A Phase 1b Open Label Clinical Trial to Evaluate HIV-1 Neutralization Antibody Breadth in Response to HIV gp120 Protein Vaccine in HIV-uninfected Adults With Quiescent Systemic Lupus Erythematosus
Phase: PHASE1
Conditions: HIV Infections, Systemic Lupus Erythematosus
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
PROTOCOL 
HVTN 121 
A phase 1b open label clinical trial to evaluate HIV-1 
neutralization antibody breadth in response to HIV 
gp120 protein vaccine in HIV-uninfected adults with 
quiescent Systemic Lupus Erythematosus 
DAIDS DOCUMENT ID 38162 
IND #018361 HELD BY DAIDS 
CLINICAL TRIAL SPONSORED BY 
Division of AIDS (DAIDS) 
National Institute of Allergy and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
Department of Health and Human Services (DHHS) 
Bethesda, Maryland, USA 
STUDY PRODUCT PROVIDED BY 
Global Solutions for Infectious Diseases (GSID) 
South San Francisco, California, USA 
September 14, 2018 
FINAL 
HVTN 121 
Version 2.0 

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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 ..............................................................................................11 
4 Background ..................................................................................................................12 
4.1 
Rationale for trial concept ............................................................................12 
4.2 
AIDSVAX® B/E ...........................................................................................19 
4.3 
Trial design rationale ....................................................................................20 
4.4 
Clinical studies .............................................................................................21 
4.5 
Potential risks of study products and administration ...................................22 
5 Objectives and endpoints .............................................................................................24 
5.1 
Primary objectives and endpoints ................................................................24 
5.2 
Secondary objectives and endpoints ............................................................24 
5.3 
Exploratory objectives ..................................................................................26 
6 Statistical considerations ..............................................................................................27 
6.1 
Accrual and sample size calculations ...........................................................27 
6.2 
Randomization .............................................................................................29 
6.3 
Statistical analyses ........................................................................................29 
7 Selection and withdrawal of participants .....................................................................34 
7.1 
Inclusion criteria ...........................................................................................34 
7.2 
Exclusion criteria ..........................................................................................37 
7.3 
Participant departure from vaccination schedule or withdrawal ..................41 
8 Study product preparation and administration .............................................................44 
8.1 
Vaccine regimen ...........................................................................................44 
8.2 
Study product formulation ...........................................................................44 
8.3 
Preparation of study product ........................................................................44 
8.4 
Administration ..............................................................................................45 
8.5 
Acquisition of study products ......................................................................46 
8.6 
Pharmacy records .........................................................................................46 
8.7 
Final disposition of study products ..............................................................46 
9 Clinical procedures ......................................................................................................47 
9.1 
Informed consent ..........................................................................................47 
9.2 
Pre-enrollment procedures ...........................................................................49 
9.3 
Enrollment and vaccination visits ................................................................50 
9.4 
Follow-up visits ............................................................................................52 
9.5 
HIV counseling and testing ..........................................................................53 

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9.6 
Contraception status .....................................................................................55 
9.7 
Urinalysis and urine protein:creatinine ratio ................................................55 
9.8 
Assessments of reactogenicity .....................................................................55 
9.9 
Visit windows and missed visits ..................................................................57 
9.10 Early termination visit ..................................................................................57 
9.11 Pregnancy .....................................................................................................57 
9.12 HIV infection during the study .....................................................................58 
10 Laboratory procedures .................................................................................................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 ..............................................................................60 
10.5 Endpoint assays: humoral .............................................................................60 
10.6 Innate immunity assays ................................................................................61 
10.7 Exploratory studies .......................................................................................61 
10.8 Specimen storage and other use of specimens .............................................63 
10.9 Biohazard containment .................................................................................63 
11 Safety monitoring and safety review ...........................................................................64 
11.1 Safety monitoring and oversight ..................................................................64 
11.2 Safety reporting ............................................................................................65 
11.3 Safety pause and prompt PSRT AE review..................................................70 
11.4 Review of cumulative safety data ................................................................72 
11.5 Study termination .........................................................................................72 
12 Protocol conduct ..........................................................................................................74 
12.1 Social impacts ..............................................................................................75 
12.2 Emergency communication with study participants ....................................75 
13 Version history .............................................................................................................76 
14 Document references (other than literature citations) ..................................................77 
15 Acronyms and abbreviations........................................................................................79 
16 Literature cited .............................................................................................................82 
Appendix A Sample informed consent form (SICF) ........................................................92 
Appendix B Approved birth control methods (for sample informed consent form) ......110 
Appendix C Sample consent form for use of samples and information in other studies 111 
Appendix D Table of procedures (for sample informed consent form) ..........................115 
Appendix E Laboratory procedures ................................................................................116 
Appendix F Procedures at HVTN CRS ..........................................................................118 
Appendix G SELENA-SLEDAI Instrument ...................................................................120 
Appendix H HVTN low risk guidelines for the US ........................................................121 
Appendix I Protocol signature page ..............................................................................123 
 

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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 International Council for 
Harmonisation (ICH) and/or Good Clinical Practice (GCP) guidelines. 
• HVTN scientists and operational staff incorporate the philosophies underlying 
major codes (1-3), declarations, and other guidance documents relevant to 
human subjects research into the design and conduct of HIV vaccine clinical 
trials. 
• HVTN scientists and operational staff are committed to substantive 
community input—into the planning, conduct, and follow-up of its research—
to help ensure that locally appropriate cultural and linguistic needs of study 
populations are met. Community Advisory Boards (CAB) are required by 
DAIDS and supported at all HVTN research sites to ensure community input. 
• HVTN clinical trial staff counsel study participants routinely on how to 
reduce HIV risk. Participants who become HIV-infected during the trial are 
provided counseling on notifying their partners and about HIV infection 
according to local guidelines. Staff members will also counsel them about 
reducing their risk of transmitting HIV to others. 
• Participants who become HIV-infected during the trial are referred to medical 
practitioners to manage their HIV infection and to identify potential clinical 
trials they may want to join. If a program for ART provision is not available at 
a site and ART is needed, a privately established fund will be used to pay for 
access to treatment to the fullest extent possible. 
• The HVTN provides training so that all participating sites similarly ensure fair 
participant selection, protect the privacy of research participants, and obtain 
meaningful informed consent. During the study, participants will have their 
wellbeing monitored, and to the fullest extent possible, their privacy 
protected. Participants may withdraw from the study at any time. 
• Prior to implementation, HVTN trials are rigorously reviewed by scientists 
who are not involved in the conduct of the trials under consideration.  

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

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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 participant are not as apparent as they would be in 
treatment protocols, where a study participant may receive therapeutic benefit 
from the experimental treatment for their illness. However, this protocol is 
designed to minimize the risks to participants while maximizing the potential 
value of the knowledge it is designed to generate.  

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2.3 
Equitable participant selection  
45 CFR 46.111 (a) 3 and 21 CFR 56.111 (a) 3: Subject selection is 
equitable 
This protocol has specific inclusion and exclusion criteria for investigators to 
follow in admitting participants into the protocol. Participants are selected 
because of these criteria and not because of positions of vulnerability or privilege. 
Investigators are required to maintain screening and enrollment logs to document 
volunteers who screened into and out of the protocol and for what reasons. 
2.4 
Appropriate informed consent 
45 CFR 46.111 (a) 4 and 5 and 21 CFR 56.111 (a) 4 and 5: Informed 
consent is sought from each prospective subject or the subject’s 
legally authorized representative as required by 45 CFR 46.116 and 
21 CFR Part 50; informed consent is appropriately documented as 
required by 45 CFR 46.117 and 21 CFR 50.27 
The protocol specifies that informed consent must be obtained before any study 
procedures are initiated and assessed throughout the trial (see Section 9.1). Each 
site is provided training in informed consent by the HVTN as part of its entering 
the HVTN. The HVTN requires a signed consent document for documentation, in 
addition to chart notes or a consent checklist. 
2.5 
Adequate safety monitoring 
45 CFR 46.111 (a) 6 and 21 CFR 56.111 (a) 6: There is adequate 
provision for monitoring the data collected to ensure the safety of 
subjects. 
This protocol has extensive safety monitoring in place (see Section 11). Safety is 
monitored daily by HVTN Core and routinely by the HVTN 121 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 

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research participants or potential research participants as individuals whereas the 
term “confidentiality” is used to refer to the treatment of information about those 
individuals. This protocol respects the privacy of participants by informing them 
about who will have access to their personal information and study data (see 
Appendix A). The privacy of participants is protected by assigning unique 
identifiers in place of the participant’s name on study data and 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 study site in this protocol signs an Agreement on 
Confidentiality and Use of Data and Specimens or comparable confidentiality 
agreement with the HVTN. In some cases, a comparable confidentiality 
agreement process may be acceptable. Each study site participating in the protocol 
is required to have a standard operating procedure on how the staff members will 
protect the confidentiality of study participants. 

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3 
Overview 
Title  
A phase 1b open label clinical trial to evaluate HIV-1 neutralization antibody 
breadth in response to HIV gp120 protein vaccine in HIV-uninfected adults with 
quiescent Systemic Lupus Erythematosus 
Primary objectives 
To evaluate the breadth and potency of HIV-1 neutralizing antibody (nAb) 
responses and 
To examine the safety and tolerability of AIDSVAX® B/E in a population of 
participants diagnosed with Systemic Lupus Erythematosus (SLE) who have 
stable disease 
Study product and route of administration 
• AIDSVAX® B/E: a bivalent HIV-1 vaccine to be provided by Global 
Solutions for Infectious Diseases (GSID). The vaccine consists of 300 mcg of 
subtype B (MN) HIV gp120 glycoprotein and 300 mcg of subtype E (A244) 
HIV gp120 glycoprotein adsorbed onto 600 mcg of aluminum as aluminum 
hydroxide gel suspension as adjuvant. Vaccine will be injected IM (1 mL) into 
the deltoid muscle at Day 0 and Months 1 and 6. The vaccine was originally 
developed and manufactured by Genentech Inc. The development and 
manufacturing rights were subsequently transferred to VaxGen, Inc. and 
finally transferred to its current developer, GSID. 
Table 3-1 Schema 
 
Injection schedule in months 
N 
Month 0 
Day 0 
Month 1 
Day 28 
Month 6 
Day 168 
16 
AIDSVAX® B/E 
AIDSVAX® B/E 
AIDSVAX® B/E 
Participants 
16 low-risk, HIV-1–uninfected volunteers aged 18 to 50 years, diagnosed with 
SLE who have quiescent disease at the time of enrollment 
Design 
Open label trial 

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Duration per participant 
12 months of scheduled clinic visits 
Estimated total study duration 
20 months (includes enrollment and follow-up) 
Investigational New Drug (IND) sponsor 
DAIDS, NIAID, NIH, DHHS (Bethesda, Maryland, USA) 
Study product provider 
• AIDSVAX® B/E: GSID (South San Francisco, California, 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) 
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 121 PSRT; HVTN SMB 

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3.1 
Protocol Team 
Protocol leadership 
Chair 
M. Anthony Moody 
Duke University 
919-668-2551 
tony.moody@duke.edu 
Statistician 
Abby Isaacs 
SCHARP, FHCRC 
206-667-7919 
aisaacs@fredhutch.org 
Co-chair 
Paul Goepfert 
University of Alabama 
205-975-5667 
paulg@uab.edu 
Medical officer 
Laura Polakowski 
DAIDS, NIAID 
240-627-3040 
laura.polakowski@nih.gov 
Protocol Team 
leader 
Cecilia Morgan 
HVTN Core, FHCRC 
206-667-5875 
cmorgan@fredhutch.org 
Laboratory lead 
Georgia Tomaras 
HVTN Laboratory 
Program, Duke University 
919-681-5598 
georgia.tomaras@duke.edu 
Other contributors to the original protocol 
Core medical monitor 
Carmen Paez 
HVTN Core, FHCRC 
Clinical safety specialist 
Jill Zeller 
HVTN Core, FHCRC 
Clinical trial 
investigator 
Ankoor Shah 
Duke University 
Clinical trials manager 
Shelly Ramirez 
HVTN Core, FHCRC 
Study product developer 
representative 
Carter Lee 
GSID 
Study product developer 
representative 
Vineeta Gulati 
GSID 
Laboratory protocol 
operations manager 
On Ho 
HVTN Laboratory 
Program, FHCRC 
SDMC Associate 
director of lab science 
April Randhawa 
SCHARP, FHCRC 
Regulatory affairs 
associate 
Denelle Reilly 
HVTN Core, FHCRC 
Clinical data manager 
Claire Chapdu 
SCHARP, FHCRC 
Clinic coordinator 
Amanda Stemke 
Duke University 
Protocol development 
manager 
Ramey Fair 
HVTN Core, FHCRC 
Community Advisory 
Board (CAB) member 
Terl Paul Gleason 
Duke University 
CAB 
DAIDS protocol 
pharmacist 
Oladapo Alli 
DAIDS, NIAID 
240-627-3593 
Community 
educator/recruiter 
Julieta Giner 
Duke University 
Community engagement 
unit representative 
Gail Broder  
HVTN Core, FHCRC 
 
 
Technical editor 
Richa Chaturvedi 
HVTN Core, FHCRC 

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4 
Background 
4.1 
Rationale for trial concept 
The search for an effective HIV-1 vaccine is one of the top priorities of current 
research efforts (4). Despite decades of research, an HIV-1 vaccine that induces 
robust nAbs and prevents infection has not been achieved (5). Antibodies with the 
ability to block HIV-1 infection in vitro are called nAbs, and antibodies that do 
this potently and against a large number of diverse HIV-1 strains are called 
broadly neutralizing antibodies (bnAbs). A number of bnAbs against HIV-1 have 
been found, and while some of them have been shown to block infection after 
passive transfer in nonhuman primate models (6), our ability to routinely induce 
such antibodies through vaccines has not been successful (5, 7). Finding ways to 
elicit those kinds of antibodies is a major focus of HIV-1 vaccine development. 
BnAbs against HIV-1 have a number of common characteristics that are unusual 
for vaccine-induced antibodies, including at least one of the following: long, 
hydrophobic complementarity-determining region 3 loops; high mutation 
frequency; and/or autoreactivity (8). These characteristics are, however, 
frequently found in autoantibodies derived from those with autoimmune diseases 
like systemic lupus erythematosus (SLE). Moreover, these antibody 
characteristics of bnAbs are typical of antibodies controlled by host tolerance 
mechanisms (9). A number of investigators have noted that coincident SLE and 
HIV-1 infection is rare (10), while others have suggested that the kinds of 
antibodies that are made during SLE might be protective against HIV-1 infection 
(11). This has led to a hypothesis that antibody production in patients with 
autoimmune diseases like SLE and defective immune tolerance mechanisms 
similar to what SLE patients are known to exhibit may permit the development of 
antibodies with enhanced ability to block HIV-1 infection that are not normally 
produced by individuals without autoimmune disease (12). Based on these data, a 
primary hypothesis of this study is that an HIV-1 vaccine given to participants 
with SLE will elicit antibodies with characteristics of bnAbs, including increased 
neutralization breadth and/or gene usage and maturation patterns similar to bnAbs 
that have arisen during HIV-1 infection. It is currently unknown whether an 
HIV-1 vaccine will enhance the amount or activity of potentially protective 
HIV-1 antibodies in patients with SLE. 
Preliminary studies in mice including wild type and knock-in models of bnAbs 
have repeatedly demonstrated that antibodies of this type are controlled by 
tolerance mechanisms (9, 13-18). There are multiple murine models that have 
been used to examine the pathophysiology of SLE including therapeutic 
interventions (19), but such models do not have human B or T cell repertoires, 
suggesting that such models will be of limited use in evaluating vaccines that will 
be given to humans. 
In support of the idea that SLE may be permissive for the development of bnAbs, 
an individual has been studied who developed SLE after becoming infected with 

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HIV-1. Although not protected from infection, over time this individual 
developed bnAbs and was able to control the virus without antiretroviral therapy 
(ART) (20). A monoclonal antibody (mAb), CH98, was isolated from blood 
B cells from this individual; this antibody broadly neutralized HIV-1 by binding 
to the HIV-1 gp120 Env CD4 binding site and displayed characteristics shared 
among HIV-1 bnAbs and antibodies commonly identified in autoimmune disease 
(long complementarity-determining region 3 loops and high mutation frequency). 
In particular, antibody CH98 is polyreactive (it reacts with more than 90% of 
9,400 human host cellular antigens), and it specifically binds to double-strand 
DNA (dsDNA), a specificity that is commonly induced during SLE (21) and 
which was present in this patient whose plasma also contained anti-dsDNA 
autoantibodies (20). 
While no human trial of HIV-1 vaccine candidates has elicited bnAbs, a number 
of results have suggested that an effective HIV-1 vaccine might be possible. The 
RV144 ALVAC-prime AIDSVAX-boost phase 2b vaccine efficacy trial, 
performed on HIV-uninfected individuals in Thailand, demonstrated 31% efficacy 
against acquisition of infection in low-risk subjects (22). The correlates of risk 
analysis showed that protection from infection correlated with antibodies directed 
against HIV-1 envelope protein (23). This has raised the possibility that with 
proper modification for enhanced vaccine efficacy, this vaccine could be made 
effective for general deployment. 
One of the immunogens used in the RV144 trial, Env gp120 AE.A244 has been 
shown to bind to the unmutated common ancestor of V1V2 glycan epitope bnAbs 
CH01-04 (24) with an affinity sufficient to stimulate B cells bearing such 
antibodies to undergo affinity maturation (25, 26). This raises the hypothesis that 
this immunogen could stimulate precursors of V1V2 glycan epitope bnAbs to 
expand following vaccination. In addition, this immunogen has also been 
associated with the elicitation of CD4 binding site antibodies: RV144 vaccinees 
who were boosted 6-8 years after the initial RV144 vaccine regimen (a trial called 
RV305) have been recently studied, and at a level of approximately 3 per million 
B cells, the vaccine boosts with either ALVAC + AIDSVAX® B/E or 
AIDSVAX® B/E alone induced the expansion of B cells that have characteristics 
suggesting they are early members of heavy chain complementarity determining 
region 3 (HCDR3)-binder CD4 binding site bnAb lineages (27). B cells in such 
lineages produce antibodies with long HCDR3 regions that differentially bind to 
wild type Env but not to Env with a deletion of isoleucine at amino acid position 
371, and that neutralize one or more tier 2 (difficult-to-neutralize) HIV-1 strains. 
These two lines of evidence suggest that in the right immunologic setting, a better 
quality of serum nAbs and/or a higher frequency of B cells with characteristics of 
bnAb precursors might be elicited by vaccination. Thus, one of the 
immunogenicity hypotheses of this protocol is that SLE vaccinees will have 
qualitatively better gp120 antibody responses than were found in RV144 
vaccinees, as tested by serum neutralization. In addition, another hypothesis is 
that repertoire analysis of memory B cells and plasmablast / plasma cells induced 
by gp120 in SLE patients will demonstrate an expansion of the pool of V1V2 
glycan epitope and/or CD4 binding site bnAb precursors, that this expanded pool 

