A Phase 2b Study to Evaluate the Safety and Efficacy of VRC01 Broadly Neutralizing Monoclonal Antibody in Reducing Acquisition of HIV-1 Infection Among Men and Transgender Persons Who Have Sex With Men
Phase: PHASE2
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
PROTOCOL 
HVTN 704/HPTN 085 
A phase 2b study to evaluate the safety and 
efficacy of VRC01 broadly neutralizing monoclonal 
antibody in reducing acquisition of HIV-1 infection 
among men and transgender persons who have sex 
with men  
DAIDS DOCUMENT ID 30095 
IND 113,611 HELD BY DAIDS 
CLINICAL TRIAL SPONSORED BY 
Division of AIDS (DAIDS) 
National Institute of Allergy and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
Department of Health and Human Services (DHHS) 
Bethesda, Maryland, USA 
STUDY PRODUCT(S) PROVIDED BY 
Dale and Betty Bumpers Vaccine Research Center (VRC), NIAID, NIH, DHHS 
Bethesda, Maryland, USA 
June 15, 2017 
HVTN 704/HPTN 085 
Version 3.0 

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Contents 
1 
Overview .................................................................................................................. 5 
1.1 
Protocol Team ................................................................................................ 8 
2 
Background ............................................................................................................ 11 
2.1 
Rationale for trial concept ........................................................................... 11 
2.2 
bnAbs to HIV-1 ........................................................................................... 12 
2.3 
VRC01: VRC-HIVMAB060-00-AB ........................................................... 14 
2.4 
Trial design rationale ................................................................................... 15 
2.5 
Combination Prevention for HIV acquisition .............................................. 20 
2.6 
Plans for future product development and testing ....................................... 23 
2.7 
Preclinical safety studies .............................................................................. 23 
2.8 
Nonhuman primate (NHP) studies of VRC01 ............................................. 26 
2.9 
Clinical trial experience ............................................................................... 28 
2.10 Potential risks of study products and administration ................................... 35 
3 
Objectives and endpoints ....................................................................................... 38 
3.1 
Primary objectives and endpoints ................................................................ 38 
3.2 
Secondary objectives and endpoints ............................................................ 38 
3.3 
Exploratory objectives ................................................................................. 39 
4 
Statistical considerations ........................................................................................ 40 
4.1 
Outline of the statistical considerations section ........................................... 40 
4.2 
PE parameter for the primary analysis of prevention efficacy .................... 40 
4.3 
PE parameters for secondary analyses of prevention efficacy ..................... 41 
4.4 
Statistical rationale for the 3-arm design compared to a 2-arm design ........ 42 
4.5 
Use of safety run-in data in the analyses of prevention efficacy ................. 43 
4.6 
Sample size calculations for testing for overall PE (Primary objective 2) .. 43 
4.7 
Power for the secondary analysis comparing HIV-1 incidence between the 
10 mg/kg mAb group versus the 30 mg/kg mAb group .............................. 51 
4.8 
Sample size calculations for safety .............................................................. 52 
4.9 
Monitoring of the trial ................................................................................. 54 
4.10 Assessment of PrEP use............................................................................... 58 
4.11 Randomization ............................................................................................. 58 
4.12 Blinding ....................................................................................................... 58 
4.13 Statistical analyses ....................................................................................... 59 
5 
Selection and withdrawal of participants ............................................................... 72 
5.1 
Inclusion criteria .......................................................................................... 72 
5.2 
Exclusion criteria ......................................................................................... 74 
5.3 
Participant departure from infusion schedule or withdrawal ....................... 75 
6 
Study product preparation and administration ....................................................... 78 
6.1 
Study product regimen ................................................................................. 78 
6.2 
Study product formulation ........................................................................... 78 
6.3 
Preparation of study products ...................................................................... 79 
6.4 
Administration ............................................................................................. 81 
6.5 
Acquisition of study products ...................................................................... 82 
6.6 
Pharmacy records......................................................................................... 82 
6.7 
Final disposition of study products .............................................................. 82 
7 
Clinical procedures ................................................................................................ 83 
7.1 
Informed consent ......................................................................................... 83 

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7.2 
Pre-enrollment procedures ........................................................................... 85 
7.3 
Enrollment and infusion visits ..................................................................... 86 
7.4 
Post-infusion visits for HIV-uninfected study participants ......................... 87 
7.5 
HIV counseling and testing ......................................................................... 88 
7.6 
Follow-up visits for HIV-infected participants ............................................ 89 
7.7 
Follow-up visits for participants who discontinue infusions for reasons other 
than HIV infection ....................................................................................... 90 
7.8 
Contraception status..................................................................................... 90 
7.9 
Urine testing ................................................................................................ 91 
7.10 Assessments of reactogenicity ..................................................................... 91 
7.11 Visit windows and missed visits .................................................................. 92 
7.12 Early termination visit ................................................................................. 92 
7.13 Pregnancy .................................................................................................... 93 
8 
HIV infection assessment and clinical response .................................................... 94 
8.1 
HIV symptom assessment ............................................................................ 94 
8.2 
HIV screening test (prior to randomization) ................................................ 94 
8.3 
HIV testing postinfusion .............................................................................. 94 
8.4 
Endpoint adjudication .................................................................................. 95 
8.5 
HIV infection during the study .................................................................... 95 
8.6 
Medical care for participants who become HIV infected ............................ 96 
9 
Laboratory .............................................................................................................. 97 
9.1 
CRS laboratory procedures .......................................................................... 97 
9.2 
Total blood volume ...................................................................................... 97 
9.3 
Assay timepoints .......................................................................................... 97 
9.4 
VRC01 mAb levels ...................................................................................... 97 
9.5 
Endpoint assays: humoral ............................................................................ 98 
9.6 
ARV detection ............................................................................................. 98 
9.7 
Host (human) genotyping ............................................................................ 98 
9.8 
Lab assay algorithm ..................................................................................... 99 
9.9 
Possible additional studies ........................................................................... 99 
9.10 Other use of stored specimens ..................................................................... 99 
9.11 Biohazard containment ................................................................................ 99 
10 
Safety monitoring and safety review ................................................................... 101 
10.1 Safety monitoring and oversight ................................................................ 101 
10.2 Safety reporting ......................................................................................... 102 
10.3 Safety pause and prompt PSRT AE review ............................................... 105 
10.4 Review of cumulative safety data .............................................................. 106 
10.5 Study termination....................................................................................... 106 
10.6 Social impact reporting .............................................................................. 107 
11 
Protocol conduct .................................................................................................. 108 
11.1 Emergency communication with study participants .................................. 109 
12 
Ethical considerations .......................................................................................... 110 
13 
IRB/EC/RE review considerations....................................................................... 112 
13.1 Minimized risks to participants ................................................................. 112 
13.2 Reasonable risk/benefit balance ................................................................ 113 
13.3 Equitable subject selection ........................................................................ 113 
13.4 Appropriate informed consent ................................................................... 113 
13.5 Adequate safety monitoring ....................................................................... 113 
13.6 Protect privacy/confidentiality ................................................................... 114 

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14 
Version history ..................................................................................................... 115 
15 
Document references (other than literature citations) .......................................... 118 
16 
Acronyms and abbreviations ................................................................................ 120 
17 
Literature cited ..................................................................................................... 123 
Appendix A Sample informed consent form .................................................................. 137 
Appendix B Approved birth control methods for transgender men (for sample informed 
consent form) .................................................................................................................. 156 
Appendix C Sample consent form for use of samples and information in other studies 157 
Appendix D Tables of procedures (for sample informed consent form) ........................ 161 
Appendix E Sample consent form for participants with HIV infection at enrollment or 
during the study .............................................................................................................. 163 
Appendix F Schedule 1—Laboratory procedures for HIV-uninfected participants ...... 167 
Appendix G Schedule 2—Laboratory procedures for HIV-1–infected participants ...... 168 
Appendix H Schedule 3―Laboratory procedures for participants discovered to have 
been HIV-1–infected at enrollment or who become HIV-2–infected ............................. 169 
Appendix I Schedule 4―Laboratory procedures for participants who discontinue 
infusions for reasons other than HIV infection ............................................................... 170 
Appendix J Schedule 1―Procedures at CRS for HIV-uninfected participants ............ 171 
Appendix K Schedule 2―Procedures at CRS for HIV-1–infected participants ............ 172 
Appendix L Schedule 3―Procedures at CRS for participants discovered to have been 
HIV-1–infected at enrollment or who become HIV-2–infected ..................................... 173 
Appendix M Schedule 4―Procedures at CRS for participants who discontinue infusions 
for reasons other than HIV infection .............................................................................. 174 
Appendix N Protocol Signature Page ............................................................................. 175 
 

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1 
Overview 
Title  
A phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing 
monoclonal antibody in reducing acquisition of HIV-1 infection among men and 
transgender persons who have sex with men  
Primary objectives 
 
 
To evaluate the safety and tolerability of VRC01 mAb administered through IV 
infusion in MSM+TG 
 
To determine if the VRC01 mAb prevents HIV-1 infection and to estimate the level 
of efficacy in MSM+TG  
MSM = men who have sex with men. TG = male-to-female and female-to-male transgender 
persons. 
Study products and routes of administration 
 
VRC01: human monoclonal antibody (mAb) VRC-HIVMAB060-00-AB in 
formulation buffer at pH 5.8 in sufficient normal saline (Sodium Chloride for 
Injection 0.9%, USP) to be administered at a final volume of 150 mL intravenously 
(IV) 
 
Control for VRC01: Sodium Chloride for Injection 0.9%, USP administered at a 
volume of 150 mL IV 
Table 1-1 Schema 
 
 
 
Infusion schedule (Weeks) 
[A = VRC01 infusion; C = Control infusion] 
 
Treatment 
N* 
W0 
W8 
W16 
W24 
W32 
W40 
W48 
W56 
W64 
W72 
W80♦ 
W104† 
Group 
1 
VRC01  
10 mg/kg  
900 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
 
 
Group 
2 
VRC01  
30 mg/kg  
900 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
 
 
Group 
3 
Control 
900 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
 
 
 
 Total: 2700 (900 VRC01 30 mg/kg; 900 VRC01 10 mg/kg; 900 control) 
* Due to the randomization scheme, the numbers of VRC01 and control recipients may differ slightly. 
♦ Week 80 is the last study visit for the primary endpoint analysis of prevention efficacy. 
† Week 104 is the last study visit for the co-primary endpoint analysis of safety and tolerability. 
Interim safety assessments will be performed for participants who reach the Week 16 
visit by November 19, 2016 and also through the Week 24 visit for the first 450 enrolled 
participants. Infusions and enrollment will continue while these interim safety 
assessments are conducted. The interim safety reports will be submitted to the DSMB and 
to the US FDA.  

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Participants 
2700 HIV-1–uninfected MSM and TG who have sex with men or TG, aged 18 to 50 
years, in North America, South America, and Switzerland 
Design 
Multicenter, randomized, controlled, double-blind trial 
Duration per participant 
24 months of scheduled clinic visits  
Estimated total study duration 
62 months (includes enrollment and follow-up, including follow-up for HIV-infected 
participants) 
Investigational New Drug (IND) sponsor 
DAIDS, NIAID, NIH, DHHS (Bethesda, Maryland, USA) 
Study product providers 
Dale and Betty Bumpers Vaccine Research Center (VRC), NIAID, NIH, DHHS 
(Bethesda, Maryland, USA) 
Core operations 
HIV Vaccine Trials Network (HVTN) Leadership Group/Core Operations Center, Fred 
Hutchinson Cancer Research Center (FHCRC) (Seattle, Washington, USA) 
HIV Prevention Trials Network (HPTN) Leadership and Operations Center (LOC), 
FHI360 (Durham, North Carolina, USA) 
Statistical and data management center (SDMC) 
Statistical Center for HIV/AIDS Research and Prevention (SCHARP), FHCRC (Seattle, 
Washington, USA) 
DF/Net Research (Seattle, Washington, USA) 
Endpoint assay laboratories 
 
University of Washington Virology Specialty Laboratory (UW-VSL) (Seattle, 
Washington, USA) 
 
Duke University Medical Center (Durham, North Carolina, USA)  
 
FHCRC/University of Washington (Seattle, Washington, USA) 
 
South Africa Immunology Laboratory, National Institute for Communicable Diseases 
(SAIL-NICD) (Johannesburg, South Africa) 

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 
NIAID Vaccine Immune T-Cell Antibody Laboratory (NVITAL) (Gaithersburg, 
Maryland, USA) 
 
(NIAID) Vaccine Research Center (VRC) (Bethesda, Maryland, USA) 
 
HPTN Laboratory Center, Johns Hopkins University (JHU) (Baltimore, Maryland, 
USA) 
 
University of Colorado, Denver (Aurora, Colorado, USA) 
 
Peru CTU Laboratory (Lima, Peru) 
 
CADIG - Immunodiagnostic Lab (INI-FIOCRUZ) (Rio de Janeiro, Brazil) 
Study sites 
Clinical Research Sites (CRSs) to be specified in the Site Announcement Memo 
Safety monitoring 
HVTN 704/HPTN 085 Protocol Safety Review Team (PSRT); NIAID Data and Safety 
Monitoring Board (DSMB) 

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1.1 
Protocol Team 
Protocol leadership 
Chair 
Lawrence Corey 
HVTN; FHCRC  
206-667-6770 
lcorey@fhcrc.org 
Statisticians 
Allan DeCamp 
SCHARP, FHCRC 
206-667-7892 
adecamp@scharp.org 
Chair 
Myron Cohen 
HPTN; University of 
North Carolina 
919-966-2536 
mscohen@med.unc.edu  
 
Peter Gilbert 
SCHARP, FHCRC 
206-667-7299 
pgilbert@scharp.org 
Cochairs 
Srilatha Edupuganti 
Emory University 
404-712-1434 
sedupug@emory.edu 
 
Michal Juraska 
SCHARP, FHCRC 
206-667-5568 
mjuraska@scharp.org 
 
Nyaradzo Mgodi 
UZ-UCSF 
Collaborative Research 
Programme, Harare, 
Zimbabwe 
263-4-704890 
nmmgodi@uz-
ucsf.co.zw 
 
Deborah Donnell 
SCHARP, FHCRC 
206-667-5661 
deborah@scharp.org 
Protocol Team 
leader 
Shelly Karuna 
HVTN Core, FHCRC 
206-667-4355 
skaruna@hvtn.org 
Medical officers 
Margarita Gomez 
Lorenzo 
Vaccine Research 
Program (VRP), DAIDS, 
NIAID 
240-627-3510 
gomezmm@niaid.nih.gov 
HVTN Laboratory 
lead 
John Hural 
HVTN Laboratory 
Program 
206-667-1683 
jhural@hvtn.org 
 
David Burns 
Prevention Sciences 
Program (PSP), DAIDS, 
NIAID 
301-435-8896 
burnsda@niaid.nih.gov 
 
 
 
 
Other contributors to the original protocol 
HVTN Core 
medical monitor 
Shelly Karuna 
HVTN Core, FHCRC 
DAIDS Protocol 
pharmacist 
Katherine Shin 
DAIDS, NIAID 
240-627-3047 
Bioethics 
consultant 
Mark Barnes 
HPTN Ethics Working Group 
HVTN Regional 
medical liaison, 
Southern Africa 
Simba Takuva 
HVTN Core, FHCRC 
HVTN/HPTN 
Consultative 
investigators 
Ken Mayer 
Fenway Health, Boston, USA 
 
 
 

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LaRon Nelson 
Univ. of Rochester Rochester, 
NY, USA 
HVTN Regional 
medical liaison, South 
America 
Robert De La Grecca 
HVTN Core, FHCRC 
 
Manuel Villarán 
IMPACTA, Lima, Peru 
HVTN Clinical safety 
specialist 
Maija Anderson 
HVTN Core, FHCRC 
 
Sinead Delany-Moretlwe  
Wits Reproductive Health 
and HIV Institute, 
Johannesburg, South Africa 
HVTN Statistical 
research associates 
Nidhi Kochar 
SCHARP, FHCRC 
Product developer 
representatives 
John Mascola 
VRC 
 
Abby Isaacs 
SCHARP, FHCRC 
 
Barney Graham 
VRC 
 
Jing Wang 
SCHARP, FHCRC 
 
Julie Ledgerwood 
VRC 
HVTN Social 
behavioral scientist 
Michele Andrasik 
HVTN Core, FHCRC 
HVTN Laboratory 
Program 
representatives 
On Ho 
HVTN Laboratory Program, 
FHCRC 
HPTN LOC director 
Nirupama Sista 
HPTN LOC, FHI360 
 
David Montefiori  
HVTN Laboratory Program, 
Duke Univ., Durham, NC, 
USA 
HPTN Clinical research 
managers 
Philip Andrew 
HPTN LOC, FHI360 
 
Robert Coombs  
University of Washington 
Virology Specialty 
Laboratory, Seattle, WA, 
USA 
 
Elizabeth Greene 
HPTN LOC, FHI360 
HPTN Laboratory 
Center 
representatives 
Susan Eshleman 
HPTN Laboratory Center 
(LC), Johns Hopkins Univ., 
Baltimore, MD, USA 
HVTN Clinical trials 
manager 
Carissa Karg 
HVTN Core, FHCRC 
 
Vanessa Cummings 
HPTN LC, Johns Hopkins 
Univ. 
HPTN SDMC Associate 
director 
Lynda Emel 
SCHARP, FHCRC 
 
Estelle Piwowar-Manning 
HPTN LC, Johns Hopkins 
Univ. 
HVTN SDMC Program 
manager 
Gina Escamilla 
SCHARP, FHCRC 
HVTN Regulatory 
affairs 
Megan Brandon 
HVTN Core, FHCRC 
HVTN Protocol 
development manager 
Carter Bentley 
HVTN Core, FHCRC 
Clinic coordinators 
Debora Dunbar 
University of Pennsylvania, 
Philadelphia, PA, USA 
HVTN Communications 
unit representative 
Jim Maynard  
HVTN Core, FHCRC 
 
Ana Patricia Rimachi Quiroz 
Asociación Civil Selva 
Amazónica, Iquitos, Peru 
HVTN Community 
engagement unit 
representative 
Gail Broder  
HVTN Core, FHCRC 
 
Christie Heiberg 
Desmond Tutu HIV 
Centre, University of 
Cape Town, Cape 
Town, South Africa 
HPTN Community program 
associates 
Jonathan Lucas  
HPTN LOC, FHI360 

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Community 
Advisory Board 
(CAB) members 
Mark Hubbard 
Vanderbilt University Nashville, 
TN, USA 
 
Jontraye Davis  
HPTN LOC, FHI360 
 
Likhapha Faku 
HVTN Global CAB Member at 
Large Rustenberg, South Africa 
Community 
educator/recruiters 
DaShawn Usher 
New York Blood Center, 
New York, NY, USA  
 
Jim Wick 
Bridge HIV CAB, San Francisco, 
CA, USA 
 
Luciana Kamel 
Instituto de Pesquisa 
Clinica Evandro Chagas 
(IPEC), Rio de Janeiro, 
Brazil 
 
 
HVTN Technical 
editor 
Erik Schwab 
HVTN Core, FHCRC 

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2 
Background 
2.1 
Rationale for trial concept 
Effective biomedical interventions are needed to reduce the acquisition of HIV. The 
global HIV-1 epidemic continues and while many countries have made progress toward 
leveling HIV prevalence over the last few years, micro-epidemics of infection continue to 
occur in nearly all regions, even in countries possessing the full toolkit of proven 
prevention approaches [1-4]. The World Health Organization (WHO) estimates that there 
were 2 million new HIV infections worldwide in 2014, the last year for which data are 
available [5]. 
Antiretroviral drugs (ARVs) have been shown to be effective for HIV prevention in 
serodiscordant couples when administered to HIV-infected individuals as treatment as 
prevention (TasP) and clinical trials are now underway to evaluate the efficacy of TasP at 
a population level [6]. ARVs have also been shown to be effective as pre- or post-
exposure prophylaxis (PrEP or PEP) [7]. At present daily oral emtricitabine 
(FTC)/tenofovir disoproxil fumarate (TDF) (Truvada) is the only drug approved for PrEP 
use, but this drug combination has significant known side effects [8]. The requirement for 
daily use and the side effect profile have made adherence to this drug regimen 
challenging, especially over long periods of time [9]. As a consequence, the capacity of 
currently available ARV regimens to reduce HIV incidence or prevalence is less than 
optimal. Furthermore, sustained use of ARVs for HIV prevention will increase the 
already significant burden of ARV manufacturing and delivery for HIV treatment, 
especially in countries bearing the highest burden of HIV disease. For these reasons, a 
biomedical HIV prevention approach that exhibits sustained activity over an extended 
time period, that has a safety profile acceptable for healthy persons, and whose 
effectiveness is less dependent upon individual adherence, is still needed.  
An alternative approach to prevention and/or treatment of infectious diseases is passive 
administration of antibodies, a strategy that has been employed for more than 100 years 
against diverse disease targets and that is still used for hepatitis A and B prophylaxis 
[10,11] and for PEP for rabies, measles, varicella zoster, and other infectious diseases 
[12]. Most notably, palivizumab has been used for respiratory syncytial virus (RSV) 
prophylaxis in pre-term and other high-risk infants for nearly two decades. In 1998, a 
multinational, randomized controlled trial showed that palivizumab administered during 
the RSV season reduced RSV-associated hospitalizations by 39–78% in premature 
infants and in children with bronchopulmonary dysplasia [13]. Subsequent studies have 
confirmed palivizumab’s safety, efficacy, and clinical benefit for infants at high risk for 
RSV infection [14,15]. Hence, palivizumab serves as a model for the use of mAbs to 
block a mucosally-acquired infection. Significantly, passive administration of this 
antibody has also set a standard by which candidate RSV vaccines are evaluated, by 
defining antibody levels that effectively inhibit fusion by RSV. This precedent has 
informed the conceptual framework for this study. 
Over the past several years, there has been a concerted and notably successful effort to 
isolate broadly neutralizing antibodies (bnAb) to HIV-1 from chronically infected donors 
[16-32]. Subsequent research has provided considerable insight into the sites these 
antibodies target on HIV-1 and their functionality (ie, the mechanisms by which they 

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neutralize the virus) [19,20,29,33]. This research has informed efforts to design 
recombinant protein immunogens that can elicit such antibodies [34-37], prompting 
optimism that vaccines that elicit bnAbs against HIV-1 can be developed [35,38]. In 
addition, the availability of bnAbs against HIV opens the exciting possibility of antibody-
mediated prevention (AMP) of HIV infection. 
The Vaccine Research Center (VRC), NIAID, NIH has developed VRC01, a broadly 
neutralizing human mAb that targets the HIV-1 CD4 binding site [18]. This mAb was 
originally discovered in a participant infected with HIV-1 for more than 15 years who 
maintained viral control without use of antiretroviral therapy (ART) [39]. VRC01 has the 
capacity to neutralize a broad range of HIV-1 strains in vitro (Section 2.3) and has 
conferred protection against simian-human immunodeficiency virus (SHIV) challenges in 
nonhuman primate (NHP) studies [40-49] (Section 2.8). It has an acceptable safety 
profile, as seen in previous phase 1 studies (Section 2.9).  
In addition to potentially developing a new HIV prevention modality, evaluating the 
preventive efficacy of mAbs can be expected to inform future HIV vaccine development. 
An important requisite for designing vaccines that elicit bnAbs is determining the level of 
neutralizing activity required to achieve a reasonable degree of protection in humans. It 
will also be important to know whether such levels vary by route of infection or 
neutralizing sensitivity of the infecting isolate. Notably, VRC01 contains the Fc portion 
of IgG1 and has demonstrated other effector functions. Evaluating the role of antibody-
mediated effector functions (eg, antibody-dependent cellular cytotoxicity [ADCC], 
antibody-dependent cellular phagocytosis [ADCP], antibody-dependent cell-mediated 
viral inhibition [ADCVI], antibody-mediated virion capture in mucus, or inhibition of 
viral translocation across epithelial barriers, etc.) in protection is also of critical 
importance (see, eg, [50-53]).  
Although it is not anticipated that this trial will lead directly to licensure, further assessment 
of this VRC01 product will depend on the results of this and other studies. 
2.2 
bnAbs to HIV-1 
The last several years have seen a marked increase in the number of well-characterized 
bnAbs to HIV-1. Figure 2-1 shows the names and binding sites of many of these.  
 
 
Figure 2-1 Neutralizing antibody epitopes on native Env timer  

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As shown in Figure 2-2, several of these antibodies have shown considerable breadth of 
neutralization in in vitro testing.  
 
 
 
 
Figure 2-2 Percentage of viruses neutralized at different serum concentrations. 
(A) < 50 mcg/mL; (B) < 10 mcg/mL; (C) < 1 mcg/mL [32,49,54-57].  
B 
C 
A

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Two antibodies to the CD4 binding site of the HIV-1 envelope, VRC01 and 3BNC117 
(highlighted in red in Figure 2-1), have entered phase 1 clinical trials.  
2.3 
VRC01: VRC-HIVMAB060-00-AB 
VRC01 is a human mAb, developed by VRC/NIAID/NIH, directed against the CD4-
binding site of HIV-1. The bulk lot of the drug substance was manufactured under current 
Good Manufacturing Practice (cGMP) conditions in a Chinese Hamster Ovary (CHO) 
cell line and the drug product vials were filled and labeled at the VRC Vaccine Pilot Plant 
(Frederick, Maryland, USA) operated by Leidos Biomedical Research, Inc. (formerly 
SAIC-Frederick), Frederick, Maryland (USA). Product is vialed at a concentration of 100 
mg/mL VRC01 in formulation buffer containing 25 mM sodium citrate, 50 mM sodium 
chloride, and 150 mM L-arginine hydrochloride at pH 5.8. VRC01 was produced using 
recombinant DNA technology. Briefly, using polymerase chain reaction (PCR) 
amplification and cloning of the heavy and light chain variable region genes, a mAb was 
initially isolated from a single B cell from an HIV-1–infected subject who displayed 
bnAbs. VRC01 is an IgG1 antibody and is highly somatically mutated from the germ-line 
precursor.  
The VRC01 antibody has been well characterized preclinically and has demonstrated 
favorable characteristics in potency and half-life [19]. In addition, it has demonstrated 
protection in NHP challenge studies (see Section 2.8.1 below). Figure 2-2 shows 
graphically the impressive breadth of VRC01, with 90% of 190 HIV-1 isolates across all 
clades tested showing sensitivity to neutralization by VRC01. As shown in Figure 2-3, 
VRC01 has a 50% inhibitory concentration (IC50) of < 50 mcg/mL against 91% of 
primary HIV-1 isolates and IC50 < 1 mcg/mL against 72% of HIV-1 isolates. Notably, the 
IC50 for the vast majority of HIV-1 isolates tested is < 1 mcg/mL; the geometric mean 
IC50 for HIV-1 strains from all clades tested is 0.33 mcg/mL.  

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Virus clade 
Number of viruses 
IC50 < 50 mcg/mL 
IC50 < 10 mcg/mL 
IC50 < 1 mcg/mL 
A 
22 
100% 
100% 
95% 
B 
49 
96% 
94% 
80% 
C 
38 
87% 
84% 
66% 
D 
8 
88% 
88% 
50% 
CrRF01_AE 
18 
89% 
83% 
61% 
CRF02_AG 
16 
81% 
75% 
56% 
G 
10 
90% 
90% 
90% 
CRF07_BC 
11 
100% 
91% 
45% 
Other 
18 
83% 
83% 
78% 
Total 
190 
91% 
88% 
72% 
Figure 2-3 CD4 binding site antibody: VRC01 [18,19] 
Details on VRC01 composition and manufacturing can be found in the investigator’s 
brochure (IB). 
2.4 
Trial design rationale 
Several considerations inform the design of this test-of-concept phase 2b study. The first 
is to establish that passive administration of bnAbs can block HIV acquisition. Based on 
data from in vitro neutralization studies, the NHP challenge studies described below, and 
pharmacokinetic (PK) data from the phase 1 clinical trials VRC 602 and HVTN 104, the 
doses selected are designed to elucidate the activity of the antibody across a range of 
serum concentrations in a diverse population of at-risk persons in multiple geographic 
regions of the world. The study is designed to define the optimal dosage for widespread 
use of the antibody or its subsequent derivatives as well as to benchmark the types of 
effector functions associated with efficacy, thus constituting an important bridge to other 
types of bnAbs and other bnAb delivery systems.  
Inclusion of different doses (ie, in a 3-arm study) is important for a number of reasons. 
First, while the in vitro and NHP challenge data are informative, the VRC01 antibody 
serum level required to provide protection against HIV-1 infection in humans is 
unknown. Some studies suggest that transmitted-founder HIV strains may be more 
sensitive to neutralization than other strains (particularly by VRC01) [58,59], and 
therefore potentially susceptible to even lower antibody doses than those suggested by 
SHIV challenge studies in NHP. It must also be recognized that the lowest challenge 

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doses used in the NHP model likely exceed natural exposure in the majority of 
transmissions in humans.  
Defining the lowest efficacious VRC01 dose is essential for establishing a target product 
profile (TPP), including optimal dosing for clinical use, for this antibody and its 
derivatives. Typically, higher doses of drug products are associated with lower 
tolerability due to side effect profiles or operational features such as length of drug 
administration time (eg, IV infusion time). At present the high dose (30 mg/kg) cannot be 
administered subcutaneously (SC), limiting the feasibility of long-term clinical use. The 
extreme difficulty of scaling IV administration to the populations most in need of 
protection against HIV infection and the complexity and cost of manufacturing mAbs 
would severely limit implementation of this potentially important HIV prevention tool if 
higher doses are required for efficacy. Therefore, it is important to evaluate the efficacy 
achieved at lower antibody concentrations. That lower doses of mAbs may prevent HIV 
acquisition is supported by the high percentage of isolates susceptible in vitro to antibody 
concentrations as low as 1 mcg/mL of VRC01, 1/10 the mean trough level anticipated 
with 30 mg/kg VRC01 dosing every 8 weeks.  
Including a range of doses in this study also facilitates evaluation of antibody effector 
functions, in addition to neutralization, that are associated with protection (eg, virion 
binding, ADCC, ADCP). Note that the relationship of these important functions to 
neutralization is not linear and therefore cannot be inferred directly. This information will 
have important implications for the development of other bnAbs and other biomedical 
HIV prevention modalities. 
Hence, in addition to providing a test of concept for AMP for HIV, if breakthrough 
infections are observed, the data generated by this trial will help guide development of 
functionally-enhanced mAbs and of long-term delivery strategies (eg, vaccine 
immunogen or vectored immunoprophylaxis). This trial affords a unique opportunity to 
correlate serum antibody levels and the potency of effector functions with protective 
efficacy in a trial in which these parameters can be measured close to the time of HIV 
acquisition, providing benchmarks for vaccine development and helping define “targets” 
of antibody effector mechanisms for protein or viral vector based vaccines. The data will 
also provide critical information by which to identify which NHP models (eg, SHIV 
challenge stocks) are most predictive of bnAb efficacy in humans. 
2.4.1 
Cohort selection 
The study will be conducted among 2700 men and TG in North America, South America, 
and Switzerland who have anal sex with men or TG partners. The trial sample size is 
designed to provide 90% power to detect a prevention efficacy (PE) of 60% (rejecting the 
null hypothesis of 0% PE), based on reasonable assumptions regarding background HIV-
1 incidence, retention, and frequency of infusions.  
With respect to HIV incidence, over the past 25 years, MSM and TG who have sex with 
men have been the only risk groups in the US for which estimated HIV incidence has 
increased, with more recent increases in incidence noted particularly among young MSM 
of color [60,61]. In the US, Latin America, and Switzerland, MSM and TG account for 
more than half of new HIV infections [60,62-64]. In 2013, the estimated rate of new HIV 
diagnoses among Hispanic/Latino males was three times the rate of White males and 
79% of these infections were attributed to male-to-male sexual intercourse [65]. Among 
gay and bisexual men, Black MSM – especially those between the ages of 13 and 24 – 

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are most affected by HIV [66]. Indeed, the HPTN 061 study found incidence of almost 
6% annually among young Black MSM [67]; this is far higher than HIV incidence 
reported previously in White MSM. A second study found higher HIV prevalence in 
Black MSM than in White MSM [68].  
We note that a parallel study assessing the safety and preventive efficacy of VRC01 is 
being conducted among 1500 women in sub-Saharan Africa who are at risk of acquiring 
HIV-1 through sexual contact. That study, designated HVTN 703/HPTN 081, will be 
conducted over approximately the same time period as HVTN 704/HPTN 085.  
2.4.2 
Dose and schedule  
An equal number of study participants will be randomized to receive VRC01 mAb by IV 
infusion at a dose of 10 mg/kg or 30 mg/kg every 8 weeks or to receive the control by 
infusions every 8 weeks. The 8 week infusion interval represents approximately 4 half-
lives of the study drug (half-life ~14 days based on previous clinical testing; see the IB). 
Infusions will continue for 72 weeks for all groups, with a final primary follow-up visit 
(without infusion) at week 80 and an additional 24 weeks of follow-up without infusions. 
Hence, the study duration for each participant is 104 weeks (2 years). 
Projected serum concentrations of VRC01 are shown in Figure 2-4. This figure plots 
predicted median VRC01 serum concentrations over time based on PK models for 
VRC01 administered at 10 mg/kg every 8 weeks (Panel A) and for VRC01 administered 
at 30 mg/kg every 8 weeks (Panel B). The plots include shaded regions illustrating time 
regions where the study participants have serum concentrations in low, medium, and high 
ranges. Based on in vitro neutralization studies (see Section 2.3) and NHP challenge 
studies (see Section 2.8.1) and assuming that these accurately predict protection in 
humans, the expected trough levels of VRC01 are projected to be an order of magnitude 
higher than the levels required to protect against a majority of circulating HIV-1 strains. 
See Section 2.9.3 and Figure 2-9 for VRC01 serum concentrations reported to date for 
participants administered 10mg/kg and 30mg/kg of VRC01 every 8 weeks in HVTN 104. 

