved PBMC collected at baseline, initially in participants who demonstrate vaccine-induced T-cell 
responses at postvaccination timepoints. 
8 For a participant who was born female, pregnancy test must be performed on the day of vaccination with negative results received prior to vaccination. Persons who are NOT of 
reproductive potential due to having undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing.  
9 At an early termination visit for a withdrawn or terminated participant (see Section 9.10), blood should be drawn for HIV diagnostic testing, as shown for visit 11 above.  
10 And microscopy if needed. 
y = SST blood collected for serum storage will also cover specimen needs for the Vaccinia neutralizing Ab assay; no separate blood draw is needed. 
z = ACD blood collected for PBMC storage will also cover specimen needs for the pTfh, pTfr, and plasmablasts assay; no separate blood draw is needed. 
 
 

HVTN 122 Version 1.0 / September 27, 2017 
HVTN122_v1.0_FINAL / Page 107 of 109 
Appendix F 
Procedures at HVTN CRS  
Visit: 011  
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
Post 
Day:
 
D0 
D7 
D14 
D56 
D70 
D168 
D175 
D182 
D273 
D364 
 
Month:
 
M0 
M0.25 
M0.5 
M2 
M2.5 
M6 
M6.25 
M6.5 
M9 
M12 
 
Procedure Scr. 
VAC1 
 
 
VAC2 
 
VAC3 
 
 
 
 
 
Study procedures2 
 
 
 
 
 
 
 
 
 
 
 
 
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 
— 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Risk reduction counseling 
X 
X 
— 
X 
X 
X 
X 
— 
X 
X 
X 
— 
Pregnancy prevention assessment4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Behavioral risk assessment 
X 
— 
— 
— 
— 
X 
X 
— 
— 
X 
X 
— 
Confirm eligibility, obtain demographics, randomize  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Social impact assessment 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
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 
— 
Intercurrent illness/adverse experience 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
HIV infection assessment5 
X 
— 
— 
— 
— 
X 
X 
— 
— 
X 
X 
— 
Confirm HIV test results provided to participant 
— 
X 
— 
— 
— 
— 
X 
— 
X 
— 
X 
X 
Local lab assessment 
 
 
 
 
 
 
 
 
 
 
 
 
Urine dipstick 
X 
— 
— 
X 
— 
— 
— 
— 
X 
— 
— 
— 
Pregnancy (urine or serum HCG)6 
X 
X 
— 
— 
X 
— 
X 
— 
— 
X 
— 
— 
CBC, differential 
X 
— 
— 
X 
— 
X 
— 
— 
X 
X 
— 
— 
Chemistry panel (see Section 9.2)  
X 
— 
— 
X 
— 
X 
— 
— 
X 
X 
— 
— 
Syphilis, Hepatitis B, Hepatitis C 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Vaccination procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination7 
— 
X 
— 
— 
X 
— 
X 
— 
— 
— 
— 
— 
Reactogenicity assessments8 
— 
X 
— 
— 
X 
— 
X 
— 
— 
— 
— 
— 
Poststudy 
 
 
 
 
 
 
 
 
 
 
 
 
Unblind participant  
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
  
1 Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination. 
2 For specimen collection requirements, see Appendix E. 
3 Includes exam for clinical evidence of vaccinia scarification. 

HVTN 122 Version 1.0 / September 27, 2017 
HVTN122_v1.0_FINAL / Page 108 of 109 
  
4 Pregnancy prevention assessment is required only for participants who were born female and are capable of becoming pregnant. 
5 Includes pre-test counseling. A subsequent follow-up contact is conducted to provide post-test counseling and to report results to participant. 
6 For a participant who was born female, pregnancy test must be performed on urine or blood specimens within 24 hours of vaccination with negative results 
received prior to vaccination. Pregnancy test to determine initial eligibility may be performed at screening, but must also be done on day 0 prior to first 
vaccination. Persons who are NOT of reproductive potential due to having undergone total hysterectomy or bilateral oophorectomy (verified by medical records), 
are not required to undergo pregnancy testing. Serum pregnancy tests may be used to confirm the results of, or substitute for, a urine pregnancy test. 
7 Blood draws required at vaccination visits must be performed prior to administration of study product; however, it is not necessary to have results prior to 
administration, except for results of a serum pregnancy test, if indicated. Lab tests may be drawn within the 3 days prior to vaccination. 
8 Reactogenicity assessments performed daily for at least 7 days postvaccination (see Section 9.8). 

HVTN 122 Version 1.0 / September 27, 2017 
HVTN122_v1.0_FINAL / Page 109 of 109 
Appendix G 
Protocol Signature Page 
 
A phase 1 double-blind, randomized clinical trial to evaluate the safety and 
immunogenicity of a recombinant oligomeric gp145 clade C Env protein (gp145 
C.6980) in healthy, HIV-1–uninfected adult participants in the US 
I will conduct the study in accordance with the provisions of this protocol and all 
applicable protocol-related documents. I agree to conduct this study in 
compliance with United States (US) Health and Human Service regulations (45 
CFR 46); applicable U.S. Food and Drug Administration regulations; standards of 
the International Conference on Harmonization Guideline for Good Clinical 
Practice (E6); Institutional Review Board/Ethics Committee determinations; all 
applicable in-country, state, and local laws and regulations; and other applicable 
requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies 
 
 
 
 
 
 
 
 
 
Investigator of Record Name (print) 
 
Investigator of Record Signature 
 
Date 
 
 
DAIDS Protocol Number: HVTN 122 
DAIDS Protocol Version: Version 1.0 
Protocol Date: September 27, 2017