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will consist of antibodies that are more mutated than those found in RV305, and 
that these antibodies will demonstrate a greater degree of neutralization breadth 
(9, 20). To test this, the analysis will quantify the frequency of V1V2 glycan 
epitope and CD4 binding site bnAb precursors in memory B cells and 
plasmablast / plasma cells in SLE patients vaccinated with AIDSVAX® B/E to 
determine if the induced gp120 response in SLE vaccinees is enhanced, as 
manifested by induction of bnAbs. 
4.1.1 
Rationale for HIV-1 immunization for persons with SLE 
It is unlikely that the vaccine regimen used in this study will provide direct 
protection against HIV-1 infection to participants. The primary immunological 
objective of this study is to determine whether an HIV-1 vaccine that can engage 
precursors of V1V2 glycan epitope bnAbs and has been associated with eliciting 
antibodies directed at the CD4 binding site can more robustly expand those pools 
of B cells in the presence of altered immune tolerance.  
The specific rationale for performing the study in a group of persons with SLE is 
that 1) HIV-1 bnAbs have characteristics indicating they arose from B cells under 
immune tolerance control (i.e., lacking tolerance to self antigens) and persons 
with SLE are known to exhibit this type of altered immune tolerance, 2) several 
investigators have noted an underreporting of coincident SLE and HIV-1, and 
have suggested that SLE may permit protective immune responses and 3) a bnAb 
cross reactive with dsDNA was isolated from a person who had both SLE and 
HIV-1 (20, 28, 29). In addition, a recent study showed that autoimmune-prone 
mice immunized with HIV-1 Env were able to develop neutralization breadth 
(30). 
To date, no HIV-1 vaccine trial has been performed in patients with SLE. While it 
is likely that patients with SLE and other autoimmune diseases will be one of 
many targeted populations (along with pregnant women and children) for any 
widely deployed HIV-1 vaccine, the primary purpose of this study is investigating 
immunological questions related to HIV-1 vaccine response in the setting of 
altered immune tolerance, as in patients with SLE. If SLE patients demonstrate 
production of nAbs upon receipt of an HIV-1 vaccine, further evaluation of the 
immunological conditions present in these patients might reveal mechanisms that 
can be simulated in healthy individuals with a specific type of vaccine transient 
immune modulation (vTIM), which consists of the use of immune system-
modulating drugs (e.g., chloroquine, monoclonal antibodies used in the treatment 
of cancer that alter immune tolerance) given at or around the time of 
immunization that can permit antibody responses typically suppressed under 
tolerance control in healthy individuals. Importantly, this study might identify a 
critical pathway of immune tolerance for which no drugs currently exist, and 
could provide crucial data that support the development of novel directed 
therapies that permit protective HIV-1 responses in the vTIM setting. 
In performing the first HIV-1 vaccine trial in SLE patients, it is appropriate to use 
a vaccine with the most extensive safety data and a non-live vaccine product that 

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is generally considered safe for persons with SLE and fits the criteria outlined in 
the EULAR recommendations for vaccination of patients with autoimmune 
inflammatory rheumatic diseases (31, 32). For this study, the bivalent HIV-1 
envelope (Env) protein vaccine, AIDSVAX® B/E, will be used; this vaccine has 
been administered to > 10,000 human volunteers and has been demonstrated to be 
safe (22, 33). Furthermore, this vaccine was a component of the only HIV-1 
vaccine trial to show efficacy, the ALVAC-prime/AIDSVAX® B/E-boost RV144 
trial (22). Using the alum-adjuvanted AIDSVAX® B/E vaccine in this trial will 
also present an opportunity to directly evaluate the effect of an alum-adjuvanted 
vaccine on immune system activation in people with SLE. 
4.1.2 
Safety considerations for immunization of persons with SLE 
Data on the safety of vaccines in persons with SLE are readily available. The 
majority of published guidelines have emphasized the safety of killed or subunit 
vaccines in autoimmune disease patients (31, 32, 34, 35); and while live 
attenuated vaccines should be used cautiously, they also have been demonstrated 
to be safe in this population (34).  
Vaccination of persons with SLE has been studied using a variety of immunogens 
and study designs. Between 1978 and 2016, there were at least 40 published 
studies examining vaccination in adults and children with SLE. The studies 
examined 2,595 persons with SLE who were vaccinated, 287 persons with SLE 
who were not vaccinated as a part of the published studies, and 1,169 vaccinated 
controls (36-77). The methods used to evaluate study participants were variable, 
with 29/40 using the SLE Disease Activity Index (SLEDAI). A summary of the 
findings follows. 
• 11 studies that compared vaccinated and unvaccinated persons with SLE 
(including 5 randomized controlled trials) showed no difference in disease 
activity between groups (36-38, 42, 46, 51, 57, 67, 72, 73, 76, 77). 
• 9 studies that compared disease activity pre- and post-vaccination in persons 
with SLE showed no significant difference in disease activity (48, 49, 52, 53, 
57, 58, 63, 64, 69). 
• 21 studies (including some of the above-noted studies) examined SLE disease 
flares post-vaccination (40, 47, 54, 56, 58, 59, 61, 67, 68). 
▪ 13 reported that the rate of flares among vaccinated SLE patients was 
similar to that among unvaccinated SLE patients (40, 42, 47, 51, 54, 56-
59, 61, 67, 68, 72, 77). 
▪ 4 studies each reported one vaccinated SLE participant who experienced a 
single flare (3 glomerulonephritis, 1 optic neuritis, 1 unspecified) (55, 62, 
74, 75). 

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▪ 1 reported 7/62 SLE participants experienced a flare (1 with a severe flare 
of glomerulonephritis and 6 with mild to moderate disease flares of 
varying symptoms post-influenza vaccination) (71). 
▪ 1 recruited SLE patients with SLEDAI < 4, and reported 3/28 participants 
experienced a flare (rash/alopecia, photosensitivity/discoid rash, 
polyarthritis) (60).  
▪ 1 reported 4/20 participants with flare (joint symptoms, vasculitis, altered 
affect, increased nephritis) (41). 
▪ 1 reported 20/72 participants with moderate to severe flares; this study 
enrolled participants with moderate to high disease activity (41/72 
participants with ≥ 6 SLEDAI at baseline) (50). 
In summary, the findings of these studies suggest that vaccines are generally safe 
and well tolerated by persons with SLE, but that safety concerns do exist and that 
careful study design, recruiting of participants with low disease activity at 
baseline, and monitoring is important. 
The most commonly used adjuvant for vaccines in the studies referenced above 
was alum. Until recently, alum was the only adjuvant licensed for use in the US 
(78), and alum remains the most commonly used adjuvant for recommended 
vaccines in the US for children (79) and adults (80). Studies in murine models of 
SLE have suggested that alum could exacerbate SLE-like disease (81), but studies 
in humans are limited. Direct study of the effect of vaccines in patients with 
autoimmune disease has focused on safety and immunogenicity measures, 
particularly in light of increased use of immunosuppressant medications in the 
treatment of autoimmune disease. An observational study of 218 autoimmune-
disease patients immunized against influenza detected a slight increase in 
autoantibodies, although the findings were not statistically significant (82); data 
from this study suggested that anti-cardiolipin antibodies may have transiently 
risen, but that they subsequently fell below baseline levels upon 6-month follow-
up (82). Another observational study of 1,668 patients found that influenza 
vaccination was immunogenic and that moderate and severe side effects were not 
observed, but that vaccine response was blunted in patients with autoimmune 
disease (66). A Serbian study of autoimmune disease patients noted that 
47 influenza-immunized patients had a decreased incidence of respiratory 
infections compared with 52 unimmunized patients; no increase in underlying 
autoimmune phenomena were observed (38). 
The HIV-1 vaccine product to be used in this clinical trial (AIDSVAX® B/E 
consisting of envelope (Env) gp120 of HIV MN clade B and HIV A244 clade 
CRF01_AE) is formulated in alum, and was previously used in other large-scale 
human trials, including RV144, the large-scale efficacy trial of AIDSVAX® B/E 
among 16,402 healthy men and women in Thailand, and VAX003, an efficacy 
trial of AIDSVAX® B/E among 2,527 injection drug users in Thailand (22, 33). In 
RV144, 2 participants (of 16,402 total) developed autoimmune disease while 
enrolled and both received at least part of the complete vaccine regimen (Kim JH 

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and Haynes BF, unpublished observations). One participant who developed 
immune thrombocytopenic purpura more than one year after the complete vaccine 
regimen did not have detectable autoantibodies before or after the vaccination 
schedule. The other participant was diagnosed with SLE during the course of the 
vaccine regimen and had antibodies against Sjögren's syndrome A (SSA) 
(value 215) and centromere B before vaccination; this participant was positive 
only for SSA (value 142) after vaccination, showing that the vaccine product to be 
used in this protocol did not induce autoantibodies in these susceptible subjects. 
However, the second individual was diagnosed with SLE after 3 vaccinations with 
a live canarypox (ALVAC) vector and one vaccination with B/E gp120, and the 
final trial ALVAC/AIDSVAX immunization was not given. Importantly, neither 
participant experienced any vaccine-related adverse events (AEs). In this study, 
no live vector vaccines will be used, only AIDSVAX® B/E protein formulated 
with alum. This study plan is consistent with vaccine guidance for participants 
with SLE and will use both an HIV-1 immunogen and adjuvant with the greatest 
amount of safety data in human participants. 
One important outcome of this trial will be a prospective assessment of the effect 
of this alum-adjuvanted vaccine on immune system activation in SLE patients. 
We plan to assess this using state of the art assays including systemic cytokine 
measurements, immune cell phenotyping, and single cell sorting of B and T cells 
to quantify vaccine-induced transcripts. Immune cell activation will be assessed 
by quantitative polymerase chain reaction (qPCR). We plan to assess changes to 
the frequency and activation state of both B and T cell populations for this cohort 
and a group of historical control subjects drawn from a prior study of this vaccine 
formulation—specifically, RV328, a phase I/II trial assessing the immunogenicity 
of AIDSVAX® B/E among 40 HIV-uninfected individuals in Thailand. Data 
obtained for the safety and immune activation outcomes in RV328 will be 
compared to the AE reports and immunogenicity data obtained in this study, to 
compare the effects of alum-adjuvanted vaccine administration between healthy 
subjects and SLE patients. After correction for multiple comparisons, this small 
study will not be able to detect statistically significant differences between those 
with SLE and the historical controls. In addition, this study is not powered to 
identify rare safety events. However, this study will provide a first and critical 
dataset for participants with SLE to which future HIV-1 vaccine/adjuvant 
candidates can be compared. In addition, differences observed in this study will 
provide a dataset to help guide development of future studies and for the 
assessment of future vaccine candidates in patients with SLE. Given the 
importance of vaccines in prevention of disease in SLE patients (31, 32, 34, 35, 
83), these data will fill a critical gap in current knowledge and inform risk 
assessments of current and future vaccines. By using the non-replicating 
component of the only HIV-1 vaccine regimen to have shown any efficacy in 
preventing HIV-1 transmission, we will obtain information about alum-
adjuvanted vaccine immune activation in persons with SLE, and also assess how 
individuals with SLE can respond to a protein-based HIV-1 vaccine. 

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4.1.3 
Potential impact of this study on development of future HIV-1 
vaccine candidates 
This trial aims to provide information that will inform vaccine design for people 
who do not have SLE by quantifying the effect that altered immune tolerance has 
on HIV-1 bnAb development. It has been observed that bnAbs against HIV-1, and 
specifically antibodies reactive with many different virus subtypes, are not made 
by the majority of infected patients. When such antibodies are made, they usually 
occur after several years of infection (84). These bnAbs have a number of 
characteristics commonly found in autoantibodies, such as long and hydrophobic 
antigen binding loops, high levels of somatic mutation, and/or polyreactivity with 
human antigens (85). Antibodies with these characteristics are usually under 
tolerance control during B cell development and maturation (9, 12, 15), and 
antibodies reactive with self-antigens are commonly found in patients with defects 
in immune tolerance (eg, autoimmune diseases such as SLE) (86, 87). 
Importantly, studies with bnAb knock-in mice have shown that indeed some 
bnAbs are directly eliminated by numerous tolerance mechanisms including 
deletion, anergy and receptor editing (9, 15, 17). 
In addition, several investigators have noted an underreporting of coincident SLE 
and HIV-1 infection (10, 29, 88, 89) and early in the HIV-1 epidemic it was 
speculated that antibody responses in SLE may be protective against HIV-1 
infection (11). To date, there have been no prospective studies of either HIV-1 
infection or vaccination in patients with autoimmune diseases; thus, whether 
patients with autoimmune diseases can make qualitatively or quantitatively better 
responses to HIV-1 vaccine antigens, or to any other type of vaccine, is unknown. 
There are, however, data that suggest SLE could be permissive for the 
development of bnAbs against HIV-1. In mouse studies of bnAb development, 
B cells expressing these antibodies were subject to strict tolerance control (15, 
17). BnAb 2F5 was shown to react with a human antigen; mice that have the same 
antigenic epitope restrict the creation of 2F5-epitope specific antibodies while 
opossums that lack the same epitope are not restricted (90). Taken together, these 
data suggest that some bnAbs are under similar tolerance controls in humans and 
would be difficult to elicit with vaccines (9, 12, 18). This is corroborated by the 
fact that none of the large-scale HIV-1 vaccine trials in humans have elicited 
bnAbs (91). In order to make an effective vaccine against HIV-1, we must 
determine the roadblocks and potential solutions in order to guide future vaccine 
development. If patients with SLE are capable of making a better antibody 
response after HIV-1 vaccination, this will suggest that modulation of tolerance 
may be required to induce those kinds of responses in people without autoimmune 
disease. 
In support of this idea, a recently published study has shown that the development 
of bnAbs by individuals with chronic HIV-1 infection is associated with the 
presence of plasma autoantibodies and with a lower frequency of regulatory 
CD4+ T cells, a higher frequency of circulating memory T follicular helper (Tfh) 
CD4+ cells, and a higher T regulatory (Treg) cell level of programmed cell death–

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1 expression (92). This vaccine trial in participants with SLE will allow us to 
assess for these same alterations of T cell populations in this group of vaccine 
recipients. The data generated by this study will provide critical information as to 
whether naturally occurring variations in immune tolerance control, as exist in 
SLE, are permissive for bnAb development. 
Thus, a critical question to be posed by this vaccine study is whether the 
AIDSVAX® B/E immunogen can induce nAbs in patients with known SLE and 
whether these antibodies can block infection in vitro. This is particularly 
important to test for the AIDSVAX® B/E immunogen, as it was part of the 
vaccine regimen that induced a modest degree of protection in the RV144 trial 
(22). Of note, the two participants in RV144 who developed autoimmune disease 
were studied and did not develop neutralizing breadth in any of the samples 
tested. Neither were followed beyond the end of the study, and neither were 
recruited into the follow-on studies, so data collected in this study could provide 
valuable information about the effects of altered immune tolerance on HIV 
vaccine immunogenicity. If bnAbs are produced by any SLE patients in this 
study, we will further evaluate the effect of altered immune tolerance on their 
production.  By measuring potential genetic influences, the specific cytokine 
milieu, differences in B-cell and T-cell populations, differences in innate 
immunity, etc., we can attempt to assess for differences that might exist between 
SLE patients who develop bnAbs and healthy patients who do not.  If we are able 
to determine what is different in those with SLE, we can try simulating these 
differences in animals to evaluate whether specific interventions with specific 
effects on immune tolerance induce bnAb development in healthy (non-
autoimmune) animals, and—if successful—work towards implementing similar 
regimens in humans. The results of this study could help guide the development 
of future vaccine candidates and adjuvant systems that could induce such 
responses in the general population. 
4.2 
AIDSVAX® B/E 
AIDSVAX® B/E is a bivalent HIV gp120 glycoprotein originally developed and 
manufactured by Genentech Inc. The development and manufacturing rights were 
subsequently transferred to VaxGen, Inc. and finally transferred to its current 
developer, GSID. It is a purified mixture of gp120 proteins produced by 
recombinant DNA procedures using Chinese hamster ovary (CHO) cell 
expression. The sequences of MN gp120/HIV-1 and A244 gp120/HIV-1 are 
expressed as fusion proteins where a 27 amino acid sequence found in the 
glycoprotein D (gD) of herpes simplex virus type 1 is fused to the amino terminus 
of each protein. MN and A244 rgp120/HIV-1 are combined to produce the 
bivalent AIDSVAX® B/E vaccine. AIDSVAX® B/E encompasses both subtype B 
(MN) and subtype E (A244) proteins that are adsorbed onto 600mcg of aluminum 
as aluminum hydroxide gel suspension as adjuvant. 

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4.3 
Trial design rationale 
In this study, 16 eligible participants, who have a physician-confirmed diagnosis 
of SLE as defined by the classification criteria established by the ACR (86, 87) 
and who are free of HIV-1 infection, will be administered three doses of alum-
adjuvanted AIDSVAX® B/E. This will be an open-label single arm study. 
AIDSVAX® B/E has an extensive safety history in clinical trials (93, 94). Given 
this, as well as the knowledge that no prior AIDSVAX® B/E vaccinees have 
developed HIV-1 bnAbs, the inclusion of a concurrent non-SLE control group is 
not felt to be necessary. We expect that all participants without autoimmune 
disease in a control arm would have a similar response and not produce bnAbs; 
we do not expect a concurrent control arm of healthy participants to provide 
additional information beyond what can be obtained with historical controls. The 
study group will therefore be compared with an historical control group 
comprised of non-SLE subjects previously enrolled in RV328, a similar study 
assessing immunogenicity of AIDSVAX® B/E administered at the same time 
points as proposed in this study (Day 0 and Months 1 and 6), plus additional later 
time points not proposed in this study. 
With regards to RV328, an analysis of all participants found that 0/40 participants 
(30 vaccinated with AIDSVAX® B/E, 10 with placebo) developed neutralization 
breadth. Given the small study size, we will include all 30 AIDSVAX® B/E 
vaccinees in the historical control group. As previously noted, RV328 was 
performed in Thailand, and thus cannot be matched for ethnicity or country of 
origin. 
As part of the original Center for HIV-AIDS Vaccine Immunology 
(CHAVI)program, the CHAVI 005 study examined a group of participants with 
known autoimmune disease to determine if any had undiagnosed HIV-1 infection, 
and if their plasma had any evidence of existing neutralizing antibodies that could 
account for the previously noted disparity between SLE and HIV-1 infection. This 
cohort, including 100 participants without autoimmune disease and 125 
participants with SLE, was recruited from the Duke Lupus Clinic between 2005-
2011. The CHAVI program tested this cohort using both HIV-1 antibody and 
viral load assays and found that none of the participants were HIV-1-infected. 
Testing of a subset of the participants did not reveal evidence of HIV-1 
neutralizing antibodies or reactivity with HIV-1 Env proteins, although it should 
be noted that the study participants did not receive any HIV-1 vaccinations. 
Samples from this study are available for testing using the same assays planned 
for the present study, and for all participants, there are plasma, serum, and PBMC 
stored in the CHAVI Repository. This cohort was drawn from the same patient 
population at Duke that will be recruited for this study, and because the second of 
two sites participating in this study is in Alabama, the demographics of the two 
populations is likely to be similar. We can therefore use the SLE patients in the 
CHAVI 005 study as unvaccinated SLE controls, serving as a cross-sectional 
comparison group. 