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Figure 2-4 Predicted VRC01 serum concentrations over time. Panel A: Predicted VRC01 
median serum concentration over time (solid lines) for 10 mg/kg IV infusions of VRC01 at 
Weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, 72, with 95% confidence intervals (CI) (dashed lines). 
The shaded regions classify the serum concentration marker S(t) into high, medium, and 
low ranges based on the cut-points 10 and 50 mcg/mL. Panel B: Predicted median VRC01 
serum concentration over time for 30 mg/kg IV infusions of VRC01 at Weeks 0, 8, 16, 24, 32, 
40, 48, 56, 64, 72. The shaded regions classify the serum concentration marker S(t) into 
high, medium, and low ranges based on the cut-points 10 and 50 mcg/mL. PYR = person-
year at risk. 
There is a substantial overlap in the mAb concentrations between the low and high dose 
groups during a considerable period of time after each infusion. This is shown in Figure 
2-5.  

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10 mg/kg 
30 mg/kg 
Overlap 
High (> 50 mcg/mL) 
10% PYRs 
50% PYRs 
10% PYRs 
Medium (10 to 50 mcg/mL) 
40% PYRs 
40% PYRs 
40% PYRs 
Low (< 10 mcg/mL) 
50% PYRs 
10 % PYRs 
10 % PYRs 
 
Total overlap = 60% PYRs 
Figure 2-5 Projected overlap in serum VRC01 concentrations and PYRs of HIV exposure 
between high dose (30 mg/kg) and low dose (10 mg/kg) VRC01 administration 
2.4.3 
Choice of control 
Sodium Chloride for Injection 0.9%, USP (referred to as Control) administered IV at a 
volume of 150 mL will serve as an inert control. 
Use of a placebo control in this trial is warranted based on the scientific and public health 
importance of the questions it seeks to answer, the necessity of a placebo control in order 
to assess VRC01 efficacy in preventing HIV-1 infection, and an acceptable risk/benefit 
ratio considering the minimal risk associated with the placebo control selected and its 
administration via a procedure commonly used in clinical care. In addition, the placebo 
control is essential to maintain double-blinding to ensure unbiased assessments of study 
product safety and efficacy, and the use of the placebo control is disclosed fully to study 
participants (see Section 10 of Appendix A). Hence, this trial meets the standards 
commonly required for ethical use of placebo controls in clinical trials [69-71]. 
2.4.4 
HIV diagnostic testing  
HIV diagnostic testing will be scheduled at least every four weeks and at any time 
following participant report of possible exposure during the study. See Section 8 for 
further detail on HIV-infection assessment. Participants who are diagnosed with HIV 
infection after enrollment will not receive additional infusions. Infusions will also be 
permanently discontinued for participants who have 2 reactive HIV tests, even if 
subsequent testing indicated that the participant is not HIV infected.  
Based on the schedule of testing, it is possible that a newly infected participant may 
receive an infusion of VRC01 (or Control). This does not appear to pose a safety risk for 
participants based on existing preclinical, clinical, and in vitro data. Specifically, 

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passively-infused VRC01 given to NHP on Day 7 after SHIV SF162P3 infection reduces 
viremia and does not cause clinical harm (see IB). Additionally, passive transfer of 
neutralizing antibodies (at non-protective levels) prior to infection improved control of 
SHIV viremia and was associated with early nAb development in infected infant 
macaques [72]. Furthermore, VRC01 has been evaluated in viremic and aviremic HIV-
infected participants (see Section 2.9.1). VRC01 administration is associated with 
statistically significant transient reductions in HIV viral load in adults with chronic HIV 
infection (see IB), and HIV variants that escape from in vitro VRC01 neutralization have 
reduced viral fitness [73]. Studies evaluating VRC01 in acutely infected subjects are 
being initiated based on these data. 
2.4.5 
Trial monitoring 
As this is the first large-scale phase 2b study with IV administration of a biomedical 
intervention for prevention of sexual HIV-1 transmission, the trial design includes an 
early feasibility check. After approximately 120 participants have completed the Week 32 
visit, a treatment-blinded analysis of infusion feasibility will be conducted and reported 
to the DSMB. Enrollment of the remaining study participants will be deemed feasible if 
≥ 80% of those 120 participants remain engaged in the trial and have not declined further 
infusions. Enrollment will not be paused for this feasibility assessment.  
In addition to the feasibility assessment, the study design includes sequential monitoring 
for potential harm, non-efficacy, high efficacy, and futility for assessing prevention 
efficacy. Following similar monitoring procedures developed and implemented for the 
HVTN 505 phase 2b vaccine efficacy trial, potential harm monitoring is maximally 
vigilant by testing for a higher HIV infection rate in the pooled mAb group versus the 
control group after each HIV infection and providing the results to the DSMB after each 
infection starting with the 20th total infection pooled over the study groups. This ensures 
that any potential risk of increased HIV acquisition (negative prevention efficacy [PE]) 
would be detected as early as possible, such that infusions of the mAb could be 
discontinued expeditiously. In addition, the operating characteristics of the trial (Figure 
4-3 and Table 4-2) show that this potential harm-monitoring approach has a low risk of 
stopping the study prematurely if the true PE is 0% or higher. The non-efficacy 
monitoring is conducted approximately every 6 months, and is based on a trigger 
specified in the study monitoring plan. 
At the 6-month intervals, statistical interim analysis reports are provided to the DSMB. 
Gilbert et al [74] describe the conceptual approach to the sequential monitoring of PE, 
where the implementation for the current trial is slightly different. Additional information 
is provided in Section 4.9. Full details regarding implementation of monitoring for this 
trial are contained in a separate trial monitoring plan. 
2.5 
Combination Prevention for HIV acquisition 
Participants in all arms of the study will be provided with a comprehensive HIV 
prevention package consistent with all HIV prevention clinical trials. This package 
includes evidence-based behavioral risk reduction counseling [75], free condoms and 
lubricant, explanation and referral for post exposure prophylaxis (PEP) when indicated, 
and access to oral pre-exposure prophylaxis (PrEP, see below). These activities can be 
expected to reduce HIV acquisition below historical levels for MSM. The contribution of 
these efforts will be monitored. Further details on these efforts are provided in the HVTN 

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704/HPTN 085 Study Specific Procedures (SSP) and the HVTN 704/HPTN 085 website. 
It should be emphasized that because the benefit of VRCO1 monoclonal antibody is 
unknown, subjects in each arm of the study will receive the same prevention package. 
2.5.1 
Evidence for PrEP efficacy 
Multiple studies in multiple settings have established that daily or pericoital FTC/TDF 
can be highly efficacious in preventing HIV infection in MSM [7,76-80] (see Figure 2-6). 
In addition, evidence suggests that less than perfect adherence to a daily FTC/TDF 
regimen may still provide protection against infection in MSM. For example, post hoc 
analyses from the open label extension to the iPrEx study (iPrEx OLE) suggest that 
consuming 4 tablets of TDF-FTC per week is required to confer protection [76]. 
 
Figure 2-6 Clinical trial efficacy summary of FTC/TDF in MSM 
2.5.2 
Evolving PrEP guidelines 
Guidelines for use of fixed dose FTC/TDF for HIV prophylaxis have evolved rapidly. In 
2011, the US Centers for Disease Control and Prevention (CDC) issued interim 
guidelines for use of FTC/TDF as PrEP for high-risk MSM [81]. In 2012, the US FDA 
approved FTC/TDF for HIV prophylaxis in persons at high risk for HIV infection. That 
same year, the World Health Organization (WHO) issued guidance on the use of PrEP for 
serodiscordant couples and for men and TG women who have sex with men [82]. In 
2014, the US CDC issued a further PrEP guidance document and a Clinical Provider 
Supplement confirming the previous recommendation of FTC/TDF PrEP as a prevention 
option for sexually-active adult MSM at substantial risk of HIV acquisition and 
expanding the recommendation to include adult heterosexually active persons at 
substantial risk of HIV acquisition [83,84]. PrEP has since been incorporated into WHO 
guidelines for ARV use for HIV treatment and prevention [85,86]; a revised and more 
comprehensive WHO PrEP guideline is anticipated in 2016.  
2.5.3 
Operationalizing PrEP access  
While PrEP efficacy has been demonstrated and is reflected in international guidelines, 
PrEP’s effectiveness depends strongly on uptake and adherence. Only 62% of iPrEx and 
other PrEP trial participants who were eligible to enroll in iPrEx OLE chose to do so; 

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those who declined cited concerns about taking a daily pill and about side effects, among 
other reasons. Further, among those who chose to enroll, only 76% actually initiated 
PrEP [76]. Hence, only about 47% of those eligible initiated PrEP in iPrEx OLE. PrEP 
uptake would seem even less certain among individuals who have not previously chosen 
to participate in an FTC/TDF PrEP trial. 
Limited PrEP uptake has been seen in other settings as well. In a recent PrEP 
demonstration project in San Francisco, Washington DC, and Miami, 60% of those 
eligible chose to initiate PrEP [87]; in the demonstration project PrEP Brasil, 51% of 
MSM elected to start PrEP [88]. Results from HPTN 073, a trial designed specifically to 
address open label, volitional FTC/TDF uptake and usage in 226 African American MSM 
in the US, are anticipated in early 2016.  
Beyond experience in clinical trials and demonstration projects, questions remain about 
retention and adherence to PrEP in the longer term. Notably, trials of PrEP to date have 
been conducted among individuals specifically self-selecting for PrEP, and generally 
over limited time horizons.  
The continued need for additional HIV prevention tools does not negate the importance 
of PrEP as a critical part of the HIV prevention toolkit. Accordingly, access to FTC/TDF 
PrEP at no drug cost will be offered as part of a complete HIV prevention package to 
every HVTN 704/HPTN 085 participant through a model initially developed with 
extensive, multi-stakeholder input for the HVTN 505 trial [89,90]. In this model, Gilead 
provided fixed dose FTC/TDF (ie, Truvada) at no cost to interested HVTN 505 
participants, who obtained it through prescribers independent of the trial, thus facilitating 
the establishment of a provider-patient relationship that could endure beyond the duration 
of the trial. Availability of free FTC/TDF was indicated in the informed consent 
document and communicated to study participants in follow up visits. However, fewer 
than 15% of participants in the HVTN 505 trial have reported using PrEP at any time 
during the trial (in which follow-up remains ongoing).  
The past few years have seen increasing educational efforts and community awareness of 
the importance of PrEP in preventing HIV infection among MSM and we expect to see 
increased uptake of this prevention modality over the course of this trial. For self-selected 
participants under active medical care, PrEP can be very effective [91]. 
Consistent with this approach, Gilead Sciences has agreed to provide Truvada as PrEP for 
trial participants at no drug cost to them for the duration of their trial participation. This 
will be accomplished through the HVTN 704/HPTN 085 PrEP Referral Program in North 
America for US participants. This program integrates PrEP into the care provided by 
participants’ primary health care provider, ensuring that appropriate screening assays are 
performed and that drug interactions are monitored over time. Outside the US, 
participants will participate in PrEP demonstration projects in Peru and Brazil, countries 
in which Truvada is not yet licensed for HIV prophylaxis but where such demonstration 
projects are being encouraged. In Switzerland, the CRS will directly provide Truvada at 
no drug cost to interested participants. In this way, PrEP access will be provided to all 
participants in the trial and counseling about its availability will be provided as part of 
HIV risk reduction counseling, which is conducted at all infusion visits throughout the 
course of the study. This approach has been reviewed and approved by multiple 
stakeholders, including community members, medical ethicists, multiple IRBs, and the 
HVTN 704/HPTN 085 DSMB.  

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As discussed in Sections 4.10 and 9.6, periodic population-based evaluation of PrEP 
usage will be conducted during the course of the trial. The sample size and power 
calculations (see Section 4.6) and plans for trial monitoring by the DSMB (see Section 
4.9 and, specifically, Section 4.9.3) have been designed to accommodate substantial PrEP 
uptake. If the background HIV incidence rate is too low to support evaluation of VRC01 
prevention efficacy due to high PrEP uptake and adherence, these data will be made 
available to the DSMB, which will make recommendations to the team accordingly.  
2.6 
Plans for future product development and testing 
VRC01 is considered to have potential value for both preventive and therapeutic purposes 
across broad geographic regions of the HIV-1 epidemic. The product was initially 
evaluated in phase 1 studies to characterize PK and distribution in HIV-infected and 
HIV-uninfected adults (VRC 601 and 602, respectively; see Sections 2.9.1 and 2.9.2) and 
PK and safety for multiple administrations under several route and dosing regimens are 
being evaluated currently (HVTN 104; see Section 2.9.3). In parallel, IMPAACT P1112 
will evaluate the safety of VRC01 in high-risk infants born to HIV-infected mothers; data 
from this study will support a future evaluation of the efficacy of VRC01 administered to 
high-risk infants shortly after birth and continued through the period of breast-feeding for 
prevention of mother-to-child HIV transmission (PMTCT).  
The development of VRC01 for clinical use depends on a number of factors, the most 
critical of which is the level of efficacy demonstrated by the current study. If the antibody 
proves to be highly effective at preventing HIV-1 infection, its development will depend 
on identifying a partner able to provide large-scale manufacturing. Other factors that 
could influence advanced development of VRC01 or similar monoclonal antibodies 
include: 1) the potential for improving the potency of the product to allow use at a lower 
dose and perhaps by an SC route, 2) the potential for increasing the half-life of the 
product to allow less frequent dosing, and 3) the potential to use VRC01 or its derivatives 
in combination with other neutralizing mAbs to increase potency and breadth of 
coverage. Efforts to address these issues are proceeding in parallel with the current study, 
but the outcome of the current study will have the greatest influence on the future clinical 
use of VRC01 in adult prevention or PMTCT. 
2.7 
Preclinical safety studies 
2.7.1 
Preclinical toxicology and PK study of VRC01 in rats 
Table 2-1 Summary of preclinical studies 
Study 
number 
Product 
Type of study 
Animal 
N 
Dose groups 
Route 
Schedule 
SRI No 
M896-11 
VRC-
HIVMAB060-
00-AB 
Repeat dose 
toxicity 
Sprague-
Dawley rats 
10m, 10f 
each 
50m, 50f 
total 
Vehicle* 
4mg/kg IV 
40 mg/kg IV 
400 mg/kg IV 
40 mg/kg SC 
IV & 
SC 
D1, D8 
SRI No 
M896-11 
VRC-
HIVMAB060-
00-AB 
Single-dose 
PK 
Sprague-
Dawley rats 
9m, 9f each 
27m, 27f 
total 
4 mg/kg IV 
40 mg/kg IV 
40 mg/kg SC 
IV & 
SC 
D1 
* Vehicle consists of VRC01 formulation buffer. 

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A repeat dose toxicity study of IV and SC administration and a single dose PK study was 
performed by SRI International (Menlo Park, CA) with VRC01 in male and female 
Sprague-Dawley rats in accordance with US FDA “Good Laboratory Practice (GLP) for 
Nonclinical Laboratory Studies” (Table 2-1). This study was conducted with a pre-GMP 
pilot lot of VRC01 manufactured at smaller scale using a similar purification process to 
that of the GMP clinical grade drug product. 
For the safety assessment, various doses of VRC01 (4 mg/kg, 40 mg/kg, or 400 mg/kg) or 
a comparable control vehicle was administered by tail vein infusion on Days 1 and 8 to 
Groups 1 through 4, respectively. An additional group (Group 5) received 40 mg/kg 
VRC01 via SC administration to the dorsal scapular region on Days 1 and 8. Each group 
contained 10 male and 10 female rats. Five animals of each sex were sacrificed on Day 9, 
one day after the second administration; the remaining animals were sacrificed on Day 
30, 22 days after the second administration. 
Results obtained showed that both routes of administration were well tolerated in the rats. 
All animals survived until their scheduled necropsy. No findings or changes were seen in 
clinical observation, body weight, food consumption, body temperature, infusion site 
irritation, hematology, coagulation, or organ weight evaluations that are attributed to 
administration of VRC01. VRC01 administration resulted in small, transient, dose-
dependent increases in aspartate aminotransferase (AST) and alkaline phosphatase (ALP) 
on Day 9. By Day 30, AST values had returned to normal, and ALP values were 
returning to normal.  
Other than red discoloration of the administration site in one male in the SC group on 
Day 9, there were no other gross necropsy observations attributable to VRC01 
administration. There were no histopathology findings that were considered related to IV 
administration of VRC01.  
The pre-specified IV dose studied in rats was 400 mg/kg and SC was 40 mg/kg, which 
will greatly exceed the dose levels in the adult clinical studies. A “no observed effect 
level” (NOEL) was not determined in this study because transient elevations of AST and 
ALP were observed on Day 9 after IV administration and transient inflammation at the 
dose site was observed on Day 9 after SC administration. Because the elevated AST and 
ALP levels were transient and minor and did not correlate with histopathology findings, 
the no observed adverse effect level (NOAEL) for VRC01 by the IV route of 
administration in rats was 400 mg/kg, the highest dose used in this study.  
For the PK analysis, 3 groups of rats (9 males and 9 females in each group) received 
VRC01 on Day 1 at 4 mg/kg IV, 40 mg/kg IV, and 40 mg/kg SC respectively. VRC01 
levels in serum were determined using an enzyme-linked immunosorbent assay (ELISA) 
with samples collected predose from each animal and from an additional 3 males and 3 
females to provide untreated control serum. Blood was collected from 3 rats/sex/PK 
group for a total of 4–5 collections per PK animal at each of the following postdose 
timepoints: 1, 4, 8, 24, 48, and 72 hours and 7, 14, 21, and 29 days.  
VRC01 administration by the IV route resulted in dose-proportional exposure. The 
terminal elimination phase half-life was about 10 days, with clearance of approximately 
20 mL/day/kg and volume of distribution that was about 0.28 L/kg, indicating that the 
drug was distributed primarily in the serum and eliminated slowly. VRC01 administration 
by the SC route resulted in mean peak serum levels at 7 days for male or 3 days for 
female animals. The maximum serum concentration and area under the concentration-

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time curve to the last timepoint values were lower when 40 mg/kg was administered by 
the SC route compared with the IV route. The bioavailability of 40 mg/kg VRC01 
administered by the SC route was estimated to be 31.4% (males) and 42.3% (females). 
After the peak concentration of VRC01 was achieved in the SC group, the serum levels 
decreased much more rapidly from 7 to 14 days than they did in the IV groups, and 
VRC01 concentrations in the SC group were not quantifiable at timepoints after 14 days. 
These data indicate that clearance of VRC01 in rats was markedly enhanced when it was 
administered by the SC route. The development of anti-drug antibodies that contribute to 
an increased rate of clearance is often observed in preclinical safety studies of protein-
based test articles when they are not tested in the species of origin. Although 
immunogenicity was not examined in this study, the presence of such antibodies might 
have contributed to the increased rate of clearance of VRC01 after SC administration that 
was observed in this study [92,93]. 
2.7.2 
Tissue cross reactivity GLP study of VRC01 with human tissues in vitro  
A tissue cross-reactivity study of VRC01 using normal adult and neonatal human tissues 
in vitro (Testing Facility Study No. A255-12) was performed by Charles River 
Laboratories (Reno, NV) in accordance with U.S. FDA “Good Laboratory Practice for 
Nonclinical Laboratory Studies” (GLP). The tissue panels used as the test system for this 
in vitro cross-reactivity study included all of the tissues on the “Suggested list of human 
tissues to be used for immunohistochemical or cytochemical investigations of cross 
reactivity of monoclonal antibodies” in Annex I of the “European Medicines Agency 
Guideline on Development, Production, Characterization and Specifications for 
Monoclonal Antibodies and Related Product, Adopted by the Committee for Medicinal 
Products for Human Use on December 18, 2008” and all of the tissues recommended in 
the FDA/Center for Biologics Evaluation and Research “Points to Consider in the 
Manufacture and Testing of Monoclonal Antibody Products for Human Use (February 
28, 1997).” In addition, the tissue cross-reactivity study used additional neonate/infant 
tissues suggested by the FDA to support future trials in infants.  
To determine the cross-reactivity of VRC01 binding, VRC01 was applied to cryosections 
from a full panel of tissues from normal human adults and a limited panel of human 
neonatal tissues, immunohistochemically detected using a biotinylated rabbit anti-human 
IgG secondary antibody, and binding was visualized with a streptavidin-horseradish 
peroxidase complex and a diaminobenzidine chromogen substrate. VRC01 binding was 
evaluated at concentrations of 5 and 50 mcg/mL. 
Specific VRC01 staining was not observed in any normal adult human or neonatal human 
tissues evaluated. Therefore, in vitro evaluation of cross-reactivity in tissue specimens 
did not identify potential tissue sites or organ systems to more thoroughly evaluate in 
subsequent preclinical studies, and it supports the future use of VRC01 in humans. 
2.7.3 
Other toxicity studies 
Several in vitro studies were conducted to assess antibody activity against self-antigens 
by VRC01. Several anti-HIV neutralizing mAbs will cross-react to lipid or nuclear 
antigens or Hep-2 cells [94,95]. Anti-lipid binding activity is understandable when 
considering that the HIV-1 gp41 protein is membrane-spanning and the epitopes (MPER: 
Membrane-Proximal External Region) recognized by some mAbs (eg, 4E10 and 2F5) are 
membrane-proximal and likely extend into the membrane itself. Therefore, the ability (or 
lack thereof) of VRC01 to cross-react with lipids was assessed in collaboration with Dr. 

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Barton Haynes of Duke University. Binding of antibody to cardiolipin was assessed in a 
luminescent assay, expressed in relative units. VRC01 was compared to 4E10, an anti-
gp41 mAb known to bind to cardiolipin and nuclear antigens, and Synagis, a licensed 
anti-RSV antibody used as a negative control. Synagis is included because it is the 
licensed mAb product most analogous to the intended clinical use of the VRC mAb [13]. 
Individual studies are summarized in Table 2-2. Unlike other anti-HIV neutralizing 
mAbs, VRC01 does not react to phospholipids or anti-nuclear antigens or Hep-2 cells. 
Additional details are provided in the IB. 
Table 2-2 In vitro preclinical safety studies 
Study Purpose 
Study Outcome 
Assessment of anti-phospholipid reactivity 
VRC01 does not react to phospholipids 
Assessment of anti-nuclear antigen 
reactivity 
VRC01 does not react with nuclear 
antigens 
Assessment of anti-phospholipid 
characteristics by impact on activated partial 
thromboplastin time (aPTT) 
VRC01 does not impact aPTT by binding 
phospholipids 
Assessment of Binding to a Human Cell 
Line by Immunohistochemistry 
Fluorescently labeled VRC01 does not bind 
Hep-2 cells 
2.8 
Nonhuman primate (NHP) studies of VRC01  
Several non-Good Laboratory Practices (ie, non-GLP) studies of VRC01 have been 
completed in NHP to assess for preclinical evidence of potential efficacy for prevention 
of HIV infection. Table 2-3 summarizes the studies performed.  
Table 2-3 Summary of NHP pharmacology and challenge studies 
Study 
Product 
Animal 
N 
Dose/Route  
Infusion 
schedule 
Challenge 
route 
Challenge 
stock/dose 
Challenge 
schedule 
Pharmacology 
VRC01 
 (Pilot lot) 
Rhesus 
macaques 
4f  
4f 
40 mg/kg IV 
40 mg/kg SC 
Day 0 
NA 
NA 
NA 
High-dose 
challenge 
VRC01 
(Research 
Grade) 
Rhesus 
macaques 
4m 
4m 
4m 
5 mg/kg IV 
20 mg/kg IV 
Human IgG 
IV (control) 
Day 0 
Intrarectal 
SHIV-SF162P3 
(300 TCID50*) 
Day 2 
postinfusion 
High-dose 
challenge 
VRC01 
(Research 
Grade) 
Rhesus 
macaques 
4f  
4f 
20 mg/kg IV 
Human IgG 
IV (control) 
Day 0 
Intravaginal 
SHIV-SF162P3 
(300 TCID50) 
Day 2 
postinfusion 
High-dose 
challenge 
VRC01 
(Research 
Grade) 
Rhesus 
macaques 
6m 
6m 
4m 
16m 
14m 
20 mg/kg IV 
5 mg/kg IV 
1.25 mg/kg IV 
0.3 mg/kg IV 
Human IgG 
IV (control) 
Day 0 
Intrarectal 
SHIV-BaL 
(TCID50 12,800 
in TZM-bl) 
Day 2 
postinfusion 
*TCID50 = 50% tissue culture infectious dose 
In the pharmacology study, plasma and mucosal (ie, rectal, vaginal, and nasal) samples 
were collected at frequent intervals through Day 28. A dose of 40 mg/kg IV or SC in 
female rhesus macaques resulted in plasma concentration of VRC01 exceeding 50 
mcg/mL in 7 of 8 animals at Day 14 and greater than 10 mcg/mL in 7 of 8 animals at Day 
28. 

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Please see the VRC01 IB for more details.  
2.8.1 
Protection against challenge in NHP models 
Both neutralizing and non-neutralizing antibodies to HIV and SIV have been shown to 
protect against experimental challenge in the NHP model [40-42,96-100]. In these studies 
the degree of protection has varied with the neutralizing potency of the antibodies and 
with the dose, route, and sensitivity of the challenge stocks. Low antibody concentrations 
have in some instances been quite protective, especially against repeat low-dose mucosal 
challenges [44,45]. However, neutralization-resistant SHIVs have been developed and 
have been shown to be resistant to protection [101,102]. This has permitted estimation of 
neutralization titers for different mAbs against SHIVs representing a broad range of 
neutralization resistance. 
VRC01 has been tested in several NHP challenge experiments (see Table 2-3). In a rectal 
challenge model with SHIV BaLP4, a dose of 20 mg/kg IV protected 6/6 NHP; a 5 mg/ 
kg IV dose protected 6/6; and a 0.3 mg/kg IV dose protected 2/6 [47]. Using a more 
resistant SHIV-162P3 challenge, a 20 mg/kg IV dose protected all 4 male animals from 
rectal challenge and all 4 female animals from vaginal challenge [47]. Analyses of the 
combined data from the NHP challenge studies show complete protection against 
SHIV162P3 challenge at a VRC01 plasma concentration of 50 mcg/ml and partial 
protection (IC50 [50% inhibitory concentration]) at 20 mcg/mL. For the more sensitive 
BaLP4 virus the IC50 is only 1.5 mcg/mL. Based on preclinical studies, an antibody 
serum concentration of about 40 to 50 mcg/mL is projected to provide protection against 
the vast majority of circulating strains of HIV [103]. In the NHP studies, both the virus 
sensitivity and serum antibody titers appear to influence protection from mucosal 
challenge. A summary of serum concentrations associated with protection against diverse 
SHIV strains of varying resistance to neutralization is shown in Figure 2-7. 
  
Figure 2-7 VRC01 IC80 values (170 Isolates) and serum concentrations in NHP SHIV 
challenge studies 
It is particularly interesting to note that following administration of VRC01 to NHP, the 
antibody is found in mucosal tissues (see Figure 2-8). This is likely a product of active 
antibody transport to mucosal tissues through neonatal Fc receptor (FcRn) binding [48].  
 

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Figure 2-8 VRC01 mucosal pharmacokinetics in rhesus macaques [48] 
NHP challenge studies have also shown that, in addition to classic neutralization, bnAbs 
such as VRC01 often elicit antibody-mediated cellular effector functions [45,104]. As a 
result, protection against experimental challenge has sometimes been achieved with 
notably low doses of VRC01 [47,103]. Similar mechanisms of protection have been 
implicated in studies of other bnAbs showing protection despite barely detectable 
neutralization activity (1:1) at challenge [44].  
Recent NHP studies of VRC01 and other highly potent mAbs, such as PGT121, 
demonstrate protection at infusion doses of 5 mg/kg and even at 1 mg/kg 
[46,49,103,105]. There is also evidence that such protection can be durable; a simianized 
version of VRC01 was shown to protect monkeys against SHIV challenge nearly 8 weeks 
after their last 5 mg/kg antibody infusion, when plasma concentrations of VRC01 ranged 
from ~0.5 mcg/mL to undetectable [105]. These data suggest that a 10 mg/kg infusion 
dose of VRC01 administered every 8 weeks may offer protection against HIV 
acquisition. 
Please see the VRC01 IB for more details on the NHP challenge studies.  
2.9 
Clinical trial experience 
Completed phase 1 clinical studies of VRC01 include first-in-humans dose escalation 
studies for safety, tolerability, and PK assessments in HIV-infected (VRC 601) and HIV-
uninfected (VRC 602) adults. Studies to characterize the neutralizing activity and other 
functional assays as a function of plasma concentration are also underway. As of April 
2017, more than 1200 clinical trial participants have received VRC01 in phase 1 trials 
and in the phase 2b AMP studies. 
Both the IV and SC routes of administration have been evaluated. Ultimately, the best 
route for clinical use may depend upon the age of the recipient (adult or infant), stage of 
product development, formulation, and important considerations related to volume 
needed and maintenance of a target VRC01 blood level considered to be in the 
therapeutic range. 

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2.9.1 
VRC 601 
VRC 601 (NCT01950325) titled, “A Phase 1, Open-Label, Dose-Escalation Study of the 
Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB060-00-
AB (VRC01), with Broad HIV-1 Neutralizing Activity, Administered Intravenously or 
Subcutaneously to HIV-Infected Adults.” 
VRC 601 (Table 2-4) was the first study of the VRC01 mAb in HIV-infected participants 
[106]. It was a dose-escalation study to examine safety, tolerability, dose, PK, and anti-
antibody immune responses. VRC 601 opened in September 2013 as a single site study at 
the NIH Clinical Center, Bethesda, Maryland and in total, 23 HIV-infected participants, 
including 15 aviremic ARV-treated participants and 8 viremic non-ARV treated 
participants, were infused with one or two doses of VRC01 at doses up to 40 mg/kg IV. 
Table 2-4 VRC 601 study schema 
VRC 601 Dose Groups 
VRC01 Administration Schedule 
Group 
No. of 
evaluable 
participants* 
Day 0 
Week 4 
1 
3-5 
1 mg/kg IV 
1 mg/kg IV 
2 
3-5 
5 mg/kg IV 
5 mg/kg IV 
3 
3-5 
5 mg/kg SC 
5 mg/kg SC 
4 
3-5 
20 mg/kg IV 
20 mg/kg IV 
5 
3-5 
40 mg/kg IV 
40 mg/kg IV 
Total 
15-25 
IV doses administered in 100 mL of normal saline over 30-60 
minutes. 
SC doses administered in the minimum volume at 15 mL/hr. 
*Only participants who begin infusion are evaluable. Only 3 
evaluable participants per group will be enrolled into the dose group 
until the safety review is completed. Additional slots are available, if 
needed, to have sufficient data for the safety review or to include at 
least one eligible subject with a detectable viral load later after the 
dose escalation is complete. 
The first infusion at 1 mg/kg IV was administered in the VRC 601 study on September 
30, 2013. Beginning on March 28, 2014, the dose escalation proceeded according to the 
schema. The first 40 mg/kg IV administration in this study occurred May 12, 2014 and 
the last infusion in VRC 601 occurred on April 6, 2015. All IV and/or SC infusions have 
been well-tolerated with no serious adverse events (SAEs) or dose limiting toxicity. 
VRC 601 demonstrated evidence of VRC01-mediated antiviral effect. An interim 
analysis of the VRC 601 viral load data obtained from 8 viremic adults through April 30, 
2015 shows that VRC01 has a statistically significant in vivo virological effect on HIV 
viral load when administered as a single 40 mg/kg IV dose. None of these adults were 
taking antiretroviral therapy (ART) when enrolled into the study and had not started ART 
during the time period when the viral load data were collected. Six of the eight adult 
participants had ≥ 1 log10 copies/mL decrease in viral load and two participants had a 
viral load drop of 0.26 and 0.18 log10 copies/mL respectively. These interim data indicate 
the following for a single dose of VRC01 at 40 mg/kg IV:  
 
A statistically significant change from baseline viral load postinfusion days 5 to 16; 

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 
The median time to reach ≥ 0.5 log10 decrease in viral load is 5 days; and, 
 
The median time to greatest decrease in viral load is 7 days. 
A 0.5 log10 copies/mL or greater decrease in viral load is considered to be a positive 
response to ART. To have clinical benefit, such a change would need to be sustained. In 
VRC 601, participants were administered only one dose of VRC01 at 40 mg/kg and, thus, 
a sustained effect on viral load was not expected. However, the data demonstrate a 
VRC01 mediated anti-viral effect. 
2.9.2 
VRC 602 
VRC 602 (NCT01993706) is titled, “A Phase 1 Dose-Escalation Study of the Safety and 
Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB060-00-AB 
(VRC01), Administered Intravenously or Subcutaneously to Healthy Adults.” 
VRC 602 was the first study of the VRC01 mAb in HIV-uninfected adults. It was a dose-
escalation study to examine safety, tolerability, dose, and PK of VRC01 [107]. VRC 602 
opened in December 2013 as a single site study at the NIH Clinical Center, Bethesda, 
Maryland and the final infusion was administered in August 2014. 
As shown in Table 2-5, there were 3 open-label, dose escalation groups (Groups 1, 2, and 
3) for IV administration and 1 double-blinded, placebo-controlled group (Group 4) for 
SC administration.  
Table 2-5 VRC 602 study schema 
VRC 602 Groups 
VRC01 Administration Schedule 
Group 
Initial 
Enrollments  
Additional 
Enrollments 
Day 0 
Week 4 
1 
3 
2 
5 mg/kg IV 
5 mg/kg IV 
2 
3 
2 
20 mg/kg IV 
20 mg/kg IV 
3 
3 
2 
40 mg/kg IV 
40 mg/kg IV 
4 
SC administration 
4A 
3 
2 
5 mg/kg SC 
5 mg/kg SC 
4B 
3 
2 
Placebo SC 
Placebo SC 
Total 
25 
20 participants treated with VRC01 at 
different dosage levels and 5 participants 
treated with placebo administered SC 
IV doses administered in 100 mL of normal saline over 1 hr. 
First SC dose administered at about 15 mL/hr via SC infusion pump; subject option for 
second dose administration (Week 4) by direct SC injection with needle and syringe. 
All IV and/or SC infusions were well-tolerated with no SAEs or dose limiting toxicity 
[107].  
PK analysis from VRC 602 revealed a VRC01 terminal half-life of 15 days across all IV 
infused dose groups. After the first infusion, 28-day trough levels were 35 mcg/mL and 
57 mcg/mL for the 20 mg/kg and 40 mg/kg dose groups, respectively. Following the 