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The primary outcome is to evaluate whether persons with SLE vaccinated with an 
HIV-1 vaccine will develop HIV-1 nAbs with greater breadth and potency than 
persons without SLE. In addition, our immunogenicity hypotheses are that this 
cohort of participants with SLE will make a qualitatively and quantitatively 
superior antibody response against HIV-1. An additional secondary outcome will 
address the hypothesis that the vaccine regimen will be safe and well tolerated by 
participants. The proposed number of participants is not sufficiently powered to 
detect uncommon or rare events. Participants will be monitored for sentinel events 
indicative of SLE disease activation (ie, SLE flare); detection of an SLE flare will 
trigger additional review.  
4.3.1 
Dose (amount and number) 
The AIDSVAX® B/E dose of 600 mcg / 1 mL is the same as was used in the 
RV328, RV144 (22) and VAX003 (33) trials. The sequence of AIDSVAX® B/E 
immunizations is similar to that given in all three of these trials, however, we 
have reduced the number of vaccinations to three (3) to reduce the time needed 
for completion of the study. 
4.3.2 
Schedule 
The schedule for AIDSVAX® B/E was chosen to be consistent with, but shorter 
than, the schedule used in RV328, RV144 (93) and VAX003 (33). The present 
study will only use the first 3 immunization timepoints: Day 0 and Months 1 and 
6. 
4.4 
Clinical studies 
4.4.1 
AIDSVAX® B/E 
The AIDSVAX® B/E (HIV B.MN gp120/HIV AE.A244) gp120 vaccine 
preparation used in this study has been used in 3 phase 3 human studies (22, 33, 
95). In these trials, more than 9000 participants received the vaccine product. In 
all trials, this vaccine was found to be safe and well tolerated, with observed 
adverse vaccine reactions being primarily local reactogenicity (eg, pain or 
inflammation at the injection site). Other reported side effects of this vaccine 
include induration, erythema, edema, and subcutaneous nodules at the injection 
site. Systemic side effects include headache, rash, fever, fatigue, malaise, 
myalgia, or allergic reactions. Administration of related vaccine preparations have 
been given to 287 HIV-1–infected individuals without evidence of adverse 
outcome (96). 
One serious adverse event (SAE) was reported in the phase I/II trial, RV328, 
conducted more recently in Thailand. It was deemed related to AIDSVAX® B/E 
vaccine. A participant developed a case of severe hypersensitivity reaction after 
receiving the 4th and final dose of AIDSVAX® B/E. Within 3 minutes of 
receiving the vaccine, the participant developed a generalized pruritic rash, facial 

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swelling, and malaise, but had no difficulty breathing or hypotension. This 
individual had received 3 prior vaccinations with AIDSVAX®B/E with no 
concomitant symptoms. The participant was treated and recovered completely 
within a few hours. 
In one of the phase 3 studies of this vaccine, VAX003, the vaccine product was 
injected 7 times over the course of the protocol (at months 0, 1, 6, 12, 18, 24, and 
30). This protocol (HVTN 121) has a planned course of 3 vaccinations, thus this 
study will not exceed the prior experience with AIDSVAX® B/E. 
Prior vaccine studies using AIDSVAX® B/E did not induce bnAbs either 
following canarypox priming, as in the RV144 trial (22), or when administered 
alone, as in the VAX003 trial (33). In these 2 studies, nAbs were restricted to 
easy-to-neutralize (tier 1) isolates from clade AE circulating recombinant form 
CRF01_AE (91). Antigenicity studies of the AIDSVAX® B/E immunogen have 
shown that Env variable loop 1 and 2 (V1V2) glycan bnAbs such as PG9 and 
CH01 bind readily to epitopes expressed on the AE.A244 gp120 vaccine 
components, and the putative naïve B cell receptor of the CH01 bnAb lineage also 
binds well to the AE.A244 gp120 (97). Thus, the AIDSVAX® B/E immunogen is 
antigenic for V1V2 bnAbs, but no plasma V1V2 bnAb activity was induced in the 
RV144 vaccine trial (91). Thus, a secondary hypothesis to be tested in this trial is 
whether the AIDSVAX® B/E immunogen can induce V1V2 glycan nAbs when 
administered to trial participants with SLE. 
Intriguingly, another vaccine trial (VAX003) administered the same AIDSVAX® 
B/E immunogen used in the boost phase of RV144 and produced robust Env 
antibody responses that were higher than those seen in RV144 (33). Despite these 
responses, VAX003 did not prevent HIV-1 acquisition in a high-risk population 
of intravenous (IV) drug users in Thailand. It has recently been found that the use 
of ALVAC and a prime and boost in RV144 induced higher levels of IgG3 Env 
antibodies than in VAX003 and these IgG3 antibodies against V1V2 correlated 
with decreased transmission risk (98). Thus, the RV144 vaccine may have been 
protective because of induction of IgG3 V1V2 responses, but efficacy was limited 
by minimal potency and short duration of the induced antibody responses (98). 
These data would suggest that ALVAC priming may be required for V1V2 
responses in adults lacking autoimmune disease, thus it will be important to 
carefully assess for these responses in patients with SLE receiving AIDSVAX® 
B/E. Furthermore, given concerns over the use of live vector vaccines in patients 
with SLE (31, 32), determining whether AIDSVAX® B/E alone can elicit V1V2 
responses will guide the deployment of future HIV-1 vaccine candidates in this 
vulnerable population. 
4.5 
Potential risks of study products and administration 
The vaccine has been extensively tested in healthy populations. Prior work has 
shown that vaccination of autoimmune disease patients with killed or subunit 
vaccines are generally well tolerated (99).  

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Table 4-1 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 or exacerbation of 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 
* See section 4.1.2 for a review of studies evaluating other vaccines in people with SLE and the potential for 
exacerbation of autoimmune disease. There are no prior studies evaluating AIDVAX B/E® in participants 
with SLE or other autoimmune disease, and therefore the risk of exacerbating autoimmune diseases is 
unknown for this study vaccine.  

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5 
Objectives and endpoints 
5.1 
Primary objectives and endpoints 
Primary objective 1:  
To evaluate the breadth and potency of HIV-1 nAb responses 
Primary endpoint 1:  
Response rates, magnitude and breadth of nAb responses to the vaccine strains 
and a global panel of heterologous env-pseudotyped viruses at baseline and two 
weeks after the third vaccination 
Primary objective 2:  
To examine the safety and tolerability of AIDSVAX® B/E in a population of 
participants diagnosed with SLE who have stable disease 
Primary endpoints 2:  
• Frequency and severity of local and systemic reactogenicity signs and 
symptoms 
• Laboratory measures of safety: white blood cells (WBC), neutrophils, 
lymphocytes, hemoglobin, platelets, ALT, complement, anti-dsDNA titers, 
urinalysis and spot urine protein:creatinine ratio 
• Frequency of adverse events categorized by Medical Dictionary for 
Regulatory Activities (MedDRA) System Organ Class, and MedDRA 
Preferred Term, severity and assessed relationship to study products; detailed 
description of all AE meeting DAIDS criteria for expedited reporting 
• Measures of SLE disease activity and functional status: Safety of Estrogens in 
Lupus Erythematosus National Assessment-SLE Disease Activity Index 
(SELENA-SLEDAI) and Routine Assessment of Patient Index Data 
(RAPID3) 
5.2 
Secondary objectives and endpoints 
Secondary objective 1: 
To characterize isolated antibodies for evidence of HCDR3-binding CD4 binding 
site bnAb lineages elicited by the vaccine 
Secondary endpoint 1: 

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The degree of somatic hypermutation, length of antibody binding loops and 
germline gene usage in participants with SLE compared with historical controls 
after the third vaccination 
Secondary objective 2: 
To assess the induction of bnAb precursors  
Secondary endpoint 2: 
NAb responses to viruses with altered glycosylation, indicative of bnAb 
precursors, at baseline and two weeks after the second and third vaccinations 
Secondary objective 3: 
To determine the effect of an HIV vaccine on immune system activation  
Secondary endpoint 3: 
Vaccine-induced immune activation as assessed by serum cytokine analysis and B 
and T cell phenotyping, as well as expression of Treg and Tfh markers one week 
after the second and third vaccinations 
Secondary objective 4: 
To evaluate the level of HIV-1–specific binding antibody production in response 
to vaccination  
Secondary endpoint 4: 
Response rate and magnitude of HIV-1–specific IgG binding antibodies at 
baseline and two weeks after the second and third vaccinations 
Secondary objective 5: 
To further characterize the epitopic specificity of HIV-1 binding antibodies  
Secondary endpoint 5: 
Specificity of antibody responses by epitope mapping of functional and binding 
antibodies two weeks after the second and third vaccinations 
Secondary objective 6: 
To determine whether CD4+ T-cell responses are associated with the observed 
antibody responses 
Secondary endpoint 6: 

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Response rate, magnitude and polyfunctionality of Env-specific CD4+ T cells 2 
weeks after the third vaccination 
5.3 
Exploratory objectives 
Exploratory objective 1: 
To determine the breadth and potency of the antibody-dependent cellular 
cytotoxicity (ADCC)-mediating antibody response against HIV-1 to vaccination  
Exploratory objective 2: 
To determine if there are common genetic mutations in this group of SLE 
participants  
Exploratory objective 3: 
To further evaluate immunogenicity of the vaccine regimen, additional 
immunogenicity assays may be performed, including on samples from other 
timepoints 
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 for this single arm study will target enrolling 16 low-risk, HIV-
uninfected adult participants, aged 18-50, who have also been diagnosed with 
SLE. 
The primary purpose of this study is to explore the possibility that AIDSVAX® 
B/E may induce bnAbs in a population of participants diagnosed with SLE and to 
closely monitor participant safety. Since enrollment is concurrent with receiving 
the first study vaccination, all participants will provide some safety data. 
However, for immunogenicity analyses, it is possible that data may be missing for 
various reasons, such as participants terminating from the study early, problems in 
shipping specimens, low cell viability of processed peripheral blood mononuclear 
cells (PBMCs). Immunogenicity data from 17 phase 1 and 2 phase 2a HVTN 
vaccine trials, which began enrolling after June 2005 (data as of September 2014), 
indicate that 15% is a reasonable estimate for the rate of missing data at day 182. 
For this reason, the sample size calculations in Section 6.1.2 account for 15% of 
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. This participant population is at risk for at 
least two different categories of AEs—vaccine-related reactogenicity (or other 
side effects) and the development of a flare of SLE disease activity. For this 
reason, we will treat these events separately for the following calculations. 
6.1.1.1 
Vaccine-related AEs 
The ability of the study to detect SAEs (see Section 11) can be expressed by the 
true event rate above which at least 1 SAE would likely be observed and the true 
event rate below which no events would likely be observed. Specifically, for the 
vaccine arm of the study (n = 16), there is an 81.5% chance of observing at least 1 
event if the true rate of such an event is 10% or more; and there is an 85.1% 
chance of observing no events if the true rate is 1% or less. 
Probabilities of observing 0, 1 or more, and up to 5 or more events among arms of 
size 16 are presented in Table 6-1 for a range of possible true AE rates. These 
calculations provide a more complete picture of the sensitivity of this study design 
to identify potential safety problems with the vaccine. 
 

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Table 6-1 Probability of observing 0 events, 1 or more events, and up to 5 or more events, 
among arms of size 16, for different true event rates 
True event rate 
(%) 
Pr(0/16) 
Pr(1+/16) 
Pr(2+/16) 
Pr(3+/16) 
Pr(4+/16) 
Pr(5+/16) 
1 
0.851 
0.149 
0.011 
0.001 
0 
0 
5 
0.440 
0.560 
0.189 
0.043 
0.007 
0.001 
10 
0.185 
0.815 
0.485 
0.211 
0.068 
0.017 
For this study, suspected adverse reactions are any AEs for which there is a 
reasonable possibility that the vaccine caused the event, suggesting a causal 
relationship. Using exponential hazard time-to-event methods in simulation 
(N = 1000), if there is a 5% chance per year of a related non-serious AE, we 
would be expected, on average, to have 0.8 incidents (95% CI: <1, 2.5) during the 
12 months of follow-up in this study. If the AE rate is 7.5%, we would expect, on 
average, to have 1.1 events (95% CI: <1, 3.2); if the AE rate is 10%, we would 
expect, on average, to have 1.6 events (95% CI: <1, 3.9). 
6.1.1.2 
Flare of SLE disease activity 
This subject cohort may be expected to have an SLE flare rate as high as 20% 
(defined as an increase of 4 or more in SLEDAI (100) between study visits), 
indicating that a more conservative threshold is appropriate. For example, if we 
base the expected SLE flare rates on the control arm of Ruiz-Irastorza et al (101), 
where the monthly percentage of patients with flares was 3.9%, we expect a 
possibly higher rate of SLE flare than that described above. Using exponential 
hazard time-to-event methods in simulation (N = 1,000), if there is a 3.9% chance 
per patient-month of flare, we would be expected, on average, to have 6.1 
incidents (95% CI 2.1, 10.1) per year of follow-up in this study. If flare events are 
independent, then there is 14.4% chance of a participant having 2 flare events in 
one year. 
6.1.2 
Sample size calculations for immunogenicity 
The primary immunogenicity endpoint will be the production of bnAbs. This will 
be defined as a nAb geometric mean titer (GMT) greater than 100 against a 
standard HIV-1 pseudovirus panel. The sample size of 16 was selected such that if 
the true proportion of participants producing bnAbs in this population is at least 
10 percent, we will have 81.5% probability of detecting bnAbs in at least one 
participant. If there is a dropout rate of 10% then we will still have a 77.1% 
probability of detecting bnAbs in at least one participant (Table 6-2). 

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Table 6-2 Probability of detecting bnAbs in at least one participant, among different arm 
sizes, for different true event rates 
Number of 
Participants 
True Population Percentage of SLE Participants Producing BnAbs 
1% 
5% 
10% 
25% 
12 
0.114 
0.460 
0.718 
0.968 
14 
0.131 
0.512 
0.771 
0.982 
16 
0.149 
0.560 
0.815 
0.990 
18 
0.165 
0.603 
0.850 
0.994 
6.2 
Randomization  
Since there is only one treatment assignment in this study, participants will not be 
randomized. 
6.3 
Statistical analyses 
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 or multiple primary immunogenicity 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). 
6.3.1 
Analysis variables 
The analysis variables consist of baseline participant characteristics, safety, and 
immunogenicity for primary- and secondary-objective analyses. 
6.3.2 
Baseline comparability 
Selection of historical controls from RV328 that were vaccinated and underwent 
immunogenicity testing on a similar timeline will serve as a suitable non-SLE 
control group. Although, given the small study population (40 total), all 30 who 
received AIDSVAX® B/E will be included as comparators. 
The 125 SLE patients in the CHAVI 005 study, with similar demographic 
characteristics to this study population, will serve as a cross-sectional, 
unvaccinated SLE control group for immunogenicity comparisons.  
6.3.3 
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. 

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6.3.3.1 
Reactogenicity 
The number and percentage of participants experiencing each type of 
reactogenicity sign or symptom will be tabulated by severity 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. 
6.3.3.2 
AEs and SAEs 
AEs will be summarized using MedDRA System Organ Class and preferred 
terms. Tables will show 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. 
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.  
6.3.3.3 
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 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 study 
cohort 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 (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events (Section 9.8) will be tabulated for each postvaccination timepoint. 
Reportable clinical laboratory abnormalities without an associated clinical 
diagnosis will also be included in the tabulation of AEs described above. 
6.3.3.4 
SELENA-SLEDAI 
Box plots will be generated for baseline values and for values measured during 
the course of the study. Each box plot will show the first quartile, the median, and 
the third quartile. Outliers (values outside the box plot) will also be plotted. Each 
participant’s points will be connected with a line. Summary statistics will be 
presented by study cohort and timepoint. A listing of participants who discontinue 
vaccination due to related SLE flares (of any severity), as defined in Appendix G 
and Section 7.3.3, will also be produced. 

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6.3.3.5 
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. 
6.3.4 
Immunogenicity analysis 
The primary immunogenicity analysis of the study will be to evaluate the 
magnitude and breadth of nAb responses and as secondary objective to evaluate 
immune system activation in individuals with SLE. 
6.3.4.1 
General approach 
For the statistical analysis of immunogenicity endpoints, data from enrolled 
participants will be used regardless of how many injections they received. 
Additional analyses may be performed, limited to participants who received all 
scheduled injections per protocol. 
Discrete categorical assay endpoints (eg, response rates) will be analyzed by 
tabulating the frequency of positive response for each assay by antigen 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 exact method (102).  
For quantitative assay data (eg, cytokine quantification by Luminex assay), 
graphical and tabular summaries of the distributions by antigen, timepoint will be 
made. Additionally, comparisons to controls selected from other studies may be 
made by treatment group. For all primary and secondary immunogenicity 
endpoints, box plots and plots of estimated reverse cumulative distribution curves 
will be used for graphical display. 
6.3.4.2 
Primary analyses of neutralization breadth and magnitude 
The area-under-the-magnitude-breadth curve (AUC-MB) to a global panel of 
isolates (103) will be computed for each participant with evaluable neutralization 
data, as described in (104). Participant-level AUC-MB may also be computed for 
the historical controls, ideally based on the same global panel of isolates. The 
95% CIs about the mean-differences in AUC-MBs between study cohorts will be 
reported. Regression models may be used to compare the AUC-MB between 
study cohorts, accounting for potential confounding factors such as age, gender, 
or other immune responses etc.  
The analyses of magnitude-breadth described above are based on the endpoint 
area-under-the-curve, which is interpreted as the average log10 IC50 to the set of 
isolates in the test panel. Use of this endpoint is maximally statistically powerful 
if one study cohort has greater magnitude and breadth than the comparator study 
cohort, but may miss an effect wherein one study cohort has greater magnitude 
and the comparator has greater breadth. Therefore, a secondary analysis may 
compare the distribution of magnitude-breadth curves among cohorts using the 

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test statistic max|BdG| from Huang, et al (104), which is designed to detect general 
differences in magnitude-breadth curve distributions.  
In addition, the geometric mean titers of Nab responses across a panel of isolates 
will be computed to determine the presence of bnAbs. 
6.3.4.3 
Analyses of immune activation 
Box plots of systemic cytokines, B and T cell populations, and B and T cell 
activation will be generated for baseline values and for values measured during 
the course of the study by 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. 
For each assessment of immune activation, summary statistics will be presented 
by timepoint, as well as changes from baseline for postenrollment values. 
6.3.4.4 
Multivariate display of immunogenicity endpoints 
Data visualization techniques may be used to explore the relationship among 
immunogenicity readouts. The set of readouts may be based on one of the primary 
endpoints (eg, nAb), on the set of primary endpoints, or on immunogenicity 
endpoints that also include secondary or exploratory endpoints. To understand the 
relationship between pairs of readouts, scatter plots may be used when the number 
of readouts is small or for a larger number of readouts, a heatmap showing the 
degree of correlation between any two pairs. Principal component analysis (PCA) 
and associated ‘biplots’ of the scores and loadings are particularly useful to 
understand associations between readouts, especially when readouts are 
correlated. 
6.3.5 
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.  
6.3.5.1 
Safety 
During the course of the trial, 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 121 PSRT.  
6.3.5.2 
Immunogenicity analyses 
This is an open label vaccine study for which immunogenicity, as measured by 
neutralization GMT against a standard panel of HIV-1 pseudoviruses, is a primary 
endpoint of the study. In addition, there are immunogenicity secondary endpoints, 
and statistical analysis of the secondary immunogenicity endpoint(s) may be 
performed during the course of the study. Every effort will be made to reduce bias 

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by not performing early analysis of samples from this study. Where possible, 
analyses of these secondary endpoints will be performed when all participants 
have completed the corresponding final immunogenicity visit and data are 
available for analysis from at least 80% of these participants. 
The Laboratory Program will review the analysis report prior to distribution to the 
protocol chairs, DAIDS, study product developer, and other key HVTN members 
and investigators. Reports for distribution or presentation should use pubIDs and 
not PTIDS for individual responses. Distribution of reports will be limited to 
those with a need to know for the purpose of informing future trial-related 
decisions. The HVTN leadership must approve any other requests for HVTN 
immunogenicity analyses prior to the end of the scheduled follow-up visits. 

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7 
Selection and withdrawal of participants 
Participants will be low-risk, HIV-uninfected (seronegative) adults, who have 
been diagnosed with SLE, who comprehend the purpose of the study and have 
provided written informed consent. Potentially eligible participants will be 
identified in collaboration with rheumatology clinic(s) and through community 
advertising, and will then be screened by an initial interview. Volunteers will be 
recruited and screened; those determined to be eligible, based on the inclusion and 
exclusion criteria, will be enrolled in the study. Final eligibility determination will 
depend on results of laboratory tests, medical history, physical examinations, 
answers to self-administered and/or interview questions and review of medical 
records as appropriate. 
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 28 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. Weight > 110 pounds 
3. Meets ACR criteria for the classification of SLE (86, 87, 105) with serologic 
evidence of disease including a positive test for antinuclear antibodies at a titer of 
1:640 or greater, or the presence of a positive test for antibodies to dsDNA, or the 
presence of anti-Sm, anti-RNP, or anti-Ro antibodies, as documented by medical 
records and as assessed by a rheumatologist or designee. 
4. Currently taking hydroxychloroquine for SLE and for at least 6 months prior to 
enrollment 
5. Access to a participating HVTN CRS and willingness to be followed for the 
planned duration of the study 
6. Ability and willingness to provide informed consent 

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7. Allows ongoing access to medical records pertaining to their rheumatologic 
disease 
8. Assessment of understanding: volunteer demonstrates understanding of this 
study; completes a questionnaire prior to first vaccination with verbal 
demonstration of understanding of all questionnaire items answered incorrectly 
9. Agrees not to enroll in another study of an investigational research agent before 
the last required protocol clinic visit 
HIV-Related Criteria: 
10. Willingness to receive HIV test results  
11. Willingness to discuss HIV infection risks and amenable to HIV risk reduction 
counseling.  
12. 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 (see Appendix H) 
Laboratory Inclusion Values 
Hemogram/Complete blood count (CBC) 
13. Hemoglobin ≥ 11.0 g/dL for volunteers who were assigned female sex at 
birth, ≥ 12.0 g/dL for volunteers who were assigned male sex at birth. 
14. White blood cell count = 2,500 to 12,000 cells/mm3 
15. Total lymphocyte count ≥ 800 cells/mm3 
16. Remaining differential either within institutional normal range or with site 
physician approval 
17. Platelets = 100,000 to 550,000/mm3 
Chemistry 
18. Chemistry panel: alanine amino transferase (ALT) and aspartate 
aminotransferase (AST) < 1.25 times the institutional upper limit of normal; 
creatinine ≤ institutional upper limit of normal. 
Virology 
19. Negative HIV-1 and -2 blood test: volunteers must have a negative FDA-
approved enzyme immunoassay (EIA) within 56 days prior to enrollment. 

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20. Negative Hepatitis B surface antigen (HBsAg) within 56 days prior to 
enrollment 
21. Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV 
polymerase chain reaction (PCR) if the anti-HCV is positive within 56 days prior 
to enrollment 
Urine 
22. Normal urine by urinalysis: 
• Negative urine glucose, and 
• Negative or trace urine protein, and 
• Red blood cell (RBC) levels within institutional normal range, and 
• No RBC casts 
Reproductive Status 
23. Volunteers who were assigned female sex at birth: negative serum or urine beta 
human chorionic gonadotropin (β-HCG) pregnancy test in accordance with local 
regulatory requirements, 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. 
24. Reproductive status: A volunteer who was assigned female sex at birth must: 
• Agree to use effective contraception for sexual activity that could lead to 
pregnancy from at least 21 days prior to enrollment through the last required 
protocol clinic visit. Effective contraception is defined as using the following 
methods: 
▪ Condoms (male or female) with or without a spermicide, 
▪ Diaphragm or cervical cap with spermicide, 
▪ Intrauterine device (IUD), 
▪ Hormonal contraception, or 
▪ Any other contraceptive method approved by the HVTN 121 PSRT 
▪ Successful vasectomy in any partner assigned male sex at birth 
(considered successful if a volunteer reports that a male partner has [1] 
documentation of azoospermia by microscopy, or [2] a vasectomy more 
than 2 years ago with no resultant pregnancy despite sexual activity 
postvasectomy); 

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• 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. 
25. Volunteers who were assigned female sex at birth must also agree not to seek 
pregnancy through alternative methods, such as artificial insemination or in 
vitro fertilization until after the last required protocol clinic visit 
7.2 
Exclusion criteria 
General 
1. Blood products received within 120 days before first vaccination  
2. Investigational research agents not used to treat SLE received within 30 days 
before first vaccination (additional exclusions may apply, see 13 below) 
3. 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 121 study  
4. Pregnant or breastfeeding 
5.  Active duty and reserve US military personnel 
SLE status. The following criteria must be verified by a rheumatologist or 
designee 
6. Currently with active lupus as defined by a Systemic Lupus Erythematosus 
Disease Activity Index (100) (SELENA-SLEDAI) > 4 (106) (see Appendix G). 
7. Documented SLEDAI score of > 20 in medical record at any time indicating 
severe activity (106), or evidence of moderate disease activity (SELENA-
SLEDAI > 6) within the last six months, (see Appendix G). 
8. Has had a condition listed on the Systemic Lupus International 
Collaborating Clinics/American College of Rheumatology Damage Index 
(SLICC/ACR DI) (105) or has had an increase in the SLICC/ACR D1 score 
within the last 12 months other than cataracts, premature ovarian failure or 
diabetes mellitus with approval of the PSRT 
http://www.clinexprheumatol.org/article.asp?a=2697 
9. A history of central nervous system (CNS) disease 

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10. Thrombotic event within the past 12 months in association with confirmed 
antiphospholipid antibody  
11. A history of renal disease (SLE-related renal injury) confirmed by prior biopsy, 
active urine sediment, or proteinuria 
12. Prednisone dose > 10 mg/day for more than 6 months within the past year 
13. Administration of anti-B-cell therapy (rituximab or belimumab) or any 
investigational research agents used to treat SLE within the preceding 2 years 
14. Administration of cyclophosphamide within the preceding year; or 
administration of mycophenolate mofetil within the last 6 months; or 
administration of methotrexate, leflunomide, or azathioprine within the last 3 
months 
15. Administration of any investigational immunosuppressant medication within 
the last year 
16. Administration of other immunosuppressive medications not listed above, 
with the exception of topical steroids, topical immunosuppressives (eg, 
cyclosporine, FK506), or ophthalmic immunosuppressives (eg, steroids, 
cyclosporine), within 6 months before first vaccination, unless approved by the 
HVTN 121 PSRT 
Vaccines and other Injections 
17. HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have 
received control/placebo in an HIV vaccine trial, the HVTN 121 PSRT will 
determine eligibility on a case-by-case basis. 
18. Non-HIV experimental vaccine(s) received within the last 5 years in a prior 
vaccine trial. Exceptions may be made by the HVTN 121 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 121 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 121 PSRT on a case-by-case basis. 
19. Vaccines received within 30 days before first study vaccination or scheduled 
within 30 days after injection (eg, influenza, tetanus, pneumococcal, Hepatitis A 
or B, measles, mumps, and rubella [MMR]; oral polio vaccine [OPV]; varicella; 
yellow fever) 
20. Allergy treatment with antigen injections within 30 days before first 
vaccination or that are scheduled within 14 days after first vaccination 
Immune System  

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21. Serious adverse reactions to vaccines or to vaccine components (such as yeast 
protein, amorphous aluminum hydroxyphosphate sulfate, L-histidine, polysorbate 
80, sodium borate), 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.) 
22. Immunoglobulin received within 60 days before first vaccination 
23. Immunodeficiency, such as common variable immunodeficiency 
Clinically significant medical conditions  
24. Ongoing bleeding or hemorrhage (excluding menstruation), or any subject on 
anticoagulant therapy 
25. Clinically significant medical condition, physical examination findings, 
clinically significant abnormal laboratory results, or past medical history with 
clinically significant implications for current health, other than SLE and its 
manifestations. 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. 
26. 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 
27. 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. 
28. Current anti-tuberculosis (TB) prophylaxis or therapy 
29. Asthma exclusion criteria: 

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Asthma other than mild, well-controlled asthma. (Symptoms of asthma severity 
as defined in the most recent National Asthma Education and Prevention Program 
(NAEPP) Expert Panel report).  
 
Exclude a volunteer who: 
• Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or 
• Uses moderate/high dose inhaled corticosteroids, or 
• In the past year has either of the following: 
▪ Greater than 1 exacerbation of symptoms treated with oral/parenteral 
corticosteroids; 
▪  Needed emergency care, urgent care, hospitalization, or intubation for 
asthma. 
30. Uncontrolled diabetes mellitus, Hb A1C > 7.0. (not excluded: history of 
isolated gestational diabetes.) 
31. Uncontrolled hypertension: 
• If a person has a history of hypertension, or is found to have elevated blood 
pressure or hypertension during screening, 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 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. 
32. Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or 
platelet disorder requiring special precautions) 
33. 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) 
34. Seizure disorder: History of seizure(s) within past three years. Also exclude if 
volunteer has used medications in order to prevent or treat seizure(s) at any time 
within the past 3 years. 

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35. Asplenia: any condition resulting in the absence of a functional spleen (not 
excluded: splenectomy for splenic trauma) 
36. 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 study product 
administration schedule. Pause rules for the trial are described in Section 11.3. 
7.3.1 
Delaying vaccinations for a participant 
Under certain circumstances, a participant’s scheduled vaccination will be 
delayed. The factors to be considered in such a decision include but are not 
limited to the following: 
• Within 45 days prior to any study injection  
▪ Receipt of blood products or immunoglobulin 
• Within 30 days prior to any study injection 
▪ Receipt of other vaccines (eg, influenza, tetanus, pneumococcal, Hepatitis 
A or B, MMR; OPV; varicella; yellow fever)  
▪ Receipt of allergy treatment with antigen injections 
• Prevaccination 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 121 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; for example, 
reactions to these substances could be misattributed to study product. Therefore, if 
circumstances allow, these substances should also be avoided in the 30 days after 
a study vaccination. 
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). 
However, missed vaccinations may be indicative of medical or social 
circumstances that indicate the participant should be excluded from future 
vaccination, and the study team should take this into account when assessing 
missed vaccinations. 
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 121 PSRT) 
• Clinically significant condition (ie, a condition that affects the immune system 
or for which continued vaccinations and/or blood draws may pose additional 
risk), including but not limited to the following: 
▪ Pregnancy (regardless of outcome) 
▪ HIV infection 
▪ Any grade 4 local or systemic reactogenicity symptom, lab abnormality, or 
AE that is subsequently considered to be related to vaccination 
▪ Any grade 3 lab abnormality that is subsequently considered to be related 
to vaccination 
▪ Other grade 3 clinical AE that is subsequently considered to be related to 
vaccination with the exception of fever, vomiting, and subjective local and 
systemic symptoms. For grade 3 injection site erythema and/or induration, 
upon review, the HVTN 121 PSRT may allow continuation of vaccination 
▪ SAE that is subsequently considered to be related to vaccination 
▪ Clinically significant type 1 hypersensitivity reaction associated with 
study vaccination. Consultation with the HVTN 121 PSRT is required 
prior to subsequent vaccinations following any type 1 hypersensitivity 
reaction associated with study vaccination 
▪ Related “Severe” SLE flare, as defined by application of the SELENA-
SLEDAI instrument (Appendix G) 
▪ SLE flare is defined clinically by a rheumatologist as severe enough to 
warrant discontinuation of vaccination 
▪ New use of mycophenolate mofetil 

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• Investigator determination in consultation with Protocol Team leadership 
(e.g., for repeated nonadherence to study staff instructions) 
Participants discontinuing study product for reasons other than HIV infection 
should be counseled on the importance of continuing with the study and strongly 
encouraged to participate in follow-up visits and protocol-related procedures per 
the protocol for the remainder of the trial, unless medically contraindicated (see 
HVTN 121 SSP). 
Participants diagnosed with HIV infection during the study should be encouraged 
to participate in follow-up visits as indicated in Section 9.12. 
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 is not possible, 
• HVTN CRS determines that the participant is lost to follow-up, or 
• Investigator decides, in consultation with Protocol Team leadership, to 
terminate participation (eg, if participant exhibits inappropriate behavior 
toward clinic staff). 
• Any condition where termination from the study is required by applicable 
regulations. 

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8 
Study product preparation and administration 
CRS pharmacists should consult the Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks for standard pharmacy operations. The protocol 
schema is shown in Table 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.  
AIDSVAX® B/E (600 mcg/mL) to be administered as a 1 mL IM injection into 
the deltoid of the non-dominant arm (unless medically contraindicated) at months 
0, 1, and 6. 
8.2 
Study product formulation 
Please refer to the IB for additional information about study product. 
AIDSVAX® B/E (labeled as AIDSVAX® B/E active (MN/A244 rgp 120/HIV-
1) is supplied as a 600mcg/mL sterile suspension in single-use glass vials with a 
volume to deliver 1 mL consisting of 300 mcg of subtype B (MN) HIV gp120 
glycoprotein and 300 mcg of subtype E (A244) HIV gp120 glycoprotein adsorbed 
onto a total of 600 mcg aluminum as aluminum hydroxide gel suspension as 
adjuvant. Product is a white to slightly grey suspension with possible product-
related particles. Some gel may be visibly adhering to the sides and neck of the 
vial and should be resuspended using the recommended protocol. The product 
must be stored upright and kept refrigerated (2° to 8°C). Do not freeze. Do not 
shake. 
8.3 
Preparation of study product 
8.3.1 
AIDSVAX® B/E 
One vial of AIDSVAX® B/E will be needed to prepare the dose. 
Prior to dispensing, the pharmacist will remove the study product from the 
refrigerator to allow the vial to equilibrate to room temperature for at least 20 
minutes. The pharmacist must then:  
1. Gently roll the vial horizontally between the palms or on a hard surface for 
approximately 10 seconds to wet the interior wall of the vial and to suspend 
the material.  

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2. Grasp the vial by the sides. Firmly and forcefully tap the bottom of the vial on 
a solid surface such that the vial hits squarely on a solid surface, in a rapid 
series of three (3) taps. Tap with enough force to dislodge any material that 
may be on the sides of the vial while using care not to chip or break the vial.  
3. Repeat the gentle rolling and forceful tapping two more times, resulting in one 
(1) cycle of 9 taps.  
4. Visually inspect the neck of the vial for presence or absence of product-related 
material (grayish film) as well as the sides of the vial. Vaccine that is stored at 
2°C to 8°C can form an appearance of a cloudy ring or ‘halo’ on the vial neck 
and/or have product related material adhering on the sidewalls. If either 
scenario is observed, the pharmacist should continue to follow the steps as 
directed below to dislodge and uniformly resuspend such product-related 
material.  
5. If residual product-related material still persists at the neck/sides of the vial at 
the end of the first cycle, repeat steps 1 to 4, for up to two (2) more cycles.  
6. If the product-related material is still visible at the end of the third repeated 
cycle DO NOT use the vial.  
After completing these steps, the pharmacist, using aseptic technique, will gently 
roll the mixture in the vial one more time and then withdraw 1 mL into a 3mL 
syringe using a 21 or 23 gauge needle. 
The syringe should be labeled as “AIDSVAX® B/E 600 mcg.” The syringe must 
also be labeled “for administration into the deltoid of the non-dominant arm.” The 
study product should be administered within 2 hours of being drawn into the 
syringe. 
Any unused portion of entered vials or expired prefilled syringes should be 
autoclaved immediately prior to disposal and disposed of in accordance with 
institutional or pharmacy policy. If they will be incinerated, they do not need to be 
autoclaved. 
8.4 
Administration 
When preparing a dose in a syringe and administering the dose, consideration 
should be given to the volume of solution in the needle before and after the dose 
is administered. Particularly, if the needle used to withdraw the product is 
replaced prior to vaccine administration, consideration should be given to 
conserving the full dose of product. The pharmacy and clinic staff members are 
encouraged to work together to administer the dose specified in the protocol.  

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For all AIDSVAX B/E injections, the person administering the injection should 
gently roll the syringe prior to administration of the study product. For these 
injections, a 21 or 23 gauge needle must be used for administration.  
Vaccines will be injected intramuscularly (IM) into the deltoid muscle of the non-
dominant arm.  
AIDSVAX® B/E will be administered on months 0, 1, and 6.  
8.5 
Acquisition of study products 
AIDSVAX® B/E will be provided by GSID (San Francisco, California, USA). 
Once an HVTN CRS is protocol registered, the pharmacist can obtain study 
products from the NIAID Clinical Research Products Management Center 
(CRPMC) by following the ordering procedures outlined in Pharmacy Guidelines 
and Instructions for DAIDS Clinical Trials Networks. 
8.6 
Pharmacy records 
The HVTN CRS pharmacist is required to maintain complete records of all study 
products. The pharmacist of record is responsible for maintaining randomization 
codes and randomization confirmation notices for each participant in a secure 
manner. 
8.7 
Final disposition of study products 
For US clinical research sites, all unused study products must be returned to the 
CRPMC after the study is completed or terminated unless otherwise instructed by 
thestudy sponsor. The procedures are included in the Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks.  

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9 
Clinical procedures 
The schedule of clinical procedures is shown in Appendix 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 (ICF) 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 ICFs. 
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 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 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, GCP: 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 forms include instructions throughout the document 
for developing specific content. 
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 ICF with the 
participant, allowing time for the participant to reflect on the procedures and 
issues presented, and answering all questions completely.  
An Assessment of Understanding is used to document the participant’s 
understanding of key concepts in this HIV vaccine trial. The participant must 
complete the Assessment of Understanding before enrollment. Staff may provide 
assistance in reading and understanding the questions and responses, if necessary. 

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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 28 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, to include medical 
records review for verification of the diagnosis of SLE where appropriate, and 
for the presence of any exclusionary medications/conditions; 
• 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 
• SLE assessment, as determined by a rheumatologist or designee, using 
standard instruments for this purpose (SELENA-SLEDAI, including 
Complement profile [C3/C4/CH50] and anti-dsDNA, and SLICC/ACR); and 
functional status assessment by a staff member using RAPID3;  
• Laboratory tests as defined in the inclusion and exclusion criteria, including: 
▪ Screening HIV test 
▪ HBsAg 
▪ Anti-HCV antibodies 
▪ Syphilis test 

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▪ CBC with differential and platelets 
▪ Chemistry panel (ALT, AST, and creatinine) 
▪ Complement Profile (C3/C4/CH50) 
▪ HbA1C 
▪ Anti-DNA, Double Stranded (Anti-dsDNA) 
▪ Urinalysis (as described in section 9.7) 
▪ Urine or serum pregnancy test (participants who were born female), in 
accordance with local regulatory requirements 
• 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 
• 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 assigned 
female sex at birth and who reports no current sexual activity that could lead 
to that participant becoming pregnant to have a plan to begin adequate birth 
control. This plan would be put to use if, during the study, the participant 
becomes sexually active in a way that could lead to that participant becoming 
pregnant. 
9.3 
Enrollment and vaccination visits 
Enrollment is simultaneous with first vaccination. 
At all vaccination visits, the following procedures are performed before 
vaccination: 
• 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;  
• CBC/differential/platelets; 

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• SLE assessment, as determined by a rheumatologist or designee, using 
standard instruments for this purpose (SELENA-SLEDAI, including 
Complement profile [C3/C4/CH50] and anti-dsDNA); and functional status 
assessment by a staff member using RAPID3. Lab results for assessing SLE 
status must be conducted within 28 days of vaccination and can include using 
results from a prior visit; 
• Assessment of baseline reactogenicity parameters; 
• Assessment of concomitant medications (as described in Section 9.2); 
• Assessment of any new or unresolved AEs/intercurrent illnesses; 
• Serum or urine pregnancy test, in accordance with local regulatory 
requirements, (for participants who were assigned female sex at birth). 
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; 
• Urinalysis (see Section 9.7); and 
• Specimen collection (should be completed prior to vaccination) 
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 Participant Diary and is instructed on how to 
complete it. The site will make arrangements to be in contact with the participant 
during the reactogenicity period (as described in Section 9.8). 
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 and9.6); 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. 