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second infusion, the 28-day trough values rose to 57 mcg/mL and 89 mcg/mL for the 20 
mg/kg and 40 mg/kg dose groups, respectively [107].  
In addition, after infusion VRC01 retained the expected neutralizing activity in serum and 
no anti-VRC01 antibodies were detected [107]. 
2.9.3 
HVTN 104 
HVTN 104, titled A phase 1 clinical trial to evaluate the safety and drug levels of a 
human monoclonal antibody, VRC-HIVMAB060-00-AB (VRC01) administered in 
multiple doses intravenously and subcutaneously in different dosing schedules to healthy, 
HIV-uninfected adults, is examining safety profiles and serum levels of 5 different 
regimens for the IV and SC administration of VRC01 (Table 2-6). IV administration is 
being evaluated at doses of 10, 20, 30, and 40 mg/kg; SC administration is being tested at 
5 mg/kg. 
Table 2-6 HVTN 104 study schema 
Dose 
Groups 
Study product administration schedule in months (days) 
Group N 
0 
0.5 (14) 
1 (28) 
1.5 (42) 
2 (56) 
2.5 (70) 
3 (84) 
3.5 (98) 
4 (112) 
4.5 (126) 
5 (140) 
5.5 (154) 
1 
20 
VRC01 
40mg/kg 
IV 
 
VRC01 
20mg/kg 
IV 
 
VRC01 
20mg/kg 
IV 
 
VRC01 
20mg/kg 
IV 
 
VRC01 
20mg/kg 
IV 
 
VRC01 
20mg/kg 
IV 
 
2 
20 
VRC01 
40mg/kg 
IV 
 
 
 
VRC01 
40mg/kg 
IV 
 
 
 
VRC01 
40mg/kg 
IV 
 
 
 
3 
20 
VRC01 
40mg/kg 
IV 
VRC01 
5mg/kg 
SC 
VRC01 
5mg/kg 
SC 
VRC01 
5mg/kg 
SC 
VRC01 
5mg/kg 
SC 
VRC01 
5mg/kg 
SC 
VRC01 
5mg/kg 
SC 
VRC01 
5mg/kg 
SC 
VRC01 
5mg/kg 
SC 
VRC01 
5mg/kg 
SC 
VRC01 
5mg/kg 
SC 
VRC01 
5mg/kg 
SC 
4 
IV 
placebo 
for 
VRC01  
SC 
placebo 
for 
VRC01  
SC 
placebo 
for 
VRC01 
SC 
placebo 
for 
VRC01 
SC 
placebo 
for 
VRC01 
SC 
placebo 
for 
VRC01 
SC 
placebo 
for 
VRC01 
SC 
placebo 
for 
VRC01 
SC 
placebo 
for 
VRC01 
SC 
placebo 
for 
VRC01 
SC 
placebo 
for 
VRC01 
SC 
placebo 
for 
VRC01 
4 
12 
VRC01 
10mg/kg 
IV 
 
 
 
VRC01 
10mg/kg 
IV 
 
 
 
VRC01 
10mg/kg 
IV 
 
 
 
5 
12 
VRC01 
30mg/kg 
IV 
 
 
 
VRC01 
30mg/kg 
IV 
 
 
 
VRC01 
30mg/kg 
IV 
 
 
 
Total 
88 Intravenous (IV) doses administered in 100 mL of normal saline over 1 hr 
Subcutaneous (SC) doses administered by needle and syringe injection 
HVTN 104 is a phase 1 clinical trial designed to evaluate the safety and drug levels of 
VRC01 administered in multiple intravenous or subcutaneous doses and different dosing 
schedules to 88 healthy, HIV-uninfected adults at 6 HVTN CRSs in 4 US cities: Boston, 
New York, Philadelphia, and Cleveland. The first participant enrolled in HVTN 104 on 
September 9, 2014 and the last participant enrolled on July 15, 2015. Study product 
administration for all participants was complete as of November 30, 2015. The study has 
5 arms: Group 1 is evaluating the IV administration of a 40 mg/kg loading dose, with 2 
subsequent 20 mg/kg doses given at 8 week intervals. Groups 2, 4, and 5 are evaluating 3 
infusions of 40 mg/kg, 10 mg/kg, or 30 mg/kg, respectively, given 8 weeks apart. Group 
3 is evaluating 5 mg/kg given every 2 weeks subcutaneously for 24 weeks after an initial 
IV administration at 40 mg/kg; this will inform the design of perinatal prophylaxis 
studies. Secondary aims of HVTN 104 are: (1) to evaluate the kinetics of in vitro 
neutralization in serum of a single VRC01 sensitive virus isolate (TZM.bl assay); (2) to 

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determine whether anti-idiotypic antibody (AIA) can be detected and whether there is a 
correlation of VRC01 levels and AIA levels in serum; (3) to determine if measurable 
levels of VRC01 can be found in genital, rectal, and oral secretions; (4) to evaluate the 
kinetics of in vitro neutralization in mucosal secretions of a single VRC01 sensitive virus 
isolate; and (5) to assess binding of VRC01 to multiple Env proteins. 
A total of 249 IV infusions and 208 SC injections of VRC01 were administered in HVTN 
104. The infusions and injections were well tolerated,  with 28% of infusions and 14% of 
injections associated with mild pain and/or tenderness. 55% of VRC01 and 50% of 
placebo recipients experienced mild pain and/or tenderness at the infusion or injection 
site sometime during the trial. One participant experienced moderate pain and/or 
tenderness following an SC injection of VRC01. Mild infusion site erythema/induration 
reactions were reported for 2 VRC01 participants and 1 placebo recipient. Two moderate 
erythema/induration reactions were reported, 1 following IV VRC01 and 1 following 
VRC01 SC injection. For 76% of the infusions and injections administered in the trial, no 
systemic reactogenicity symptoms were reported. 56% of VRC01 and 75% of placebo 
recipients experienced systemic reactogenicity symptoms following at least one study 
product administration. These were all graded as mild in the placebo recipients; of 
VRC01 recipients who experienced any systemic symptoms, the maximum severeity was 
mild in 70%, moderate in 23%, and severe in 6% (3 participants). The most commonly 
reported symptoms were malaise/fatigue, headaches, and myalgias.   
The severe systemic reactogenicity symptoms reported in 3 VRC01 recipients are 
detailed as follows:  
 
1 participant developed severe malaise, myalgia, headache and chills, mild nausea, 
and moderate arthralgia symptoms within 3 days after the first infusion of study 
product. These symtoms had resolved by Day 7. The participant had a concomitant 
AE of laboratory confirmed Influenza A infection diagnosed on Day 2 and was 
treated with Ibuprofen.  
 
1 participant reported a viral illness AE of moderate intensity beginning 3 days prior 
to the 9th SC injection (10th study product administration), characterized by nausea 
and vomiting, sore throat, runny nose but no fevers; a household contact was also ill. 
At baseline on Day 0 of the 9th SC injection, mild malaise/fatigue was still present. At 
the early assessment timepoint on Day 0, this was still present and also grade 1 
nausea. Within 3 days of the injection, the participant developed severe malaise, 
myalgia, headache, chills, and arthralgia; these all resolved on Day 6, which was the 
date the AE for viral illness was resolved. There was no reported use of concomitant 
medications for these symptoms. 
 
1 participant reported severe malaise/fatigue on the day of the first infusion, resolving 
spontaneously the next day. During this reactogenicity period, this participant also 
reported a grade 1 headache on Day, resolving the next day. 
There were no study product discontinuations due to reactogenicity symptoms. 
There were 235 AEs occurring in 70 participants (79.5%), with similar rates of 
occurrence across all treatment groups. 74% of AEs were graded as mild, 22.5% as 
moderate, and 3.4% as severe. 9 AEs (3.8% of all AEs) occurring in 8 participants were 
deemed product-related by the investigators; all were mild and transient. Those occurring 

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following VRC01 administration included elevations of hepatic transaminases (AST and 
ALT in 1 individual), elevated creatinine, neutropenia, localized injection site pruritus, 
diarrhea, generalized rash, and Varicella zoster infection. No VRC01-related 
hypersensitivity reactions or CRS symptoms were observed during the study. 
Study product administration was discontinued in 8 participants. Reasons for 
discontinuing study product included: AEs (3 participants), relocation from study site (2), 
unable to adhere to visit schedule (1), unable to contact (1), and pregnancy (1). Of those 
participants for whom study product was discontinued due to an AE, 1 participant 
developed a mild, localized pruritic, maculopapular rash 3 days after receiving the first 
SC injection of VRC01, which resolved within 4 hours after applying inert lotion; this 
was deemed related to study product. Another participant had a brief syncopal episode 
several hours after receiving a VRC01 infusion; this was deemed not related to study 
product. A third participant had mild, brief chest tightness following the first SC injection 
that resolved spontaneously; this was deemed related to study product, however this 
participant was determined after unblinding to have received the placebo.In sum, VRC01 
was well-tolerated when administered IV or SC.  
Of note, safety experience with VRC01 has remained consistent whether 1-2 doses were 
administered, as in VRC 601 and 602, or multiple doses were administered, as in HVTN 
104. No trends toward recurrence of lab abnormalities or AEs deemed related to study 
product or increase in frequency or severity of local or systemic reactogenicity symptoms 
has been observed with multiple administrations of VRC01. 
Figure 2-9 shows serum VRC01 levels following the first 2 infusions (samples collected 
as of October 19, 2015) for participants in Group 4 (10 mg/kg of VRC01) and Group 5 
(30 mg/kg) of HVTN 104. The number of study participants with samples assayed at 
each time point is shown on the X axis of each graph. As expected, trough levels 
following the second infusion are somewhat higher than following the first infusion. The 
median antibody concentration in the 10 mg/kg group is above 10 mcg/mL for 
approximately 37 of the 56 days (66%) following the second infusion with a median 
trough concentration of 4.6 mcg/mL (25-75% interquartile range 2.6 – 6.3). For the 
30mg/kg group the median trough level is 9 mcg/mL (25-75% interquartile range 6.5 – 
9.4).  
These levels are quite similar to those modeled for the study and they show the desired 
overlap in concentrations achieved with the two doses selected for the study. 

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Figure 2-9 VRC01 serum levels through month 4 observed in HVTN 104 Group 4 (10mg/kg 
IV) and Group 5 (30mg/kg IV) 
2.9.4 
Safety summary of VRC01  
As of February 23, 2016, approximately 130 adult participants received one or more 
VRC01 administrations, including 23 in VRC 601, 23 in VRC 602 (5 additional 
participants received placebo), and 84 in HVTN 104 (4 additional participants received 
placebo). 249 VRC01 infusions and 208 SC injections were given in HVTN 104. 
Cumulatively, there have been no expedited safety reports to the FDA or study safety 
pauses for adverse events and no reactions during the VRC01 or placebo/control product 
administration that resulted in an incomplete administration.  

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VRC01 SC or IV administrations are generally associated with mild or moderate local 
reactions of pruritus, redness, and pain/tenderness, which resolve within a few minutes to 
a few hours after the administration is completed. When present, most systemic reactions 
after administration of VRC01 SC or IV are mild and include: malaise, myalgia, 
headache, chills, nausea, and joint pain. 
Unsolicited AEs of grade 3 or higher severity and deemed related to study product have 
not been reported. 
Other AEs attributed to study product administration have included mild or moderate 
AST elevation, alanine aminotransferase (ALT) elevation, creatinine elevation, and 
decreased neutrophil count. Mild or moderate elevated transaminases were reported in 4 
of 21 (19%) HIV-infected participants in VRC 601 (all of whom were taking ARVs). 
These laboratory changes resolved spontaneously and did not require discontinuation of 
study product administration. Among HIV-uninfected participants in VRC 602 or HVTN 
104, 1 participant had grade 1 (mild) transiently elevated ALT assessed as possibly 
attributed to VRC01 in the VRC 602 study and 2 participants had grade 1 (mild) 
transiently elevated ALT/AST values assessed as related to VRC01 in HVTN 104. These 
3 participants all received VRC01. 
In the HVTN 104 trial, there were 3 product discontinuations for AEs, 2 of which were 
deemed related to study product infusion or injection. One discontinuation was for a 20-
minute episode of chest tightness occurring approximately 25 minutes after SC 
injectionof placebo in a participant who is a chronic smoker on nicotine replacement 
while smoking. One discontinuation was in a participant who reported a generalized rash 
that began three days after SC injection of VRC01, and resolved within 4 hours with 
ibuprofen and the application of an over-the-counter non-steroidal cream. The third 
discontinuation was in a young, otherwise healthy participant who experienced a brief 
episode of syncope, deemed not related to study product, approximately 4 hours after IV 
infusion of VRC01. In addition, one person in HVTN 104 had study product discontinued 
due to pregnancy occurring during the trial. 
Overall, VRC01 administration in the dose range from 10 to 40 mg/kg IV and at 5 mg/kg 
SC has been assessed as well-tolerated and safe for further evaluation.  
2.9.5 
Particle formation 
VRC01 is a highly concentrated protein solution and may develop white-to-translucent 
particles after thawing. In previous phase 1 studies, particles have been observed in 
approximately 1-3% of the vials and generally disappear over a few hours at room 
temperature. Particle formation upon thawing has no effect on product quality. For 
additional information, see the IB. 
2.10 
Potential risks of study products and administration 
In a preclinical study performed in rats, there was a small dose-dependent, but transient, 
increase in AST and ALP, but not in ALT following IV administration. In rats, there were 
no histopathology findings following IV administration.  
Thus far in VRC 601, VRC 602, and HVTN 104 there have been no SAEs deemed 
related to study product (see Section 2.9.4). Administration of mAb may have a risk of 

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immune reactions such as acute anaphylaxis, serum sickness, and the generation of auto-
reactive antibodies; however, these reactions are rare and more often associated with 
mAbs targeted to human proteins or with the use of murine mAbs, which would have a 
risk of human anti-mouse antibodies [108]. In this regard, as VRC01 is targeted to a viral 
antigen and is a human mAb, it is expected to have a low risk of such side effects.  
Typically, the side effects of mAbs are mild but may include fever, flushing, chills, 
rigors, nausea, vomiting, pain, headache, dizziness, shortness of breath, bronchospasm, 
hypotension, hypertension, pruritus, rash, urticaria, angioedema, diarrhea, tachycardia, or 
chest pain. Clinical use of mAbs that are targeted to cytokines or antigens associated with 
human cells may be associated with an increased risk of infections [108]; however, this is 
not expected to be a risk for a mAb targeted to a viral antigen. 
It is known from published experience with human mAbs directed against the cell surface 
targets on lymphocytes that infusion of a mAb may be associated with cytokine release, 
causing a reaction known as cytokine release syndrome [109]. Cytokine release syndrome 
and other immune reactions such as tumor lysis syndrome have been observed with 
administration of chimeric and humanized mAb [108]. Most infusion-related events 
occur within the first 24 hours after beginning administration. Specifically, with regard to 
cytokine release syndrome reactions, these most commonly occur within the first few 
hours of beginning the infusion and are more common with the first mAb infusion 
received. This is because the cytokine release is associated with lysis of the cells targeted 
by the mAb and the burden of target cells is greatest at the time of the first mAb 
treatment. With licensed therapeutic mAbs, cytokine release syndrome is managed by 
temporarily stopping the infusion, administering histamine blockers, and restarting the 
infusion at a slower rate [110]. Severe reactions such as anaphylaxis, angioedema, 
bronchospasm, hypotension, and hypoxia are infrequent and more often associated with 
mAbs targeted to human proteins or with a non-human mAb, such as a murine mAb 
[108].  
Delayed allergic reactions to a mAb may include a serum sickness type of reaction, 
which is characterized by urticaria, fever, lymph node enlargement, and joint pains. 
These symptoms may not appear until several days after exposure to the mAb and are 
noted to be more common with chimeric types of mAb [108]. Serum sickness has not 
been described with administration of licensed fully human mAbs. 
There are several FDA-licensed mAbs for which reactions related to the rate of infusion 
have been described. Some symptoms may be treated by slowing or stopping the 
infusion.  
Other side effects of licensed mAbs include infections, thrombocytopenia, autoimmune 
diseases, cancer, dermatitis, and cardiotoxicity [108]. 
The HVTN laboratory tested plasma from HIV-uninfected individuals that was spiked 
with VRC01 in a range of concentrations that encompasses those likely to be observed in 
this clinical trial. VRC01 did not cause a reactive test result using several standard 
antibody-based HIV-1/2 diagnostic tests used in the US. However, VRC01 is an antibody 
to an HIV protein, so it may be theoretically possible for a standard antibody-based HIV 
diagnostic test to detect VRC01 for a short time period postinfusion or postinjection. This 
has not been observed in clinical studies to date.  

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Risks of Blood Drawing: Blood drawing may cause pain and bruising and may, 
infrequently, cause a feeling of lightheadedness or fainting. Rarely, it may cause infection 
at the site where the blood is taken. Problems from use of an IV for blood drawing are 
generally mild and may include pain, bruising, minor swelling, or bleeding at the IV site 
and, rarely, infection, vein inflammation (phlebitis), or blood clot.  
Risks of IV Infusion: The placement of an IV catheter can allow for the development of 
bacteremia because of the contact between the catheter and unsterile skin during 
insertion. Risk of infection from IV infusion will be minimized through careful 
decontamination of skin prior to catheter placement and through the use of infection 
control practices during infusion. The risk of product contamination will be minimized 
through the use of aseptic techniques during product preparation and administration.  

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3 
Objectives and endpoints 
3.1 
Primary objectives and endpoints 
Primary objective 1:  
To evaluate the safety and tolerability of VRC01 mAb administered through IV infusion 
in MSM+TG in North America, South America, and Switzerland  
Primary endpoint 1:  
Local and systemic reactogenicity signs and symptoms, laboratory measures of safety, 
AEs, SAEs, and rates of discontinuation 
Primary objective 2: 
To determine if the VRC01 mAb prevents HIV-1 infection and to estimate the level of 
efficacy in MSM+TG in North America, South America, and Switzerland  
Primary endpoint 2: 
Documented HIV-1 infection by the Week 80 study visit  
3.2 
Secondary objectives and endpoints 
Secondary objective 1: 
To develop a marker(s) of the VRC01 mAb that correlates with the level and antigenic 
specificity of protection against HIV-1 infection and to provide insight into the 
mechanistic correlates of protection 
Secondary endpoints 1: 
Serum concentration of VRC01 in participants assigned to receive the mAb (ELISA, 
neutralizing assay) 
Serum mAb effector functions to HIV-1 Envs representing variability of the VRC01 
antibody footprint 
Sequences of breakthrough HIV infections from the earliest available HIV-positive 
plasma samples 
VRC01 neutralization-sensitivity of, and effector function against, HIV strains from 
infected trial participants from the earliest available post–HIV-infection serum samples 

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3.3 
Exploratory objectives 
Exploratory objective 1: 
To assess use of FTC/TDF in the study cohort 
Exploratory objective 2: 
To assess if prevention efficacy is modified by FTC/TDF use 
Exploratory objective 3: 
To understand changes in risk behavior and the potential for risk compensation for all 
study participants 
Exploratory objective 4: 
To measure anti-idiotype antibodies to VRC01 

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4 
Statistical considerations 
4.1 
Outline of the statistical considerations section 
The statistical considerations section is organized as follows. Section 4.2 states the 
primary and secondary efficacy objectives in terms of the target prevention efficacy (PE) 
parameters that are estimated in the trial, and describes the hypothesis tests regarding 
these efficacy parameters. Section 4.4 summarizes a statistical rationale for using a 3-arm 
design, which adds to the scientific rationale provided in Section 2.4. Section 4.6 
describes sample size and power considerations for the primary efficacy objectives, 
which justify the sample size of the trial. Section 4.6 also provides operating 
characteristics of the trial design for addressing the primary efficacy objective. Section 
4.7 describes statistical power available for the secondary objective that compares PE 
between the two mAb dose groups. Section 4.8 describes statistical power available for 
detecting safety problems of the mAb in terms of SAEs. Section 4.9 summarizes the 
approach to monitoring the trial including interim analysis reports provided to the 
DSMB. Sections 4.10, 4.11, and 4.12 describe PrEP assessments, randomization, and 
blinding, respectively. Section 4.13 describes the approach to statistical analysis, ordered 
first by the approach to the analysis of PE, and secondly by the approach to the 
assessment of correlates of protection. 
4.2 
PE parameter for the primary analysis of prevention efficacy 
Let PE denote the overall PE of the 10 mg/kg and 30 mg/kg mAb groups pooled together 
compared to the control group. This PE parameter is defined as 
PE = [1 – Cumul. incid. ratio (pooled mAb grp/control) of HIV-1 Dx by 80 Wks] × 
100%, 
where the cumulative incidence ratio is the probability of HIV-1 diagnosis by the Week 
80 visit for participants assigned to receive the mAb divided by the probability of HIV-1 
diagnosis by the Week 80 visit for participants assigned to receive control. PE is the 
target parameter for the primary analysis of overall PE.  
The primary analysis tests the null hypothesis 
H0: PE = 0% versus the alternative hypothesis H1: PE ≠ 0% 
using a 2-sided alpha = 0.05 level test that accounts for sequential monitoring for 
potential harm, non-efficacy, and high efficacy.  
4.2.1 
Rationale for the PE parameter that measures prevention efficacy averaging over 
participant subgroups that access different elements of the HIV-1 prevention 
package 
The primary PE parameter measures the efficacy of VRC01 averaging over the 10 mg/kg 
and 30 mg/kg subgroups, in the population-based context of study participants with 
different risk characteristics including host genetics, HIV-1 risk taking behaviors, and 

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participant decision to use different elements of the HIV-1 prevention package. The HIV-
1 prevention package includes FTC/TDF PrEP, and is in harmony with the World Health 
Organization’s November 2015 guideline on PrEP use that states “PrEP should be an 
additional prevention choice in a comprehensive package of services that also includes 
HIV testing, counseling, male and female condoms, lubricants, ARV treatment for 
partners with HIV infection, voluntary medical male circumcision and harm reduction 
interventions for people who use drugs” [111]. The HIV-1 prevention package includes 
all of these elements, and study staff educate participants about the comprehensive 
package and facilitate access to and use of each measure. By conducting the study in a 
cohort of study participants who make the informed choice to use different elements of 
the package, the primary analysis result generalizes to a population with such 
heterogeneity of choice and aims to reflect efficacy in a real-world setting where such 
heterogeneity occurs. In particular, all study participants are counseled about the known 
high efficacy of FTC/TDF and are encouraged to take it. Because past experience and 
research has found that some individuals may prefer to not take FTC/TDF, the primary 
analysis conducted in a cohort reflecting such heterogeneity in prevention choices allows 
a representative population of individuals to participate in the trial. This approach also 
accommodates changes in prevention choices during the course of the trial, where the 
primary PE parameter is estimated in the context of these changes.  
How many MSM/TG persons will initiate and adhere to fixed dose FTC/TDF when it is 
offered as part of an HIV prevention package is unclear; estimates vary considerably in 
the literature. Open label extensions of the PrEP clinical trials and reporting from the first 
demonstration projects of PrEP offer some insights into PrEP uptake and adherence in 
high risk MSM. As discussed in Section 2.5.1, uptake of PrEP has ranged from 76% in 
iPrEX OLE to 60% in the US-based Demo Project and 51% in PrEP Brasil [76,87,88]. 
While the uptake is substantial, from these studies it is also clear that a substantial 
fraction of high risk MSM will not initiate PrEP. Moreover, even in the context of 
intensive counseling, long-term adherence– especially adherence during periods of 
highest risk–is also unclear. It is thus most pertinent to advancing the science of HIV 
prevention to conduct the VRC01 primary PE analysis in a cohort reflecting 
heterogeneity in prevention choices, representative of the population at risk. This 
approach will also accommodate changes in prevention choices that emerge during the 
course of the trial, as the primary PE parameter will be estimated in the context of these 
changes.  
4.3 
PE parameters for secondary analyses of prevention efficacy 
Secondary analyses assess PE parameters for the mAb dose groups separately. Let PE10 
be the overall PE of the 10 mg/kg mAb group and let PE30 be the overall PE of the 30 
mg/kg mAb group, defined as 
PE10 = [1 – Cumul. incid. ratio (mAb-10 mg/kg grp/control) of HIV-1 Dx by 80 
Wks] ×100% 
and 
PE30 = [1 – Cumul. incid. ratio (mAb-30 mg/kg grp/control) of HIV-1 Dx by 80 
Wks] ×100%. 
Secondary analyses test the null hypotheses 

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H0: PE10 = 0% versus the alternative hypothesis H1: PE10 ≠ 0% 
and 
H0: PE30 = 0% versus the alternative hypothesis H1: PE30 ≠ 0% 
using 2-sided alpha = 0.05 level tests. Both unadjusted p-values and Holm-Bonferroni p-
values will be reported for each of the individual dose versus placebo group analyses.  
In addition, the following secondary analyses of PE are conducted: 
 
Assess a dose-response effect by testing the null hypothesis 
H0: Cumul. HIV-1 incidence by 80 Wks equal in the 3 groups versus H1: 0% ≤ PE10 
≤ PE30 with at least one strict inequality 
 
Test the complete null hypothesis that the HIV-1 incidence is the same in the three 
treatment groups versus the alternative hypothesis that there are some differences 
 
Test for different HIV-1 incidence between the two mAb groups, where a finding of 
PE30 significantly greater than PE10 would demonstrate that assignment to a higher 
mAb dose level causes higher PE 
4.4 
Statistical rationale for the 3-arm design compared to a 2-arm design 
An alternative design would compare a single dose and schedule of the VRC01 mAb 
versus control. However, the 3-arm design allows addressing additional scientific 
questions and improves the assessment of correlates of protection, without requiring more 
participants by virtue of the primary analysis being based on the pooled mAb groups 
versus control. Specifically, consider a 2-arm design with 2:1 allocation to a single dose 
of VRC01 versus placebo, compared to the 3-arm design in the protocol with 1:1:1 
allocation. For scenarios where the average of PE10 and PE30 equal PE set to a number 
greater than 0 and less than 1, power to reject H0: PE ≤ 0% in favor or H1: PE > 0% is 
very similar between the two trial designs, for the same total number of study 
participants. By providing results about estimated PE10 and estimated PE30 as well as 
about pooled estimated PE, the trial provides data for modeling of how PE would change 
given a new dose and/or schedule.  
A second advantage of the 3-arm design is that it allows a direct assessment of the causal 
effect of different mAb infusion doses on HIV-1 incidence based on randomization of 
treatment assignments (a so-called ‘group-level’ correlate of protection), which can 
directly prove the concept that a higher mAb dose causes a greater level of protection. In 
contrast, with a 2-arm design the association between mAb marker characteristics and the 
level of PE can only be inferred with non-randomized epidemiological analysis 
approaches for which the results cannot be guaranteed to be free from postrandomization 
selection bias [112,113]. That is, without a randomization to multiple mAb interventions 
a result that a mAb characteristic is associated with reduced incidence of HIV-1 infection 
may not imply that mAb recipients with the characteristic have a higher level of PE. For 
instance, the implication may fail if participants tend to have fewer HIV-1 exposures 
during the few weeks after infusion visits compared to during the few weeks before 
infusion visits, which could possibly occur related to the counseling and informed 
consent process. Or, the implication may fail if the mAb characteristic marks an intrinsic 

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HIV-1 susceptibility factor that is not caused by administration of the mAb [114-116]. A 
third advantage of the 3-arm design is that the random assignment of two mAb doses 
creates greater inter-individual variability in mAb characteristics, which improves 
statistical power for the assessment of individual-level correlates of protection.  
In sum, the dose-response 3-arm design has the advantages of allowing more insightful 
and rigorous inferences about causal effects of the mAb and greater resolution of 
correlates of protection, and allows addressing the additional question of whether a 
higher dose confers greater PE than a lower dose. 
4.5 
Use of safety run-in data in the analyses of prevention efficacy 
Data from all participants, irrespective of enrollment into the safety run-in cohort, are 
included in analyses of prevention efficacy. This is valid because all enrolled participants 
have the same schedule for infusions and follow-up. In the event that infusions are 
paused, the analysis plan would be amended to censor participant follow-up more than 
approximately 10 weeks beyond the last infusion after the pause is instituted.  
4.6 
Sample size calculations for testing for overall PE (Primary objective 
2) 
The trial is designed to have 90% power to test 
H0: PE ≤ 0% versus the alternative hypothesis H1: PE > 0% 
if the level of overall pooled PE is 60% (with a 1-sided 0.025 α-level test); the design fits 
the paradigm of an intermediate-sized phase 2b screening efficacy trial proposed for 
HIV-1 vaccine efficacy trials by Rida, Fleming et al [117]. 
The sample size calculations are based on the power of a 1-sided 0.025-level Wald test 
for comparing log-transformed cumulative incidences of HIV-1 infection by the Week 80 
visit between randomized groups, in the presence of the sequential monitoring described 
below. Power is computed based on simulating 10,000 efficacy trials under assumptions 
described below using the R package seqDesign. 
4.6.1 
Assumptions of the sample size calculations including sequential monitoring for 
PE 
The following assumptions are made for the sample size calculations: 
 
10% annual dropout incidence in each of the three study groups 
 
32 month uniform accrual with halved accrual during the first three months 
(approximating current accrual projections) 
 
visits every 4 weeks for HIV-1 diagnostic tests through Week 80 and HIV-1 status at 
Week 80 is known 
 
3% annual HIV-1 incidence in the control group 

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 
For each of the mAb treatment groups, average PE versus control within an 8-week 
infusion interval is assumed to be the same for each of the 10 infusion intervals  
 
Sequential monitoring of the mAb groups versus control to stop early for: 
o Potential harm [Establish that PE (pooled over the mAb groups) < 0% based on a 
2-sided monitoring adjusted 90% CI lying below 0%]  
o Non-efficacy [Establish that PE (pooled over the mAb groups) ≤ 40% based on a 
2-sided 95% nominal CI lying below 40%] 
o High efficacy [Establish that PE (pooled over the mAb groups) > 70% based on a 
2-sided 95% nominal CI lying above 70%] 
With the exception of the potential harm monitoring, the sequential monitoring of PE 
does not use critical values adjusted for the number of analyses. Examination of the 
design operating characteristics (reported in the figures and tables below) was used to 
ensure that this approach provides a fitting trade-off of the control of false negative and 
false positive error rates. 
Justification for the incidence assumptions is provided in Section 4.6.6. 
We also show power calculations allowing for lower levels of HIV-1 incidence or higher 
levels of dropout. In particular, we show power calculations assuming 1.65% annual 
HIV-1 incidence in the control group, which would account for lower than expected 
incidence rates due to increased PrEP usage. Similarly, power calculations based on 15% 
annual dropout incidence are also considered. 
4.6.2 
Power curves and operating characteristics of the design (Primary objective 2)  
Required sample sizes to achieve 90% power to reject H0: PE ≤ 0% in favor of H1: PE > 
0% for different values of PE are determined based on 1-sided 0.025 level Wald tests as 
described above. The power calculations are repeated for a range of sample sizes to 
determine the required sample size to achieve 90% power as reported in Figure 4-1. 
These power calculations are conducted using the open source R package seqDesign 
developed by the protocol statisticians [118], which computes power based on simulating 
many thousands of efficacy trials, applying the sequential monitoring procedures to each 
trial, and computing power as the fraction of the trials where the 1-sided 0.025-level 
Wald test rejects the null hypothesis. The calculations are based on a large number of 
simulated efficacy trials.  
Figure 4-1 shows the sample size per group in the three treatment groups required to have 
90% power to reject H0: PE ≤ 0% in favor of H1: PE > 0% for different values of 
PE = PE10 = PE30. The results show that about N = 2300 total participants are needed to 
achieve 90% power to detect PE = 60%; the sample size N = 2700 total participants (900 
per arm) is selected to build in a provision of robustness to the control group annual 
incidence being lower than 3.0%. In particular, the lowest control group annual HIV-1 
incidence to retain power of at least 90% to detect PE = 60% is 2.3%. 

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Figure 4-1 Total sample size for 90% power to reject H0: PE ≤ 0% in favor of H1: PE > 0% in a 
1:1:1 allocation design with 80 weeks of follow-up for HIV-1 infection for each trial 
participant 
Table 4-1 shows power available to reject the null hypothesis under different levels of 
true PE.  
Table 4-1 Power for rejecting H0: PE ≤ 0% in favor of H1: PE > 0% under different effect sizes 
PE = PE10 = PE30 
 
Unconditional Power (× 100) 
0% 
2.4 
10% 
7.8 
20% 
19.0 
30% 
38.6 
40% 
62.9 
50% 
84.2 
60% 
96.0 
70% 
99.5 
80% 
>99.9 
90% 
>99.9 
95% 
>99.9 
The power calculations for the primary analysis of prevention efficacy were done 
assuming PE10 = PE30, and it is of importance to also understand power available in the 
primary analysis in the event that PE10 differs from PE30. Power for rejecting 
H0: PE ≤ 0% in favor of H1: PE > 0% when PE equals a fixed constant PE0
 greater than 0 
and less than 1 is very similar for different values of (PE10, PE30) subject to the 
constraint of average value (PE10+PE30)/2 = PE0. For example, power to test H0 vs. H1 
is very similar for (PE10, PE30) = (60%, 60%) and for (PE10, PE30) = (30%, 90%). This 
result attains because all of these scenarios have the same number of expected HIV-1 
infection events among study participants assigned to receive VRC01. Power tends to be 
slightly greater for differential scenarios like (PE10, PE30) = (30%, 90%) compared to 
the equal scenario (PE10, PE30) = (60%, 60%), because the hypothesis testing procedure 
stratifies by VRC01 dose group, gaining efficiency by accounting for a baseline variable 
that predicts HIV infection. Therefore, the trial is powered to detect the design alternative 

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of a dose-pooled VRC01 efficacy PE equal to 60%, regardless of whether VRC01 
efficacy differs by dose group. 
4.6.3 
Additional operating characteristics of the design for assessing primary objective 
2 
For the selected sample size (N = 2700), Figure 4-2 shows the power curves for rejecting 
H0: PE ≤ 0% in favor of H0: PE > 0% for a range of fixed values of the pooled PE. The 
power for rejecting H0 when the HIV-1 incidence rate is lower than projected or dropout 
rate is higher than projected are included in the figure.  
The scenario of 1.65% annual HIV-1 incidence represents various amounts of PrEP use 
among study participants. In particular, this 1.65% assumption is attained if 50% of 
person-years at–risk are not during PrEP use with annual incidence of 3.0%, and the other 
50% of person-years at-risk are during PrEP use at PrEP efficacy of 90% and hence with 
annual incidence of 0.3% [1.65% = (3.0% + 0.3%)/2]. In addition, a slightly higher 
control group annual incidence of 2.0% is attained under each of the following three 
scenarios, all of which assume 90% PrEP efficacy during PrEP use and 3% annual HIV-1 
incidence during person-years at-risk without PrEP use: (A) 50% of person-years at-risk 
during PrEP use in the U.S. and Switzerland; 25% in Peru and Brazil; and 69% 
participants enrolled in the U.S. and Switzerland; (B) 60% of person-years at–risk during 
PrEP use in the U.S., 30% in Peru and Brazil, and 61% of participants enrolled in the 
U.S. and Switzerland; (C) 75% of person-years at–risk during PrEP use in the U.S. and 
Switzerland, 40% in Peru and Brazil, and 48% of participants enrolled in the U.S. and 
Switzerland. These calculations support that the study has adequate power to meet the 
primary efficacy objective if there is substantial PrEP use. 
Moreover, we also conducted power calculations assuming 50% of person-years at-risk 
during PrEP use in all three countries, which means that the overall annual HIV-1 
incidence in the placebo group is 1.65% [= (3.0% + 0.3%)/2]. In this scenario, the trial 
has 78% power to detect PE = 60%. 

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Figure 4-2 Unconditional power to reject H0: PE ≤ 0% in favor of H1: PE > 0% for a range of 
fixed values of pooled PE based on primary assumptions for HIV-1 incidence and dropout 
rate. Power curves are also shown for a lower than expected HIV-1 incidence rate and a 
higher than expected dropout rate. 
4.6.4 
Additional operating characteristics of the primary analysis accounting for the 
sequential monitoring 
For the selected sample size (N = 2700), Figure 4-3 shows probabilities of reaching each 
possible trial monitoring outcome, pooling over the two mAb treatments (under the 
primary assumptions about HIV-1 incidence and dropout rates). More specifically, the 
monitoring outcomes include potential harm, non-efficacy, and high efficacy. Table 4-2 
provides the same information in tabular form. In addition, the figure and table show 
unconditional power in the primary analysis to reject the null hypothesis H0: PE ≤ 0% in 
favor of the alternative hypothesis H1: PE > 0%. 

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Figure 4-3 Probabilities of reaching each possible trial monitoring outcome, and 
unconditional power to reject the primary null hypothesis H0: PE ≤ 0%with 900 control 
recipients and 1800 mAb recipients (1-sided 0.025-level tests) 
Table 4-2 Probabilities (x 100) of reaching each possible trial monitoring outcome, and 
unconditional power (x 100) to reject the null hypothesis H0: PE ≤ 0% in favor of the 
alternative hypothesis H1: PE > 0%, pooling over the two mAb groups (1-sided 0.025-level 
tests) 
 
 
Weed Out at Interim Analysis 
 
 
PE 
HR 
Potential Harm 
PE < 0% 
Non-Efficacy 
PE < 40% 
High Efficacy 
PE > 70% 
Unconditional Power 
PE > 0% 
 
3.0 
95.3 
4.7 
0.0 
0.0 
2.5 
87.8 
12.2 
0.0 
0.0 
2.0 
69.1 
30.9 
0.0 
0.0 
1.5 
34.0 
66.0 
0.0 
0.0 
0% 
1.0 
4.9 
92.7 
0.0 
2.4 
10% 
0.9 
2.6 
89.6 
0.0 
7.8 
20% 
0.8 
1.1 
79.8 
0.0 
19.0 
30% 
0.7 
0.4 
61.0 
0.0 
38.6 
40% 
0.6 
0.1 
37.0 
0.0 
62.9 
50% 
0.5 
0.0 
15.8 
0.0 
84.2 
60% 
0.4 
0.0 
4.0 
0.1 
96.0 
70% 
0.3 
0.0 
0.5 
2.0 
99.5 
80% 
0.2 
0.0 
0.0 
23.6 
100.0 
90% 
0.1 
0.0 
0.0 
85.4 
100.0 
95% 
0.0 
0.0 
0.0 
99.2 
100.0 
N = 900:1800 Control:mAb group 
3% annual incidence in the Control group 
10% annual dropout 
Cumulative incidence-based non-efficacy monitoring 
Cumulative incidence-based high-efficacy monitoring 
Cumulative incidence-based unconditional power 
Table 4-3 shows the numbers of HIV-1 infection endpoints during the trial expected 
under the null hypothesis scenario PE = PE10 = PE30 = 0% and under the design 

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alternative hypothesis scenario PE = PE10 = PE30 = 60%. Under the design alternative 
hypothesis scenario, the calculations show that 37 HIV-1 infection endpoints are 
expected in the control group and 30 HIV-1 infection endpoints are expected in the two 
mAb groups combined after 80 weeks of follow-up. 
Table 4-3 Cumulative number of HIV-1 infection endpoints over 80 weeks of follow-up under 
the null hypothesis scenario PE10 = PE30 = 0% and under the design alternative hypothesis 
scenario PE = PE10 = PE30 = 60%. Medians are computed based on simulating a large 
number of efficacy trials. 
PE10 = PE30 
Weeks since first person in 
Median number of 
control endpoints 
Median number of 
pooled mAb group 
endpoints 
0% 
0 
0 
0 
0% 
26 
0 
1 
0% 
52 
3 
7 
0% 
78 
9 
18 
0% 
104 
16 
32 
0% 
130 
22 
45 
0% 
156 
25 
50 
0% 
182 
26 
54 
0% 
208 
26 
55 
0% 
210 
26 
55 
60% 
0 
0 
0 
60% 
26 
0 
0 
60% 
52 
3 
3 
60% 
78 
9 
7 
60% 
104 
16 
13 
60% 
130 
23 
19 
60% 
156 
30 
24 
60% 
182 
35 
28 
60% 
208 
37 
30 
60% 
219 
37 
30 
4.6.5 
Power curves for secondary hypothesis tests about PE in each mAb group 
Figure 4-4 shows unconditional power to reject the null hypothesis H0: PE10 ≤ 0% 
versus the alternative hypothesis H1: PE10 > 0% (or, equivalently, the null hypothesis 
H0: PE30 ≤ 0% versus the alternative hypothesis H1: PE30 > 0%), where PE10 and PE30 
measure prevention efficacy in each mAb group separately. 

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Figure 4-4 Unconditional power to reject H0: PE10 ≤ 0% in favor of H1: PE10 > 0% (or H0: 
PE30 ≤ 0% in favor of H1: PE30 > 0%) based on primary assumptions about HIV-1 incidence 
rate and dropout rate (1-sided 0.025-level tests). Power curves are also shown for lower than 
expected HIV-1 incidence rate and a higher than expected dropout rate. 
4.6.6 
Rationale for the HIV-1 incidence assumptions 
The assumption of 3% annual HIV-1 incidence in the control group accommodates 
background PrEP use by assuming incidence is decreased by two parameters: (1) the 
fraction of person-years at-risk during which PrEP is used; and (2) the level of efficacy of 
PrEP during PrEP use. Figure 4-5 shows the annual HIV-1 incidence in the control group 
as a function of these two factors, for a scenario where the annual HIV-1 incidence is 4% 
in the absence of any PrEP use. Based on HVTN 505 data (US participants only) through 
September 30, 2014, the annual HIV-1 incidence in the control group was 2.0% (95% CI 
1.5%—2.7%) and in the vaccine and control groups pooled was 2.1% (95% CI 1.5%—
2.8%). From HVTN 505, based upon case report form (CRF) collection of PEP/PrEP 
med usage and responses to questions regarding usage posed on the ‘anonymous’ (to the 
site) ACASI questionnaire through June 1, 2014, 5% of participants reported ever using 
PrEP. In HVTN 505 the amount of person-years at risk during periods of PrEP use was 
likely well below 5%, and, therefore, the 2.1% annual incidence is a reasonable 
assumption for the baseline rate without PrEP. In particular, assuming 1.6% annual 
control incidence in the US and Switzerland (which is expected if 27% of person-years at 
risk are during PrEP use and PrEP efficacy is 90% during use) and assuming 5% annual 
control incidence in South American participants [7], (with 5% of person-years at risk 
during PrEP use and 90% PrEP efficacy during use), 44% of participants enrolled at 
South American sites would yield the assumed 3% annual control incidence rate. 

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Figure 4-5 Annual HIV-1 incidence in the control group assuming 4% annual HIV-1 incidence 
in the hypothetical scenario of no PrEP use, under different levels of PrEP use and levels of 
PrEP efficacy 
Higher than expected use of PrEP would be reflected in lower than expected annual 
incidence rates, as shown in Figure 4-5. As shown in Figure 4-2, the trial would still 
provide enough statistical information to be powered to detect highly relevant prevention 
efficacy effect sizes if annual incidence rates are lower than we have estimated here due 
to higher than expected use of PrEP. 
4.7 
Power for the secondary analysis comparing HIV-1 incidence 
between the 10 mg/kg mAb group versus the 30 mg/kg mAb group 
Table 4-4 reports power calculations for comparing HIV-1 incidence between the 
10 mg/kg and 30 mg/kg mAb groups. The calculations assume the scenarios for true 
values of PE10 and PE30 indicated in the first two columns of the table. The results show 
that the study is well-powered to detect large differences, for example, with about 87% 
power to discriminate 30% vs. 80% PE and 40% vs. 85% PE, but may miss moderate 
differences (e.g., 34% power to discriminate 30% vs. 60% PE). In contrast, the study has 
high power to correctly select the best mAb dose group given moderate efficacy 
differences. Specifically, if the true PE30 is moderately greater than the true PE10, then 
there is high probability that the estimated PE30 would be greater than the estimated 
PE10, such that the 30 mg/kg mAb dose group would be selected. 

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Table 4-4 Statistical power for comparing the 10 versus 30 mg/kg mAb groups: Power to 
correctly rank-and-select the best mAb group and power to detect superiority of the 30 
mg/kg mAb group over the 10 mg/kg mAb group in a head-to-head comparison 
PE10 
PE30 
Power to Rank-and-Select 
Best mAb Dose Group$ 
Power to Detect PE10 
Different from PE30# 
20% 
60% 
88.3 
58.3 
30% 
60% 
86.7 
39.5 
40% 
60% 
81.7 
21.6 
20% 
70% 
97.2 
83.7 
30% 
70% 
96.8 
69.4 
30% 
80% 
99.8 
91.5 
40% 
85% 
>99.9 
90.8 
50% 
85% 
99.7 
77.0 
$ Probability that the mAb dose group that is truly better (the 30 mg/kg dose group in the scenarios considered in the 
table) is correctly selected based on the point estimate for PE30 exceeding that for PE10. Specifically, correct selection 
entails that the estimated PE30 is greater than the estimated PE10 and PE30 is significantly > 0% (1-sided α = 0.025) 
# Cumulative hazard-based 2-sided Wald tests comparing HIV-1 incidence between the 10 mg/kg and 30 mg/kg mAb 
groups. Rejection of the null hypothesis requires that PE30 is significantly > 0% (1-sided α = 0.025) 
4.8 
Sample size calculations for safety 
We consider the statistical power of Fisher’s exact test to detect a higher rate of SAEs in 
a mAb group (Group 1 or 2 with n = 900 participants) versus the control group (Group 3 
with n = 900). Based on HVTN vaccine trials from December 2000 through April 2014, 
about 4% of participants who received placebos experienced an SAE. The tests use a 2-
sided α-level of 0.05. This level does not correct for the 4 comparisons; however, this is 
appropriate because it is desirable to maximize power to detect a safety problem. For the 
safety calculations, we assume no missing data as almost all participants will have some 
follow-up data for safety.  
To describe the precision of the study to characterize differences in SAE rates between 
groups, Table 4-5 shows 2-sided 95% CIs for different levels of observed differences 
(mAb group-control) of event rates between a mAb group of size n1 = 900 (or the 
combined mAb groups n2 = 1800) and a control group of size n0 = 900. For example, an 
observed rate difference of 6% between the combined mAb groups and control group will 
lie between 3.5% and 8.7% with 95% confidence, when the observed event rate in the 
control group is 4%.  

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Table 4-5 Two-sided 95% CIs for different observed event rate differences of safety 
endpoints between the mAb recipient and control groups* 
Observed 
event rate in 
controls 
(n0 = 900) 
Observed event 
rate in a single 
mAb group 
(n1 = 900) 
Observed event 
rate in combined  
mAb groups 
(n2 = 1800) 
Rate 
difference 
(mAb group 
– control) 
95 % CI  
(n1 = 900) 
95% CI  
(n2 = 1800) 
0/900 = 0% 
0/900 = 0% 
0/1800 = 0% 
0% 
(-0.0050, 0.0050) 
(-0.0050, 0.0022) 
 
18/900 = 2% 
36/1800 = 2% 
2% 
(0.0125, 0.0317) 
(0.0143, 0.0278) 
 
36/900 = 4% 
72/1800 = 4% 
4% 
(0.0289, 0.0550) 
(0.0317, 0.0503) 
 
90/900 = 10% 
180/1800 = 10% 
10% 
(0.0817, 0.1217) 
 (0.0869, 0.1150) 
 
180/900 = 20% 
360/1800 = 20% 
20% 
(0.1750, 0.2279) 
(0.1819, 0.2192) 
 
 
 
 
 
 
18/900 = 2% 
0/900 = 0% 
0/1800 = 0% 
-2% 
 (-0.0317, -0.0125) 
(-0.0317, -0.0125) 
 
16/900 = 2% 
36/1800 = 2% 
0% 
(-0.0136, 0.0136) 
(-0.0127, 0.0106) 
 
32/900 = 4% 
72/1800 = 4% 
2% 
(0.0041, 0.0369) 
(0.0060, 0.0327) 
 
80/900 = 10% 
180/1800 = 10% 
8% 
(0.0592, 0.1030) 
(0.0631, 0.0968) 
 
160/900 = 20% 
360/1800 = 20% 
18% 
 (0.1531, 0.2088) 
(0.1594, 0.2009) 
 
 
 
 
 
 
36/900 = 4% 
0/900 = 0% 
0/1800 = 0% 
-4% 
(-0.0550, - 0.0289) 
(-0.0550, -0.0289) 
 
18/900 = 2% 
36/1800 = 2% 
-2 % 
(-0.0369, -0.0041) 
(-0.0360, -0.0067) 
 
36/900 = 4% 
72/1800 = 4% 
0% 
(-0.0188, 0.0186) 
(-0.0170, 0.0150) 
 
90/900 = 10% 
180/1800 = 10% 
6% 
(0.0369, 0.0842) 
(0.0405, 0.0787) 
 
180/900 = 20% 
360/1800 = 20% 
16% 
(0.1314, 0.1899) 
( 0.1372, 0.1826) 
*95% CIs are computed using the method of Berger and Boos [119].  
Figure 4-6 shows the power to detect an elevated SAE rate as a function of the true rate in 
the mAb group under consideration. 
 
Figure 4-6 Power to detect a greater SAE rate in a mAb group (n = 1800) versus the control 
group (n = 900) given a 4% SAE rate in the control group (2-sided 0.05-level test) 
Figure 4-6 shows that there is 80% power to detect a higher SAE rate in a mAb arm if the 
true SAE rate is 7.1% and 90% power if the true rate is 7.6%. 

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4.9 
Monitoring of the trial 
4.9.1 
Role of the Data Safety Monitoring Board (DSMB) 
The study DSMB will review study data at 6-monthly interim analyses to evaluate safety, 
integrity, and efficacy of the ongoing trial. Following each DSMB meeting, the DSMB 
reports to the Oversight Committee (OC) a summary of the trial review, which may 
include recommendations to modify or terminate the trial. The DSMB is guided by a trial 
monitoring plan, and reviews and approves the monitoring plan before the trial initiates. 
Each 6-monthly DSMB report will include a complete analysis of safety data. If a total of 
N = 20 participants reach the Week 12 study visit before the first DSMB report is 
generated, then a safety report based on these data will be provided to the DSMB as soon 
as possible and before the first DSMB meeting. The contents of the early report are the 
same as the contents in the scheduled 6-monthly DSMB reports. 
In addition, as soon as 10 grade 2 or higher AEs occur, a report will be generated 
describing these AEs and will be provided to the DSMB. The DSMB reports will also 
tabulate occurrence of SAEs, and of AEs judged related to product, accounting for the 
number of infusions received.  
4.9.1.1 
Sequential monitoring for potential harm, non-efficacy, and high efficacy 
The trial uses sequential monitoring of the mAb groups versus control to stop early for: 
 
Potential harm [Establish that PE (pooled over the mAb groups) < 0% based on a 
2-sided monitoring-adjusted 90% CI lying below 0%]  
 
Non-efficacy [Establish that PE (pooled over the mAb groups) < 40% based on a 
2-sided 95% nominal CI lying below 40%] 
 
High efficacy [Establish that PE (pooled over the mAb groups) > 70% based on a 
2-sided 95% nominal CI lying above 70%] 
The sequential monitoring is based on CIs in order that the result of the study that would 
be reported would convey evidence supporting the conclusion of potential harm, non-
efficacy, or high efficacy. Freidlin, Korn, and Gray [120] discuss a rationale for this 
approach to non-efficacy monitoring. The sequential monitoring for potential harm is 
based on monitoring-adjusted 1-sided 0.05-level tests (instead of 1-sided 0.025-level 
tests) for prudence to protect the safety of study participants (ie, less precision is required 
to meet a guideline for potential harm than to meet guidelines for non-efficacy or high-
efficacy). Once non-efficacy monitoring commences, the potential harm monitoring after 
each infection ceases, as the non-efficacy monitoring now provides the function of 
detecting an elevated rate of HIV-1 infection. The non-efficacy monitoring is 
supplemented with conditional power calculations that report estimates of the probability 
of rejecting the null hypothesis of zero PE under different assumptions about the 
estimated PE if the trial were to continue to the end. The sequential monitoring plan is 
summarized in Table 4-6 and Figure 4-7. 

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Table 4-6 Summary of sequential monitoring of PE  
Monitoring 
Type 
Hypotheses 
Testing Approach 
Size of 
Test 
Stopping Boundary 
Timing of Interim 
Analyses 
Potential 
Harm 
H0: PE ≥ 0%  
vs  
H1: PE < 0% 
Exact 1-sided binomial 
test of the fraction of 
infections assigned to 
receive the mAb 
Specified 
in the 
monitoring 
plan 
Near-constant 1-sided p-
value cut-off controlling 
the FWER at α = 0.05* 
After every 
infection from 20th 
total until first non-
efficacy analysis 
Non-
Efficacy 
H0: PE ≥ 40%  
vs  
H1: PE < 40% 
2-sided Wald test and 
1:1 corresponding 2-
sided 95% CI 
1-sided  
α = 0.025 
Nominal 2-sided 95% CI 
below 40% supplemented 
with conditional power 
(specified in the 
monitoring plan) 
6-monthly starting 
based on an event-
driven trigger 
specified in the 
monitoring plan 
High 
Efficacy 
H0: PE ≤ 70%  
vs  
H1: PE > 70% 
2-sided Wald test and 
1:1 corresponding 2-
sided 95% CI 
1-sided  
α = 0.025 
Nominal 2-sided 95% CI 
above 70% 
6-monthly starting 
at the same time as 
for non-efficacy 
* Equivalently, a monitoring-adjusted 2-sided 90% CI based on inversion of the test statistic lies below 0%. 
The 1-sided p-value significance threshold stopping boundaries after each infection event are specified in the 
study monitoring plan. 
 
Figure 4-7 Stopping boundaries for the sequential monitoring based on 2-sided CIs (or on 
the corresponding 1-sided p values) 
Details of the sequential monitoring plan will be provided in a separate trial monitoring 
plan. The sequential monitoring is closely related to what was done for the HVTN 505 
HIV-1 vaccine efficacy trial [121] (background discussion in [74]).  
4.9.2 
Feasibility check and guideline for continuing enrollment as planned  
In addition to the sequential monitoring of PE, feasibility monitoring is done for the first 
120 enrolled participants. This feasibility monitoring is based on the first four 8-week 
intervals (Weeks 1 through 32) and evaluates whether an adequately high percentage of 
participants attend clinical visits and receive the infusions per the protocol. The guideline 
is based on an adequately high rate of study participation (participants remain engaged in 
the trial and have not declined further infusions) supplemented by data on visit 
attendance, which corresponds to adherence to receipt of infusions. Additional details 
will be provided in the trial monitoring plan. 

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The feasibility monitoring based on the first 120 enrolled participants will use the 
following guideline for continuing enrollment as planned: continued participation by the 
Week 32 visit pooled over the 3 groups is greater than 80%. 
If the blinded criterion fails to be met, the Protocol Team, in discussions with the DSMB 
and OC, will discuss whether modification or termination of the trial is warranted. 
4.9.3 
Monitoring for futility to assess PE 
The objective of monitoring the trial for futility to assess PE is to monitor progress 
toward the minimum needed target number of treatment arm-pooled HIV-1 primary 
endpoint infections by the Week 80 visit in the MITT cohort. Two targets are monitored 
for: 
1. the total number of HIV-1 infections needed to achieve the planned 90% power to 
detect PE = 60%, and 
2. the total number of HIV-1 infections needed to achieve 65% power to detect PE = 
60%, 
each using a 1-sided 0.025-level Wald test of H0: PE ≤ 0% against H1: PE > 0%, 
assuming proportional hazards of HIV-1 infection in the pooled VRC01 and control 
groups. The target numbers in (1) and (2) are 56 and 29, respectively (calculated by 
solving equation (1) in Schoenfeld [122]. The rationale for considering the two targets is 
as follows: (i) if the trial cannot achieve the planned 90% power to detect PE = 60%, 
considerations about enrollment modification or expansion are warranted, and (ii) if the 
trial cannot achieve even 65% power to detect PE = 60%, considerations about 
completing the trial early for futility to assess PE are warranted. 
Two versions of the futility monitoring report will be generated. A report provided to the 
DSMB will be included in 6-monthly closed DSMB reports, starting in April 2018, and 
will report: 
a. the estimated distribution of the total (i.e., treatment arm-pooled) number of HIV-1 
infections, with corresponding power to reject H0: PE ≤ 0% using a 1-sided 0.025-
level Wald test under the alternative hypothesis PE = 60% throughout the trial, 
b. the estimated probability that the total number of HIV-1 infections is ≥ 56 (target 1) 
with 95% credible intervals, 
c. the estimated probability that the total number of HIV-1 infections is ≥ 29 (target 2) 
with 95% credible intervals, 
d. the estimated distribution of the number of HIV-1 infections in each of the three 
treatment arms. 
The distributions in (a) and (d) will also be summarized by the mean number of HIV-1 
infections with a Wald 95% confidence interval. The estimation procedure for (a)−(d) 
will be conducted under each of the following two scenarios: 

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 
the treatment arm-pooled infection rate in (a)−(c) and the three treatment arm-
specific infection rates in (d) used for generating future data are based on a Bayesian 
model and the prior assumption that PE = 60% (the design alternative), and 
 
the treatment arm-pooled infection rate in (a)−(c) and the three treatment arm-
specific infection rates in (d) used for generating future data are based on a Bayesian 
model and the prior assumption that PE = 0% (the null hypothesis). 
The reason for conducting the estimation procedure twice is that the purpose of the 
results for the 56 endpoint target (b) is to trigger considerations for trial modifications, 
whereas the purpose of the results for (c) is to trigger considerations for early trial 
completion due to futility, where it is desired to reach the guideline (b) more 
easily/readily than the guideline (c). Accordingly, the results for (b) are interpreted 
focusing on the prior of PE = 60%, which makes it more likely to reach a guideline than 
the prior of PE = 0%, and the results for the 29 endpoint target (c) are interpreted 
focusing on the prior of PE = 0%, which makes it less likely to reach a guideline than the 
prior of PE = 60%. 
Furthermore, a treatment-blinded report will be generated for distribution to the OC after 
each DSMB meeting takes place and will report estimates listed in (a)−(c) above 
calculated based only on treatment-blinded data. The reported results pertaining to 
estimates (a)−(c) will be identical to those in the DSMB report. 
While it is the primary responsibility of the OC to make decisions regarding trial 
operations and modifications based on the monitoring of treatment-blinded primary 
endpoints, given the resource issues involved, DSMB review is also needed because 
issues of scientific integrity are also involved. More specifically, the DSMB can evaluate 
the progress toward primary endpoint targets in the context of the treatment-unblinded 
data, and based on this review may recommend to the OC to complete the trial early due 
to reaching a guideline for futility to assess PE (specified below).  
The monitoring for futility to assess PE includes the following guidelines for trial 
modifications: 
 
[Guideline for enrollment modifications] If, in the PE = 60% scenario for the prior 
distribution, the estimated probability of reaching 56 total infections is less than 25%, 
the OC may consider enrollment modifications with the intention to be able to 
conduct the primary PE analysis with adequate power. 
 
[Guideline for futility] If, in the PE = 0% scenario for the prior distribution, the 
estimated probability of reaching 29 total infections is less than 25%, the DSMB may 
recommend completing the trial early based on the inability to conduct the primary 
PE analysis with adequate power. However, since this is a proof-of-concept trial, a 
high bar is desired for completing the trial early for futility, and therefore if this event 
occurs yet the non-efficacy monitoring has not started or the non-efficacy boundary 
has not been reached, then this guideline for futility also requires that the estimated 
PE for the pooled VRC01 vs. control arm is < 30% and the estimated PE for the 
VRC01 30 mg/kg vs. control arm is < 30%.  
If enrollment is incomplete at the time of an interim futility analysis, then the outlined 
estimation procedures will use the average observed enrollment rate in approximately the 

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last 6 months for generating future enrollment data. In addition, a Bayesian approach will 
be used for generating future HIV-1 incidence data, conditional on observed data to-date. 
More specifically, the estimates in (a)−(c) will condition on the observed to-date 
treatment arm-pooled HIV-1 incidence rate, whereas the estimates in (d) will condition 
on the observed to-date (three) treatment arm-specific HIV-1 incidence rates. All 
estimates in (a)−(d) will also use the observed to-date treatment arm-pooled dropout rate 
for generating future dropout data. 
If, at any time, these guidelines for futility to assess PE are met and yet it appears that 
value exists in continuing the trial, the statisticians will provide the DSMB and the OC 
with additional information, as appropriate, for use in their consideration of whether to 
recommend early trial completion. 
4.10 
Assessment of PrEP use 
The use of oral FTC/TDF as PrEP (either off-study or provided in the study) may impact 
study outcomes (eg, by lowering HIV incidence with a loss of study power). Dried blood 
spot samples will be collected and stored for assessment of quantitative concentrations of 
intracellular tenofovir (TFV) (see Section 9.6). A detailed testing plan, specified in the 
study monitoring plan, has been developed to prospectively monitor FTC/TDF use during 
the trial to inform the DSMB, and assess the potential impact of FTC/TDF use on PE of 
the study product. This plan employs testing samples from a calendar-based selection of 
visits that will ensure representative sampling of participants across the entire visit 
schedule at all sites throughout the study. Prevalence of PrEP will be reported both as the 
estimated proportion of participant visits with highly adherent PrEP use (above the 
concentration of TFV designated as consistent with daily dosing) and the proportion of 
participant visits with any detectable PrEP use (concentration of TFV above the lower 
limit of detection for the dried blood spot assay). Additionally, we will use knowledge of 
PK quantitative levels to estimate the proportion of study person years protected by 
highly adherent use of FTC/TDF. PrEP use measures will be reported by arm to the 
DSMB; in addition both the OC and the protocol team leadership will see pooled 
estimates of FTC/TDF use. 
4.11 
Randomization  
The randomization sequence will be obtained by computer-generated random numbers 
and provided to each CRS through a Web-based randomization system. The 
randomization will be done in blocks to ensure balance across arms. At each institution, 
the pharmacist with primary responsibility for dispensing study products is charged with 
maintaining security of the treatment assignments (except in emergency situations as 
specified in the SSP).  
4.12 
Blinding 
Participants and site staff (except for site pharmacists) will be blinded as to participant 
treatment arm assignments. Study product assignments are accessible to those CRS 
pharmacists, DAIDS protocol pharmacists and contract monitors, and SDMC staff who 
are required to know this information in order to ensure proper trial conduct. Any 

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discussion of study product assignment between pharmacy staff and any other CRS staff 
is prohibited.  
When a participant leaves the trial prior to study completion, the participant will be told 
he or she must wait until all participants are unblinded to learn his or her treatment 
assignment.  
Emergency unblinding decisions will be made by the site investigator. If time permits, 
the HVTN 704/HPTN 085 PSRT should be consulted before emergency unblinding 
occurs. 
4.13 
Statistical analyses 
This section describes the final study analyses, unblinded as to treatment arm assignment. 
All data from enrolled participants will be analyzed according to the initial randomization 
assignment regardless of how many infusions they received. In the rare instance that a 
participant receives the wrong treatment at a specific infusion visit, the Statistical 
Analysis Plan will address how to analyze the participant’s safety data. Analyses are 
modified intent-to-treat (MITT) in that individuals who are randomized but not enrolled 
do not contribute data and hence are excluded. Because of blinding and the brief length of 
time between randomization and enrollment—typically no more than 4 working days—
very few such individuals are expected. 
Analyses for primary endpoints will be performed using SAS and R. All other descriptive 
and inferential statistical analyses will be performed using SAS, StatXact, or R statistical 
software. 
4.13.1 
Analysis variables 
The analysis variables consist of baseline participant characteristics, safety, efficacy, and 
markers of mAb characteristics for primary- and secondary-objective analyses. 
4.13.2 
Baseline comparability 
Treatment arms will be compared for baseline participant characteristics using descriptive 
statistics. 
4.13.3 
Safety/tolerability analysis 
Since enrollment is concurrent with receiving the first infusion, all participants will have 
received at least 1 infusion and therefore will provide some safety data. 
4.13.3.1 
Reactogenicity 
The number and percentage of participants experiencing each type of reactogenicity sign 
or symptom will be tabulated by severity and treatment arm and the percentages 
displayed graphically by arm. For a given sign or symptom, each participant’s 
reactogenicity will be counted once under the maximum severity for all injection visits. 
In addition, to the individual types of events, the maximum severity of local pain or 
tenderness, induration, or erythema, and of systemic symptoms will be calculated. 
Kruskal-Wallis tests will be used to test for differences in severity between arms. 