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• Behavioral risk assessment; and 
• Confirm that participants received HIV test results from previous visit. If not, 
provide test results and post-test counseling as appropriate. 
9.4 
Follow-up visits 
The following procedures are performed at all scheduled follow-up visits: 
• 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; 
• Risk reduction counseling (as described in Section 9.5); 
• Pregnancy prevention assessment (as described in Section 9.2 and 9.6); 
• Assessment of new or unresolved social impacts (site staff will ask participant 
about the status of any unresolved social impacts and if s/he has experienced 
any new social impacts as a result of the trial participation); 
• Assessment of new or continuing concomitant medications (as described in 
Section 9.2); and 
• Assessment of new or unresolved AEs/intercurrent illnesses. 
Additional procedures will be performed at scheduled follow-up visits as 
specified in Appendix 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); 
• HIV infection assessment including pretest counseling and HIV testing. A 
subsequent follow-up contact is conducted to provide post-test counseling and 
to report results to participant; 
• Confirm that participants received HIV test results from previous visit. If not, 
provide test results and post-test counseling as appropriate; 
• SLE assessment, as determined by a rheumatologist or designee, using 
standard instruments for this purpose (SELENA-SLEDAI, including 
Complement profile [C3/C4/CH50] and anti-dsDNA); and functional status 
assessment by a staff member using RAPID3; 

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• CBC/differential/platelets; 
• Urinalysis (see Section 9.7); 
• Urine or serum pregnancy test (for participants who were assigned female sex 
at birth), in accordance with local regulatory requirements. 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; and 
• Health contact (see HVTN 121 SSP). 
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 provide participants with CRS contact 
information and should encourage participants to ask medical providers to contact 
the CRS. The CRS can verify that the participant is in an HIV vaccine clinical 
trial and should only be tested at the study CRS. 
Potential participants identified as being HIV-infected during screening are not 
enrolled. Potential and enrolled participants identified as being HIV-infected will 
be referred for medical treatment, counseling, and management of the HIV 
infection. Participants who are found to be HIV-infected after enrollment will not 
receive any additional study product but will continue to be followed in the study 

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for safety assessments. These individuals may also be referred to appropriate 
ongoing clinical trials or observational studies. 
9.5.1 
Distinguishing intercurrent HIV infection from vaccine-induced 
positive serology 
The AIDSVAX B/E® 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 E). The Laboratory Program (or approved diagnostic 
laboratory) will follow the HVTN HIV testing algorithm (see Study Specific 
Procedures), 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 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 the end of study 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 antibody testing is no longer the standard 
test in clinical settings.  
9.5.2 
Vaccine-induced seropositivity (VISP) registry 
Experimental HIV vaccines may induce antibody production to HIV antigens, 
producing reactive results on commercially available HIV test kits. This is called 
“vaccine-induced seropositivity” (VISP). In order to provide poststudy HIV 
testing to distinguish between VISP and HIV infection, and to mitigate potential 
social harms resulting from VISP in HIV vaccine recipients who are not infected 
with HIV, the HVTN has created a VISP registry. At the end of the study, 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 

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contains the names of all study participants, unless they request that their names 
be removed. 
9.6 
Contraception status 
Contraception status is assessed and documented at every scheduled clinic visit 
for a participant who was assigned female sex at birth and who is sexually active 
in a way that could cause that participant to become pregnant. Prior to enrollment 
and throughout the study, staff will ask participants to verbally confirm their use 
of adequate contraceptive methods. A participant who was assigned female sex at 
birth 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 and urine protein:creatinine ratio 
A complete urinalysis with microscopy is performed on urine obtained by clean 
catch. Spot urine protein:creatinine ratio will also be performed. 
If the screening urinalysis 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 
urinalysis 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 urinalysis is abnormal due 
to a participant’s menstrual period, document in the comment section of the case 
report form (CRF) and repeat the urinalysis once the participant is no longer 
menstruating. 
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 DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 
2.1, July, 2017, except as noted in Section 11.2.2. 

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The reactogenicity assessment period is 7 full days following each vaccination per 
the assessment schedule shown in Table 9-1. Participants are instructed to record 
symptoms using a Participant Diary. Contact between the participant and the site 
staff should take place at least once within 72 hours/3 days postvaccination. In 
general, a participant who self-reports any postvaccination reaction greater than 
mild is seen by a clinician within 48 hours after onset, unless the reaction is 
improving and/or has completely resolved. Clinic staff will follow new or 
unresolved reactogenicity symptoms present at day 7 to resolution. Participants 
are instructed to contact the clinic for events that arise during the period between 
vaccination and the next scheduled visit. 
Reactogenicity events are reported using CRFs that correspond to the time of 
assessment in Table 9-1. Reactogenicity assessments include assessments of 
systemic and local symptoms and vaccine-related lesions. Events not listed on a 
CRF, or with an onset after the reactogenicity assessment period (day of 
vaccination and 7 full days after), or those meeting SAE/AEs requiring expedited 
reporting to DAIDS criteria, are recorded on an adverse experience log form.  
Table 9-1 Schedule of reactogenicity assessments 
Day 
Time 
Performed by 
0a 
Baseline: before vaccination 
HVTN CRS clinician 
 
Early: 25-60 minutes after vaccination 
HVTN CRS clinician 
 
Between early assessment and 11:59pm 
day 0 
HVTN CRS clinician or 
participant 
1-7b 
Between 12:00am and 11:59pm on the 
respective day 
HVTN CRS clinician or 
participant 
a Day of vaccination 
b New or unresolved reactogenicity symptoms present on day 7 are followed until resolution 
9.8.1 
Assessment of systemic and local symptoms 
Systemic symptoms include increased body temperature, malaise and/or fatigue, 
myalgia, headache, chills, arthralgia, and nausea. Local symptoms include pain 
and/or tenderness at the injection site. The daily maximum severity reached for 
each symptom during the assessment period is reported. 
Body temperature is measured by oral or infrared thermometry. All temperatures 
must be measured by non-axillary thermometry. This includes temperatures taken 
in the clinic, as well as temperatures taken by participants during the 
reactogenicity period. 
Temperature is reported in degrees Celsius. 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. 

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9.8.2 
Assessment of injection site 
Typical injection site reactions are erythema/redness and induration/swelling. The 
maximum diameter for all injection site reactions is recorded. 
All injection site reactions are monitored until resolution. Reactions with 
diameters greater than 5 cm are followed daily; otherwise, the frequency of 
follow-up is based on clinician judgment. 
9.9 
Visit windows and missed visits 
Visit windows are defined in HVTN 121 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 CBC with differential, C3, C4, CH50, anti-dsDNA, 
urinalysis, spot urine protein:creatinine ratio, and chemistry panel), pregnancy 
testing, social impact assessment, and HIV test. For participants who have a 
confirmed diagnosis of HIV infection, see Section 9.12. 
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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9.12 
HIV infection during the study 
If a participant becomes HIV-infected during the course of the study, no 
additional study product will be administered. Participants will be encouraged to 
continue scheduled study visits for up to 24 weeks following their last study 
product administration. Follow-up duration for participants diagnosed with HIV 
infection may be adjusted in consultation with the CRS investigator and the 
HVTN 121 PSRT (eg, to avoid interference with participant initiation of HIV 
treatment). At post-infection follow-up visits, only specimens required for 
protocol-specified safety laboratory tests, urinalysis, spot urine protein:creatinine 
ratio and pregnancy tests will be collected; in addition, some clinic procedures 
may be modified or discontinued (see Appendix E and Appendix F). 

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10 
Laboratory procedures 
10.1 
HVTN CRS laboratory procedures 
The HVTN 121 Site Lab Instructions and Study Specific Procedures 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. 
Of note, all assays described below are performed as research assays to evaluate 
the ability of the vaccine to induce immune responses in the context of the 
participants’ genetic background, and are not approved for use in medical care. 
Results from these assays are not made available to participants or medical 
professionals to guide treatment decisions. 
10.2 
Total blood volume 
Required blood volumes per visit are shown in Appendix 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 at baseline, 1 week 
and 2 weeks after the second AIDSVAX vaccination, and 1 week and 2 weeks 
after the third AIDSVAX vaccination. 
Endpoint assays for humoral and cellular responses are performed on specimens 
collected from participants at the primary immunogenicity timepoints and may be 
performed at baseline. Depending on the initial results, assays for humoral and 
cellular responses may be performed on samples collected from participants at 
other timepoints; the schedule is shown in Appendix E. 

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It is important to note that the same laboratories that will be running the 
neutralizing antibody assay and assays for the applicable secondary and 
exploratory endpoints in HVTN 121 were involved with the non-HVTN studies 
that will serve as controls (ie, RV328 and CHAVI 005). This will serve to 
minimize bias when comparing results across groups. 
10.4 
Endpoint assays: cellular 
10.4.1 
Intracellular cytokine staining (ICS) 
Flow cytometry will be used to examine vaccine-specific CD4+ 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 
interferon gamma (IFN-γ), interleukin (IL)-2, and tumor necrosis factor (TNF)-α, 
and may include other cytokines (such as cytokines relevant to Th2 and Th17 
responses) to identify T cells of specific functionality. Markers of cytotoxic 
potential (eg, granzyme B) and that identify circulating Tfh cells (eg, CXCR5 and 
PD-1) may also be included. Data will be reported as percentages of CD4+ T cells 
responding to a specific peptide pool. Additional cell surface markers, cytokines, 
or functional markers may also be analyzed. 
10.4.2 
T and B cell phenotyping 
Flow cytometry will be used to phenotype T and B cells in the peripheral blood. 
Peripheral follicular helper T (pTfh) cells and Treg cells may be characterized 
based on expression of CXCR5, PD-1, CD127, and CD25 on CD4+ T cells. 
Additional markers, comprising but not limited to indicators of activation or 
differentiation may also be included, such as CD21, CD27, CD38, and HLA-DR. 
10.5 
Endpoint assays: humoral 
10.5.1 
Neutralizing antibody assay 
HIV-1–specific nAb assays will be performed on serum samples from study 
participants taken at the primary immunogenicity timepoints. The TZM-bl assay 
will test neutralization of the vaccine strains, a single highly neutralization-
sensitive Tier 1 virus as a positive control and the global panel to assess Tier 2 
neutralization [125,135]. Additional assays will be performed with viruses that are 
engineered to detect early precursors of bnAbs. Specimens from 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. 
10.5.2 
Binding antibody multiplex assay (BAMA) 
HIV-1–specific total binding IgG antibodies will be assessed using serum samples 
from study participants taken at the primary immunogenicity timepoints and 

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baseline. In addition, HIV-1–specific total binding IgA antibodies and binding to 
IgG subclasses (IgG1, IgG2, IgG3, and IgG4) may also be assessed. Specimens 
from other timepoints may also be assayed based on the results of the initial 
assay. 
10.6 
Innate immunity assays 
10.6.1 
Serum cytokines 
Cytokine multiplex assay and/or enzyme-linked immunosorbent assay (ELISA) 
will be used to measure soluble cytokines, chemokines, and other 
immunomodulatory factors in the serum. Analytes may include IFN-γ, IL-6, TNF-
α, IL-10, IP-10, MCP-1, and/or other analytes may also be included. 
10.7 
Exploratory studies 
Samples may be used for other testing and research related to furthering the 
understanding of HIV immunology or vaccines. In addition, cryopreserved 
samples may be used to perform additional assays to support standardization and 
validation of existing or newly developed methods.  
10.7.1 
Antibody-dependent cellular cytotoxicity (ADCC) 
ADCC activity may be assessed using serum samples from study participants 
taken at the primary immunogenicity timepoints. Specimens from the baseline 
and other timepoints may also be analyzed at the discretion of the HVTN 
Laboratory Program, which may be contingent on the results of the primary 
immunogenicity timepoints. For the Granzyme B flow-based cytotoxicity assay, 
participant sera are incubated with effector cells and gp120-coated target. ADCC 
is quantified as net percent granzyme B activity which is the percent of target 
cells positive for GranToxiLux (GTL), an indicator of granzyme B uptake, minus 
the percent of target cells positive for GTL when incubated with effector cells but 
without sera. For the Luciferase-based cytotoxicity assay, participant sera are 
incubated with IMC-infected cells and percent killing is measured through the use 
of ViviRen luminescence. 
10.7.2 
BnAb epitope binding and blocking assays 
Binding will be assessed using a panel of HIV-1 Env proteins to determine the 
number and proportion of each type (eg, clade) of Env proteins recognized by 
participant plasma samples at the primary immunogenicity timepoints and 
baseline. Blocking will be assessed by the ability of plasma antibody to block the 
binding of bnAbs to proteins known to bind those bnAbs. 

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10.7.3 
Memory B cell sorts, clonal memory B cell cultures and recombinant 
antibody production 
Memory B cells may be sorted as individual cells for recovery of immunoglobulin 
genes, sequence analysis, and expression of recombinant mAbs. Genes recovered 
in this way will be analyzed by comparison to a reference gene set and for 
inference of the unmutated common ancestor of the antibody, determination of 
clonal lineage relationships among recovered genes, and compared with genes 
recovered from other vaccine studies and studies of HIV-1–infected persons. 
Recombinant mAbs may be assessed for binding, blocking, neutralization, 
ADCC, and other activities as described for plasma/serum assays.  
Blood cell samples taken at timepoints appropriate for memory B cell sorting may 
also be placed into clonal memory B cell cultures. These cultures will be used to 
expand the memory B cell populations and supernatants from those cultures may 
be analyzed for binding, blocking, neutralization, and/or ADCC, or other assays 
as deemed appropriate. Clonally expanded cells can be immortalized to produce 
stable cell lines and/or subjected to gene recovery and mAb production. 
10.7.4 
Plasma cell sorts for B cell repertoire analysis 
Blood cell samples taken at timepoints appropriate for plasma cell sorting (~7 
days after vaccination) may be sorted to isolate circulating plasmablasts/plasma 
cells. Cells isolated in this way may have gene isolation and analysis as described 
in Section 10.7.3. 
10.7.5 
Next generation sequencing (NGS) for VH and VL 
NGS will be performed by reverse transcription and PCR to amplify and sequence 
variable region gene segments from whole PBMC or isolated B cells from 
participants. Sequenced gene segments will be aligned to a reference database of 
variable regions of both heavy and light chain genes to determine gene usage and 
genetic features of each sequence. This may be performed using paired sequence 
techniques (eg, by droplet isolation) or on each chain individually. 
10.7.6 
RNAseq of Tfh and B cell populations 
Tfh and B cells will be isolated by flow cytometry either in bulk or as single cells 
and mRNA isolated. mRNA will be reverse transcribed and complementary DNA 
(cDNA) amplified for NGS. NGS reads will be aligned to the human reference 
genome and relative frequency of RNA transcripts in each population will be 
determined. 
10.7.7 
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 

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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 genes, including those associated with 
immune responses (eg, immunoglobulin, or T cell receptor genes), or HIV-1 
disease progression may also be assessed. 
10.8 
Specimen storage and other use of specimens 
The HVTN stores specimens from all study participants indefinitely, unless a 
participant requests that specimens be destroyed or if required by IRB/EC, or RE.  
Other use of specimens is defined as studies not covered by the protocol or the 
ICF for the main study (Appendix A).  
This research may relate to HIV, vaccines, the immune system, and other 
diseases. This could include genetic testing and, potentially, genome-wide studies. 
This research is done only to the extent authorized in each study site’s ICF, or as 
otherwise authorized under applicable law. Other research on specimens (“other 
use”) will occur only after review and approval by the HVTN, the IRB/EC of the 
researcher requesting the specimens, and the CRS’s IRBs/ECs/REs if required.  
As part of consenting for the study, participants document their initial decision to 
allow or not allow their specimens to be used in other research, and they may 
change their decision at any time. The participant’s initial decision about other 
use of their specimens, and any later change to that decision, is recorded by their 
CRS in a Web-based tool that documents their current decisions for other use of 
their specimens. The HVTN will only allow other research to be done on 
specimens from participants who allow such use.  
CRSs must notify HVTN Regulatory Affairs if institutional or local governmental 
requirements pose a conflict with or impose restrictions on specimen storage or 
other use of specimens. 
10.9 
Biohazard containment 
As the transmission of HIV and other blood-borne pathogens can occur through 
contact with contaminated needles, blood, and blood products, appropriate 
precautions will be employed by all personnel in the drawing of blood and 
shipping and handling of all specimens for this study, as currently recommended 
by the CDC and the NIH or other applicable agencies. 
All dangerous goods materials, including Biological Substances, Category A or 
Category B, must be transported according to instructions detailed in the 
International Air Transport Association Dangerous Goods Regulations. 

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11 
Safety monitoring and safety review 
11.1 
Safety monitoring and oversight 
11.1.1 
HVTN 121 PSRT 
The HVTN 121 PSRT is composed of the following members: 
• DAIDS medical officer representative 
• Protocol chair and co-chair 
• Protocol team leader 
• Core medical monitor 
• Protocol rheumatologist 
• Clinical safety specialist 
The clinician members of HVTN 121 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 
121 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. An independent rheumatologist will 
also be available to the SMB to provide expert input on safety concerns related to 
SLE. 
The SMB reviews safety data approximately every 4 months. The reviews consist 
of evaluation of cumulative reactogenicity events, AE, laboratory safety data, and 
individual reports of AEs requiring expedited reporting to DAIDS. The SMB 
conducts additional special reviews at the request of the HVTN 121 PSRT.  
Study sites will receive SMB summary minutes and are responsible for 
forwarding them to their IRB/EC and any applicable RE. 

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11.1.3 
SDMC roles and responsibilities in safety monitoring  
The roles and responsibilities of the SDMC in relation to safety monitoring 
include: 
• Maintaining a central database management system for HVTN clinical data; 
• Providing reports of clinical data to appropriate groups such as the HVTN 121 
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 121 PSRT AE review criteria (see Section 11.3); 
• Notifying HVTN CRSs and other groups when safety pauses or planned holds 
are instituted and lifted (see Section 11.3); 
• Querying HVTN CRSs for additional information regarding reported clinical 
data; and 
• Providing support to the HVTN 121 PSRT. 
11.2 
Safety reporting 
11.2.1 
Submission of safety forms to SDMC 
Site staff must submit all safety forms (eg, reactogenicity, adverse experience, 
urinalysis, local lab results, and concomitant medications) before the end of the 
next business day, excluding federal or bank holidays. The forms should not be 
held in anticipation of additional information at a later date. If additional 
information is received at a later date, the forms should be updated and 
resubmitted before the end of the next business day after receiving the new 
information. For the case of a longer site holiday closure, site staff must submit 
the data by the end of the 5th day (local time) after receiving the information even 
if this day is a holiday. 
For example: If the site becomes aware of an AE on Thursday (Day 0), the site 
must submit the data by the end of the next business day, on Friday. If there is a 
longer site holiday closure, then this AE must be reported no later than the end of 
the fifth day, Monday (Day 4). If Monday is a holiday as well, all safety forms 
still need to be submitted by the end of Monday (Day 4). 
11.2.2 
AE reporting 
An AE is any untoward medical occurrence in a clinical investigation participant 
administered a study product/procedure(s) and which does not necessarily have a 

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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 DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 
2.1, July 2017, available on the RSC website at http://rsc.tech-res.com/clinical-
research-sites/safety-reporting/daids-grading-tables, except: 
• Unintentional weight loss is required to be reported as an AE only if it is 
considered to be potentially deleterious to the participant’s health (see HVTN 
121 Study Specific Procedures); 
• Injection Site Erythema or Redness and Injection Site Induration or Swelling 
will not consider interference with usual social and functional activities such 
that: 
▪ Grade 1 is: 2.5 to < 5 cm in diameter OR 6.25 to < 25 cm2 surface area; 
▪ Grade 2 is: ≥ 5 to < 10 cm in diameter OR ≥ 25 to < 100 cm2 surface area; 
▪ Grade 3 is: ≥ 10 cm in diameter OR ≥ 100 cm2 surface area OR Ulceration 
OR Secondary infection OR Phlebitis OR Sterile abscess OR Drainage; 
▪ Grade 4 is: Potentially life-threatening consequences (eg, abscess, 
exfoliative dermatitis, necrosis involving dermis or deeper tissue); 
• Non-specific Rash or Skin Changes will be graded using the category of “Skin 
and subcutaneous tissue disorders – Other, specify” in the National Cancer 
Institute’s Common Terminology Criteria for Adverse Events (CTCAE), 
Version 5.0, November 2017, p.140 (Table 11-1): 
Table 11-1 Skin and subcutaneous tissue disorders 
Skin and subcutaneous disorders 
Grade 
 
 
Adverse Event 
1 
2 
3 
4 
5 
Skin and 
subcutaneous tissue 
disorders – Other, 
specify 
Asymptomatic or 
mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Moderate; minimal, 
local or noninvasive 
intervention 
indicated; limiting 
age-appropriate 
instrumental 
activities of daily 
living (ADL) 
Severe or medically 
significant, but not 
immediately life-
threatening; 
hospitalization or 
prolongation of 
existing 
hospitalization 
indicated; disabling; 
limiting self-care 
ADL 
Life-threatening 
consequences; urgent 
intervention 
indicated 
Death 
 

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• Vasculitis will be graded using the category of “Vascular disorders” in the 
National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE), Version 5.0, November 2017, p.146 (Table 11-2): 
Table 11-2 Vascular disorders 
Vascular disorders 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
Vasculitis 
Asymptomatic; 
intervention not 
indicated 
Moderate 
symptoms; medical 
intervention 
indicated 
Severe symptoms; 
medical intervention 
indicated (e.g., 
steroids) 
Life-threatening; evidence 
of peripheral or visceral 
ischemia; urgent 
intervention indicated 
Death 
Definition: A disorder characterized by inflammation involving the wall of a vessel 
• Pericarditis will be graded using the category of “Cardiac disorders” in the 
National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE), Version 5.0, November 2017, p.8 (Table 11-3): 
Table 11-3 Cardiac disorders 
Cardiac disorders 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
Pericarditis 
Asymptomatic; ECG 
or physical findings 
(e.g., rub) consistent 
with pericarditis 
Symptomatic 
pericarditis (e.g., 
chest pain) 
Pericarditis with 
physiologic 
consequences (e.g., 
pericardial 
constriction) 
Life-threatening 
consequences; urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by irritation to the layers of the pericardium (the protective sac around the heart) 
• Myositis in SLE patients typically presents as muscle weakness, as opposed to 
pain; thus, myositis will be graded using the parameter of “Neuromuscular 
Weakness” in the DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events, Corrected Version 2.1, July 2017, p.16 (Table 
11-4): 
Table 11-4 Neurologic adverse events 
Neurologic AEs 
Grade 
Adverse Event 
1 
2 
3 
4 
Neuromuscular Weakness 
(includes myopathy and 
neuropathy) 
Specify type, if applicable 
Minimal muscle 
weakness causing no or 
minimal interference 
with usual social & 
functional activities 
OR No symptoms with 
decreased strength on 
examination 
Muscle weakness 
causing greater than 
minimal 
interference with 
usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual 
social & functional 
activities 
Disabling muscle 
weakness causing 
inability to perform 
basic self-care 
functions OR 
Respiratory muscle 
weakness impairing 
ventilation 

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• Leukopenia in an SLE flare is defined with the SELENA-SLEDAI instrument 
as a white blood cell count < 3,000 cells/mm3.  The cut point below which an 
individual is considered to have leukopenia (WBC, Decreased, > 7 days of 
age) as an AE according to the DAIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 is 
2,500 cells/mm3.  For the purposes of monitoring this parameter in this study, 
the cut point for a Grade 1 AE of WBC, Decreased (> 7 days of age) will be 
<3,000 cells/mm3, such that study participants with a WBC in the range of 
2,000 to 2,999 cells/mm3 will be considered to have a Grade 1 AE of WBC, 
Decreased.  The grading table applied for WBC, Decreased (> 7 days of age) 
will therefore be as follows (Table 11-5): 
Table 11-5 Lab parameters, hematology 
Lab Parameters, Hematology 
Grade 
Adverse Event 
1 
2 
3 
4 
WBC, Decreased 
(cells/mm3; cells/L) 
> 7 days of age 
2,000 to 2,999 
2.000 x 109 to 2.999 x 109 
1,500 to 1,999 
1.500 x 109 to 1.999 x 109 
1,000 to 1,499 
1.000 x 109 to 1.499 x 109 
<1,000 
<1.000 x 109 
 
 
 
 
 
• Lupus Pleurisy will be graded according to the following table. The 
components of Pleural Effusion and Pleuritic Pain have been extracted from 
the category of “Respiratory, thoracic and mediastinal disorders” in the 
National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE), Version 5.0, November 2017, p.129 (Table 11-6): 
Table 11-6 Respiratory, thoracic and mediastinal disorders 
Respiratory, thoracic and mediastinal disorders 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
Lupus Pleurisy 
Select the highest 
grade of the 
following 
components that are 
present: 
--Pleural Effusion* 
--Pleural Rub 
--Pleural Thickening 
--Pleuritic Pain* 
Pleural Effusion: 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Pleural Effusion: 
Symptomatic; 
intervention 
indicated (e.g., 
diuretics or 
limited 
therapeutic 
thoracentesis) 
Pleural Effusion: 
Symptomatic with 
respiratory distress 
and hypoxia; 
surgical intervention 
including chest tube 
or pleurodesis 
indicated 
Pleural Effusion: 
Life-threatening 
respiratory or 
hemodynamic 
compromise; 
intubation or 
urgent intervention 
indicated 
Death 
Pleural Rub 
– 
– 
– 
– 
Pleural 
Thickening 
– 
– 
– 
– 
Pleuritic Pain: 
Mild pain 
Pleuritic Pain: 
Moderate pain; 
limiting 
instrumental 
ADL 
Pleuritic Pain: 
Severe pain; 
limiting self care 
ADL 
– 
– 

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• Pyuria in an SLE flare is defined with the SELENA/SLEDAI instrument as >5 
WBC/high power field. Pyuria is not included in the DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Corrected 
Version 2.1, July 2017 or in the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0, November 
2017; therefore, pyuria will be graded according to Table 11-7: 
Table 11-7 Lab parameters, Urine testing 
Lab Parameters, Urine testing 
Grade 
Adverse Event 
1 
2 
3 
4 
Pyuria 
6 to<10 WBCs per high 
power field 
≥10 WBCs per high power 
field 
Gross OR with WBC casts 
OR intervention indicated 
Life-
threatening 
consequences 
 
 
 
 
 
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 11.3). 
Sites are expected to notify HVTN clinical safety staff of any serious safety 
concern requiring their attention (Table 11-8). Telephone numbers and email 
addresses are found on the protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/hvtn121). Concerns requiring immediate 
attention should be communicated by calling the clinical safety phone. 
In the case of email notification, clinical safety staff will reply during working 
hours (local time) to confirm that the email has been received and reviewed. If 
email service is not available, the CRS should notify clinical safety staff of the 
event by telephone, then submit CRFs. 
In addition, site investigators are required to submit AE information in accordance 
with IRB/EC and any applicable RE requirements. 
11.2.3 
Expedited reporting of AEs to DAIDS 
Requirements, definitions and methods for expedited reporting of AEs are 
outlined in Version 2.0 (January 2010) of the Manual for Expedited Reporting of 
Adverse Events to DAIDS (DAIDS EAE Manual), which is available on the RSC 
website at http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual. 
The SAE Reporting Category will be used for this study.  
The internet-based DAIDS Adverse Experience Reporting System (DAERS) must 
be used for expedited AE (EAE) reporting to DAIDS. In the event of system 
outages or technical difficulties, EAE reports may be submitted via the DAIDS 
EAE Form. This form is available on the DAIDS RSC website at http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids/paper-eae-reporting. 

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For questions about DAERS, please contact CRMSsupport@niaid.nih.gov or 
from within the DAERS application itself. 
For questions about EAE reporting, please contact the DAIDS RSC Safety Office 
at (DAIDSRSCSafetyOffice@tech-res.com). 
The study product for which expedited reporting are required is: 
• AIDSVAX® B/E 
While the participant is in the study reporting period (see Section 3), the SAE 
Reporting Category will be used.  
After the protocol-defined AE reporting period for the study, unless otherwise 
noted, only Suspected, Unexpected Serious Adverse Reactions as defined in 
Version 2.0 of the DAIDS EAE Manual must be reported to DAIDS, if the study 
staff become aware of the events.  
The NIAID/DAIDS will report all unexpected SAEs related to the study products 
observed in this clinical trial to the FDA in accordance with 21 CFR 312.32 (IND 
Safety Reports).  
For additional impact and management of SAEs on the study, see Section 11.3. 
11.3 
Safety pause and prompt PSRT AE review 
When a trial is placed on safety pause, all enrollment and vaccination with the 
product related to the event that triggered the pause will be held until further 
notice. The AEs that will lead to a safety pause or prompt HVTN 121 PSRT AE 
review are summarized in Table 11-8. 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 121 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 11-8 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 PSRT notification 
SAE, related 
Grade 3, 2, 
or 1 
Email and submit forms 
immediately 
Immediate PSRT notification 
and prompt PSRT AE review 
to consider pause 
AEb, related 
Grade 4 or 
3 
Email and submit forms 
immediately 
Immediate PSRT notification 
and prompt PSRT AE review 
to consider pause 
 “Severe”c SLE flare, 
regardless of relationship  
N/A 
Phone immediately, 
email and submit forms 
immediately 
Prompt PSRT AE review 
“Mild or moderate”d,e SLE 
flare, related  
N/A 
Phone immediately, 
email and submit forms 
immediately 
Prompt PSRT AE review  
3 or more confirmed 
“moderate” or “severe” SLE 
flares, regardless of relatedness 
N/A 
Phone immediately, 
email and submit forms 
immediately 
Immediate pause 
a Email addresses are found on the Protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/hvtn121). Phone numbers for each pause rule are in the HVTN 121 
SSPs. 
b Does not include the following Grade 3 subjective reactogenicity symptoms: injection site pain, tenderness, 
fatigue/malaise, myalgia, arthralgia, chills, headache, nausea (unless IV rehydration required). 
c, “Severe” SLE flare is defined by application of the SELENA-SLEDAI instrument (Appendix G). 
d “Moderate” SLE flare is defined by application of the SELENA -SLEDAI instrument (Appendix G), as well 
as the determination by a rheumatologist that the participant has flare components/symptoms/lab indices 
necessitating treatment with a dosage of Prednisone (or equivalent) in the range of >7.5 mg/day to < 0.5 
mg/kg/day. 
e “Mild” SLE flare is defined by application of the SELENA-SLEDAI instrument (Appendix G), as well as the 
determination by a rheumatologist that the participant has flare components/symptoms/lab indices 
necessitating treatment with a dosage of Prednisone (or equivalent) of ≤7.5 mg/day. 
For all safety pauses, HVTN Core notifies the HVTN 121 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 121 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 121 PSRT assessment, DAIDS RAB 
notifies the FDA as needed. 
If an immediate HVTN 121 PSRT notification or prompt HVTN 121 PSRT AE 
review is triggered, HVTN Core notifies the HVTN 121 PSRT as soon as possible 

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during working hours (local time)—or, if the information was received during off 
hours, by the morning of the next work day. If a prompt HVTN 121 PSRT AE 
review cannot be completed within 72 hours of notification (excluding weekends 
and US federal holidays), an automatic safety pause occurs. 
The HVTN requires that each CRS submit to its IRB/EC and any applicable RE 
protocol-related safety information (such as IND safety reports, notification of 
vaccine holds due to the pause rules, unanticipated problems involving risks to 
participants or others, and notification of other unplanned safety pauses). CRSs 
must also follow all applicable RE reporting requirements. 
In addition, all other AEs are reviewed routinely by the HVTN 121 PSRT (see 
Section 11.4.2). 
11.4 
Review of cumulative safety data 
Routine safety review occurs at the start of enrollment and then throughout the 
study. 
Reviews proceed from a standardized set of protocol-specific safety data reports. 
These reports are produced by the SDMC and include queries to the HVTN CRSs. 
Events are tracked by internal reports until resolution.  
11.4.1 
Daily review 
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 121 PSRT AE review criteria. 
11.4.2 
Weekly review 
During the injection phase of the trial, the HVTN 121 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 121 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. 
11.5 
Study termination 
This study may be terminated early by the determination of the HVTN 121 PSRT, 
a pertinent national regulatory authority, NIH, Office for Human Research 
Protections (OHRP), the FDA, or study product developer. In addition, the 

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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; 
• Quality control; 
• Protocol monitoring and compliance; 
• Advocacy and assistance to participants regarding negative social impacts 
associated with the vaccine trial; 
• Risk reduction counseling;  
• Specimen collection, processing, and analysis;  
• Exploratory and ancillary studies and sub-studies, and 
• Destruction of specimens. 
Any policies or procedures that vary from DAIDS and HVTN standards or require 
additional instructions (eg, instructions for randomization specific to this study) 
will be described in the HVTN 121 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 can contact the participant without IRB/EC approval if 
such communication is necessary to avoid imminent harm to the study participant. 
The CRS must notify the IRB/EC and any applicable RE of the matter as soon as 
possible. 

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13 
Version history 
The Protocol Team may modify the original version of the protocol. 
Modifications are made to HVTN protocols via clarification memos, letters of 
amendment, or full protocol amendments.  
The version history of, and modifications to, Protocol HVTN 121 are described 
below. 
Protocol history and modifications 
Date: September 12, 2018 
Protocol version: 1.02 
Protocol modification: Full Protocol Amendment 1 
Item 1 
Added to the protocol cover page, IND number 018361 
Item 2 
Revised in Section 9.2, Pre-enrollment procedures, the eligibility 
assessment period from 30 to 28 days to harmonize with Section 7, 
Selection and withdrawal of participants, last paragraph 
Item 3 
Revised in Section 9.3, Enrollment and vaccination visit, SLE 
assessment and urinalysis 
Item 4 
Revised in Section 9.4, Follow-up visits, Appendix D, Table of 
procedures (for sample informed consent form), and Appendix F, 
Procedures at HVTN CRS, the timing of when SLE assessments done 
at some scheduled follow-up visits 
Item 5 
Added in 11.2.2, AE reporting, new guidance to address SLE flare 
Item 6 
Revised Table 11-1 (now Table 11-8), AE notification and safety 
pause/AE review rules, a new pause rule 
Item 7 
Updated in Section 13, Version history 
Item 8 
Corrected cross-referencing errors and updated document URLs 
 
Date: July 12, 2018 
Protocol version: 1.0 
Protocol modification: 
Original protocol 

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14 
Document references (other than literature 
citations) 
Other documents referred to in this protocol, and containing information relevant 
to the conduct of this study, include: 
• Assessment of Understanding. Accessible through the HVTN protocol-
specific website. 
• Current CDC Guidelines.  
• Revised Recommendations for HIV Testing of Adults, Adolescents, and 
Pregnant Women in Health-Care Settings. Available at 
http://www.cdc.gov/mmwr/PDF/rr/rr5514.pdf 
• Revised Guidelines for HIV Counseling, Testing, and Referral. Available at 
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5019a1.htm 
• DAIDS Clinical Research Policies and Standard Procedures Documents. 
Available at https://www.niaid.nih.gov/research/daids-clinical-research-
policies-standard-procedures  
• DAIDS Protocol Registration Manual. Available at 
https://www.niaid.nih.gov/sites/default/files/prmanual.pdf  
• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. 
Corrected Version 2.1, July 2017. Available at http://rsc.tech-res.com/clinical-
research-sites/safety-reporting/daids-grading-tables 
• The Manual for Expedited Reporting of Adverse Events to DAIDS. Version 
2.0, January 2010. Available at http://rsc.tech-res.com/clinical-research-
sites/safety-reporting/manual 
• HVTN Certificate of Confidentiality. Accessible through the HVTN website. 
• HVTN 121 Special Instructions. Accessible through the HVTN protocol-
specific website. 
• HVTN 121 Study Specific Procedures. Accessible through the HVTN 
protocol-specific website. 
• HVTN 121 Site Lab Instructions. Accessible through the HVTN protocol-
specific website. 
• HVTN Manual of Operations. Accessible through the HVTN website. 

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• Dangerous Goods Regulations (updated annually), International Air Transport 
Association. Available for purchase at 
http://www.iata.org/publications/dgr/Pages/index.aspx. 
• Lab assay algorithm (available upon request) 
• International Conference on Harmonisation (ICH) E6, Guideline for Good 
Clinical Practice: Section 4.8, Informed consent of trial subjects. Available at 
http://www.ich.org/products/guidelines/efficacy/article/efficacy-
guidelines.html 
• Participants’ Bill of Rights and Responsibilities. Accessible through the 
HVTN website. 
• NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic 
Acid Molecules. Available at http://osp.od.nih.gov/office-biotechnology-
activities/biosafety/nih-guidelines 
• NIH Policy 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, CFR, Part 50. Available at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFR
Part=50 
• Title 45, CFR, Part 46. Available at https://www.hhs.gov/ohrp/regulations-
and-policy/regulations/45-cfr-46/index.html 
See Section 16 for literature cited in the background and statistics sections of this 
protocol. 

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15 
Acronyms and abbreviations 
 
ADCC 
 
antibody-dependent cellular cytotoxicity 
AE 
 
adverse event 
ALT 
 
alanine amino transferase 
APS or APLS 
antiphospholipid syndrome or antiphospholipid antibody 
syndrome 
ART 
 
antiretroviral therapy 
ASIA 
 
autoimmune / inflammatory syndrome induced by adjuvants 
AST 
 
aspartate aminotransferase 
AUC-MB  
area-under-the-magnitude-breadth curve 
β-HCG 
 
beta human chorionic gonadotropin 
BAMA 
 
binding antibody multiplex assay 
bnAb 
 
broadly neutralizing antibody 
CAB 
 
Community Advisory Board 
CBC 
 
complete blood count 
CDC 
 
US Centers for Disease Control and Prevention 
cDNA 
 
complementary DNA 
CFR 
 
Code of Federal Regulations 
CHAVI 
 
Center for HIV-AIDS Vaccine Immunology 
CHO cell  
Chinese hamster ovary cell  
CIOMS 
 
Council for International Organizations of Medical Sciences 
CNS 
 
central nervous system 
CRF 
 
case report form 
CRPMC 
 
Clinical Research Products Management Center 
CRS 
 
clinical research site 
DAERS 
 
DAIDS Adverse Experience Reporting System 
DAIDS 
 
Division of AIDS 
DHHS 
 
US Department of Health and Human Services 
dsDNA 
 
double-strand DNA 
EAE 
 
adverse events requiring expedited reporting to DAIDS 
EC 
 
Ethics Committee 
EIA 
 
enzyme immunoassay 
ELISA 
 
enzyme-linked immunosorbent assay 
FDA 
 
US Food and Drug Administration 
FHCRC 
 
Fred Hutchinson Cancer Research Center 
GCP 
 
Good Clinical Practice 
GMT 
 
geometric mean titer 
GSID 
 
Global Solutions for Infectious Diseases 

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GTL 
 
GranToxiLux 
HBsAg 
 
hepatitis B surface antigen 
HCDR3 
 
heavy chain complementarity determining region 3 
HCV 
 
hepatitis C virus 
HIPAA 
 
Health Insurance Portability and Accountability Act 
HIV 
 
human immunodeficiency virus 
HLA 
 
human leukocyte antigen 
HVTN 
 
HIV Vaccine Trials Network 
IB 
 
Investigator’s Brochure 
ICF 
 
informed consent form 
ICH 
 
International Conference on Harmonisation 
ICS 
 
intracellular cytokine staining 
IFN-γ 
 
interferon gamma 
IL 
 
interleukin 
IM 
 
intramuscular 
IND 
 
Investigational New Drug 
IRB 
 
Institutional Review Board 
IUD 
 
intrauterine device 
mAbs 
 
monoclonal antibodies 
MedDRA  
Medical Dictionary for Regulatory Activities 
MMR 
 
measles, mumps, and rubella 
nAb 
 
neutralizing antibody 
NAEPP 
 
National Asthma Education and Prevention Program 
NGS 
 
next generation sequencing 
NIAID 
 
National Institute of Allergy and Infectious Diseases 
NIH 
 
US National Institutes of Health (US NIH) 
OHRP 
 
US Office for Human Research Protections 
OPV 
 
oral polio vaccine 
PAB 
 
Pharmaceutical Affairs Branch 
PBMC 
 
peripheral blood mononuclear cell 
PCA 
 
principal component analysis 
PCR 
 
polymerase chain reaction 
PSRT 
 
Protocol Safety Review Team 
pTfh 
 
peripheral follicular helper T 
qPCR 
 
quantitative polymerase chain reaction 
RAB 
 
Regulatory Affairs Branch 
RAPID3  
Routine Assessment of Patient Index Data 3 
RE 
 
regulatory entity 
RSC 
 
Regulatory Support Center 

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SAE 
 
serious adverse event 
SCHARP  
Statistical Center for HIV/AIDS Research and Prevention 
SDMC 
 
statistical and data management center 
SELENA  
Safety of Estrogens in Lupus Erythematosus National 
Assessment 
SICF 
 
sample informed consent form 
SLE 
 
systemic lupus erythematosus 
SLEDAI  
SLE Disease Activity Index 
SLICC/ACR DI Systemic Lupus International Collaborating Clinics/American 
College of Rheumatology Damage Index 
SMB 
 
Safety Monitoring Board 
SPT 
 
DAIDS Safety and Pharmacovigilance Team 
SSA 
 
Sjögren's syndrome A 
TB 
 
tuberculosis 
Tfh 
 
T follicular helper 
TNF-α 
 
tumor necrosis factor alpha 
Treg 
 
T regulatory 
UW-VSL  
University of Washington Virology Specialty Laboratory 
VISP 
 
Vaccine induced seropositivity 
WBC 
 
white blood cells 

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16 
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patients with quiescent disease. Ann Rheum Dis. 2006;65(7):913-8. 