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4.13.3.2 
AEs and SAEs 
AEs will be summarized using MedDRA System Organ Class and preferred terms. 
Tables will show by treatment arm the number and percentage of participants 
experiencing an AE within a System Organ Class or within preferred term category by 
severity or by relationship to study product. For the calculations in these tables, a 
participant with multiple AEs within a category will be counted once under the maximum 
severity or the strongest recorded causal relationship to study product. Formal statistical 
testing comparing arms is not planned since interpretation of differences must rely 
heavily upon clinical judgment. 
A listing of SAEs reported to the DAIDS Regulatory Support Center (RSC) Safety Office 
will provide details of the events including severity, relationship to study product, time 
between onset and last infusion, and number of infusions received.  
4.13.3.3 
Local laboratory values  
Box plots of local laboratory values will be generated for baseline values and for values 
measured during the course of the study by treatment arm and visit. Each box plot will 
show the first quartile, the median, and the third quartile. Outliers (values outside the box 
plot) will also be plotted. If appropriate, horizontal lines representing boundaries for 
abnormal values will be plotted. 
For each local laboratory measure, summary statistics will be presented by treatment arm 
and timepoint, as well as changes from baseline for postenrollment values. In addition, 
the number (percentage) of participants with local laboratory values recorded as meeting 
Grade 1 AE criteria or above as specified in the DAIDS AE Grading Table (see Section 
10.2.2) will be tabulated by treatment arm for each postinfusion timepoint. Reportable 
clinical laboratory abnormalities without an associated clinical diagnosis will also be 
included in the tabulation of AEs described above. 
4.13.3.4 
Reasons for infusion discontinuation and early study termination 
The number and percentage of participants who discontinue infusions and who terminate 
the study early will be tabulated by reason and treatment arm. 
4.13.4 
Efficacy analysis 
4.13.4.1 
General approach 
For the statistical analysis of prevention efficacy, data from enrolled participants will be 
used according to the initial randomization assignment regardless of how many infusions 
they received. Given that all or almost participants will receive the first infusion, the 
analyses are MITT, where all participants HIV-1 negative at entry receiving the initial 
infusion are included in the analysis, participants are analyzed according to their 
randomized treatment assignment, and participants retrospectively determined to be HIV-
1 infected at entry based on treatment blinded procedures are excluded from the analysis. 
Additional analyses may be performed, limited to participants who received most or all 
infusions per protocol.  
Cumulative incidences of HIV-1 infection over time for different treatment arms and 
pooled treatment arms will be estimated by a transformation of Nelson-Aalen estimators 
[123] for the respective cumulative hazard functions of HIV-1 infection. PE parameters 

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will be estimated by one minus the ratio (mAb/control group) of these cumulative 
incidence estimators. Point estimates and 95% Wald CIs about cumulative incidence 
curves and PE(t) curves will be plotted. For the final timepoint of 80 weeks, 2-sided 
Wald p-values will be reported. These procedures will be used to test the hypotheses 
listed in Section 4.2. 
As a supportive analysis for the hypotheses listed in Section 4.2, targeted maximum 
likelihood estimation (tMLE) will be used to estimate cumulative incidences of HIV-1 
infection over time for different treatment arms and pooled treatment arms [124,125]. 
The Statistical Analysis Plan will describe the details of implementation of the tMLE 
estimators in an automated and objective fashion. PE parameters will be estimated by 1 
minus the ratio (mAb group/control) of these tMLE estimators. Point estimates and 95% 
Wald CIs about cumulative incidence curves and PE(t) curves will be plotted. For the 
final timepoint of 80 weeks, 2-sided Wald p-values will be reported.  
In addition to studying PE based on cumulative incidences of HIV-1 infection over time, 
complementary secondary analyses will assess hazard-ratio based prevention efficacy 
using Cox proportional hazards models with score tests stratified by VRCO1 dose group 
for testing whether prevention efficacy differs from zero. This analysis uses as the failure 
time the time from the most recent infusion to the estimated date of HIV infection, 
entered in the Cox model as a time-dependent covariate. This analysis can have increased 
power to detect prevention efficacy compared to the primary analysis of the cumulative 
incidence based parameter PE, if instantaneous prevention efficacy is higher when 
VRC01 concentrations are lower. Goodness-of-fit diagnostics will be applied to assess 
veracity of the proportional hazards assumption. The Cox models are selected for the 
secondary analysis instead of the primary analysis in order that the validity of the primary 
analysis does not depend on the proportional hazards assumption. The Cox model will 
also be used for a secondary analysis of PE in subgroups defined by the level of 
cumulative infusion adherence over time included in the model as a time-varying 
covariate. 
Sensitivity analyses of the primary analysis will test H0: PE = 0% with a log-rank test 
and with a Gehan-Wilcoxon test stratified by VRCO1 dose group. To explore potential 
time-variations in prevention efficacy, instantaneous prevention efficacy over time 
defined based on the instantaneous hazard ratio (VRC01 vs. placebo) will be estimated 
with pointwise and simultaneous confidence bands using nonparametric kernel 
smoothing [126].  
4.13.5 
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 efficacy 
endpoint assessments.  
4.13.6 
Specific approach for assessing PE, PE10, PE30 
Primary objective 2 is addressed based on comparing cumulative HIV-1 incidence 
between the group of participants assigned to receive the VRC01 mAb (at either dose 
pooling over the two doses) and the group of participants assigned to the control group, 
and secondarily between each individual mAb dose group and the control group. For each 
prevention efficacy parameter PE, PE10 and PE30, point and 2-sided 95% CI estimates 
will be reported, along with the 2-sided p-values for testing the respective null hypotheses 

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(with 2-sided p = 0.05 the threshold for a significant effect). Unadjusted and Holm-
Bonferroni p-values will be reported for testing of the secondary endpoint efficacy 
parameters PE10 and PE30. 
4.13.7 
Assessment of individual-level markers of VRC01 mAb that correlate with 
protection against HIV infections (Secondary objective 1) 
Secondary objective 1 is addressed based on the measurement of VRC01 mAb markers 
over time in mAb group breakthrough HIV-1–infected cases and in a random sample of 
HIV-1–uninfected mAb group participants (marker subset), integrated with the genotypic 
and phenotypic sieve analysis of breakthrough HIV-1 viruses accounting for knowledge 
of the VRC01 antibody footprint. The main analyses of the secondary objective 1 pool 
over the two mAb doses to maximize statistical power.  
The design and results requirements for successful identification of correlates of 
protection in secondary objective 1 are: 
1. Sufficient sample size to observe enough participants diagnosed with incident HIV-1 
infection during the primary follow-up period of 80 weeks postenrollment in the 
mAb arms  
2. A result of significant beneficial overall mAb PE > 0%  
3. Sufficiently frequent HIV-1 testing schedule and accurate HIV-1 diagnostics  
4. Wide variability in the concentration and effector functions of the mAb over time 
and/or individuals, and the ability to measure these characteristics such that their 
timing relative to the timing of HIV-1 acquisition is estimated with adequately low 
measurement error 
5. mAb marker sampling design that allows sufficiently accurate PK modeling of mAb 
characteristics over time 
Note that the serum concentration mAb markers (secondary endpoints 2) are defined 
without reference to a particular HIV-1 Env sequence. The effector function markers 
(also secondary endpoints 2) are relative to specific HIV-1 Envs or panels of Envs, and 
thus may be linked to immunogenicity endpoints (and the antigen reagents for those 
endpoints) that would be used in future trials of candidate HIV-1 vaccines. Correlates of 
protection analyses directly assess how mAb PE depends on markers. 
4.13.7.1 
Sampling of mAb markers 
Characteristics of the mAb or immune responses to the mAb are measured in participants 
assigned to the mAb treatment groups, and in a small number of participants assigned to 
the control group. The sampling design determining the set of participants for measuring 
the markers will be finalized after the primary analysis results. This sampling design will 
include measuring the markers in all mAb group primary endpoint cases with a minimal 
number of samples available prior to diagnosis of HIV-1 infection, and on a random 
sample of participants from each mAb group who complete follow-up to the Week 96 
visit HIV-1 negative (mAb group control participants). The random sample of HIV-1 
uninfected controls is chosen to create a common control:case ratio across participant 
strata defined by factors such as dose group, infusion adherence, and calendar period of 

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enrollment. For participants assigned to the control group, a smaller number of cases and 
HIV-1 negative controls will be sampled for measurement of markers. The timing of 
marker measurements is as follows: 
 
mAb group and control group cases: visits every 4 weeks up until the time of HIV-1 
diagnosis and Day 61 (5 days post second infusion) if before diagnosis, plus the first 
positive visit and additional time-points post HIV-1 infection 
 
mAb group and control group marker subset controls: visits every 4 weeks through 
Week 80 plus Day 61 and Weeks 88 and 96 
The Day 5 post-second infusion visit is included because it occurs shortly after the end of 
the distributive phase of the mAb, which together with the samples drawn just before 
infusions (Week 0, 8, …, 72), the samples drawn 4 weeks post-infusions (Week 4, 12, …, 
76), and the Week 80, 88, and 96 samples 8−24 weeks post last infusion constitute the 
basis for modeling marker curves over time. 
4.13.7.2 
Overview of the analysis of a mAb marker as a correlate of protection  
A correlates of protection statistical analysis plan will be finalized not using any 
information on case-control status of participants; this plan will contain details of the 
statistical analysis. We provide a brief summary here. For a given mAb recipient, let S(t) 
be a marker characteristic at time t postenrollment in days, for example the time-
concentration curve. The entire curve S(t) cannot be known exactly given that the marker 
is measured at a grid of time-points. A PK model will be used to express S(t) as a 
function of the measured marker readouts and error terms. One approach to the correlates 
of protection analysis will estimate the “prevention efficacy curve” PE(S(t) = s) defined 
as 
PE(S(t) = s) = [1 – (hazard-mAb(S(t) = s))/(hazard-control(S(t) = s))] ×100% 
where hazard-mAb(S(t) = s) is the hazard rate of HIV-1 infection at time t for a 
participant assigned to either mAb group with S(t) = s and hazard-control(S(t) = s) is the 
hazard rate of HIV-1 infection at time t for a participant assigned to the control group 
who would have had S(t) = s had s/he been assigned to the same mAb group (thus S(t) is 
a counterfactual random variable for control recipients). Similar parameters are used for 
assessing time-dependent correlates of protection in vaccine efficacy trials. A time-
dependent parameter is used because interest centers on understanding how the current 
value of a mAb marker associates with the level of instantaneous PE given exposure with 
an HIV-1 virus at that time. The statistical analysis plan will describe the methods used to 
estimate PE(s) over the range of values s of a mAb marker characteristic. In addition to 
estimation, hypothesis testing will be performed to assess whether a mAb marker 
modifies PE, ie, testing 
H0: PE(S(t) = s) = PE versus H1: PE(S(t) = s) varies in s. 
(1) 
Rejecting H0 in favor of H1 supports the role of the marker in protection. The correlates 
of protection analysis pools over the two mAb groups, for the purpose of improving 
power both through a larger sample size and through greater inter-individual variability 
of the mAb markers. Given that the exact dates of infusions have a major impact on mAb 
markers S(t) such as concentration over time (eg, notice the profound influence of missed 

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infusions on S(t) in Figure 2-9, the analysis accounts for the exact dates of infusions that 
are expected to show considerable heterogeneity across trial participants. 
4.13.7.3 
A time-window approach to assessing mAb correlates of protection 
To explain the concept of this approach, first suppose all participants received all 
scheduled infusions and rigidly followed the visit schedule. Then this approach compares 
HIV-1 incidence during the first 4 weeks of the infusion intervals (ie, weeks 1-4, 9-12, 
17-20, …, 73-76) to HIV-1 incidence during the second 4 weeks of the infusion intervals 
(ie, weeks 5-8, 13-16, 21-24, …, 77-80), aggregating over the ten 8-week infusion 
intervals. Because the mAb has much higher concentration during the first halves of the 
infusion intervals compared to the second halves (eg, demonstrated in Figure 2-9), 
detection of higher HIV-1 incidence in the second halves of visit windows would imply 
that higher concentrations are associated with a lower rate of HIV-1 infection. 
However, because of missed infusions and the heterogeneity among participants of 
infusion dates (which is allowable as specified by broad visit windows), a better approach 
accounts for the set of exact infusion dates of each participant. As such, our approach to 
implementing the time-window approach compares the mean time between the last 
infusion and infection for VRC01 group cases, with the mean of the participant-specific 
weighted average time between infusions of VRC01 group control participants, where the 
weights allow for changing HIV-1 incidence over time. The analysis stratifies by the 10 
mg/kg and 30 mg/kg dose groups and aggregates estimates over these two dose groups. 
In addition, an important element of the analysis uses predictions of the HIV-1 infection 
times for all VRC01 group cases. Models for these predictions are built using information 
on HIV-1 diagnostic tests, intra-host diversity of HIV-1 sequences, HIV-1 viral loads, 
and perhaps other factors. Initial research to build predictors of HIV-1 infection time 
based on HIV-1 sequence information has been conducted using validation data sets of 
acutely HIV-1 infected individuals [127]. 
A related approach to assessing correlates of protection integrates a pharmacokinetic 
model of the serum concentration of VRC01 over time, comparing the mean VRC01 
concentration at the time of HIV infection for VRC01 group cases with the mean of 
participant-specific weighted average VRC01 concentrations over follow-up time. The 
participant-specific average VRC01 concentration over follow-up time is intended to 
reflect the expected concentration at the time of a random HIV exposure, with weighting 
used as above to allow for changing HIV-1 incidence over time. Details of these 
statistical methods will be provided in the statistical analysis plan. 
4.13.7.4 
mAb markers  
For effector function markers measured based on a sample from a mAb recipient, the 
markers are measured to each of a panel of HIV-1 Envelope proteins. The most relevant 
HIV-1 Env panel represents the VRC01 antibody footprint diversity of viruses exposing 
trial participants. For example, relevant for the study population of North/South 
American MSM + TG, Figure 4-8 shows a logo plot of the VRC01 antibody footprint 
motifs comprising 35 amino acid sites [128,129] based on 276 subtype B US and South 
American sequences deposited in the Los Alamos National Laboratory (LANL) sequence 
database between 2006 and 2014. There are 272 unique mAb footprints. 
 

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Figure 4-8 Logo plot of the VRC01 antibody footprints that occur in 276 subtype B US and 
South American sequences deposited in the LANL sequence database between 2006 and 
2014 
During the conduct of the trial the research team will determine a minimal set of Envs 
constituting a panel capturing most of the VRC01 mAb footprint diversity of exposing 
viruses. One effector function marker of interest for assessing as a correlate of protection 
is the weighted area under the magnitude-breadth neutralization curve of the mAb 
footprint Env panel, where the weighting is by the estimated prevalence of mAb 
footprints in HIV-1s circulating at the trial sites during the trial.  
For mAb group participants with a primary study endpoint (breakthrough HIV-1 
infection during the first 80 weeks), an important marker is the level at which his/her pre-
infection sample at the time of HIV-1 acquisition neutralizes his/her particular 
breakthrough virus. (This analysis requires modeling the marker at the time of HIV-1 
acquisition based on the available grid of marker measurements.) A result where sera 
from infected participants generally fail to neutralize their founding viruses would 
support neutralization as a correlate of protection. This analysis is repeated for other 
effector functions as a way to discriminate which effector functions are or are not 
correlates of protection, and to rank the effector functions by their contribution to 
explaining the level of protection.  
4.13.7.5 
Statistical power for assessing a mAb marker as a correlate of protection 
The marker S(t) must vary within mAb recipients over time and/or among mAb 
recipients in order to detect a correlate of protection, with more variability in one or both 
components providing greater statistical power to detect a correlate of protection via 
testing the null hypothesis of equation/panel (1) above. In essence, to detect correlates of 
protection it is necessary that a large fraction of person-years at risk are in high protection 
zones and a large fraction of person-years at risk are in low protection zones. (A “high 
protection zone” is a period of time during which a mAb recipient has high levels of a 
marker and high levels of efficacy.) Data from VRC 601, VRC 602, and HVTN 104 
show wide variability in the mAb concentration over time, and more limited variability 
among mAb recipients. HVTN 104 will provide more data on these two aspects of 
marker variability. The limited among-mAb recipient variability motivates the study 
design that randomly assigns participants to 2 different mAb doses in order to create 
inter-individual variability. 
Achieving adequate power to detect correlates of protection requires that the HIV-1 
diagnostic testing is more frequent than the infusion schedule. This is why diagnostic 
visits every 4 weeks are advantageous given infusions every 8 weeks, and procedures 
may be determined and applied to test for HIV-1 infection more frequently than every 4 

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weeks. The data from all of the employed diagnostic testing kits is incorporated into the 
modeling of S(t) and of HIV-1 infection times, and is integrated into the modeling of S(t) 
and into the statistical analysis for estimation and testing of PE(S(t) = s). Lastly, 
achieving adequate power to detect correlates of protection requires studying markers 
that can be measured with a high ratio of potentially protection relevant variability versus 
protection irrelevant variability, where the latter variability could stem from technical 
measurement error of the assay or to error in estimation of the timing of infection. 
Because of this fact the trial design relies on parallel assay studies to qualify marker 
variables for the analysis and relies on development and characterization of models for 
S(t) over continuous time t. 
We provide one power calculation for assessing a trichotomous marker S(t), the 
concentration of the mAb at time t post enrolment, as a correlate of protection, which 
divides the pooled mAb group at a given time t by two thresholds of marker response 
[S(t) = 0 indicates Low, S(t) = 1 indicates Medium, and S(t) = 2 indicates High for some 
pre-set definitions of Low, Medium, High]. Thus at any given time t after entry, S(t) 
divides the pooled mAb group into three subgroups. In our illustration we take “0” to be a 
VRC01 serum concentration ≤ 50 mcg/mL, “2” to be a VRC01 serum concentration > 
10 mcg/mL, and “1” to be an intermediate serum concentration.  
Based on Figure 2-4, we conduct a power calculation indexed by the percentage of 
person-years at-risk of mAb recipients that are in the (Low, Medium, High) zones, and 
indexed by the level of PE within each of these zones. As indicated in the figure, we 
expect that about (50%, 40%, and 10%) of the PYRs at risk in the 10 mg/kg mAb group 
are in the (Low, Medium, and High) regions whereas about (10%, 40%, and 50%) of the 
PYRs at risk in the 30 mg/kg mAb group are in the (Low, Medium, and High) regions. 
We consider power calculations pooling data across both mAb groups, assuming 30 mAb 
HIV-1–infected cases with data and 150 mAb group HIV-1–uninfected controls with 
data, assuming the design alternatives PE10 = PE30 = 60% approximating the numbers 
displayed in Table 4-3. The detailed mathematical assumptions of these power 
calculations will be provided in the statistical analysis plan.  
Figure 4-9 shows power curves for the scenario that (30%, 40%, 30%) of PYRs at risk 
are in the (Low, Medium, High) zones (which we approximately expect to occur based on 
Figure 2-4) and PE10 = PE30 = (15%, 60%, 85%) in these zones. The power curves also 
account for noise in the measurement of S(t) via a parameter rho that equals the 
proportion of the inter-individual marker variability that is potentially protection relevant. 
The results show that the noise level majorly affects power, underscoring that only assays 
meeting qualification criteria will be studied as correlates. The parameter rho also reflects 
noise due to uncertainty in the exact times t of HIV-1 acquisition at which values of S(t) 
are needed. For the scenario that this extra variability reduces rho to 0.7, there is about 
70% power to detect a correlate of protection (with effect size 15%, 60%, 85% efficacy) 
at the selected trial sample size. Note that the parameter rho also reflects noise due to 
uncertainty in the exact times t of HIV-1 acquisition at which values S(t) are needed. A 
more extensive set of power calculations will be conducted based on HVTN 104 study 
data. 

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Figure 4-9 Power of the trial for detecting that PE varies over the three mAb marker-defined 
subgroups S(t) = Low, S(t) = Medium, and S(t) = High at level PE=15%, 60%, 85%, 
respectively, for a marker with assay noise parameter rho = 1 (perfect marker), 0.9, 0.7, and 
0.5 and percentages of person-years at risk in the (Low, Medium, High) marker regions set 
at (30%, 40%, 30%). The calculations at 2700 total participants assume 30 mAb group HIV-1–
infected cases and 150 mAb group HIV-1–uninfected controls with data on S(t) and pool 
over both mAb groups. The dashed vertical line represents the sample size of the study. 
Figure 4-10 shows the same power analysis as Figure 4-9, fixing rho = 0.9 (indicating a 
qualifying assay) and varying the percentage of PYRs at risk that are in the (Low, 
Medium, High) zones. The results show that power increases sharply with the percentage 
of mAb recipients that are in the Low and High regions, demonstrating the principle that 
variability in the marker is a strong determinant of power to detect a correlate of 
protection. For example, the figure shows that the trial has 80% power for the PE = 15%, 
60%, 85% effect size if 25%, 50%, 25% of PYRs at risk are in the (Low, Medium, High) 
zones.  

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Figure 4-10 Power of the trial for detecting that PE varies over the three mAb marker-defined 
subgroups S(t) = Low, S(t) = Medium, and S(t) = High at level PE = 15%, 60%, 85%, 
respectively, for a marker with assay noise parameter rho = 0.9 and percentages of person-
years at risk in the Low and High marker regions varied from 10%, 15%, 20%, 25%, 30%. The 
calculations at 2700 total participants assume 30 mAb group HIV-1–infected cases and 150 
mAb group HIV-1–uninfected controls with data on S(t) and pool over both mAb groups. 
4.13.7.6 
Genotypic and phenotypic sieve analysis 
Genotypic sieve analysis analyzes sequences of breakthrough HIV-1 infecting viruses 
from the earliest available postinfection sample and seeks to identify amino acid 
“signatures” that differentiate breakthrough sequences in the mAb groups versus the 
control group, in terms of differential PE against HIV-1s according to some genotypic 
characteristics. For example, the genotypic sieve analysis assesses differential PE against 
different genotypes of HIV-1 with genotype defined by: 
 
Number of mismatches to the VRC01 mAb footprint of the subtype B consensus 
sequence (subtype selected to match the circulating HIV-1s) 
 
Number of known mAb neutralization escape mutations in the mAb footprint 
 
Number of known mAb effector function escape mutations in the mAb footprint for 
non-neutralization effector functions such as ADCC, virion capture, and phagocytosis 
 
Number of potential N-linked glycosylation (PNG) sites within a given radius of the 
mAb footprint 
 
Length of variable loops in proximity to the mAb footprint 
To illustrate the utility of genotypic sieve analysis, we consider a hypothetical result that 
would support that the mAb protects via specific neutralization targeting of the mAb’s 
epitope. In this illustration, the HIV-1 genotype is defined by four ordered genotypes 
according to whether there are 0, 1, 2, or >2 neutralization escape mutations in the 
VRC01 mAb antibody footprint. The hypothetical result would be an estimated PE of 
95% against HIV-1s with zero escape mutations and a PE of 0% against HIV-1s with >2 

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neutralization escape mutations, and intermediate and monotone decreasing level of 
estimated PE against HIV-1 with one mutation and two mutations, respectively. 
A second type of sieve analysis, phenotypic sieve analysis, compares breakthrough 
viruses between the mAb versus control groups using an immunological assay. 
Specifically, data from an “effector function checkerboard” is filled out, with the rows 
representing serum samples from a random sample of mAb recipients HIV-1 uninfected 
at the time of sampling, and the columns representing HIV-1 Env VRC01 footprint 
targets created from the breakthrough viruses. The phenotypic sieve analysis compares 
the sensitivity of the breakthrough viruses to mAb recipient sera between the mAb and 
control treatment groups. A second version of the phenotypic sieve analysis compares the 
sensitivity of the breakthrough viruses to the VRC01 mAb between the treatment groups; 
this latter analysis is simpler, based on a single column of data instead of a matrix, 
because it does not use mAb recipient sera. For an example of the second type of 
phenotypic sieve analysis, the TZM-bl neutralization assay could be performed on all 
control breakthrough HIV-1s versus VRC01 and on all mAb group breakthrough HIV-1s 
(pooled over the two mAb groups) versus VRC01, and a Wilcoxon rank sum test applied 
to assess a difference. Reduced TZM-bl neutralization sensitivity of the mAb 
breakthrough group viruses would support that neutralization had a role in protection and 
that the TZM-bl assay was able to detect this role, and would support using the TZM-bl 
assay as a tool for evaluating future candidate HIV-1 vaccines. The HVTN has previously 
conducted neutralization sieve analysis [130]. Figure 4-11 illustrates a genotypic and 
phenotypic sieve analysis. 
 
Figure 4-11 Illustration of genotypic (left panel) and phenotypic (right panel) sieve analysis, 
where the left panel shows the distribution of the number of known neutralization escape 
mutations in breakthrough control and mAb group HIV-1 sequences, and the right panel 
shows the percentage of the panel of breakthrough HIV-1s that are neutralized at level 50% 
(IC50) by the given concentration of the VRC01 mAb. 
Another phenotypic sieve analysis focuses on mAb group cases, and measures 
different effector functions of closest-to-infection participant serum samples or of the 
VRC01 mAb against the participant-matched breakthrough HIV-1s. The effector 
functions that tend to have low readouts against participant-matched breakthrough 
viruses compared to against the panel of control group HIV-1s or compared to an 
historic panel of HIV-1s are implicated as potential correlates of protection. 

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In addition, an important sieve analysis will assess PE against HIV-1s that are 
sensitive to neutralization by VRC01 as measured using the first post-infection 
sample (sensitive is defined by positive neutralization based on IC50 or IC80). This PE 
parameter measuring prevention efficacy against neutralization sensitive HIV-1s is 
estimated (with confidence intervals and p-values) in the same way as genotype-
specific PE described above. In addition, the same hypothesis testing procedure for 
detecting differential PE by two HIV-1 genotypes is applied for assessing differential 
PE by neutralization sensitive versus resistant HIV-1. Moreover, this sieve analysis 
of sensitive versus resist HIV-1 is also conducted with sensitive/resistant defined by 
positive/negative response of other assays besides neutralization (eg, ADCC, ADCP).  
4.13.7.7 
Illustration of power to detect a phenotypic sieve effect 
We conduct power calculations based on TZM-bl neutralization IC50 values (in mcg/mL) 
of VRC07 (a close cousin of VRC01) to approximately 100 viruses representing global 
HIV-1 diversity (data provided by Mark Louder, Robert Bailer, and John Mascola from 
the VRC). From the control group we sample 35 HIV-1 infections with IC50 from the 
VRC07 data set, and from the pooled mAb group we sample 30 HIV-1 infections with 
IC50 values bias sampled based on IC50-dependent PE, with PE(x) the probability an 
infected control recipient would be infected had he (or she) received the mAb with IC50 
value of x to the exposing virus. Figure 4-12 shows power for comparing the VRC01 IC50 
distribution of the pooled mAb group HIV-1s versus the control group HIV-1s, based on 
a two-sample Wilcoxon rank sum test. The effect size indexing a difference between the 
two groups is equivalently expressed in terms of the PE(x) function (where a horizontal 
line indicates the null hypothesis of no difference) or in terms of a different cumulative 
distribution function of the IC50 in the two groups. Four correlates effect sizes are 
considered, ranging from the weakest (Effect Size 1) to the strongest (Effect Size 4). The 
results show that there is moderate power to detect Effect Size 3 phenotypic sieve effects 
(second steepest curve in Figure 4-12, power = 0.793). 
 
Figure 4-12 Power calculations for comparing IC50 distributions between mAb group 
breakthrough HIV-1s and control group breakthrough HIV-1s, with difference equivalently 

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expressed in terms of the PE(x) curve or the cumulative IC50 distribution functions, where in 
the right panel the black/highest curve represents the distribution for the control group 
breakthrough HIV-1s. 
Effect Size 3 is biologically plausible based on the following argument. Under the 
design alternative of 60% PE we expect a transition between full protection against 
the most sensitive viruses and zero protection against the most resistant 
viruses. Table 4-7 shows the percentage of susceptible viruses that are completely 
blocked by the VRC01 antibody and the percentage of viruses that are completely 
resistant to the antibody for each of the four specified effect sizes PE(x) in Figure 
4-12. For example, for Effect Size 3, the most susceptible 11.6% of viruses are 
completely blocked (PE = 100%) while the most resistant 2.8% of viruses are 
completely resistant (PE = 0%) and there is a gradient of protection for the 85.6% of 
intermediate viruses between the two poles (Table 4-7). The wide range of 
neutralization (and Fc effector function) sensitivities of HIV-1s suggests that this 
range of prevention efficacies is plausible. For this effect size there is 79.3% power 
to detect a phenotypic sieve effect and hence a correlate of protection. 
Table 4-7 Percentages of HIV-1s fully susceptible to VRC01 (PE = 100%) and fully resistant 
to VRC01 (PE = 0%) for the four different effect sizes studied in Figure 4-12 
PE(x) Effect Size in Figure 1-16 
Susceptible 
[PE = 100%] 
Resistant 
[PE = 0%] 
Effect Size 4 
41.9% 
23.3% 
Effect Size 3 
11.6% 
2.8% 
Effect Size 2 
1.0% 
<0.1% 
Effect Size 1 
<0.1% 
<0.1% 
Null Hypothesis 
NA 
NA 
The sieve analyses will be done including all MITT infected participants, as well as only 
including mAb group infected participants who received an infusion at the beginning of 
the 8-weekly interval during which HIV-1 infection was diagnosed. 

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5 
Selection and withdrawal of participants 
Participants will be healthy, HIV-uninfected (seronegative) adults who comprehend the 
purpose of the study and have provided written informed consent. Volunteers will be 
recruited and screened; those determined to be eligible, based on the inclusion and 
exclusion criteria, will be enrolled in the study. Final eligibility determination will 
depend on results of laboratory tests, medical history, physical examinations, and answers 
to self-administered and/or interview questions.  
Investigators should always use good clinical judgment in considering a volunteer’s 
overall fitness for trial participation. Some volunteers may not be appropriate for 
enrollment even if they meet all inclusion/exclusion criteria. Medical, psychiatric, 
occupational, or other conditions may make evaluation of safety and/or serum mAb 
concentration and efficacy difficult, and some volunteers may be poor candidates for 
retention. 
Determination of eligibility, taking into account all inclusion and exclusion criteria, must 
be made within 56 days prior to enrollment unless otherwise noted in Sections 5.1 and 
5.2. 
5.1 
Inclusion criteria 
General and Demographic Criteria 
1. Age of 18 to 50 years 
2. Access to a participating CRS and willingness to be followed for the planned duration 
of the study 
3. Ability and willingness to provide informed consent 
4. Assessment of understanding: volunteer demonstrates understanding of this study and 
completes a questionnaire prior to first infusion with verbal demonstration of 
understanding of all questionnaire items answered incorrectly 
5. Agrees not to enroll in another study of an investigational research agent for the 
duration of the participant’s trial participation  
6. Good general health as shown by medical history, physical exam, and screening 
laboratory tests 
HIV-Related Criteria: 
7. Willingness to receive HIV test results 
8. Willingness to discuss HIV infection risks and amenable to HIV risk reduction 
counseling  

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9. Persons born Male or identifying as Transgender (TG) (male-to-female or female-to-
male, see HVTN 704/HPTN 085 SSP) who, in the 6 months prior to randomization, 
experienced 1 or both of the following HIV risk criteria: 
 
Condomless anal intercourse with 1 or more male or transgender partner(s) 
 
Anal intercourse with 2 or more male or transgender partners  
Note: Receipt of hormonal therapy does not make a TG volunteer ineligible. 
Volunteers who have been in a mutually monogamous relationship with an HIV-1 
seronegative partner for > 1 year are excluded. 
Laboratory Inclusion Values 
Hematology 
10. Hemoglobin (Hgb) ≥ 10.5 g/dL for volunteers who were born female, ≥ 13.0 g/dL for 
volunteers who were born male (≥ 12.0 g/dL for transgender women taking feminizing 
hormones [eg, anti-androgens, estrogens]) 
11. Platelets ≥ 100,000 cells/mm3 
Chemistry 
12. ALT < 2.5 times the institutional upper limit of normal and creatinine ≤ 1.25 times the 
institutional upper limit of normal 
Virology 
13. HIV uninfected, as defined in the SSP, within 30 days prior to enrollment 
Urine 
14. Negative, trace, or 1+ (30 g/L for semi-quantitative) urine protein by dipstick 
Reproductive Status 
15. Volunteers capable of becoming pregnant: negative serum or urine beta human 
chorionic gonadotropin (β-HCG) pregnancy test performed at the screening visit and 
prior to infusion on the day of initial infusion. Persons who are NOT capable of 
becoming pregnant due to having undergone total hysterectomy or bilateral 
oophorectomy (verified by medical records) are not required to undergo pregnancy 
testing. 
16. Reproductive status: A volunteer who is capable of becoming pregnant must agree to 
consistently use effective contraception (see Appendix B, and SSP) for sexual activity 
that could lead to pregnancy from at least 21 days prior to enrollment through the last 
required protocol clinic visit. 
17. Volunteers capable of becoming pregnant 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 

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5.2 
Exclusion criteria 
General 
1. Investigational research agents received within 30 days before first infusion 
2. Body mass index (BMI) ≥ 40 
3. Pregnant or breastfeeding 
4. Any reactive, indeterminate, or positive HIV test, even if subsequent testing indicates 
that the individual is not HIV infected, except as permitted by the HVTN 704/HPTN 085 
PSRT. 
Vaccines 
5. HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received 
control/placebo in an HIV vaccine trial, the HVTN 704/HPTN 085 PSRT will determine 
eligibility on a case-by-case basis. 
Immune System  
6. Serious adverse reactions to VRC01 formulation components such as sodium 
citrate, sodium chloride, and L-arginine hydrochloride, including history of 
anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, 
and/or abdominal pain.  
7. Autoimmune disease, including Type I diabetes mellitus (Not excluded from 
participation: Volunteer with mild, stable and uncomplicated autoimmune disease that 
does not require consistent immunosuppressive medication and that, in the judgment of 
the site investigator, is likely not subject to exacerbation and likely not to complicate 
reactogenicity and AE assessments) 
8. Immunodeficiency syndrome 
Clinically significant medical conditions  
9. Clinically significant medical condition, physical examination findings, clinically 
significant abnormal laboratory results, or past medical history with clinically significant 
implications for current health. A clinically significant condition or process includes but 
is not limited to: 
 
Any contraindication to repeated infusions or blood draws, including inability to 
establish venous access; 
 
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; or 
 
A condition or process for which signs or symptoms could be confused with reactions 
to VRC01. 
10. 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, 

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assessment of safety or infusion reactions, or a volunteer’s ability to give informed 
consent 
11. 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. 
12. Asthma, other than mild, well-controlled asthma 
13. Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or platelet 
disorder requiring special precautions) 
14. 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) 
15. 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. 
16. History of hereditary angioedema, acquired angioedema, or idiopathic angioedema 
17. History of receiving transplantation of life-saving organs or tissues (includes heart, 
kidney, pancreas, lungs, liver, and intestines) 
18. Known hepatic or renal dysfunction 
5.3 
Participant departure from infusion schedule or withdrawal 
This section concerns an individual participant’s departure from the infusion schedule. 
Pause rules for the trial as a whole are described in Section 10.3. 
5.3.1 
Delaying infusions for a participant 
Under certain circumstances, a participant’s scheduled infusion will be delayed. The 
factors to be considered in such a decision include but are not limited to the following: 
 
Prior to infusion, abnormal vital signs or clinical symptoms that may mask 
assessment of a study product reaction 
 
Intercurrent illness that is assessed by the site principal investigator (or designee) to 
require delay or withdrawal from the infusion schedule. The investigator may consult 
with the HVTN 704/HPTN 085 PSRT. 
 
Pregnancy: for participants who become pregnant infusions will be stopped. If the 
participant is no longer pregnant (as demonstrated by a negative urine or serum 
pregnancy test) and wants to continue with infusions, the HVTN 704/HPTN 085 
PSRT will be consulted to determine whether the participant may resume infusions or 
whether infusions should be permanently discontinued.  