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65. Ritterhouse LL, Crowe SR, Niewold TB, Merrill JT, Roberts VC, Dedeke 
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66. Saad CG, Borba EF, Aikawa NE, Silva CA, Pereira RM, Calich AL, et al. 
Immunogenicity and safety of the 2009 non-adjuvanted influenza A/H1N1 
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2011;70(6):1068-73. 

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78. Baylor NW, Egan W, Richman P. Aluminum salts in vaccines--US 
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89. Palacios R, Santos J, Valdivielso P, Marquez M. Human immunodeficiency 
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autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 
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91. Montefiori DC, Karnasuta C, Huang Y, Ahmed H, Gilbert P, de Souza MS, et 
al. Magnitude and breadth of the neutralizing antibody response in the 
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R, et al. Immune perturbations in HIV-1–infected individuals who make 
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93. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris 
R, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 
infection in Thailand. N Engl J Med. 2009;361(23):2209-20. 
94. Pitisuttithum P, Gilbert P, Gurwith M, Heyward W, Martin M, van Griensven 
F, et al. Randomized, Double-Blind, Placebo-Controlled Efficacy Trial of a 
Bivalent Recombinant Glycoprotein 120 HIV-1 Vaccine among Injection 
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97. Liao HX, Bonsignori M, Alam SM, McLellan JS, Tomaras GD, Moody MA, 
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98. Yates NL, Liao HX, Fong Y, deCamp A, Vandergrift NA, Williams WT, et 
al. Vaccine-induced Env V1-V2 IgG3 correlates with lower HIV-1 infection 
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104. Huang Y, Gilbert P, Montefiori D, Self S. Simultaneous evaluation of the 
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Appendix A 
Sample informed consent form (SICF) 
Title: A phase 1b open label clinical trial to evaluate HIV-1 neutralization 
antibody breadth in response to HIV gp120 protein vaccine in HIV-uninfected 
adults with quiescent Systemic Lupus Erythematosus 
HVTN protocol number: HVTN 121 
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 given to people who have Systemic Lupus 
Erythematosus (SLE). Some people may just call this “Lupus.” HIV is the virus 
that causes AIDS. Vaccines against HIV are designed to teach the body to 
produce antibodies against HIV. Antibodies are one of the body’s natural ways of 
protecting against infections. 
People who have Lupus may have immune responses that are unique. The 
responses might be different from people who do not have Lupus. One of these 
responses is the body’s ability to develop antibodies in response to infections.  
Special antibodies called broadly neutralizing antibodies (bnAbs) are able to 
protect against many different types of an infection, such as the different types of 
HIV found around the world. Because bnAbs are an important focus of HIV 
vaccine research, researchers would like to understand more about this immune 
response in people who have Lupus. They want to better understand how the 
bnAb responses differ from people who do not have Lupus. 
About 16 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. 
• How do the immune systems of people with Lupus respond to the study 
vaccine? (Your immune system protects you from disease.) 

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• Do the immune systems of people with Lupus make bnAbs in response to the 
study vaccine? 
• Is the study vaccine safe to give to people without active symptoms of Lupus? 
• Are people with Lupus able to take the study vaccine without becoming too 
uncomfortable? 
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. The study vaccine likely will 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. You can remove the box around the text. 
The vaccine has been given to thousands of people in other studies. In those 
studies, most people were not protected from infection with HIV. 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 AIDSVAX® B/E. From here on, we will call it the 
study vaccine. It is an experimental HIV vaccine. This vaccine is used only in 
research studies. 
The vaccine is being provided by Global Solutions for Infectious Diseases 
(GSID). The AIDSVAX® B/E vaccine is made of man-made proteins that are 
similar to proteins from the outer surface of the HIV virus. The vaccine is also 
made with an adjuvant called aluminum hydroxide. An adjuvant is something 
added to the vaccine to help the immune system respond better. Aluminum 
hydroxide adjuvants are used in many licensed vaccines that have been given to 
millions of people. Your body’s immune system may respond to this study 
vaccine by making antibodies that recognize and fight against HIV proteins. 
Antibodies are special proteins made by the body that can recognize and prevent 
infections. The AIDSVAX® B/E vaccine has been given to over 10,000 
participants in different studies with people who do not have Lupus. 
General risks of vaccines: 
Generally, vaccinations are considered safe for people with inactive Lupus. 
All vaccines can cause fever, chills, rash, aches and pains, nausea, headache, 
dizziness, and feeling tired. Vaccines can also cause pain, redness, swelling, or 

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itching where you got the injection. Most people can still do their planned 
activities after getting a vaccine. Rarely, people have side effects that limit their 
normal activities or make them go to the doctor. 
Rarely, a vaccine can cause an allergic reaction, including a rash, hives, or trouble 
breathing. Allergic reactions can be life-threatening. You should tell us if you 
have ever had a bad reaction to any injection or vaccine. 
Very rarely, a vaccine causes an autoimmune disease in a person, or makes an 
autoimmune disease worse. An autoimmune disease happens when your immune 
system attacks your own body, instead of attacking an infection. You already have 
one autoimmune disease, Lupus. We do not know if getting the study vaccine 
could put you at risk for getting additional autoimmune diseases. 
We do not know if getting the study vaccine could impact your Lupus, causing it 
to flare up. If you have a significant lupus flare up, we will stop your vaccinations 
and continue to check on your health. We will work with your doctor to get you 
the care you need.  
Risks of the study vaccine: 
This section lists the side effects we know about. There may be others that we 
don’t yet know about, even serious ones. We will tell you if we learn about any 
new side effects. 
This AIDSVAX® B/E vaccine has been given to thousands of people who do not 
have Lupus. The most common symptoms at the injection site were pain and 
tenderness. In some cases, this resulted in some limited arm movement which 
went away on its own within a few days. Less often, some people had injection 
site hardness. The most common reactions in the body were headaches, swollen 
glands, and muscle or joint aches. Some people also reported feeling weak or 
having low energy. 
A few people had changes in blood and urine test results following injections. We 
do not know if these changes were caused by the study vaccine. The changes did 
not cause health problems. 
One person experienced a serious allergic reaction immediately after a 
vaccination with AIDSVAX® B/E. The person was treated and 
recovered completely in a few hours. 
We do not know if participants with Lupus in this study will have similar side 
effects to those seen in earlier studies with participants who did not have Lupus. 
Also, people with Lupus may have different side effects. 

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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, and 
if you have diabetes. We will also test you for: Syphilis, Hepatitis B, and 
Hepatitis C. 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 assigned 
female sex at birth, we will test you for pregnancy.  
We will assess your Lupus status to see if you have any currently active 
symptoms. This includes blood tests, a physical exam, and a questionnaire. 
We may need to review your medical records. We will ask for your permission if 
this is needed. 

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We will review the screening results with you. The screening results may show 
you are not eligible to join the study, even if you want to.  
Site: Adapt the following section so it is applicable to the care available at your site 
7. If we find that you have a health problem during screening or during the 
study, we will tell you about the care that we can give here. 
For the care that we cannot give, we will explain how we will help you get care 
elsewhere. For health problems that are unrelated to the study, we will not pay for 
care. 
8. If you were assigned female sex at birth and could become pregnant, you 
must agree to use birth control to join this study. 
Site: If you want to include Appendix 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 after your last 
required protocol clinic visit. We will talk to you about effective birth control 
methods. They are listed on a handout that we will give to you.  
Being in the study 
If you meet the study requirements and want to join, here is what will happen: 
9. You will come to the clinic for scheduled visits about [#] times over 12 
months. 
Site: Insert number of visits and range of visit lengths. (There is site-specific variation 
in screening protocols and in the number of possible follow-up visits between 
protocol-mandated visits.) 
Visits can last from [#] to [#] hours. 
You may have to come for more visits if you have a lab or health issue. 
We may contact you after the study ends (for example, to tell you about the study 
results). 
10. We will give you [Site: Insert compensation] for each study visit you 
complete. 
This amount is to cover the costs of [Site: Insert text] 

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Site: Insert any costs to participants (eg, birth control costs for female participants 
who could become pregnant). 
Site: Include the following paragraph. You can remove the box around the text. 
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. The study vaccine, the 
medical visits, and laboratory tests related to this study will be covered by the 
clinic, through the study sponsor. However, routine medical care (care you would 
have received whether or not you were in this study) will be charged to you or 
your insurance company. You may wish to contact your insurance company to 
discuss this further. 
11. We will give you the study product on a schedule. 
You will get 3 injections during the study by injection into the muscle of your 
upper arm. 
 
Injection schedule 
First vaccination visit 
1 month  
6 months  
AIDSVAX® B/E 
AIDSVAX® B/E 
AIDSVAX® B/E 
You will have to wait in the clinic for about a half hour after each injection to see 
if there are any problems. Then for that night and for 7 more days, you will need 
to keep track of how you are feeling and if you have any symptoms. Within 3 
days of each injection, we will also ask you how you are doing. Contact the clinic 
staff if you have any issues or concerns after getting an injection. If you have a 
problem, we will continue to check on you until it goes away. 
12. In addition to giving you the study product, we will: 
• Do regular HIV testing, as well as counseling on your results and on how to 
avoid getting HIV 
• Do physical exams 
• Do pregnancy tests if you were assigned female sex at birth 
• Ask questions about your health, including medications you may be taking 
• Ask questions about any personal problems or benefits you may have from 
being in the study 
• Assess your Lupus status 

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• 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 15 mL and 315 mL (1 tablespoon to 1½ cups). 
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.  
It is important that you contact the clinic if you have any symptoms between your 
vaccination and the next scheduled visit. If you think you are having a flare up, 
please contact the clinic as soon as possible. 
13. 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.  
14. The HVTN will test your samples to see how your immune system responds 
to the study product. 
We will send your samples (without your name) to labs approved by the HVTN 
for this study, which are located in the United States. In rare cases, some of your 
samples may be sent to labs approved by the HVTN in other countries for 
research related to this study. 
Researchers may also do genetic testing related to this study on your samples. 
Your genes are passed to you from your birth parents. They affect how you look 
and how your body works. The differences in people’s genes can help explain 
why some people get a disease while others do not. The genetic testing will only 
involve some of your genes, not all of your genes (your genome). The researchers 
will study only the genes related to the immune system and HIV and those that 
affect how people get HIV. 
If you become HIV infected, the researchers may look at all of the genes of the 
virus found in your samples. The researchers will use this information to learn 
more about HIV and the study product.  

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In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to contribute to this study.  
These tests done on your samples are for research purposes, not to check your 
health. The labs will not give the results to you or this clinic because their tests 
are not approved for use in making health care decisions. These labs are only 
approved to do research tests.  
When your samples are no longer needed for this study, the HVTN will continue 
to store them. 
Site: Delete next section if using separate consent for use of samples and information 
in other studies 
15. When samples are no longer needed for this study, the HVTN wants to use 
them in other studies and share them with other researchers.  
The HVTN calls these samples “extra samples”. The HVTN will only allow your 
extra samples to be used in other studies if you agree to this. You will mark your 
decision at the end of this form. If you have any questions, please ask. 
Do I have to agree? No. You are free to say yes or no, or to change your mind 
after you sign this form. At your request, we will destroy all extra samples that we 
have. Your decision will not affect your being in this study or have any negative 
consequences here.  
Where are the samples stored? Extra samples are stored in a secure central place 
called a repository. Your samples will be stored in the HVTN repository in the 
United States. 
How long will the samples be stored? There is no limit on how long your extra 
samples will be stored. [Site: Revise the previous sentence to insert limits if your 
regulatory authority imposes them.] 
Will I be paid for the use of my samples? No. Also, a researcher may make a new 
scientific discovery or product based on the use of your samples. If this happens, 
there is no plan to share any money with you. The researcher is not likely to ever 
know who you are. 
Will I benefit from allowing my samples to be used in other studies? Probably not. 
Results from these other studies are not given to you, this clinic, or your doctor. 
They are not part of your medical record. The studies are only being done for 
research purposes. 
Will the HVTN sell my samples and information? No, but the HVTN may share 
your samples with HVTN or other researchers. Once we share your samples and 
information, we may not be able to get them back. 

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How do other researchers get my samples and information? When a researcher 
wants to use your samples and information, their research plan must be approved 
by the HVTN. Also, the researcher’s institutional review board (IRB) or ethics 
committee (EC) will review their plan. [Site: If review by your institution’s 
IRB/EC/RE is also required, insert a sentence stating this.] IRBs/ECs protect the 
rights and well-being of people in research. If the research plan is approved, the 
HVTN will send your samples to the researcher’s location.  
What information is shared with HVTN or other researchers? The samples and 
information will be labeled with a code number. Your name will not be part of the 
information. However, some information that we share may be personal, such as 
your race, ethnicity, sex, health information from the study, and HIV status. We 
may share information about the study product you received and how your body 
responded to the study product.  
What kind of studies might be done with my extra samples and information? The 
studies will be related to HIV, vaccines, the immune system and other diseases.  
Researchers may also do genetic testing on your samples.  
In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to do research with them.  
If you agree, your samples could also be used for genome-ide studies. In these 
studies, researchers will look at all of your genes (your genome). The researchers 
compare the genomes of many people, looking for common patterns of genes that 
could help them understand diseases. The researchers may put the information 
from the genome-wide studies into a protected database so that other researchers 
can access it, but your name and other personal information will not be included. 
Usually, no one would be able to look at your genome and link it to you as a 
person. However, if another database exists that also has information on your 
genome and your name, someone might be able to compare the databases and 
identify you. If others found out, it could lead to discrimination or other problems. 
The risk of this is very small. There may be other unknown risks. 
Who will have access to my information in studies using my extra samples?  
People who may see your information are: 
• Researchers who use your extra samples and information for other research 
• Government agencies that fund or monitor the research using your extra 
samples and information 
• The researcher’s Institutional Review Board or Ethics Committee 
• Any regulatory agency that reviews clinical trials 

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• The people who work with the researcher  
All of these people will do their best to protect your information. The results of 
any new studies that use your extra samples and information may be published. 
No publication will use your name or identify you personally. 
16. We will do our best to protect your private information. 
Site: Check Health Insurance Portability and Accountability Act (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. You can remove the box around the text. 
We do need to share your name with the HVTN in case you need proof in the 
future that you participated in an HIV vaccine study. The HVTN will keep your 
name in a secure file with these items:  
• The name of your study  
• Your age or date of birth  
• Your study ID number  
• What study product 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 (NIH) and its study monitors, 
• The US Food and Drug Administration (FDA), 
• Any regulatory agency that reviews clinical trials 
• [Insert name of local IRB/EC] , 

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• [Insert name of local and/or national regulatory authority as appropriate], 
• Global Solutions for Infectious Diseases (GSID) 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 (OHRP). 
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] 
Site: Include the following boxed text. You can remove the box around the text. 
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. 

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17. 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 have more than a mild Lupus flare, 
• 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. 
18. We will stop your injections if you become pregnant.  
We will encourage you to stay in the study if you choose. We will discuss your 
study options with you. 
If you leave the study while you are still pregnant, we will contact you after your 
due date to ask some questions about your pregnancy and delivery. 
19. If you get infected with HIV during the study, we will stop your injections, 
take fewer samples, and help you get care and support. 
We will encourage you to stay in the study for up to 24 weeks if you choose. We 
will discuss your study options with you. 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 
20. There are other risks to being in this study. 
This section describes the other risks and restrictions we know about. There may 
also be unknown risks, even serious ones. We will tell you if we learn anything 
new that may affect your willingness to stay in the study. 
Risks of routine medical procedures: 

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In this study, we will do some routine medical procedures. These are taking blood 
and giving injections. These procedures can cause bruising, pain, fainting, 
soreness, redness, swelling, itching, a sore, bleeding, and (rarely) muscle damage 
or infection where you got the injection. Taking blood can cause a low blood cell 
count (anemia), making you feel tired. 
Personal problems/discrimination/testing HIV antibody positive: 
About 10 to 20% of people who join HVTN studies report personal problems or 
discrimination because of joining an HIV vaccine study. Family or friends may 
worry, get upset or angry, or assume that you are infected with HIV or at high risk 
and treat you unfairly as a result. Rarely, a person has lost a job because the study 
took too much time away from work, or because their employer thought they had 
HIV.  
The body makes antibodies to fight or prevent infection. Most vaccines cause the 
body to make antibodies as a way of preventing infection. Your body may make 
antibodies to HIV because you received an HIV 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 / is likely to]  say you have HIV, even if you don’t. For this reason, 
you should plan to get HIV tests only at this clinic during the study. Our tests can 
tell the difference between true HIV infection and a positive result that is caused 
by the study 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 

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

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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. 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 
21. The study may not benefit you. 
We do not expect that the study vaccine will benefit you in any way. We do not 
know if there will be benefit from this research for the larger community of 
people who have Lupus. 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. The information 
learned in this study will help to inform the larger field of HIV vaccine research. 
However, if the study vaccine later becomes approved and sold, there are no plans 
to share any money with you.  
Your rights and responsibilities 
22. If you join the study, you have rights and responsibilities. 
You have many rights that we will respect. You also have responsibilities. We list 
these in the Participant’s Bill of Rights and Responsibilities. We will give you a 
copy of it. 
Leaving the study 
23. Tell us if you decide to leave the study.  
You are free to leave the study at any time and for any reason. Your care at this 
clinic and your legal rights will not be affected, but it is important for you to let us 
know.  
We will ask you to come back to the clinic one last time for a physical exam, and 
we may ask to take some blood and urine samples. We will also ask about any 
personal problems or benefits you have experienced from being in the study. We 
believe these steps are important to protecting your health, but it is up to you 
whether to complete them. 

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Injuries 
Site: Approval from HVTN Regulatory Affairs (at vtn.core.reg@hvtn.org) is needed 
for any change (other than those that the instructions specifically request or those 
previously approved by HVTN Regulatory Affairs) to the boxed text. You can remove 
the box around the text. 
24. If you get sick or injured during the study, contact us immediately. 
Your health is important to us. (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 help you get care 
elsewhere by referring you for treatment. 
If you become sick or injured in this study, please tell your study doctor. There 
are no funds to pay for treatment of study-related injuries or Lupus flares 
(regardless of whether or not they are study related). Your insurance company 
may not be willing to pay for study-related injury or for Lupus flares that occur 
while you are in the study. If you have no insurance, you would be responsible for 
any costs. 
Questions  
25. If you have questions or problems at any time during your participation in 
this study, use the following important contacts. 
If you have questions about this study, contact 
[name or title and telephone number of the investigator or other study staff]. 
If you have any symptoms that you think may be related to this study, contact 
[name or title and telephone number of the investigator or other study staff]. 
This study has been reviewed and approved by a committee called the 
[name of local IRB/EC]. If you have questions about your rights as a research 
participant, or problems or concerns about how you are being treated in this study, 
contact [name or title and telephone number of person on IRB/EC] , at the 
committee. 
If you want to leave this study, contact 
[name or title and telephone number of the investigator or other study staff]. 
Your permissions and signature 
Site: Delete this section if using a separate consent for use of samples and 
information in other studies 
26. In Section 14 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 

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options below and write your initials or make your mark in the box next to it. 
Whatever you choose, the HVTN keeps track of your decision about how 
your samples and information can be used. You can change your mind after 
signing this form. 
 