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5.3.2 
Participant departure from infusion schedule 
Every effort should be made to follow the infusion schedule per the protocol. If a 
participant misses an infusion and the visit window period for the infusion has passed, 
then sites may consult the SSP. 
5.3.3 
Discontinuing infusions for a participant 
Under certain circumstances, an individual participant’s infusions will be permanently 
discontinued. Specific events that will result in stopping a participant’s infusion schedule 
include: 
 
Co-enrollment in a study with an investigational research agent (rare exceptions 
allowing for the continuation of infusions may be granted with the unanimous 
consent of the HVTN 704/HPTN 085 PSRT); 
 
Clinically significant condition (ie, a condition that affects the immune system or for 
which continued infusions and/or blood draws may pose additional risk), including 
but not limited to the following: 
 
Any grade 4 local or systemic reactogenicity symptom or AE that is subsequently 
considered to be related to study product; 
 
An SAE that is subsequently considered to be related to study product; 
 
Any grade 3 clinical AE (exception: fever or vomiting and subjective local and 
systemic symptoms) that is subsequently considered to be related to study 
product;  
 
Any grade 3 or 4 lab abnormality confirmed by a repeated value that is 
subsequently considered to be related to study product; 
 
Clinically significant hypersensitivity reaction including but not limited to type 1 
hypersensitivity reaction and/or serum sickness associated with study product. 
Consultation with the HVTN 704/HPTN 085 PSRT is required prior to 
subsequent infusion following any hypersensitivity reaction associated with study 
product; or 
 
Investigator determination in consultation with Protocol Team leadership (eg, for 
repeated nonadherence to study staff instructions). 
Infusions will be permanently discontinued for a participant diagnosed with HIV 
infection or with 2 reactive HIV tests, even if subsequent testing indicates that the 
participant is not HIV infected. 
Participants for whom infusions are discontinued for reasons other than HIV infection 
should be counseled on the importance of continuing with the study and strongly 
encouraged to participate in Schedule 4 follow-up visits and protocol-specified 
procedures (see Appendix I and Appendix M), unless medically contraindicated. 
5.3.4 
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 

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 
Participant relocates and remote follow-up or transfer to another CRS is not possible 
 
CRS determines that the participant is lost to follow-up 
 
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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6 
Study product preparation and administration 
CRS pharmacists should consult the Pharmacy Guidelines and Instructions for DAIDS 
Clinical Trials Networks for standard pharmacy operations. The protocol schema is 
shown in Table 1-1. See the IBs for further information about study products. 
6.1 
Study product regimen 
The schedule of study product administrations is shown in Section 1 and additional 
information is given below.  
Group 1 
Treatment 1 (T1): VRC-HIVMAB060-00-AB 10 mg/kg in sufficient Sodium 
Chloride for Injection USP, 0.9% to prepare a final total volume of 150 mL to be 
administered IV at Weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, and 72. 
Group 2 
Treatment 2 (T2): VRC-HIVMAB060-00-AB 30 mg/kg in sufficient Sodium 
Chloride for Injection USP, 0.9% to prepare a final total volume of 150 mL to be 
administered IV at Weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, and 72. 
Group 3 
Control 3 (C3): Control for VRC01 (Sodium Chloride for Injection USP, 0.9%) to be 
prepared as a final total volume of 150 mL to be administered IV at Weeks 0, 8, 16, 
24, 32, 40, 48, 56, 64, and 72. 
6.2 
Study product formulation  
VRC-HIVMAB060-00-AB [VRC01, Labeled as VRC01 HIV MAb Drug Product 
VRC-HIVMAB060-00-AB] 
VRC01 will be provided as a sterile clear, colorless to yellow isotonic solution, 
essentially free of visible particles; some opaque or translucent particles may be present. 
Each vial contains 100 mg / mL of VRC-HIVMAB060-00-AB in formulation buffer. The 
formulation buffer is composed of 25 mM sodium citrate, 50 mM sodium chloride, and 
150 mM L-arginine hydrochloride at pH 5.8. Vials are intended for single use only and 
do NOT contain a preservative. The product should be stored frozen -35°C to -15°C with 
excursions permitted between -45°C and -10°C. The study products are described in 
further detail in the IB. 
Prior to preparation, vials containing VRC01 must be removed from the freezer and 
thawed for a minimum of 1 hour at room temperature. Following this 1 hour thaw, the 
unopened vials of VRC01 may be stored for up to 24 hours at room temperature (not to 
exceed 27°C) and/or up to 4 weeks at 2°C to 8°C. Product may NOT be thawed or stored 
in direct sunlight. Once thawed, product may NOT be refrozen. 

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VRC01 is a highly concentrated protein solution and may develop white-to-translucent 
particles after thawing. These particles have been observed in approximately 1-3% of the 
vials and generally disappear over a few hours at room temperature. Particle formation 
has no effect on product quality. If the particles do not disappear at room temperature, the 
vials should be placed in the refrigerator, as particles may continue to dissipate at 2°C to 
8°C (36°F to 46°F). Vials that continue to have visible particles after a maximum of 24 
hours at controlled room temperature and/or after 4 weeks at 2°C to 8°C (36°F to 46°F) 
should not be used. Instead, those vials with particles still visible should be quarantined 
[at 2°C to 8°C (36°F to 46°F)] until they are returned to the NIAID Clinical Research 
Products Management Center (CRPMC) (or manufacturer upon request of the CRPMC) 
or destroyed if directed by the CRPMC.  
Control for VRC01 [Sodium Chloride for Injection USP, 0.9%] 
Sodium Chloride for Injection USP, 0.9% will be used as the Control for VRC01. It must 
be stored as directed by the manufacturer. For sites who do not have access to Sodium 
Chloride for Injection USP, 0.9%, the Sodium Chloride for Injection, 0.9% that they use 
must meet the following criteria: a sterile solution of Sodium Chloride in Water for 
Injection which contains no antimicrobial agents. It is nonpyrogenic and is intended for 
intravenous administration. 
6.3 
Preparation of study products 
Prior to preparation of the first infusion (enrollment visit), a new prescription will be sent 
to the pharmacy. The prescription MUST contain the participant’s weight based upon the 
participant’s weight at the most recent visit where weight was measured (this includes 
screening) and randomization code (this may NOT be communicated verbally). If this 
information is NOT on the prescription, the prescription will be returned to the clinic 
from the pharmacy to be completed appropriately prior to the pharmacist beginning 
preparation of study product. Subsequent visit weights (based upon the participant’s 
weight at the most recent visit where weight was measured) must be communicated to the 
pharmacy in writing prior to the day of the visit. Any changes in weight of more than 
10% (between the prior weight and the weight on the day of the infusion visit ) will 
require an updated visit weight communication to the pharmacy in writing so that product 
can be prepared based on that weight change. 
Pharmacists should keep in mind that the preparation instructions below are considered 
medium risk per USP 38 General Chapter Physical Tests / <797> Pharmaceutical 
Compounding - Sterile, and should follow the requirements of their country, their 
institution, and their pharmacy regulatory authority regarding these procedures. 
6.3.1 
VRC-HIVMAB060-00-AB (10mg/kg IV) - (Group 1) 
To prepare an IV infusion, the pharmacist will calculate the dose [total milligrams needed 
(10 mg/kg x participant’s weight in kg)] and remove the total number of vials needed as 
well as a 100 mL IV bag of Sodium Chloride for Injection USP, 0.9% from storage. If the 
product has been stored at 2°C to 8°C, the vials should be equilibrated to room 
temperature for 30 minutes and may be held at room temperature (not to exceed 27°C) 
for up to 8 hours prior to product preparation. The pharmacist will also calculate the 
additional amount of Sodium Chloride for Injection USP, 0.9% needed to prepare a final 
total volume of 150 mL and remove this from storage.  

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Prior to preparation, the pharmacist should gently swirl the vials containing VRC01 and 
then inspect for particles. DO NOT SHAKE VIALS. If visible particles are present, the 
product will not be used (see Section 6.2 for more information). The pharmacist, using 
aseptic technique, will add the appropriate amount of Sodium Chloride for Injection USP, 
0.9% to the 100 mL IV bag of Sodium Chloride for Injection USP, 0.9%. The pharmacist, 
still using aseptic technique will add the appropriate volume of VRC01 to that same bag 
for a final total volume of 150 mL. The IV bag will be labeled as “VRC01 or Control in 
Normal Saline Total Volume = 150 mL”. The weight used for calculating the dose should 
be written on the label. A bag cover will be placed over the bag and should not be 
removed by the clinic staff. The IV bag will be labeled with a DO NOT INFUSE after 
date and time as follows: 
o 24 hours if stored at 2°C to 8°C 
o 8 hours, including completion of infusion, if stored at controlled room temperature 
(not to exceed 30°C) 
Product may NOT be stored in direct sunlight. 
Note: Site pharmacists must follow their institutional policies for expiration dates (ie, DO 
NOT INFUSE after date and time), if shorter than timeframes above. 
Any empty vials, unused portion of entered vials, or unused IV solution that contains 
study product should be discarded in a biohazard containment bag and incinerated or 
autoclaved in accordance with institutional or pharmacy policy. 
6.3.2 
VRC-HIVMAB060-00-AB (30mg/kg IV) - (Group 2) 
To prepare an IV infusion, the pharmacist will calculate the dose [total milligrams needed 
(30 mg/kg x participant’s weight in kg)] and remove the total number of vials needed as 
well as a 100 mL IV bag of Sodium Chloride for Injection USP, 0.9% from storage. If the 
product has been stored at 2°C to 8°C, the vials should be equilibrated to room 
temperature for 30 minutes and may be held at room temperature (not to exceed 27°C) 
for 8 hours prior to product preparation. The pharmacist will also calculate the additional 
amount of Sodium Chloride for Injection USP, 0.9% needed to prepare a final total 
volume of 150 mL and remove this from storage.  
Prior to preparation, the pharmacist should gently swirl the vials containing VRC01 and 
then inspect for particles. DO NOT SHAKE VIALS. If visible particles are present, the 
product will not be used (see Section 6.2 for more information). The pharmacist, using 
aseptic technique, will add the appropriate amount of Sodium Chloride for Injection USP, 
0.9%to the 100 mL IV bag of Sodium Chloride for Injection USP, 0.9%. The pharmacist, 
still using aseptic technique will then add the appropriate volume of VRC01 to that same 
bag for a final total volume of 150 mL. The IV bag will be labeled as “VRC01 or Control 
in Normal Saline Total Volume = 150 mL”. The weight used for calculating the dose 
should be written on the label. A bag cover will be placed over the bag and should not be 
removed by the clinic staff. The IV bag will be labeled with a DO NOT INFUSE after 
date and time as follows: 
o 24 hours if stored at 2°C to 8°C 
o 8 hours, including completion of infusion, if stored at controlled room temperature 
(not to exceed 30°C) 

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Product may NOT be stored in direct sunlight. 
Note: Site pharmacists must follow their institutional policies for expiration dates (ie, DO 
NOT INFUSE after date and time), if shorter than timeframes above. 
Any empty vials, unused portion of entered vials, or unused IV solution that contains 
study product should be discarded in a biohazard containment bag and incinerated or 
autoclaved in accordance with institutional or pharmacy policy. 
6.3.3 
Control for VRC01 (Group 3) 
To prepare an IV infusion, the pharmacist, using aseptic technique, will add 50 mL of 
Sodium Chloride for Injection USP, 0.9% to a 100 mL bag of Sodium Chloride for 
Injection USP, 0.9%. The IV bag will be labeled as “VRC01 or Control in Normal Saline 
Total Volume = 150 mL”. The weight used for calculating the dose should be written on 
the label. A bag cover will be placed over the bag and should not be removed by the 
clinic staff. The IV bag will be labeled with a DO NOT INFUSE after date and time as 
follows: 
o 24 hours if stored at 2°C to 8°C 
o 8 hours, including completion of infusion, if stored at controlled room temperature 
(not to exceed 30°C) 
Product may NOT be stored in direct sunlight. 
Note: Site pharmacists must follow their institutional policies for expiration dates (ie, DO 
NOT INFUSE after date and time), if shorter than timeframes above. 
6.4 
Administration 
VRC01 or Control (Intravenously) 
Prior to infusion, if the VRC01 or Control IV bag has been stored at 2°C to 8°C , the bag 
must be equilibrated to room temperature (maximum of 30°C) for 30 minutes or longer 
and may be held for up to 8 hours, including equilibration time and completion of product 
administration. (NOTE: This 8 hour period may NOT exceed the DO NOT INFUSE after 
date and time on the IV bag label.) 
The IV bag prepared by the pharmacy will include the weight that was used for 
preparation of the IV bag (VRC01 or Control). The clinician responsible for 
administration will check the bag label and confirm that the participant identifier is 
correct and that the weight on the bag label is within 10% of the participant’s current 
actual weight (refer to Section 6.3 for more information). 
An in-line filter infusion set must be used for IV administration (see SSP for 
specifications and additional details).  
The entire contents of the investigational study product solution will typically be 
administered IV over about 15 to 60 minutes using a volumetric pump. The total time 
needed to administer the dose may be longer based on factors such as participant 
tolerance.  

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6.5 
Acquisition of study products 
VRC-HIVMAB060-00-AB is provided by the VRC/DAIDS/NIAID. 
Control for VRC01 (Sodium Chloride for Injection USP, 0.9%) will not be provided 
through the protocol and must be obtained by the site. 
Once a CRS is protocol registered, the pharmacist can obtain study products from the 
CRPMC by following the ordering procedures given in Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks.  
6.6 
Pharmacy records 
The 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. 
6.7 
Final disposition of study products 
All unused study products must be returned to the CRPMC after the study is completed 
or terminated unless otherwise instructed by the CRPMC. The procedures and relevant 
form are included in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks.  

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7 
Clinical procedures 
The schedules of clinical procedures are shown in Appendix J through Appendix M. 
7.1 
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 informed 
consent form documents that a participant (1) has been informed about the potential risks, 
benefits, and alternatives to participation, and (2) is willing to participate in this study. 
Informed consent encompasses all written or verbal study information CRS staff provide 
to the participant, before and during the trial. CRS staff will obtain informed consent of 
participants according to HVTN and HPTN 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, CRS staff should consider reviewing the procedures and requirements 
for that visit and for the remaining visits. Additionally, if any new information is learned 
that might affect the participants’ decisions to stay in the trial, this information will be 
shared with trial participants. If necessary, participants will be asked to sign revised 
informed consent forms. 
A CRS may employ recruitment efforts prior to the participant consenting. For example, 
some 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. CRSs must submit recruitment and 
prescreening materials to their Institutional Review Board/Ethics Committee (IRB/EC) 
and any applicable Regulatory Entity (RE) for human subjects protection review and 
approval. 
Note: As defined in the DAIDS Protocol Registration Manual, an RE is “Any group other 
than the local IRB/EC responsible for reviewing and/or approving a clinical research 
protocol and site-specific ICFs [informed consent forms] prior to implementation at a 
site.” CRSs are responsible for knowing the requirements of their applicable REs. 
7.1.1 
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 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 prevention trial. In 
this way, CRS staff can continually screen potential participants and, when needed, 
proceed quickly to obtain protocol-specific enrollment consent. Sites conducting general 
screening or prescreening approved by their IRB/EC and any applicable RE may use the 
results from this screening to determine eligibility for this protocol, provided the tests are 
conducted within the time period specified in the eligibility criteria.  

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7.1.2 
Protocol-specific consent forms 
The protocol-specific consent forms describe the study products to be used and all 
aspects of protocol participation, including screening and enrollment procedures. A 
sample protocol-specific consent form for the main study is located in Appendix A. A 
separate sample consent form for other uses of specimens is located in Appendix C. 
Each 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 RE 
 
CRS’s institution, and 
 
Elements of informed consent as described in Title 45, CFR Part 46 and Title 21 
CFR, Part 50, and in the International Conference on Harmonisation (ICH) E6, Good 
Clinical Practice: Consolidated Guidance 4.8.  
Study sites are strongly encouraged to have their local CABs review their site-specific 
consent forms. This review should include, but should not be limited to, issues of cultural 
competence, local language considerations, and the level of understandability. 
The sample informed consent form includes instructions throughout the document for 
developing specific content. 
Sites should follow the instructions in the Protocol-specific Official Memo distributed 
along with this protocol regarding when they may begin using their site-specific protocol 
consent forms. 
Regarding protocol registration, sites should follow procedures outlined in the current 
version of the DAIDS Protocol Registration Manual. 
7.1.3 
Assessment of Understanding 
Study staff are responsible for ensuring that participants fully understand the study before 
enrolling them. This process involves reviewing the informed consent form with the 
participant, allowing time for the participant to reflect on the procedures and issues 
presented, and answering all questions completely.  
An Assessment of Understanding is used to document the participant’s understanding of 
key concepts in this clinical trial. The participant must complete the Assessment of 
Understanding before enrollment. Staff may provide assistance in reading and 
understanding the questions and responses, if necessary. Participants must verbalize 
understanding of all questions answered incorrectly. This process and the participant’s 
understanding of the key concepts should be recorded in source documentation at the site. 
IRB/EC and any applicable RE may require that a participant has signed either a 
screening or protocol-specific consent document prior to administering the Assessment of 
Understanding. The consent process (including the use of the Assessment of 
Understanding) should be explained thoroughly to the IRB/EC and any applicable RE, 
whose recommendations should be followed. 

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7.2 
Pre-enrollment procedures 
Screening may occur over the course of several contacts/visits, up to and including before 
infusion on Day 0. All inclusion and exclusion criteria must be assessed within 56 days 
before enrollment, with the exception of HIV testing, which must be performed within 30 
days before enrollment (see Section 5.1), 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; 
 
Complete physical examination, including height, weight, vital signs, and clinical 
assessments of head, ears, eyes, nose, and throat; neck; lymph nodes; heart; chest; 
abdomen; extremities; neurological function; and skin; 
 
Assessment of concomitant medications the volunteer is taking, including 
prescription and nonprescription drugs, vitamins, topical products, 
alternative/complementary medicines (eg, herbal and health food supplements), 
recreational drugs, vaccinations, and allergy shots; 
 
Laboratory tests as defined in the inclusion and exclusion criteria, including: 
 
Screening HIV testing at local lab (see SSP) 
 
CBC with differential 
 
ALT 
 
Creatinine 
 
Urine dipstick 
 
Urine or serum pregnancy test (volunteers capable of becoming pregnant); 
Persons who are not capable of becoming pregnant due to having undergone total 
hysterectomy or bilateral oophorectomy (verified by medical records), are not 
required to undergo pregnancy testing;  
 
Assessment of participant risk for HIV infection 
 
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 US 
CDC current guidelines or other local guidelines for HIV counseling, testing, and 
referral as described in Section 7.5; and 
 
Discussion of pregnancy prevention. A pregnant or breastfeeding person may not be 
enrolled in this trial. Specific criteria and assessment of contraception and pregnancy 
status are described in the study inclusion criteria and in Appendix B. Discussion of 
pregnancy prevention includes advising a participant who is capable of becoming 
pregnant but who reports no current sexual activity that could lead to pregnancy 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.  

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7.2.1 
Use of screening results from another HVTN or HPTN study 
If a participant screens for an HVTN or HPTN study at the same CRS but then does not 
join that study, screening results from that effort may be applied to the screening for this 
protocol, as long as the screening was done under participant consent, the participant has 
signed a consent form to begin screening for this study, and the tests were conducted 
within the time periods specified in the eligibility criteria (see Section 5). 
7.3 
Enrollment and infusion visits 
Enrollment is simultaneous with first infusion. The time interval between randomization 
and enrollment should not exceed 4 working days. The CRS requests the randomization 
assignment from the Web-based randomization system. Circumstances may require a 
participant’s enrollment visit to be changed. This may exceed the 4-day randomization 
time limit. 
At all infusion visits, the following procedures are performed before infusion: 
 
Abbreviated physical examination, including weight, vital signs, and a symptom-
directed evaluation by history and/or appropriate physical exam based on participant 
self-reported symptoms or complaints (see SSP for more detail); 
 
Assessment of baseline reactogenicity parameters; 
 
Assessment of any new or unresolved AEs/intercurrent illnesses;  
 
Assessment of concomitant medications (as described in Section 7.2); 
 
ALT;  
 
Creatinine; 
 
CBC with differential; 
 
Urine or serum pregnancy test (for participants who are capable of becoming 
pregnant). Persons who are NOT capable of becoming pregnant due to having 
undergone total hysterectomy or bilateral oophorectomy (verified by medical 
records), are not required to undergo pregnancy testing; and  
 
Blood collection for HIV testing, PrEP monitoring, and sample storage. 
Following completion of all procedures in the preceding list, and if results indicate that 
infusion may proceed, infusion is administered (see Sections 6.3 and 6.4). 
Administration of an infusion and infusion-related procedures must be accomplished 
within 1 calendar day. 
Immediately following the first infusion, the participant remains in the clinic for 
observation and initial reactogenicity assessment. See the SSP for details regarding 
infusion visit protocols and subsequent infusion observation and reactogenicity 
assessment procedures that CRSs must follow. The site will make arrangements to obtain 
a report of reactogenicity events from the participant after the 3-day reactogenicity period 
(as described in Section 7.10 and in the SSP). 

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The following procedures will be performed at all infusion visits. These procedures may 
be performed prior to, during, or following infusion:  
 
Administration of the participant questionnaire which may include acceptability, 
behavioral risk, study product belief, motivations, and social impact domains (must 
be done prior to risk reduction counseling);  
 
HIV infection assessment including pre-test counseling. A subsequent follow-up 
contact is conducted to provide post-test counseling and to report results to 
participant; 
 
Risk reduction counseling (as described in Section 7.5);  
 
For participants capable of becoming pregnant, pregnancy prevention assessment (as 
described in Section 7.2 and 7.6);  
 
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);  
 
Confirm that participants received HIV test results from previous visit. If not, provide 
test results and post-test counseling as appropriate; and 
 
Ship samples to HVTN Central Laboratory for HIV diagnostic testing. 
Additional procedures will be performed at scheduled visits as specified in Appendix J: 
 
Syphilis serology testing; 
 
Gonorrhea (GC)/chlamydia (CT) testing by urine and rectal swabs, and GC testing by 
oropharyngeal swab; and 
 
Urine dipstick (see Section 7.9). 
7.4 
Post-infusion visits for HIV-uninfected study participants 
The following procedures are performed at all post-infusion follow-up visits for HIV-
uninfected study participants: 
 
HIV infection assessment including pre-test counseling. A subsequent follow-up 
contact is conducted to provide post-test counseling and to report results to 
participant; 
 
Confirm that participants received HIV test results from previous visit. If not, provide 
test results and post-test counseling as appropriate; 
 
Blood collection for HIV testing, PrEP monitoring, and sample storage; and 
 
Ship samples to HVTN Central Laboratory for HIV diagnostic testing. 
Additional procedures will be performed at scheduled follow-up visits as specified in 
Appendix F and Appendix J:  

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 
Assessment of new or unresolved social impacts (site staff will ask participant about 
the status of any unresolved social impacts and if s/he has experienced any new 
social impacts as a result of the trial participation); 
 
Administration of participant questionnaire, which may include acceptability, 
behavioral risk, study product belief, motivations, and social impact domains (must 
be done prior to risk reduction counseling) 
 
Risk reduction counseling (as described in Section 7.5);  
 
Urine or serum pregnancy test (for participants who are capable of becoming 
pregnant). Persons who are NOT capable of becoming pregnant due to having 
undergone total hysterectomy or bilateral oophorectomy (verified by medical 
records), are not required to undergo pregnancy testing;  
 
For participants who are capable of becoming pregnant, pregnancy prevention 
assessment (as described in Section 7.2 and 7.8);  
 
Assessment of new or unresolved AEs/intercurrent illnesses;  
 
Urine dipstick (see Section 7.9); and 
 
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. 
7.5 
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 protocol-specific HIV testing algorithm following enrollment. 
Participants will be counseled routinely during the trial on the avoidance of HIV 
infection. In addition, study participants will be provided with HIV prevention supplies 
and referral to providers of PrEP per local and regional guidelines. Study investigators 
will ensure that participants have access to standards of care for HIV prevention in their 
local settings. As new data emerge and standards of care for HIV prevention evolve, both 
the content of risk reduction counseling and referrals for biomedical interventions will be 
updated to conform to current best practices for the populations enrolled in this trial. For 
additional details regarding PrEP provision and referrals, see the HVTN 704/HTPN 085 
website.  
7.5.1 
Study product–related seroreactivity 
Human sera containing purified VRC01 at concentrations up to 1600 mcg/mL have been 
tested using a variety of commercially available HIV test kits without any indication of 
reactivity. For this reason, we do not anticipate that receipt of VRC01 will cause a 
reactive result on currently available HIV test kits, but this remains a theoretical 
possibility.  
Because this possibility cannot be categorically eliminated, study staff will advise study 
participants to confine their HIV testing while in the study to that provided through the 
CRS. Staff will also inform study participants of the likelihood of routine HIV testing 

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being offered or performed outside the study CRS at emergency rooms, clinics, and 
medical offices and will 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/regional 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 HIV testing preemptively. CRS staff should also 
inform participants if positive HIV test results must be reported to local public health 
authorities. CRS staff should also inform participants of the need to maintain study 
blinding by getting HIV testing only at the study CRS. CRS staff should provide 
participants with CRS contact information and should encourage participants to ask 
medical providers to contact the CRS. The CRS can verify that the participant is in an 
HIV mAb clinical trial and should only be tested for HIV at the study CRS. 
Study staff should also stress that the study product is completely cleared from the body 
within a few months, so even the theoretical risk of VRC01 causing a misleading HIV 
test result will disappear before their final scheduled clinic visit. 
7.6 
Follow-up visits for HIV-infected participants 
The following procedures are performed at scheduled follow-up visits as specified in 
Appendix G, Appendix H, Appendix K, and Appendix L: 
 
Counseling on HIV testing and diagnosis; 
 
Abbreviated physical exam including weight, vital signs, and a symptom-directed 
evaluation by history and/or appropriate physical exam based on participant self-
reported symptoms or complaints (see SSP for more detail); 
 
ART assessment; 
 
Assessment of concomitant medications (as described in Section 7.2); 
 
Assessment of any new or unresolved AEs/intercurrent illnesses;  
 
HIV transmission risk reduction counseling; 
 
Behavioral risk assessment questionnaire; 
 
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);  
 
Blood collection for HIV testing, viral load testing, VRC01 Ab levels, functional 
assays, viral isolation/sequencing, and sample storage (see Appendix G, Appendix H, 
and Section 8.5); 
 
Blood collection for CD4+ T cell counts; 
 
Urine or serum pregnancy test (for participants who are capable of becoming 
pregnant). Persons who are NOT capable of becoming pregnant due to having 
undergone total hysterectomy or bilateral oophorectomy (verified by medical 
records), are not required to undergo pregnancy testing; and  

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 
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. 
7.7 
Follow-up visits for participants who discontinue infusions for 
reasons other than HIV infection 
Participants for whom infusions are discontinued for reasons other than HIV infection 
should be encouraged to continue in the study. For such participants, the following 
procedures are performed at approximately quarterly scheduled follow-up visits as 
specified in Appendix I and Appendix M: 
 
Abbreviated physical exam including weight, vital signs, and a symptom-directed 
evaluation by history and/or appropriate physical exam based on participant self-
reported symptoms or complaints (see SSP for more detail); 
 
Risk reduction counseling (as described in Section 7.5);  
 
Assessment of concomitant medications (as described in Section 7.2); 
 
Assessment of any new or unresolved AEs/intercurrent illnesses;  
 
HIV infection assessment including pre-test counseling. A subsequent follow-up 
contact is conducted to provide post-test counseling and to report results to 
participant; 
 
Confirm that participants received HIV test results from previous visit. If not, provide 
test results and post-test counseling as appropriate; 
 
Behavioral risk assessment questionnaire; 
 
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);  
 
Blood collection for HIV testing, PrEP monitoring, CBC/differential, ALT, 
creatinine, VRC01 Ab levels, functional assays, and sample storage (see Appendix I 
and Appendix M); 
 
Urine dipstick (see Section 7.9); 
 
Urine or serum pregnancy test (for participants who are capable of becoming 
pregnant). Persons who are NOT capable of becoming pregnant due to having 
undergone total hysterectomy or bilateral oophorectomy (verified by medical 
records), are not required to undergo pregnancy testing; and 
 
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. 
7.8 
Contraception status 
Contraception status is assessed and documented at screening and infusion visits for a 
participant who is capable of becoming pregnant. Prior to enrollment and throughout the 

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study, staff will ask participants to verbally confirm their use of adequate contraceptive 
methods. These participants should be reminded regularly of the importance of using 
contraception and should be referred to specific counseling, information, and advice as 
needed. (See Appendix B for further detail.) This reminder should be documented in the 
participant’s study record. 
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. 
7.9 
Urine testing 
Urine dipstick testing may be performed in the clinic or the lab. The following analytes 
should be analyzed and recorded: specific gravity, protein, blood/hemoglobin, pH, 
urobilinogen, bilirubin, ketone, leucocyte esterase, nitrite, and glucose. The examination 
is performed on urine obtained by clean catch. Urine microscopy is required when the 
protein result is 1+, 2+, 3+, or 4+ (or semi-quantitative 30, 100, 300, or 2000 g/L) and/or 
the blood/hemoglobin result is trace, 1+, 2 +, 3+, or 4+, but not required (unless 
otherwise clinically indicated) if the dipstick result is abnormal due to non-urinary 
bleeding. 
If the dipstick performed for screening is transiently abnormal with an exclusionary result 
(eg, 2+ proteinuria), then repeat the dipstick and, if within the eligibility limits specified 
in the protocol, the participant may be enrolled (see SSP for further detail). 
A follow-up urine test should be deferred if a participant is experiencing non-urinary 
bleeding (eg, menstruation), but should be performed as soon as possible. If a follow-up 
dipstick is abnormal due to non-urinary bleeding (eg, a participant’s menstrual period), 
document in the comment section of the CRF and repeat the dipstick once the participant 
is no longer experiencing non-urinary bleeding. In this case, a urine microscopy is not 
required (see SSP for further detail). If a follow-up dipstick is abnormal due to infection, 
document this issue in the participant’s source documentation and provide appropriate 
treatment and/or referral. 
7.10 
Assessments of reactogenicity 
For all participants, baseline assessments are performed before and reactogenicity 
assessments are performed after infusions per the SSP. All reactogenicity symptoms are 
graded according to the Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.1, dated March 2017, 
except as noted in Section 10.2.2. 
The reactogenicity assessment period is 3 full days following each infusion. The site staff 
and the participant will be in contact after the 3-day reactogenicity period, or sooner if 
indicated. At that time, site staff will discuss reactogenicity events with the participant 
and record the relevant information on CRF(s) or participant chart note as source (for 
more details, see the SSP). Clinic staff will follow new or unresolved reactogenicity 
symptoms present at day 3 to resolution. Participants are instructed to contact the clinic 
for events that arise during the period between infusion and the next scheduled visit. In 

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general, a participant who self-reports any postinfusion reaction greater than mild is seen 
by a clinician within 48 hours after onset, unless the reaction is improving and/or has 
completely resolved.  
Reactogenicity events are reported using CRFs that correspond to the time of assessment 
per the SSP. Reactogenicity assessments include assessments of specific systemic and 
local signs and symptoms and infusion site reactions. Events not listed on a CRF, or with 
an onset after the reactogenicity assessment period (day of infusion and 3 full days after), 
or those meeting SAE/adverse events requiring expedited reporting to DAIDS criteria, 
are recorded on an adverse event log form.  
7.10.1 
Assessment of systemic and local signs and symptoms 
Systemic signs and symptoms include increased body temperature, malaise and/or 
fatigue, myalgia, headache, chills, arthralgia, nausea, and vomiting. Local symptoms 
include pain and/or tenderness proximal to the infusion site. The maximum severity 
reached for each symptom during the assessment period per the SSP is reported.  
7.10.2 
Assessment of infusion site 
Infusion site reactions may include redness/erythema and induration/swelling. The 
maximum horizontal and maximum vertical measurements for infusion site 
redness/erythema and induration/swelling are recorded. 
All infusion site reactions are monitored until resolution. Areas greater than 25 cm2 are 
followed daily; otherwise, the frequency of follow-up is based on clinician judgment. 
7.11 
Visit windows and missed visits 
Visit windows are defined in the SSP. For a visit not performed within the window 
period, a Missed Visit form is completed.  
If a participant misses a scheduled visit, CRS staff should attempt to bring the participant 
in as soon as possible to complete the required safety assessments and other procedures. 
See the HVTN 704/HPTN 085 SSP for more details. If a participant missed an infusion 
visit or if infusions must be permanently discontinued, see Section 5.3.2 and Section 
5.3.3 for resolution. 
7.12 
Early termination visit 
In the event of early participant termination, site staff should consider if the following 
assessments are appropriate: a final physical examination, clinical laboratory tests 
(including urine dipstick, CBC with differential, ALT, and Creatinine), pregnancy 
testing, social impact assessment, and HIV test. 

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7.13 
Pregnancy 
If a participant becomes pregnant during the course of the study, no more infusions of 
study product will be given during the pregnancy, but remaining visits and study 
procedures should be completed unless medically contraindicated. For participants who 
are no longer pregnant, see Section 5.3.1. 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. 

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8 
HIV infection assessment and clinical response 
8.1 
HIV symptom assessment 
At all scheduled visits and at unscheduled visits due to illness or suspected exposure, if 
necessary, information will be collected about any signs or symptoms suggestive of acute 
HIV infection. Participants will be counseled about signs and symptoms of acute HIV 
infection and at visits following recent high-risk exposure, participants will be queried 
about any signs/symptoms suggestive of acute HIV infection. Presence of 
signs/symptoms suggestive of acute HIV infection, an intercurrent illness consistent with 
acute retroviral syndrome, or history of high-risk exposure would prompt a diagnostic 
work-up per the protocol-specific algorithm for recent exposure to determine HIV 
infection. 
8.2 
HIV screening test (prior to randomization) 
Prior to randomization, participants will be screened for HIV-1/2 infection by FDA-
approved blood tests (non-US sites may use locally available assays that have been 
approved by HVTN and HPTN Laboratory Operations [see SSP]). Volunteers identified 
as being HIV infected during screening will be referred for medical treatment and 
management of the HIV infection. These individuals may also be referred to appropriate 
ongoing clinical trials or observational studies. For volunteers who have one or more 
reactive/positive HIV tests, but whose HIV status is inconclusive, any further testing will 
be performed locally. 
8.3 
HIV testing postinfusion 
Following enrollment, HIV testing will take place at scheduled clinic visits (Appendix F).  
HIV testing will be performed using the protocol-specific HIV testing algorithms (see 
SSP). At scheduled visits that include HIV testing, specimens will be tested with an 
FDA-approved 4th generation HIV 1/2 enzyme immunoassay (EIA) or chemiluminescent 
microparticle immunoassay (CMIA). If the participant has a reactive test result, an HIV 
RNA test and an HIV 1/2 discriminatory test will be performed as indicated in the 
algorithm. Further HIV testing is required using a second specimen drawn on a later date 
to confirm a diagnosis of HIV infection. The second specimen may be collected at an 
interim visit (ie, visit #.X specified in Appendix G and Appendix H). Samples to be 
stored for future studies will also be collected at this time (see Appendix G). 
A ‘case’ will be defined as a participant who is confirmed to have acquired HIV-1 
infection after enrollment based on the protocol-specific diagnostic algorithms (see SSP). 
Before informing a participant that they are infected at or after enrollment, all HIV test 
results will be reviewed by a blinded, independent Endpoint Adjudicator(s) or designee(s) 
(Section 8.4). 
The HVTN Laboratory Program is responsible for all in-study diagnostic testing. 