 
I allow my extra samples and information to be used for other studies related to HIV, 
vaccines, the immune system, and other diseases. This may include genetic testing and 
keeping my cells growing over time.  
OR 
 
 
I agree to the option above and also to allow my extra samples and information to be 
used in genome wide studies. 
OR 
 
 
I do not allow my extra samples to be used in any other studies. This includes not 
allowing genetic testing, growing more of my cells, or genome wide studies.  
 
27. If you agree to join this study, you will need to sign or make your mark 
below. Before you sign or make your mark on this consent form, make sure 
of the following: 
• You have read this consent form, or someone has read it to you. 
• You feel that you understand what the study is about and what will happen to 
you if you join. You understand what the possible risks and benefits are. 
• You have had your questions answered and know that you can ask more. 
• You agree to join this study. 
 
You will not be giving up any of your rights by signing this consent form. 
 
 
 
 
 
 
 
Participant’s name (print) 
 
Participant’s signature or mark 
 
Date 
 
Time 
 
 
 
 
 
 
 
Clinic staff conducting consent 
discussion (print) 
 
Clinic staff signature 
 
Date 
 
Time 
For participants who are unable to read or write, a witness should complete the 
signature block below: 

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Witness’s name (print) 
 
Witness’s signature  
 
Date 
 
Time 
*Witness is impartial and was present for the entire discussion of this consent form. 
 
 

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Appendix B 
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 can remove the box around the text. 
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 after your last required protocol clinic visit.  
Effective birth control means using any of the following methods every time you 
have sex: 
• Birth control drugs that prevent pregnancy—given by pills, shots, patches, 
vaginal rings, or inserts under the skin; 
• Male or female condoms, with or without a cream or gel that kills sperm; 
• Diaphragm or cervical cap with a cream or gel that kills sperm; 
• Intrauterine device (IUD); or 
• Any other contraceptive method approved by the researchers. 
You do not have to use birth control if: 
• You are only having sex with a partner or partners who have had a vasectomy. 
(We will ask you some questions to confirm that the vasectomy was 
successful.); 
• You have reached menopause, with no menstrual periods for one year; 
• You have had a hysterectomy (your uterus removed); 
• You have had your ovaries removed; 
• You have a tubal ligation (your “tubes tied”) or confirmed successful 
placement of a product that blocks the fallopian tubes; 
• You are having sex only with a partner(s) assigned female sex at birth; 
• You only have oral sex; or, 
• You are sexually abstinent (no sex at all). 
Remember: If you are having sex, male and female condoms are the only birth 
control methods that also provide protection against HIV and other sexually 
transmitted infections. 
If you join the study, we will test you for pregnancy at some visits, including 
before each study injection. 

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Appendix C 
Sample consent form for use of samples and 
information in other studies 
Title: A phase 1b open label clinical trial to evaluate HIV-1 neutralization 
antibody breadth in response to HIV gp120 protein vaccine in HIV-uninfected 
adults with quiescent Systemic Lupus Erythematosus 
HVTN protocol number: HVTN 121 
Site: [Insert site name] 
When samples are no longer needed for this study, the HVTN wants to use them 
in other studies and share them with other researchers. The HVTN calls these 
samples “extra samples.” The HVTN will only allow your extra samples to be 
used in other studies if you agree to this. You will mark your decision at the end 
of this form. If you have any questions, please ask. 
1. Do I have to agree?  
No. You are free to say yes or no, or to change your mind after you sign this form. 
At your request, we will destroy all extra samples that we have. Your decision 
will not affect your being in this study or have any negative consequences here. 
2. Where are the samples stored?  
Extra samples are stored in a secure central place called a repository. Your 
samples will be stored in the HVTN repository in the United States. 
3. How long will the samples be stored?  
There is no limit on how long your extra samples will be stored. [Site: Revise the 
previous sentence to insert limits if your regulatory authority imposes them.] 
4. Will I be paid for the use of my samples?  
No. Also, a researcher may make a new scientific discovery or product based on 
the use of your samples. If this happens, there is no plan to share any money with 
you. The researcher is not likely to ever know who you are. 
5. Will I benefit from allowing my samples to be used in other studies?  
Probably not. Results from these other studies are not given to you, this clinic, or 
your doctor. They are not part of your medical record. The studies are only being 
done for research purposes. 

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

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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 
employers from seeing results of genetic testing when deciding about giving you 
health insurance or offering you work. GINA does not help or protect you against 
discrimination by companies that sell life, disability, or long-term care insurance.  
11. Who will have access to my information in studies using my extra samples? 
People who may see your information are: 
• Researchers who use your extra samples and information for other research 
• Government agencies that fund or monitor the research using your extra 
samples and information 
• The researcher’s Institutional Review Board or Ethics Committee 
• Any regulatory agency that reviews clinical trials 
• The people who work with the researcher  
All of these people will do their best to protect your information. The results of 
any new studies that use your extra samples and information may be published. 
No publication will use your name or identify you personally. 
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]. 

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

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Appendix 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 
1 
month 
5 
weeks 
6 
weeks 
3 
months 
6 
months 
6 ¼  
months 
6.5 
months 
7.5 
months2 
8.5 
months 
12 
months 
Injection 
 
√ 
 
 
√ 
 
 
 
√ 
 
 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
Urine test 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
 
Blood drawn 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
Pregnancy test (participants 
assigned female sex at birth)1 
√ 
√ 
 
 
√ 
 
 
 
√ 
 
 
 
 
 
HIV testing and pretest 
counseling 
√ 
 
 
 
 
 
√ 
 
 
 
√ 
 
 
√ 
Risk reduction counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
SLE status assessment 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
 
Interview/ questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
Health assessment contact 
 
 
 
 
 
 
 
 
 
 
 
√ 
 
 
1Persons who had a total hysterectomy (removal of the uterus) or removal of both ovaries (verified by medical records), are not required to have a pregnancy test. 
2Clinic staff and study participants will be in contact to collect information about their health. 
 

HVTN 121 Version 2.0 / September 14, 2018 
HVTN121_v2.0_FINAL / Page 116 of 123 
Appendix E 
Laboratory procedures 
 
1 CSR = Central Specimen Repository; UW-VSL = University of Washington Virology Specialty Laboratory (Seattle, Washington, USA). 
2 HVTN Laboratories include FHCRC = Fred Hutchinson Cancer Research Center (Seattle, Washington, USA); Duke = Duke University Medical Center (Durham, North Carolina, USA). 
Visit:
1
2
3
4
5
6
7
8
9
10
11
1211
13
14
Day:
D0
D7
D14
D28
D35
D42
D84
D168
D175
D182
D210
D238
D364
Month:
M0
M0.25
M0.5
M1
M1.25
M1.5
M3
M6
M6.25
M6.5
M7.5
M8.5
M12
AIDSVAX 
B/E
AIDSVAX 
B/E
AIDSVAX 
B/E
Procedure
Ship to1
Tube4
Tube size
(vol. capacity)4
BLOOD COLLECTION
Screening or diagnostic assays
     Screening HIV test
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     HBsAg/anti-HCV
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     Syphilis
Local Lab
Local Lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     HIV diagnostics 9
UW-VSL
UW-VSL
EDTA
10mL
—
—
—
—
—
—
10
—
—
—
10
—
—
209
40
Safety labs12
     Hb A1C
Local lab
Local lab
EDTA
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
5
     CBC/ Diff/ platelets
Local lab
Local lab
EDTA
5mL
5
5
5
5
5
5
5
5
5
5
5
—
5
—
60
     Chemistry panel5
Local lab
Local lab
SST
5mL
5
—
—
5
—
—
5
5
—
—
5
—
5
—
30
     Complement profile C3/C4/CH50
Local lab
Local lab
SST
5mL
5
5
5
5
5
5
5
5
5
5
5
—
5
—
60
     Anti-dsDNA
Local lab
Local lab
SST
5mL
5
5
5
5
5
5
5
5
5
5
5
—
5
—
60
Immunogenicity assays 6
     Host genetics 7
CSR
HVTN Labs
ACD
8.5mL
—
17
—
—
—
—
—
—
—
—
—
—
—
—
17
     Cellular assays
          ICS
CSR
HVTN Labs
ACD
8.5mL
—
25.5
—
—
—
—
—
—
—
—
25.5
—
—
25.5
76.5
          T and B cell phenotyping
CSR
HVTN Labs
ACD
8.5mL
—
34
—
—
—
42.5
17
—
42.5
42.5
34
—
—
34
246.5
          Memory B cell sorts and recombinant Ab production
CSR
Non-HVTN Labs at 
Duke-DHVI 
ACD
8.5mL
—
—
—
—
—
—
25.5
—
—
—
25.5
—
—
51
102
          Plasma cell sorts for B cell repertoire analysis
CSR
Non-HVTN Labs at 
Duke-DHVI 
ACD
8.5mL
—
—
—
—
—
—
—
—
—
25.5
—
—
—
—
25.5
     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
          ADCC
CSR
HVTN Labs
SST
8.5mL
—
y
—
—
—
—
y
—
y
—
y
—
—
y
0
          bnAb epitope binding and blocking assays
CSR
Non-HVTN Labs at 
Duke-DHVI 
ACD
8.5mL
—
z
—
—
—
z
z
—
z
z
z
—
—
z
0
Innate immunity
          Serum cytokines
CSR
HVTN Labs
SST
5mL
—
5
—
—
—
5
5
—
5
5
5
—
—
5
35
Sequencing
          Next generation sequencing for VH and VL
CSR
Non-HVTN Labs at 
Duke-DHVI 
ACD
8.5mL
—
25.5
—
—
—
—
25.5
—
—
25.5
25.5
—
—
25.5
127.5
          RNAseq of Tfh and B cell populations
CSR
Non-HVTN Labs at 
Duke-DHVI 
ACD
8.5mL
—
25.5
—
—
—
—
25.5
—
—
25.5
25.5
—
—
25.5
127.5
Specimen storage
     PBMC
CSR
ACD
8.5mL
127.5
17
—
—
—
—
—
—
17
42.5
17
—
—
85
306
     Plasma
CSR
ACD
8.5mL
z
z
—
—
—
z
z
—
z
z
z
—
—
z
0
     Serum
CSR
SST
8.5mL
17
—
—
—
—
—
—
—
—
—
—
—
—
8.5
25.5
Visit total
185
182
15
20
15
63
146
20
97
182
205
0
20
297
1444
56-Day total
185
366
381
401
416
479
480
243
97
278
483
483
225
297
URINE COLLECTION12
      Urinalysis with microscopy10
Local lab
Local lab
X
X
X
X
X
X
X
X
X
X
X
—
X
—
      Spot urine protein:creatinine ratio
Local lab
Local lab
X
X
X
X
X
X
X
X
X
X
X
—
X
—
      Pregnancy test8
Local lab
Local lab
X
X
—
—
X
—
—
—
X
—
—
—
—
—
Total
Screening 
visit3
Assay Location2
Tube volume (mL)

HVTN 121 Version 2.0 / September 14, 2018 
HVTN121_v2.0_FINAL / Page 117 of 123 
 Non-HVTN laboratory: Duke Human Vaccine Institute (Durham, North Carolina, USA). 
3 Screening may occur over the course of several contacts/visits up to and including before vaccination on day 0. Storage specimens should be drawn no later than Day -15. 
4 Local labs may assign appropriate alternative tube types for locally performed tests. 
5 Chemistry panels are defined in Section 9.2 (pre-enrollment) and Section 9.4 (Follow-up visits).  
6 Immunogenicity assays will be performed at M0, M1.25, M1.5, M6.25, 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 (ie, assigned female sex at birth), pregnancy test must be performed on urine or blood specimens within 24 hours of vaccination with negative results received 
prior to vaccination. Persons who have undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing. 
9 At an early termination visit for a withdrawn or terminated participant who is not HIV-infected (see Section 9.10), blood should be drawn for HIV diagnostic testing, as shown for visit 14 above. If a 
participant has a confirmed diagnosis of HIV infection, do not collect blood for HIV diagnostic testing (see Section 9.12). 
10 Urinalysis with microscopy is defined in Sections 7.1, 9.2, and 9.7. 
11 For information concerning the visit 12 health assessment contact, see Section 9.4 and HVTN 121 SSP. 
12 For participants with confirmed diagnosis of HIV infection, only specimens required for protocol-specified safety laboratory tests, urinalysis, spot urine protein:creatinine ratio, and pregnancy tests 
will be collected. 
y = SST collected for binding Ab and neutralizing Ab assays will also cover specimen needs for ADCC; no separate blood draw is needed. 
z = Up to 10 x 1mL aliquots of ACD plasma will be harvested during PBMC processing; no separate blood draw is needed.  

HVTN 121 Version 2.0 / September 14, 2018 
HVTN121_v2.0_FINAL / Page 118 of 123 
Appendix F 
Procedures at HVTN CRS 
Visit: 
011  
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
Day: 
 
D0 
D7 
D14 
D28 
D35 
D42 
D84 
D168 
D175 
D182 
D210 
D238 
D364 
Month: 
 
M0 
M0.25 
M0.5 
M1 
M1.25 
M1.5 
M3 
M6 
M6.25 
M6.5 
M7.5 
M8.5 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
X 
X 
Risk reduction counseling3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
X 
X 
Pregnancy prevention 
assessment4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
X 
X 
Behavioral risk assessment5 
X 
— 
— 
— 
— 
— 
— 
X 
X 
— 
— 
— 
X 
X 
Confirm eligibility, obtain 
demographics 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Social impact assessment 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
X 
X 
Social impact assessment 
questionnaire 
— 
— 
— 
— 
— 
— 
— 
X 
X 
— 
— 
— 
— 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
X 
X 
Intercurrent illness/adverse 
experience 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
X 
X 
HIV infection assessment6 
X 
— 
— 
— 
— 
— 
X 
— 
— 
— 
X 
— 
— 
X 
Confirm HIV test results 
provided to participant 
— 
X 
— 
— 
— 
— 
— 
X 
— 
— 
— 
— 
X 
— 
SLE status 
assessment/functional 
assessment7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
X 
— 
Health assessment contact8 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
Local lab assessment9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis and spot urine 
protein;creatinine ratio 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
X 
— 

HVTN 121 Version 2.0 / September 14, 2018 
HVTN121_v2.0_FINAL / Page 119 of 123 
Visit: 
011  
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
Day: 
 
D0 
D7 
D14 
D28 
D35 
D42 
D84 
D168 
D175 
D182 
D210 
D238 
D364 
Month: 
 
M0 
M0.25 
M0.5 
M1 
M1.25 
M1.5 
M3 
M6 
M6.25 
M6.5 
M7.5 
M8.5 
M12 
Procedure 
Scr. 
VAC1 
 
 
VAC2 
 
 
 
VAC3 
 
 
 
 
 
Pregnancy (urine or serum 
HCG)10 
X 
X 
— 
— 
X 
— 
— 
— 
X 
— 
— 
— 
— 
— 
CBC, differential/platelets 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
X 
— 
Chemistry panel (see Section 
9.2) 
X 
— 
— 
X 
— 
— 
X 
X 
— 
— 
X 
— 
X 
— 
Syphilis, Hepatitis B, 
Hepatitis C 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Complement profile 
(C3/C4/CH50) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
X 
— 
Anti-dsDNA  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
X 
— 
Vaccination procedures11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination12 
— 
X 
— 
— 
X 
— 
— 
— 
X 
— 
— 
— 
— 
— 
Reactogenicity assessments13 
— 
X 
— 
— 
X 
— 
— 
— 
X 
— 
— 
— 
— 
— 
1 Enrollment and screening visits can occur on the same day 
2 For specimen collection requirements, see Appendix E. 
3 Includes transmission risk reduction counseling for HIV-infected participants. 
4 Pregnancy prevention assessment is required only for participants who were assigned female sex at birth and are capable of becoming pregnant. 
5 Not applicable to HIV-infected participants. 
6 Includes pre-test counseling and HIV testing. A subsequent follow-up contact is conducted to provide post-test counseling and to report results to participant. If a participant has a confirmed 
diagnosis of HIV infection, do not perform HIV infection assessment. 
7 SELENA-SLEDAI, RAPID3. SLICC/ACR at screening only. 
8 CRS staff and study participants will be in contact to collect information about their health (see HVTN 121 SSP). 
9 For participants with a confirmed diagnosis of HIV infection, only specimens listed under “Safety labs,” urinalysis, spot urine protein:creatinine ratio, and pregnancy tests specified in Appendix E 
will be collected. 
10 For a participant who was assigned female sex at birth, pregnancy test must be performed on the day of vaccination 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, in 
accordance with local regulatory requirements. 
11 Not applicable to HIV-infected participants. 
12 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. 
13 Reactogenicity assessments performed daily for at least 7 days postvaccination (see Section 9.8) 

HVTN 121 Version 2.0 / September 14, 2018 
HVTN121_v2.0_FINAL / Page 120 of 123 
Appendix G 
SELENA-SLEDAI Instrument 
 
Categorize as “Mild or Moderate” Flare or “Severe” Flare if the patient has at least one of the listed criteria in that category: 
Mild or Moderate Flare □ 
Severe Flare □ 
□ Increase in SLEDAI ≥ 3 points, but not > 12 
□ Increase to a SLEDAI > 12 
□ New/worse: 
• Discoid, photosensitive, profundus, 
        cutaneous vasculitis, bullous lupus 
• Nasopharyngeal ulcers 
• Pleuritis 
• Pericarditis 
• Arthritis 
• Fever (SLE) 
□ New/worse:  
• CNS-SLE 
• Vasculitis 
• Nephritis 
• Myositis 
• Platelet count < 60,000 (equivalent to 60 x 109/L) 
• Hemolytic anemia: Hemoglobin <7.0 g/dL or decrease in Hemoglobin >3.0 g/dL 
Requiring a doubling of prednisone dose, or prednisone increase to >0.5 
mg/kg/day, and/or hospitalization  
□ Increase in prednisone, but not to >0.5 mg/kg/day 
□ Increase in prednisone to >0.5 mg/kg/day 
□ Added NSAID or Plaquenil (hydroxychloroquine) for SLE 
activity 
□ New Cytoxan (cyclophosphamide), Azathioprine, Methotrexate for SLE activity 
□ Hospitalization for SLE activity 
□ ≥1.0 Increase in Physician’s Global Assessment (PGA) 
score, but not to more than 2.5 
□ Increase in Physician’s Global Assessment (PGA) score to > 2.5 
 

HVTN 121 Version 2.0 / September 14, 2018 
HVTN121_v2.0_FINAL / Page 121 of 123 
Appendix H 
HVTN low risk guidelines for the US 
 

HVTN 121 Version 2.0 / September 14, 2018 
HVTN121_v2.0_FINAL / Page 122 of 123 
 

HVTN 121 Version 2.0 / September 14, 2018 
HVTN121_v2.0_FINAL / Page 123 of 123 
Appendix I 
Protocol signature page 
A phase 1b open label clinical trial to evaluate HIV-1 neutralization antibody breadth in response 
to HIV gp120 protein vaccine in HIV-uninfected adults with quiescent Systemic Lupus 
Erythematosus 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (U.S.) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (eg, U.S. National Institutes of Health, Division of AIDS) and 
institutional policies 
 
 
 
 
 
 
 
 
 
Investigator of Record (print name) 
 
Signature of Investigator of Record 
 
Date 
 
 
DAIDS Protocol Number: HVTN 121 
DAIDS Protocol Version: 2.0 
Protocol Date: September 14, 2018