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8.4 
Endpoint adjudication 
The general diagnostic criteria for HIV infection are well accepted. However, definitive 
diagnosis of HIV infection in the context of having received a study product that is even 
partially effective may be more difficult. Specifically, if VRC01 is capable of completely 
suppressing viral replication, or if the antibody alters the normal serological response 
upon exposure to HIV, standard diagnostic tests may be more difficult to assess. 
Therefore, this study will have an endpoint adjudication process to review all serological 
and virological test results in a blinded manner for each participant who tests positive per 
the HVTN 704/HPTN 085 HIV diagnostic testing algorithms. Adjudicators will also 
review HIV test results in cases where HIV infection status is not clearly resolved using 
the HIV testing algorithm. The assessment of the Endpoint Adjudicator(s) or designee(s) 
will be reported to the SDMC and to the HIV diagnostics laboratory. 
The Endpoint Adjudicator(s) or designee(s) must notify the SDMC within 1 working day 
of any confirmed HIV infection. The HIV diagnostics lab will inform the clinic of the 
outcome of the HIV testing algorithm (ie, HIV-infected, HIV-uninfected, or redraw 
required). 
The Endpoint Adjudicator(s) or designee(s) will be expert in the fields of infectious 
diseases or laboratory medicine independent of the VRC and clinical investigators 
participating in this trial. A separate Standard Operating Procedure will govern the 
activities of the Endpoint Adjudicator(s) or designee(s). 
8.5 
HIV infection during the study 
It is critical to the success of the study that HIV-infected participants be properly 
identified and all data postdiagnosis be carefully recorded. Information obtained from 
these cases of HIV-1 infection will form the basis of the primary endpoint assessment. 
Participants who develop HIV infection following the initial infusion of study product 
may remain in the study for follow-up but will receive no further infusions. This includes 
participants for whom infusions were discontinued for reasons other than HIV infection 
but for whom HIV-1 infection has subsequently been confirmed. All participants who 
become HIV-1–infected following enrollment through their final study visit will be 
monitored as indicated in Appendix G and Appendix K.  
If a participant is confirmed to have become HIV infected after enrollment, plasma HIV-
1 RNA will be measured on archived samples prior to the first positive screening test. 
HIV-1 RNA testing will also be performed at 2-week intervals up to 8 weeks 
postdiagnosis, then at 12 and 24 weeks postdiagnosis. In addition to plasma HIV-1 RNA 
testing, participants will also have specimens drawn for measurements of VRC01 Ab 
serum levels, neutralization and other antibody functions, viral isolation and sequencing; 
physical exams, recording of AEs, counseling to reduce HIV transmission risk, and social 
impact assessments will also be performed at most of these visits.  
Longer-term follow-up for these participants may be accomplished through enrollment in 
another protocol. Archived samples from earlier visits may also be tested to determine the 
earliest date of HIV infection.  

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If enrollment visit HIV testing indicates that a participant was HIV infected at enrollment 
(ie, prior to the first infusion of study product) or a participant is diagnosed with HIV-2 
infection following enrollment, then the procedures indicated in the preceding paragraph 
do not apply. Such participants should be followed as indicated in Appendix H and 
Appendix L. This also applies to participants for whom infusions are discontinued for 
reasons other than HIV infection and who subsequently are diagnosed with HIV-2 
infection. 
8.6 
Medical care for participants who become HIV infected 
It is anticipated that some study participants, whether they are randomized to receive 
VRC01 or control, will become HIV infected during the course of the trial. It is critical 
that these HIV-infected participants receive appropriate medical care. 
The investigators associated with this trial will refer participants who develop HIV 
infection while participating in this trial to medical professionals for care.  

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9 
Laboratory 
9.1 
CRS laboratory procedures 
The SSP provides 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 F through Appendix I. 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. 
9.2 
Total blood volume 
Required blood volumes per visit are shown in Appendix F through Appendix H. Not 
shown is any additional blood volume that would be required if a safety lab needs to be 
repeated, or if a serum pregnancy test needs to be performed. The additional blood 
volume would likely be minimal. The total blood volume drawn for each participant will 
not exceed 500 mL in any 56-day (8-week) period. 
9.3 
Assay timepoints 
Endpoint assays are performed on participants at the timepoints shown in Appendix F 
through Appendix I may be performed at baseline. Assays for humoral and cellular 
responses may be performed on participants or a subset of participants at other 
timepoints; the schedules are shown in Appendix F through Appendix I. 
9.4 
VRC01 mAb levels 
VRC01 levels will be measured in serum. An ELISA will be used to determine the 
concentration of the VRC01 antibody in the serum. The ELISA employs the VRC01 Fab-
specific 5C9 mAb, which is an anti-idiotype antibody cloned from a single B cell that 
was sorted by flow cytometry using a VRC01 scFv probe. The 4-parameter logistic curve 
regression of a standard curve of VRC01 covering the range from 0.031 to 1.0 mcg/mL is 
utilized in this assay to quantitate the sample concentrations based upon the average of 
sample dilutions within the range of the assay. This assay has been qualified but not 
formally validated. The functional sensitivity for the generation of the ELISA assay 
format, which is currently used at NVITAL, is 2 mcg/mL and as the technology for this 
assay continues to develop, an updated assay may be utilized. 

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9.5 
Endpoint assays: humoral 
9.5.1 
Anti-VRC01 antibody assay 
Assessment for development of anti-VRC01 antibodies in participants will be performed 
using the Meso Scale Discovery (MSD) platform based on electrochemiluminescence. 
The assay uses biotin-labeled VRC01 immobilized on a streptavidin-coated MSD plate as 
the capture molecule, and the SULFO-TAG labeled VRC01 as the reporter molecule. 
This assay is independent of the anti-VRC01 antibody isotype, and permits the detection 
of both high and low affinity antibodies. 
9.5.2 
Neutralizing antibody assay 
Depending upon the VRC01 concentrations measured in collected specimens, their 
capacity to neutralize HIV in blood and mucosal secretions may be evaluated by an in 
vitro cell-based virus neutralization assay [131-133] using pseudotyped viruses. All 
specimens testing positive for anti-VRC01 antibodies will be tested for HIV-1 
neutralizing activity. 
One or more viruses that are among the most sensitive to VRC01 (eg, MN.3 and 
MW965.26) will be assayed. The IC50 of VRC01 against both of these viruses is 0.01 – 
0.03 mcg/ml and the TZM-bl assay is validated for this level of sensitivity. 
9.6 
ARV detection 
A direct, biomedical measure is used to assess ARV use in this study. This approach is 
used because self-report of ARV use for PrEP or PEP and other purposes has been shown 
to be unreliable in a variety of settings [134-136]. For this study, ARV testing will be 
performed using a test that measures the amount of tenofovir-diphosphate (a metabolite 
of tenofovir) in red blood cells. This test utilizes a dried blood spot as the sample source 
and analyzes for tenofovir diphosphate by liquid chromatography and tandem mass-
spectroscopy, as previously described [137,138]. Because of a long half-life, high 
amounts of the metabolite in the dried blood spot correspond with consistent dosing of 
Truvada and low amounts correspond with inconsistent dosing [76].  
Dried blood spot samples are collected from all participants at all scheduled study visits. 
Periodically, a subset of participant samples will be tested in a manner that will provide 
an estimate of PrEP use across clinical sites. Storage of dried blood spots as well as 
serum and plasma (see Appendix F and Appendix I) will allow additional assessment of 
PrEP use if warranted. Individual test results will not be returned to study sites or study 
participants. 
9.7 
Host (human) genotyping 
Various markers, such as genes associated with host immune functions or HIV disease 
progression may also be assessed.  

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9.8 
Lab assay algorithm 
The HVTN Lab Assay Algorithm lists assays that characterize various types of 
immunologic activity as well as host genetics that may be conducted to characterize the 
drug activity in this study. Various types of assays may be employed to assess 
maintenance of functional drug activity at multiple timepoints selected based on drug 
level outcomes. Please note that the Lab Assay Algorithm will be updated periodically to 
include new assays. 
9.9 
Possible additional studies 
Samples may be used for other testing and research related to furthering the 
understanding of HIV immunology, monoclonal antibodies, or vaccines. In addition, 
cryopreserved samples may be used to perform additional assays to support 
standardization and validation of existing or newly developed methods.  
9.10 
Other use of stored specimens 
The Networks store 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 described in the protocol. 
This research may relate to HIV, vaccines, monoclonal antibodies, the immune system, 
and other diseases. This could include limited genetic testing and, potentially, genome-
wide studies. This research is done only to the extent authorized in each study site’s 
informed consent form, or as otherwise authorized under applicable law. Other testing on 
specimens will occur only after review and approval by the HVTN, the HPTN, the 
IRB/EC of the researcher requesting the specimens, and the CRS’s IRBs/ECs if required. 
The protocol sample informed consent form is written so that the participant either 
explicitly allows or does not allow their samples to be used in other research when they 
sign the form. Participants who initially agree to other use of their samples may rescind 
their approval once they enter the study; such participants will remain in this study and 
their samples will only be used for the studies described in this protocol. If a participant 
decides against allowing other research using his or her samples, or at any time rescinds 
prior approval for such other use, the study site investigator or designee must notify 
HVTN Regulatory Affairs in writing. In either case, HVTN Regulatory Affairs directs the 
HVTN Lab Program not to use samples from these participants for such other uses.  
CRSs must notify HVTN Regulatory Affairs if institutional or local governmental 
requirements pose a conflict with or impose restrictions on other use of specimens. 
9.11 
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 

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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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10 
Safety monitoring and safety review 
10.1 
Safety monitoring and oversight 
10.1.1 
HVTN 704/HPTN 085 PSRT 
The HVTN 704/HPTN 085 PSRT is composed of the following members: 
 
DAIDS medical officer representatives, 
 
Protocol chairs and cochairs, 
 
Protocol Team leader, 
 
Core medical monitor,  
 
Clinical safety specialist (CSS), and 
 
Regional medical liaison (RML). 
A medical officer from an organization(s) designated by the study sponsor will also 
participate in the PSRT. 
The clinician members of HVTN 704/HPTN 085 PSRT are responsible for decisions 
related to participant safety. 
The Protocol Team clinic coordinators, project managers, study product developer 
representatives, clinical research manager, clinical trial manager, and others may also be 
included in HVTN 704/HPTN 085 PSRT meetings. 
10.1.2 
NIAID DSMB 
The NIAID DSMB assesses the effects of the study product during the trial, provides 
other monitoring as described in Section 4.9.1.1, and may give advice to the HVTN 
704/HPTN 085 OC.  
10.1.3 
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 clinical data; 
 
Providing reports of clinical data to appropriate groups such as the HVTN 704/HPTN 
085 PSRT and NIAID DSMB. 
The roles and responsibilities of the HVTN CSS or HVTN Core designee in relation to 
safety monitoring include: 

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 
Daily monitoring of clinical data for events that meet the safety pause and HVTN 
704/HPTN 085 PSRT AE review criteria (see Section 10.3); 
 
Notifying CRSs and other groups when safety pauses are instituted and lifted (see 
Section 10.3); 
 
Querying CRSs for additional information regarding reported clinical data; and 
 
Providing support to the HVTN 704/HPTN 085 PSRT. 
10.2 
Safety reporting 
10.2.1 
Submission of safety forms to SDMC 
Sites must submit all safety forms (eg, reactogenicity, adverse experience, urinalysis, 
local lab results, concomitant medications) before the end of the next business day after 
receiving the information. The forms should not be held in anticipation of additional 
information at a later date. If additional information is received at a later date, the forms 
should be updated and resubmitted before the end of the next business day after receiving 
the new information. 
10.2.2 
AE reporting 
An AE is any untoward medical occurrence in a clinical investigation subject 
administered a study product/procedure(s) and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational study product/procedure(s), whether or not 
related to the investigational study product/procedure(s). The AE reporting period for this 
study comprises the entire study period for each individual participant (from study 
enrollment until study completion or discontinuation of the study). All AEs are graded 
according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events, Version 2.1, dated March 2017, available on the RSC website 
at http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables, 
except that the AEs below will be reported according to the SSP: 
 
Unintentional weight loss  
 
Infusion Site Erythema or Redness and Infusion Site Induration or Swelling  
 
Infusion reactions 
In addition, clarifying footnote 16 (page 21) in Version 2.1 of the AE Grading Table, for 
transgender participants ≥ 13 years of age who have been on feminizing hormone therapy 
for more than 6 consecutive months, grade hemoglobin based on the female sex at birth 
hemoglobin lab values. For transgender participants ≥13 years of age who have been on 
masculinizing hormone therapy for more than 6 consecutive months, grade hemoglobin 
based on the male sex at birth hemoglobin lab values. 

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As detailed in the SSP, two additional parameters, cytokine release syndrome and serum 
sickness, have been added to the DAIDS AE Grading Table for HVTN 704/HPTN 085.  
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 10.2.3) and (2) if the AE meets the criteria for a safety pause/prompt AE review 
(Section 10.2.4). 
Sites are expected to notify the CSS or RML of any serious safety concern requiring their 
attention (see Table 10-1). Telephone numbers and email addresses are found on the 
HVTN704/HPTN 085 protocol-specific website. Concerns requiring immediate attention 
should be communicated by calling the clinical safety phone. 
In the case of email notification, the CSS or RML will reply during working hours (ie, 
US Pacific Time, Peru Time, or South African Standard Time) to confirm that the email 
has been received and reviewed. If email service is not available, the CRS should notify 
the CSS or RML 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. 
10.2.3 
Expedited reporting of adverse events to DAIDS 
Requirements, definitions and methods for expedited reporting of AEs are outlined in 
Version 2.0 (January 2010) of the Manual for Expedited Reporting of Adverse Events to 
DAIDS (DAIDS EAE Manual), which is available on the RSC website at http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/manual. The SAE Reporting Category 
will be used for this study.  
The internet-based DAIDS Adverse Experience Reporting System (DAERS) must be 
used for expedited AE reporting to DAIDS. In the event of system outages or technical 
difficulties, expedited AE reports may be submitted via the DAIDS EAE Form. This 
form is available on the DAIDS RSC website at http://rsc.tech-res.com/clinical-research-
sites/safety-reporting/daids/paper-eae-reporting. 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSsupport@niaid.nih.gov or from within the DAERS application itself.  
For questions about expedited AE reporting, please contact the RSC 
(DAIDSRSCSafetyOffice@tech-res.com).  
Under ICH E2A (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting), an SAE is defined as any untoward medical occurrence that at any 
dose:  
 
results in death, 
 
is life-threatening (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the patient was at risk of death at the time of the event; it 
does not refer to an event, which hypothetically might have caused death, if it were 
more severe), 

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 
requires patient hospitalization or prolongation of existing hospitalization,  
 
results in persistent or significant disability/incapacity,  
 
is a congenital anomaly/birth defect, or 
 
is a medically important event or reaction. 
Medical and scientific judgment should be exercised when deciding if other situations are 
serious. Such instances could include medical events that may not be immediately life-
threatening or result in death or hospitalization, but which may jeopardize the patient or 
may require intervention to prevent one of the outcomes listed in the definition above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias, or convulsions not resulting in hospitalization, 
or development of drug dependency or drug abuse. 
The expedited reporting period for this study comprises the entire study period for each 
individual participant (from study enrolment until study completion or discontinuation 
from the study).  
The study products for which expedited reporting are required are:  
 
VRC01, and  
 
Control.  
The NIAID/DAIDS will report all unexpected SAEs related to the study products 
observed in this clinical trial to the FDA in accordance with 21 CFR 312.32 (IND Safety 
Reports). However, because safety is a primary study endpoint, the Sponsor Medical 
Officer will not be unblinded to study treatment assignment when there is an assessment 
of relatedness of the SAE with the study product(s); and the safety report will be sent to 
the FDA based on the blinded attribution assessment. 
If the PSRT believes unblinding of the site PI to treatment assignment will assist with the 
clinical management of the SAE, the PSRT may consult the independent NIAID DSMB 
for a recommendation. In the event the PSRT and/or the NIAID DSMB determines that 
unblinding is indicated, the unblinded statistician, DSMB Chair, or designee will inform 
the site physician of the participant’s treatment assignment in such a manner as to 
maintain the study blind of the PSRT and study team. For additional impact and 
management of SAEs on the study, refer to Section 10.3. 
10.2.4 
Expedited reporting of AEs to pertinent national regulatory authorities  
The study sponsor or designee(s) prepares and files expedited reports to appropriate 
regulatory authorities within the timelines required by pertinent national regulatory 
authorities.  
Site IoRs/designees will submit AE information and any other relevant safety information 
to their ECs/IRBs in accordance with EC/IRB requirements. 

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10.3 
Safety pause and prompt PSRT AE review 
When a trial is placed on safety pause, all enrollment and infusion 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 704/HPTN 085 PSRT AE review are 
summarized in Table 10-1. Infusions 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 704/HPTN 085 PSRT, participant safety may be threatened. Criteria for an 
individual participant’s departure from the schedule of infusions are listed in Section 5.3. 
Table 10-1 AE notification and safety pause/AE review rules 
Event and 
relationship to study 
products 
Severity 
CRS actiona 
HVTN Coreb action 
SAE, related 
Grade 4 
or 5 
Phone immediately, email 
and submit forms 
immediately 
Immediate pause 
SAE, not related 
Grade 5 
Phone immediately, email 
and submit forms 
immediately 
Immediate HVTN 704/HPTN 
085 PSRT notification 
SAE, related 
Grade 3 
E-mail and submit forms 
immediately 
Prompt HVTN 704/HPTN 
085 PSRT AE review to 
consider pause 
AEc, related 
Grade 4 
or 3 
Email and submit forms 
immediately 
Prompt HVTN 704/HPTN 
085 PSRT AE review to 
consider pause 
a Phone numbers and email addresses are found on the Protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/hvtn704/HPTN085). 
b HVTN CSS or HVTN Core designee 
c Does not include subjective reactogenicity symptoms (injection site pain, tenderness, fatigue/malaise, myalgia, arthralgia, chills, headache, 
nausea). 
For all safety pauses, HVTN Core notifies the HVTN 704/HPTN 085 PSRT, HVTN 
Regulatory Affairs, DAIDS Pharmaceutical Affairs Branch (PAB), DAIDS Regulatory 
Affairs Branch (RAB), DAIDS Safety and Pharmacovigilance Team (SPT), and 
participating HVTN and HPTN CRSs. When an immediate safety pause is triggered, 
HVTN Core notifies the NIAID DSMB.  
Once a trial is paused, the HVTN 704/HPTN 085 PSRT reviews safety data and decides 
whether the pause can be lifted or permanent discontinuation of infusions is appropriate, 
consulting the NIAID DSMB if necessary. HVTN Core notifies the participating HVTN 
and HPTN CRSs, HVTN Regulatory Affairs, DAIDS PAB, DAIDS RAB, and DAIDS 
SPT of the decision regarding resumption or discontinuation of study infusions. Based on 
the HVTN 704/HPTN 085 PSRT assessment, DAIDS RAB notifies the FDA as needed. 
If an immediate HVTN 704/HPTN 085 PSRT notification or prompt HVTN 704/HPTN 
085 PSRT AE review is triggered, HVTN Core notifies the HVTN 704/HPTN 085 PSRT 
as soon as possible during working hours (US Pacific Time)—or, if the information was 
received during off hours, by the morning of the next work day. If a prompt HVTN 
704/HPTN 085 PSRT AE review cannot be completed within 72 hours of notification 
(excluding weekends and US federal holidays), an automatic safety pause occurs. 

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The HVTN and HPTN require that each CRS submit to its IRB/EC and an applicable RE 
protocol-related safety information (such as IND safety reports, notification of study 
product holds due to the pause rules, and notification of other unplanned safety pauses). 
CRSs must also follow all applicable RE reporting requirements. 
In addition, all other AEs are reviewed routinely by the HVTN 704/HPTN 085 PSRT 
(see Section 10.4.2). 
10.4 
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 CRSs. Events are tracked 
by internal reports until resolution.  
10.4.1 
Daily review 
Blinded daily safety reviews are routinely conducted by HVTN Core for events requiring 
expedited reporting to DAIDS, and events that meet safety pause criteria or prompt 
HVTN 704/HPTN 085 PSRT AE review criteria. 
10.4.2 
Twice monthly review 
During the infusion phase of the trial, the HVTN 704/HPTN 085 PSRT reviews clinical 
safety reports twice each month and conducts calls to review the data as appropriate. 
After the infusions and the final postinfusion safety visits are completed, less frequent 
reporting and safety reviews may be conducted at the discretion of the HVTN 704/HPTN 
085 PSRT. The HVTN CSS or HVTN Core designee reviews reports of clinical and 
laboratory AEs. Events identified during the review that are considered questionable, 
inconsistent, or unexplained are referred to the CRS clinic coordinator for verification. 
10.4.3 
DSMB review of cumulative safety data 
The DSMB will periodically review accumulating safety data. Prior to each such review, 
the SDMC will provide the DSMB with data as described in Section 4.9.1. Reports will 
be cumulative, generated from an up-to-date data file. Reports will show the data coded 
by treatment group; however, upon request of the DSMB, the SDMC will provide the 
Board with the actual treatment group.  
10.5 
Study termination 
This study may be terminated early by NIAID upon recommendation by the DSMB, a 
pertinent national regulatory authority, Office for Human Research Protections (OHRP), 
or study product developer. In addition, the conduct of this study at an individual CRS 
may be terminated by the determination of the IRB/EC and any applicable RE. 

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10.6 
Social impact reporting 
It is possible that participants’ involvement in the study could result in social impacts. 
For example, a participant’s involvement in the study could become known to others, and 
a social harm may result (ie, because participants could be perceived as being HIV 
infected or at “high risk” for HIV infection). Participants could be treated unfairly, or 
could have problems being accepted by their families and/or communities. Alternatively, 
a social benefit may result (eg, a participant could feel good helping others). 
Social harms are negative social impact events and social benefits are positive social 
impact events that a participant reports as affecting them as a result of being involved in a 
research study. It is not the researcher’s opinion of how they perceive an event has 
affected a participant. Social impacts will be collected and reported on CRFs during 
scheduled visits (see Appendix J through Appendix M). A social harm that is reported by 
the participant and judged by the IoR/designee to be serious or unexpected will be 
reported to the responsible site’s IRB at least annually, or according to their individual 
requirements. In the event that a participant reports a social harm, every effort will be 
made by study staff to provide appropriate care and counseling to the participant as 
necessary, and/or referral to appropriate resources for the safety of the participant. While 
maintaining participant confidentiality, study sites may engage their Community 
Advisory Board (CAB) in exploring the social context surrounding instances of social 
harms to minimize the potential occurrence of such an impact. 

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11 
Protocol conduct 
This protocol and all actions and activities connected with it will be conducted in 
compliance with Good Clinical Practice (GCP) (ICHe6), the HVTN and HPTN network-
specific Manuals of Operations, and DAIDS Clinical Research Policies and Standard 
Procedures Documents, including procedures for the following: 
 
Protocol registration, activation, and implementation; 
 
Informed consent, screening, and enrollment; 
 
Study participant reimbursement; 
 
Clinical and safety assessments; 
 
Safety monitoring and reporting; 
 
Data collection, documentation, transfer, and storage; 
 
Participant confidentiality; 
 
Study follow-up and close-out; 
 
Unblinding of staff and participants; 
 
Quality control; 
 
Protocol monitoring and compliance; 
 
Advocacy and assistance to participants regarding negative social impacts associated 
with the trial; 
 
Risk reduction counseling;  
 
Specimen collection, processing, and analysis;  
 
Ancillary studies, and 
 
Destruction of specimens. 
Any policies or procedures that vary from DAIDS, HVTN, or HPTN standards or require 
additional instructions (eg, instructions for randomization specific to this study) will be 
described in the SSP.  

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11.1 
Emergency communication with study participants 
As in all clinical research, this study may generate a need to reach participants quickly to 
avoid imminent harm, or to report study findings that may otherwise concern their health 
or welfare.  
When such communication is needed, the CRS will request that its IRB/EC and any 
applicable RE expedite review of the message. If this review cannot be completed in a 
timeframe consistent with the urgency of the required communication, the site should 
contact the participant first, and then notify the IRB/EC and any applicable RE of the 
matter as soon as possible. 

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12 
Ethical considerations 
It is critical that universally accepted ethical guidelines are followed at all sites involved 
in the conduct of clinical trials. The HVTN and HPTN (hereafter, referred to as the 
“Networks”) have addressed ethical concerns in the following ways: 
 
Network trials are designed and conducted to enhance the knowledge base necessary 
to find new methods for preventing HIV infection, using methods that are 
scientifically rigorous and valid, and in accordance with GCP guidelines. 
 
Network scientists and operational staff incorporate the philosophies underlying 
major codes [139-141], declarations, and other guidance documents relevant to 
human subjects research into the design and conduct of HIV prevention clinical trials. 
 
Network 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. CABs 
are required by DAIDS and supported at all Network research sites to ensure 
community input, in accordance with Good Participatory Practices (GPP) and all 
local and national guidelines [142].  
 
Network 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. 
 
The Networks require that all international Network sites lacking national plans for 
providing ART develop plans for the care and treatment of participants who acquire 
HIV infection during a trial. Each plan is developed in consultation with 
representatives of host countries, communities from which potential trial participants 
will be drawn, sponsors, and the Networks. Participants will be referred to programs 
for ART provision when the appropriate criteria for starting ART are met. If a 
program 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 Networks agree that appropriate referrals for access to PrEP and PEP should be 
provided according to national and/or local guidelines. 
 
The Networks provide 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, Network trials are rigorously reviewed by scientists who are 
not involved in the conduct of the trials under consideration.  
 
Network trials are reviewed by local and national regulatory bodies and are 
conducted in compliance with all applicable national and local regulations. 

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 
The Networks design their research to minimize risk and maximize benefit to both 
study participants and their local communities. For example, Network 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. Network protocols also include careful medical review of each 
research participant’s health conditions and reactions to study products while in the 
study.  
 
Network 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 Network trials are able to conduct other critical research in 
their local research settings. 
 
The Networks recognize the importance of institutional review and values the role of 
in country IRBs, ECs, and any applicable REs as custodians responsible for ensuring 
the ethical conduct of research in each setting. 

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13 
IRB/EC/RE review considerations 
US Food and Drug Administration (FDA) and other US federal regulations require 
IRBs/ECs 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 Network Investigator welcomes IRB/EC and any 
applicable RE questions or concerns regarding these research requirements. 
This trial is being conducted in North America, South America, and Switzerland with 
funding from the US NIH. Due to this, the trial is subject to both US and local regulations 
and guidelines on the protection of human research subjects and ethical research conduct. 
Where there is a conflict in regulations or guidelines, the regulation or guideline 
providing the maximum protection of human research subjects will be followed. 
In compliance with international and local (as appropriate) GCP, each research location 
has a locally based Principal Investigator (PI) who is qualified to conduct (and supervise 
the conduct of) the research; and the research addresses an important local health need for 
an HIV prevention method. In addition, the investigators take responsibility for the 
conduct of the study and the control of the study products, including obtaining all 
appropriate regulatory and ethical reviews of the research. Each participating site has a 
standard operating procedure for ensuring that participants have the necessary 
information to make a decision whether or not to consent to the research.  
The sections below address each of the review concerns by IRBs/ECs and any applicable 
REs regarding how the research will be conducted. 
13.1 
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 following study product administration and 
collecting information regarding side effects for several days following study product 
administration; (d) having staff properly trained in administering study procedures that 
may cause physical harm or psychological distress, such as blood draws, study product 
infusions, HIV testing and counseling and HIV risk reduction counseling; (e) providing 
HIV risk reduction counseling and checking on contraception use (for participants 
capable of becoming pregnant); and (f) providing safety monitoring. 

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13.2 
Reasonable risk/benefit balance 
45 CFR 46.111(a) 2 and 21 CFR 56.111(a) 2: Risks to subjects are reasonable in 
relation to anticipated benefits, if any, to subjects, and the importance of the 
knowledge that may reasonably be expected to result. 
In all public health research, the risk-benefit ratio may be difficult to assess because the 
benefits to a healthy participant are not as apparent as they would be in treatment 
protocols, where a study participant may be ill and may have exhausted all conventional 
treatment options. However, this protocol is designed to minimize the risks to participants 
while maximizing the potential value of the knowledge it is designed to generate.  
13.3 
Equitable subject 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. 
13.4 
Appropriate informed consent 
45 CFR 46.111 (a) 4 & 5 and 21 CFR 56.111 (a) 4 & 5: Informed consent is sought 
from each prospective subject or the subject’s legally authorized representative as 
required by 45 CFR 46.116 and 21 CFR Part 50; informed consent is appropriately 
documented as required by 45 CFR 46.117 and 21 CFR 50.27 
The protocol specifies that informed consent must be obtained before any study 
procedures are initiated and assessed throughout the trial (see Section 7.1). Each site is 
provided training in informed consent by the Networks as part of its entering the 
respective Network. The Networks require a signed consent document for documentation, 
in addition to chart notes or a consent checklist. 
13.5 
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 (Section 10). Safety is monitored 
daily by the HVTN CSS or HVTN Core designee and routinely by the HVTN 704/HPTN 
085 PSRT. In addition, a DSMB periodically reviews study data. 

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13.6 
Protect privacy/confidentiality 
45 CFR 46.111 (a) 7 and 21 CFR 56.111 (a) 7: There are adequate provisions to 
protect the privacy of subjects and maintain the confidentiality of data. 
Privacy refers to an individual’s right to be free from unauthorized or unreasonable 
intrusion into his/her private life and the right to control access to individually 
identifiable information about him/her. The term “privacy” concerns research participants 
or potential research participants as individuals whereas the term “confidentiality” is used 
to refer to the treatment of information about those individuals. This protocol respects the 
privacy of participants by informing them about who will have access to their personal 
information and study data (see Appendix A). 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 Network protocols are protected 
by a Certificate of Confidentiality from the US NIH, which can prevent disclosure of 
study participation even when that information is requested by subpoena. Participants are 
told of the use and limits of the certificate in the study consent form. In addition, each 
staff member at each study site in this protocol signs an Agreement on Confidentiality 
and Use of Data/Specimens with the Networks and each study site participating in the 
protocol is required to have a standard operating procedure on how the staff members 
will protect the confidentiality of study participants. 

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14 
Version history 
The Protocol Team may modify the original version of the protocol. Modifications are 
made to Network protocols via clarification memos, letters of amendment, or full 
protocol amendments.  
The version history of, and modifications to, Protocol HVTN 704/HPTN 085 are 
described below. 
Protocol history and modifications 
Date: June 15, 2017 
Protocol version: Version 3.0 
Protocol modification: Full Protocol Amendment 2 
Item 1 
Revised: Study duration and participant follow-up 
Item 2 
Updated in Section 1.1: Protocol team membership 
Item 3 
Updated in Sections 2.9, 2.9.3, 2.9.4, and Appendix A: VRC01 clinical 
experience in HVTN 104 
Item 4 
Revised in Section 4.9.3: Monitoring for futility to assess PE 
Item 5 
Clarified in Section 5.1,  Inclusion criteria: Transgender volunteer 
eligibility 
Item 6 
Added in Section 5.1, Inclusion criteria: Hgb criterion adjustment for MTF 
transgender volunteers using feminizing hormones 
Item 7 
Clarified in Section 5.2, Exclusion criteria: Tissue or organ transplantation 
exclusion criterion 
Item 8 
Updated in Section 6.2, Study product formulation: VRC01 description and 
storage temperature 
Item 9 
Revised in Sections 6.3 and 6.4: Holding times for study products after 
preparation 
Item 10 Updated in Section 6.4 and Appendix A: Minimum infusion time 
Item 11 Added in Section 6.4, Administration: In-line filter set requirement 
Item 12 Clarified in Section 6.4, Administration: IV bag temperature equilibration 
and label weight 
Item 13 Clarified in Section 7.3, Enrollment and infusion visits: Timing of HIV 
infection assessment and HIV testing 
Item 14 Updated in Section 7.10, Assessments of reactogenicity, and Section 10.2.2, 
AE reporting: DAIDS AE grading table version and exceptions 
Item 15 Updated in Section 10.2, Safety reporting: URLs for referenced documents 
Item 16 Clarified in Section 10.2.2, AE reporting: Working hours for CSS or RML 
response 
Item 17 Updated in Section 10.2.3: Expedited reporting of adverse events to DAIDS 

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Item 18 Updated in Section 14: Version history 
Item 19 Updated in Section 15, Document references (other than literature 
citations): Documents and URLs 
Item 20 Corrected in Section 16: Acronyms and abbreviations 
Item 21 Corrected in Appendix A, Sample informed consent form: Blood draw 
volumes 
Item 22 Clarified in Appendix A, Sample informed consent form: Early termination 
Item 23 Added in Appendix B, Approved birth control methods for transgender 
men (for sample informed consent form): Condom use and pregnancy 
testing 
Item 24 Corrected in Appendix D, Tables of procedures (for sample informed 
consent form): Procedure timepoints 
Item 25 Updated in Appendices F through I: Assay locations, HVTN laboratory 
listings, and blood draw totals 
Item 26 Revised in Appendices G, H, K, and L: Table format and Schedule 3 blood 
draws at Visit #.X 
Item 27 Removed in Appendices G and H: Footnote regarding whole blood for HIV 
diagnostics 
Item 28 Clarified in Appendices J and M: Provision of HIV test results 
Item 29 Added as Appendix N: Protocol signature page 
Item 30 Revised in Letter of Amendment 1 to Version 2.0: Interim safety and 
feasibility assessments 
Item 31 Corrected: Minor typographical, grammatical, and formatting errors 
 
Date: December 14, 2016 
Protocol version: Version 2.0 
Protocol modification: Letter of Amendment 1 
Item 1 
Revised in Section 1, Overview and Section 4.9.1, Role of the Data Safety 
Monitoring Board (DSMB): Interim safety assessments 
Item 2 
Revised in Section 2.4.5, Trial monitoring: Feasibility assessment 
Date: July 19, 2016 
Protocol version: Version 2.0 
Protocol modification: Full Protocol Amendment 1 
Item 1 
Corrected in Section 1, Overview: Estimated total study duration 
Item 2 
Added: Switzerland as study location 
Item 3 
Added in Section 1 and Appendices F through I: HIV diagnostic laboratories in 
Peru and Brazil 
Item 4 
Updated in Section 1.1: Protocol team membership 
Item 5 
Revised: PrEP monitoring 

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Item 6 
Removed in Section 2.9.3, HVTN 104: Incorrect systemic reactogenicity rate 
Item 7 
Clarified in Sections 4.9.1 and 10.4.3: Data reporting to DSMB 
Item 8 
Clarified in Section 4.9.1.1, Sequential monitoring for potential harm, non-
efficacy, and high efficacy: Caption to Figure 4-6 
Item 9 
Added in Section 5.1, Inclusion criteria: Reference to SSP for clarification of 
transgender eligibility 
Item 10 
Clarified in Section 5.2, Exclusion criteria: PSRT may permit exceptions to 
Exclusion criterion #4 
Item 11 
Clarified in Section 6, Study product preparation and administration: 
Administration volumes, bag covers, and expiration prompts 
Item 12 
Removed in Section 7.2, Pre-enrollment procedures: Required recording of 
generic names for concomitant medications 
Item 13 
Clarified in Section 7.3, Enrollment and infusion visits and Section 7.10, 
Assessment of reactogenicity: Recording and source documentation for 
reactogenicity events 
Item 14 
Clarified in Section 7.3, Enrollment and infusion visits, and Appendices D, F, and 
J: STI testing 
Item 15 
Clarified in Section 7.9, Urine testing: Follow-up to abnormal urine dipstick result 
at screening 
Item 16 
Clarified in Appendix A, Sample informed consent form: VRC01 not being 
developed for sale 
Item 17 
Added in Appendix A, Sample informed consent form: Option to include consent 
for HIV-infected study participants 
Item 18 
Renumbered in Appendix A: Section 19, “If you stop getting IVs for reasons other 
than HIV infection…” 
Item 19 
Added in Appendix D: Procedure tables for HIV-infected participants and for 
participants whose infusions have been stopped for reasons other than HIV 
infection 
Item 20 
Clarified in Appendix E, Sample consent form for participants with HIV infection 
at enrollment or during the study: Number of visits, physical exams, and HIV 
transmission risk counseling 
Item 21 
Throughout protocol document: Minor errors corrected 
Item 22 
Updated: Section 14, Version history 
Date: March 9, 2016 
Protocol version: 
1.0 
Protocol modification: Original protocol 
 

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15 
Document references (other than literature 
citations) 
Other documents referred to in this protocol, and containing information relevant to the 
conduct of this study, include: 
 
Assessment of Understanding. Accessible through the HVTN protocol-specific 
website. 
 
Current CDC Guidelines. Revised Recommendations for HIV Testing of Adults, 
Adolescents, and Pregnant Women in Health-Care Settings. Available at 
http://www.cdc.gov/mmwr/PDF/rr/rr5514.pdf   
 
Division of AIDS (DAIDS) Clinical Research Policies and Standard Procedures 
Documents. Available at https://www.niaid.nih.gov/research/daids-clinical-research-
policies-standard-procedures  
 
Division of AIDS Protocol Registration Manual. Available at 
https://www.niaid.nih.gov/sites/default/files/prmanual.pdf  
 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events. Version 2.1, dated March 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 704/HPTN 085 Special Instructions. Accessible through the HVTN protocol-
specific website. 
 
HVTN 704/HPTN 085 Study Specific Procedures. Accessible through the HVTN 
protocol-specific website. 
 
HVTN Manual of Operations. Accessible through the HVTN website. 
 
Dangerous Goods Regulations (updated annually), International Air Transport 
Association. Available for purchase at 
http://www.iata.org/publications/dgr/Pages/index.aspx  
 
HVTN Lab Assay Algorithm (available upon request) 
 
International Conference on Harmonisation (ICH) E6 (R1), Guideline for Good 
Clinical Practice: Section 4.8, Informed consent of trial subjects. Available at 
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html 

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 
HVTN 704/HPTN 085 Participants’ Bill of Rights and Responsibilities. Accessible 
through the HVTN website. 
 
NIH Policy on Reporting Race and Ethnicity Data: Subjects in Clinical Research. 
Available at http://grants1.nih.gov/grants/guide/notice-files/NOT-OD-01-053.html 
 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks, July 
2008. 
 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials. Available at  
https://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/Pages/ClinicalS
ite.aspx  
 
Title 21, Code of Federal Regulations, Part 50. Available at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=5
0 
 
Title 45, Code of Federal Regulations, Part 46. Available at 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html 
See Section 17 for literature cited in the background and statistics sections of this 
protocol. 

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16 
Acronyms and abbreviations 
ACASI 
audio computer assisted self-interview 
ADCC 
antibody-dependent cellular cytotoxicity 
ADCP 
antibody-dependent cellular phagocytosis 
ADCVI 
antibody-dependent cellular viral inhibition 
AIA 
anti-idiotypic antibody 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ART 
antiretroviral therapy 
ARV 
antiretroviral (drug) 
AST 
aspartate aminotransferase 
bnAb 
broadly neutralizing antibody 
CAB 
Community Advisory Board 
CBC 
complete blood count 
CDC 
US Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary 
CI 
confidence intervals 
CRF 
case report form 
CRPMC 
(NIAID) Clinical Research Products Management Center 
CRS* 
clinical research site 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS (US NIH) 
DHHS 
US Department of Health and Human Services 
DSMB 
(NIAID) Data and Safety Monitoring Board 
EAE 
adverse events requiring expedited reporting to DAIDS 
EC 
Ethics Committee 
EIA 
enzyme immunoassay 
ELISA 
enzyme-linked immunosorbent assay 
FcRn 
neonatal Fc receptor 
FDA 
US Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 
FTC 
emtricitabine 
GC 
gonorrhea 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
Hgb 
hemoglobin 
 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 

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HPTN 
HIV Prevention Trials Network 
HVTN 
HIV Vaccine Trials Network 
IB 
Investigator’s Brochure 
IC50 
inhibitory concentration (50%) 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
IgG 
immunoglobulin G 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
IV 
intravenous 
LANL 
Los Alamos National Laboratory 
LC 
Laboratory Center 
LOC 
Leadership and Operations Center 
mAb 
monoclonal antibody 
MITT 
modified intent-to-treat 
MSM 
men who have sex with men 
NHP 
nonhuman primate 
NIAID 
National Institute of Allergy and Infectious Diseases (US NIH) 
NICD 
National Institute for Communicable Diseases (Johannesburg, South Africa) 
NIH 
US National Institutes of Health 
NVITAL 
NIAID Vaccine Immune T-Cell Antibody Laboratory 
OC 
Oversight Committee 
PBMC 
peripheral blood mononuclear cell 
PE 
prevention efficacy 
PEP 
postexposure prophylaxis 
PI 
Principal Investigator 
PK 
pharmacokinetic 
PMTCT 
prevention of mother-to-child (HIV) transmission 
PrEP 
pre-exposure prophylaxis 
PSRT 
Protocol Safety Review Team 
PYR 
person year  
RAB 
DAIDS Regulatory Affairs Branch 
RE 
regulatory entity 
RSC 
(DAIDS) Regulatory Support Center 
RSV 
respiratory syncytial virus 
SAE 
serious adverse event 
SC 
subcutaneous  
SCHARP Statistical Center for HIV/AIDS Research and Prevention 
SDMC 
statistical and data management center 
SHIV 
simian-human immunodeficiency virus 
SPT 
DAIDS Safety and Pharmacovigilance Team 
SSP 
study specific procedures 

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STI 
sexually transmitted infection 
TasP 
treatment as prevention 
TCID50 
tissue culture infectious dose (50%) 
TDF 
tenofovir disoproxil fumarate 
TFV 
tenofovir 
TG 
transgender 
tMLE 
targeted maximum likelihood estimation 
USP 
United States Pharmacopeia 
UW-VSL University of Washington Virology Specialty Laboratory 
VRC 
Vaccine Research Center (NIAID) 
VRP 
Vaccine Research Program 
WHO 
World Health Organization 
* CRSs were formerly referred to as HIV Vaccine Trial Units (HVTUs). Conversion to 
use of the term CRS is in process, and some HVTN documents may still refer to HVTUs. 

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17 
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Appendix A 
Sample informed consent form 
Title: A phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing 
monoclonal antibody in reducing acquisition of HIV-1 infection among men and 
transgender persons who have sex with men 
Protocol number: HVTN 704/HPTN 085, The AMP Study 
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), the HIV Prevention Trials Network (HPTN), 
and [Insert site name] are doing a study to test the antibody called VRC01 against HIV. 
HIV is the virus that causes AIDS. Antibodies are one of the natural ways the body fights 
infection. Researchers can also make antibodies in laboratories and give them to people 
intravenously (with an IV). We will tell you more about this procedure below. This has 
been done successfully to prevent or treat some other health problems, such as a virus 
that causes respiratory infections in infants. 
About 2700 people will take part in this study at multiple sites in North America, South 
America, and Switzerland. 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.  
In addition, a similar study will be done with 1500 women in sub-Saharan Africa. 
1. We are doing this study to answer several questions. 
 
Is the antibody safe to give to people? 
 
Are people able to take the antibody without becoming too uncomfortable? 
 
Does the antibody lower people’s chances of getting infected with HIV? 
 
If the antibody does lower people’s chances of getting infected with HIV, how much 
of it is needed to provide protection from HIV? 
2. The antibody cannot give you HIV. 
It is impossible for the antibody to give you HIV. Also, it cannot cause you to give HIV 
to someone else. However, we do not know if the antibody will decrease, increase, or not 
change your chance of becoming infected with HIV if you are exposed to the virus. 

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3. The antibody is experimental. 
The antibody being tested is called VRC-HIVMAB060-00-AB. It is an antibody against 
the HIV virus. From here on, we will call it VRC01 or the antibody. It is an experimental 
product. That means we do not know whether the antibody will be safe to use in people, 
or whether it will work to prevent HIV infection. This antibody is used only in research 
studies. 
VRC01 was developed by the Vaccine Research Center at the US National Institutes of 
Health (NIH).  
In laboratory and animal studies, VRC01 attached to and prevented infection by many 
strains of HIV viruses from around the world. We do not know if antibodies can prevent 
HIV infection when they are given to people. This study is designed to help us answer 
that question. At this time there are no plans to make VRC01 for sale. 
Risks of VRC01 antibody: 
As of April 2017, VRC01 has been given to people in 12 clinical studies in the United 
States, Peru, Brazil, Switzerland, and in sub-Saharan Africa. In these studies, more than 
1800 adults and 33 infants have gotten VRC01 or a placebo (a liquid with no antibody in 
it).  
Many of these studies are still going on and we don’t know which people got VRC01 and 
which got a placebo. In early trials, more than 100 people got VRC01 and it did not make 
them too uncomfortable or cause serious health problems. After receiving the antibody, 
most people said that they had mild pain, itching, or redness where the antibody was 
given to them. Of these people, some said they felt like they had the flu after getting the 
antibody, but that this feeling lasted a few hours at most. 
In a previous study, one person who got a VRC01 injection had a rash. One person had a 
brief fainting spell several hours after getting a VRC01 infusion.To be safe, no more 
injections or infusions were given to these people. Some participants had mild body 
discomfort, muscle pain, or joint pain after getting the VRC01 antibody.  
VRC01 may have other side effects that we do not know about yet. 
General risks of antibodies: 
Antibodies that are different from VRC01 have been given to people for other illnesses. 
With those antibodies most side effects happen within the first 24 hours. Those antibodies 
have caused fever, chills, shaking, nausea, vomiting, pain, headache, dizziness, trouble 
breathing, high or low blood pressure, itchiness, rash, hives, lip or face swelling, diarrhea, 
racing heartbeat or chest pain.  
Rarely, some antibodies have caused serious reactions. These reactions may be life-
threatening. Please tell us if you have ever had any of the following reactions. 
 
One type of serious reaction, called anaphylaxis, may occur soon after getting an 
antibody. It includes difficulty breathing possibly leading to low blood oxygen, low 
blood pressure, hives or rash, and swelling in the mouth and face.  

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 
A second type of serious reaction, called serum sickness, may occur several days to 3 
weeks after getting an antibody. It includes hives or a rash, fever, big lymph nodes, 
muscle and joint pains, chest discomfort and shortness of breath.  
Rarely, antibodies licensed for treatment of other diseases have been linked to a blood 
disorder that interferes with blood clotting, to cancer, to damage to the heart muscle, and 
to the body’s immune system attacking healthy cells. 
These rare side effects and reactions have not been seen in other studies with the VRC01 
antibody.  
When antibodies are given to a person by IV they do not last in the body more than a few 
months. Any antibody given to you in this study should be gone from your body several 
months after your last dose.  
Joining the study 
4. 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 some other kinds of HIV prevention 
studies now or in the future. You cannot be in this study while you are in another study 
where you get a study product. Also during the study, you should not donate blood or 
tissue. 
If you choose not to join this study, you may be able to join another study. 
Site: Remove item 5 if you use a separate screening consent that covers these procedures. 
5. 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) 
 
Checking your veins to see how easy it might be to start an IV  
We will also do blood and urine tests. These tests tell us about some aspects of your 
health, such as how healthy your kidneys, liver, and immune system are. We will also ask 
you about medications you are taking. We will ask you about behaviors that might put 

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you at risk for getting HIV. If you could become pregnant, we will test you for 
pregnancy. If you have had your uterus or ovaries removed (a hysterectomy or 
oophorectomy), verified by medical records, you are not required to have a pregnancy 
test. 
We will review the screening results with you. The screening results may show you are 
not eligible to join the study, even if you want to.  
(Sites: adapt the following section so it is applicable to the care available at your site) 
6. If we find that you have a health problem during screening or during the study, we 
will tell you about the care that we can give here for free.  
 
For the care that we cannot give, we will explain how we will help you get care 
elsewhere. 
For health problems that are unrelated to the study, we will not pay for care.  
7. If you 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 transgender 
men (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 
antibody could affect the developing baby. You must agree to use effective birth control 
from 21 days before you first receive the antibody until your last scheduled clinic visit 
(about 1¾ years after your first IV). 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: 
8. You will come to the clinic for scheduled visits about [#] times over about 2 years. 
The study will require [#] visits. That is aabout 1 visit every month for about the first 1½ 
years and then about every 2 months after that. You may have to come for more visits if 
you have a lab or health issue. 
Visits can last from about [#] minutes to [#] hours. The IV procedure can take about 15 
minutes to an hour.  
We may contact you after the main study ends (for example, to tell you about the study 
results). 
9. 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 participants capable of 
becoming pregnant). 
Following paragraph for US sites only: 
 
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. 
10. We will give you either the antibody or a placebo.  
Not everyone in this study will get the VRC01 antibody. Some people will get a placebo, 
a liquid that does not contain any antibody. We will compare the results from people who 
got the placebo with results from people who got the VRC01 antibody. In this study, the 
placebo is sterile salt water, which is found naturally in the body. 
There are three groups in this study. One group will get a lower dose of the VRC01 
antibody, one group will get a higher dose, and one group will get the placebo. The high 
and low doses of the antibody will be adjusted for your body weight. We will weigh you 
to determine the amount you will get. 
Overall, if you join this study, you have a 2-in-3 chance of getting the study antibody.  
Site: Modify the randomization metaphor in the next sentence as appropriate to your 
local culture. 
Whether you get the low dose of the antibody, the high dose of the antibody, or the 
placebo is completely random, like flipping a coin. 
We have no say in whether you get the antibody or the placebo. If you get the antibody, 
we have no say in which dose you get. We will not know what you are getting, and 
neither will you. Only the pharmacist at this clinic will have this information while the 
study is going on.  
You will have to wait until everyone completes their final study visits to find out whether 
you got the antibody or the placebo. This could be up to about 5 years. But, if you have a 
serious medical problem and need to know what you got before the end of the study, we 
can tell you. 
If it is found to be effective, there are no plans to give the antibody to participants after 
the study. Instead, we will use what is learned in this study to determine if the antibody 
would be useful to prevent HIV, how the antibody could be improved, and how to 
produce it for wide public use. 
11. We will give you the antibody or placebo on a schedule. 
You will get the VRC01 antibody or the placebo during the study by IV. To get an IV, a 
needle is used to place a small plastic tube into a vein in your arm. The tube is connected 
to a small bag of fluid that contains the antibody or placebo. An IV pump controls how 

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fast the fluid drips from the bag, through the tube, and into your vein. There will be 10 IV 
procedures, one IV every 8 weeks. Other study visits will not include IVs.  
Infusion schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks after first IV 
Group 
Dose 
First 
IV 
Wk 
8 
Wk 
16 
Wk 
24 
Wk 
32 
Wk 
40 
Wk 
48 
Wk 
56 
Wk 
64 
Wk 
72 
Group  
1 
Lower dose 
VRC01 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Group  
2 
Higher dose 
VRC01 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Group  
3 
Placebo 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
You will have to wait in the clinic for about 30 minutes after the first IV to see if there 
are any problems. You probably will not have to wait after the IVs at the rest of the IV 
visits. After each IV visit, for that night and for three more days, you will be asked to 
keep track of how you feel. To help you do this, we can give you tools and show you how 
to use them. We will ask you the ways we can contact you. We will contact you about 3 
days after each IV visit to ask how you have been feeling. Contact the clinic staff if you 
have any concerns after getting an infusion. If you have a problem, we will continue to 
check on you until it goes away 
12. In addition to giving you the antibody or placebo, we will:  
 
Do regular HIV testing, as well as counseling on your results and on how to avoid 
getting HIV; 
 
Do physical exams; 
 
Do pregnancy tests if you could become pregnant;  
 
Ask questions about your health, including medications you may be taking; 
 
Ask questions about any personal problems or benefits you may have from being in 
the study; and 
 
Take urine and blood samples. 
When we take blood, the amount will depend on the lab tests we need to do. It will be 
some amount between 30 mL and 180 mL (6 teaspoons to ¾ cup). Your body will make 
new blood to replace the blood we take out.  
Site: You may want to add a sentence to the end of the previous paragraph 
contextualizing the blood volumes described (eg, “To compare, people who donate blood 
in the US can give a total of about 500 mL in an 8-week period.”). Modify the example 
for cultural relevance and alter blood volumes as necessary. 
6 months 
1 year 

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Site: Insert the first table in 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 do blood tests for syphilis and urine tests for gonorrhea and chlamydia. We will 
also test for gonorrhea and chlamydia using rectal swabs. We will do these tests at 4 
visits. We will also test for gonorrhea and chlamydia using mouth and throat swabs at 
your first infusion visit. We will explain what each of these infections is. If the tests show 
that you have an infection, we will provide counseling and will help you get treatment. 
This study cannot pay for that treatment. [Site: Revise preceding sentence if you provide 
or pay for STI treatment.] 
We will review the results of the procedures and tests with you at your next visit, or 
sooner if necessary. If any of the results are important to your health, we will tell you.  
13. We will test your samples for this study. 
We will send your samples (without your name) to labs approved by the HVTN and the 
HPTN for this study. These labs are located in the United States, South America, and 
South Africa. The samples will be tested to: 
 
measure how much antibody is in your blood, 
 
see how your immune system responds to the antibody, and  
 
see if there is antiretroviral medicine (also called ART/ARV) in your blood. 
Researchers may also do genetic testing related to this study on your samples. Your genes 
are passed to you from your birth parents. They affect how you look and how your body 
works. The differences in people’s genes can help explain why some people get a disease 
while others do not. These types of genetic tests involve only some of your genes, not all 
of your genes (your genome). The researchers will study the genes related to the immune 
system and HIV and those that affect how people get HIV.  
If you become HIV infected, the researchers may look at all of the genes of the virus 
found in your samples. The researchers will use this information to learn more about HIV 
and the antibody.  
In some cases, researchers may take cells from your samples and grow more of them over 
time, so that they can continue to contribute to this study.  
Tests done on your samples are for research purposes only. The labs will not give the 
results to you or this clinic, and the results will not become part of your study record. 
When your samples are no longer needed for this study, the HVTN will continue to store 
them.  
Site: Delete next section if using separate consent for use of samples and information in 
other studies 

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14. When samples are no longer needed for this study, the study sponsors want to keep 
them for use in other studies by HVTN, HPTN, or other researchers. We will call 
these “extra samples.” 
This section gives you information so you can decide if you want your extra samples and 
information used in other studies. You will mark your decision at the end of the form. If 
you have any questions, please ask.  
Do I have to agree? No. You are free to say yes or no, or to change your mind after you 
sign this form. At your request, we will destroy all extra samples that we have. Your 
decision will not affect your being in this study or have any negative consequences here.  
Where are the samples stored? Extra samples are stored in a secure central place called a 
repository. Your samples will be stored in the HVTN repository in the United States.  
How long will the samples be stored? There is no limit on how long your extra samples 
will be stored. [Site: insert limits if your regulatory authority imposes them.] 
Will I be paid for the use of my samples? No. Also, a researcher may make a new 
scientific discovery or product based on the use of your samples. If this happens, there is 
no plan to share any money with you. The researcher is not likely to ever know who you 
are. 
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 needed for your medical care. They are not part of your medical record. The studies 
are only being done for research purposes. 
Will the HVTN or HPTN sell my samples and information? No, but the HVTN and HPTN 
may share your samples with other researchers. Once we share your samples and 
information, we will not be able to get them back. 
How do other researchers get my samples and information? When a researcher wants to 
use your samples and/or information, their research plan must be approved by the HVTN 
and HPTN. 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 and HPTN will send your 
samples to the researcher’s location.  
What information is shared with other researchers? The samples and limited information 
will be labeled with a code number. Your name will not be part of the information. 
However, some information that we share may be personal, such as your race, ethnicity, 
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.  
What kind of studies might be done with my extra samples and information? The studies 
will be related to HIV prevention or infection, the immune system, and other diseases.  
Researchers may also do genetic testing on your samples.  

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If you become HIV infected, the researchers may look at all of the genes of the virus 
found in your samples. The researchers will use this information to learn more about HIV 
and the study product(s).  
In some cases, researchers may take cells from your samples and grow more of them over 
time, so that they can continue to contribute to this study.  
If you agree, your samples could also be used for genome wide studies. In these studies, 
researchers will look at all of your genes (your genome). The researchers compare the 
genomes of many people, looking for common patterns of genes that could help them 
understand diseases. The researchers may put the information from the genome-wide 
studies into a protected database so that other researchers can access it. Usually, no one 
would be able to look at your genome and link it to you as a person. However, if another 
database exists that also has information on your genome and your name, someone might 
be able to compare the databases and identify you. If others found out, it could lead to 
discrimination or other problems. The risk of this is very small. 
 Who will have access to my information in studies using my extra samples?  
People who may see your information are: 
 
Researchers who use your stored samples and limited information for other research 
 
Government agencies that fund or monitor the research using your samples or 
information 
 
The researcher’s Institutional Review Board or Ethics Committee 
 
The people who work with the researcher  
All of these people will do their best to protect your information. The results of any new 
studies that use your extra samples or information may be published. No publication will 
use your name or identify you personally. 
15. We will counsel you on reducing your risk for HIV infection. 
We will ask you personal questions about your HIV risk factors such as sexual behavior 
and drug use. We will provide you with condoms and lubricant. We will talk with you 
about ways of lowering your risk of getting HIV. We will help you develop a risk 
reduction plan. Some topics we may discuss include: 
 
What you think causes risky behavior for you, and 
 
Ways to avoid getting HIV or giving it to someone else 
[Site: adjust the language in this paragraph about PrEP provision to meet local 
availability.] These methods may include not having sex, using condoms, or other 
behavior changes. We will talk about new methods of HIV prevention, including pre-
exposure prophylaxis (PrEP) with a drug called Truvada, and help you decide which of 
these methods is right for you.  

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[Site: The text in the next two paragraphs applies to US sites only. Sites should adjust the 
language in this paragraph to meet local PrEP availability.] Gilead Sciences, Inc. (the 
maker of Truvada) has agreed to provide Truvada as PrEP to study participants in HVTN 
704/HPTN 085 through a mail order pharmacy. If you are interested, we can give you 
more information about this program. We can refer you to health care providers who can 
prescribe PrEP either through the Gilead program or from a different source. 
If you accept the Gilead Sciences, Inc. offer to receive Truvada as PrEP during the study, 
the following study data will be shared with Gilead Sciences, Inc.: 
 
Your study ID code number 
 
Information such as your age, sex at birth, and gender  
 
Your past and present health conditions 
Truvada has been shown to substantially lower people’s risk of getting HIV when taken 
every day. The US FDA has approved it for use as PrEP in adults at risk of HIV infection 
through sexual contact. There are several considerations to talk about with your health 
care provider to see if PrEP is the right choice for you. If you decide to take Truvada 
PrEP, your health care provider will prescribe it for you and monitor your health while 
you use it. 
[Site: The text in the next two paragraphs applies to South American sites only. Sites 
should adjust the language in this paragraph to meet local PrEP availability.] Gilead 
Sciences, Inc. (the maker of Truvada) has agreed to provide Truvada as PrEP to study 
participants in HVTN 704/HPTN 085 through a local project. If you are interested, clinic 
staff can give you more information about this project and can refer you to it for PrEP.  
PrEP has been shown to lower people’s risk of getting HIV when taken once every day. 
There are several medical considerations to talk about with health care providers at the 
project to see if PrEP is the right choice for you. A provider at the project will prescribe 
PrEP for you and monitor your health while you use it. 
In this study, we will look at how many participants use PrEP. We will also try to find out 
if using PrEP has any effect on how VRC01 works. 
[Site: If you prefer to use Appendix E, Sample consent form for participants with HIV 
infection at enrollment or during the study, INCLUDE the following section and 
DELETE the two succeeding sections that are highlighted in green. If you prefer not to 
use Appendix E, DELETE the following section and INCLUDE the two sections 
highlighted in green.] 
16. If you are HIV infected when you enroll or become infected during the study, we 
will help you get care and support. 
We will test your blood for HIV before your first IV and during the study. Each time, it 
will take a few days to complete the tests. If you are infected with HIV, you cannot stay 
in the study for its whole length. If that happens, we will tell you as soon as possible. We 
will also ask you to come to the clinic for 3-6 more visits. We will tell you more about 
what will happen at these visits in another form. 

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17. If you are found to have been HIV-1 infected when you enrolled, or if you have 
HIV-2 infection: 
If you are found to have been HIV infected when you enrolled, you were already infected 
with HIV before you got the antibody or placebo. It takes a few days to complete the tests 
to see if you have HIV, so your infection was not found until after you got your first IV. 
HIV-2 is a rare kind of HIV, most often found in West Africa. In North and South 
America, there are only about a dozen cases reported each year. 
We will counsel you about your HIV infection, talk with you about ways to avoid 
transmission and about telling your partner(s).  
We are asking you to come to the clinic for 1-2 more visits (including today) within about 
6 months of your diagnosis. At these visits, we will: 
 
Ask questions about your health; 
 
Do physical exams based on your complaints or side effects; 
 
Ask questions about your risk of infecting others with HIV, including sexual 
behavior and drug use;  
 
Counsel you on how to avoid transmitting HIV to other people; 
 
Collect blood samples (between 30 and 45 mL, or about 2 to 3 tablespoons, at each 
visit); and  
 
Ask questions about any personal problems or benefits you may have from 
participating in the study.  
[Site: Insert the second table in Appendix D, Tables 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.] 
18. If you got infected with HIV-1 during the study: 
If you became infected with HIV-1, we will counsel you about your HIV infection, talk 
with you about ways to avoid transmission and about telling your partner(s). You will not 
get any more IVs. We will ask you to come in for 4-5 more visits within about 6 months 
of your diagnosis. At these visits, we will: 
 
Ask questions about your health; 
 
Do physical exams based on your complaints or side effects; 
 
Ask questions about your risk of infecting others with HIV, including sexual 
behavior and drug use;  
 
Counsel you on ways to avoid transmitting HIV to other people; 

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 
Collect blood samples (between 70 mL and 130 mL, about ⅓ to ½ cup, at each visit); 
and  
 
Ask questions about any personal problems or benefits you may have from 
participating in the study.  
[Site: Insert the third table in Appendix D, Tables 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.] 
19. If you stop getting IVs for reasons other than HIV infection, we may encourage you 
to stay in the study.  
In this case, we will ask you to come in for study visits about every 3-4 months until 104 
weeks (2 years) after your first infusion. That is how long you would be in the study if 
you got all the infusions on schedule. Because you got some IVs, we want to keep track 
of your health. How many visits you will have will depend on when you stopped getting 
IVs. At these visits we will:  
 
Ask questions about your health, including medications you may be taking; 
 
Do physical exams based on your complaints or side effects; 
 
Do regular HIV testing, as well as counseling on your results and on how to avoid 
getting HIV; 
 
Ask questions about any personal problems or benefits you may have from 
participating in the study;  
 
Do pregnancy tests if you could become pregnant; and  
 
Collect blood samples (between 70 mL and 120 mL, about ⅓ to ½ cup, at each visit). 
[Site: Insert the last table in Appendix D, Tables 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.] 
20. We may stop your IVs and 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 IVs.  
This may happen if: 
 
we learn that you were enrolled in the study in error, 
 
you are unable to follow instructions, 
 
we think that staying in the study might harm you, 
 
you enroll in a different research study where you get another study product, or 
 
the study is stopped for any reason. 

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If we take you out of the study, 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. 
21. We will stop your IVs if you become pregnant during the study. 
We will encourage you to stay in the study if you choose. We will discuss your study 
options with you. If you leave the study while you are still pregnant, we will contact you 
after your due date to ask some questions about your pregnancy and delivery. 
22. We will do our best to protect your private information. 
US sites: Check HIPAA authorization for conflicts with this section. 
Your study records and samples will be kept in a secure location. We will label all of 
your samples and most of your records with a code number, not your name or other 
personal information. However, it is possible to identify you, if necessary. We will not 
share your name with the lab that does the tests on your samples, or with anyone else who 
does not need to know your name. 
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, people who work for them, its study monitors, 
and its chosen South African representatives, 
 
The US Food and Drug Administration, 
 
[Insert name of local IRB/EC] , 
 
[Insert name of local and/or national regulatory authority as appropriate], 
 
The HVTN and HPTN and people who work for them,  
 
The US National Institutes for Allergy and Infectious Diseases Data and Safety 
Monitoring Board, and 
 
The US Office for Human Research Protections. 
All reviewers will take steps to keep your records private. 
We cannot guarantee absolute privacy. At this clinic, we have to report the following 
information:  
Site: Include any public health or legal reporting requirements. Bulleted examples should 
include all appropriate cases (reportable communicable disease, risk of harm to self or 
others, etc.). 
 
[Item 1] 

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 
[Item 2] 
 
[Item 3] 
US sites: Include the following boxed text. You can remove the box. 
We have a Certificate of Confidentiality from the US government, to help protect your 
privacy. With the certificate, we do not have to release information about you to someone 
who is not connected to the study, such as the courts or police. Sometimes we can’t use 
the certificate. Since the US government funds this research, we cannot withhold 
information from it. Also, you can still release information about yourself and your study 
participation to others. 
The results of this study may be published. No publication will use your name or identify 
you personally. 
We may share information from the study with other researchers. We will not share your 
name or information that can identify you. 
Sites: The text below may not be deleted or changed, per FDA requirement. It’s OK to 
remove the box around it. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. 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. 
Other Risks 
23. There are other risks to being in this study. 
This section describes the other risks and restrictions we know about. There may also be 
unknown risks, even serious ones. We will tell you if we learn anything new that may 
affect your willingness to stay in the study. 
Risks of taking blood:  
Taking blood can cause bruising, pain, fainting, soreness, redness, swelling, itching, a 
sore, bleeding, and (rarely) muscle damage or infection where the needle was inserted. 
Taking blood can cause a low blood cell count (anemia), making you feel tired. 
Risks of the IV procedures: 
Getting an IV may cause stinging, discomfort, pain, soreness, redness, bruising, itching, 
rash, and swelling where the needle goes into the skin. Rarely, needle sticks can result in 
infections. 
Personal problems/discrimination: 
Some people who join HVTN or HPTN studies report personal problems or 
discrimination because of joining an HIV prevention study. Family or friends may worry, 

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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.  
HIV testing 
HIV antibody tests are the usual way to test for HIV infections. Although 2 out of 3 
people in this study will get an HIV antibody, we do not expect them to test positive on 
HIV antibody tests. We have used several common HIV antibody tests to test samples of 
blood containing the VRC01 antibody and none of them detected the antibody.  
Although it has not been seen so far, getting VRC01 may cause common HIV antibody 
tests to show that someone is HIV-negative, even if they are actually infected.  
To be absolutely safe we ask you to get HIV tests only at this clinic during the study. Our 
tests can always detect true HIV infection. They can also tell if someone is really not HIV 
infected. Since the antibodies do not last long in the body, we do not expect you to have 
any problems with HIV testing after the study ends. 
Embarrassment/anxiety:  
You may feel embarrassed when we ask about your HIV risks, such as having sex and 
using drugs. Also, waiting for your HIV test results or other health test results could 
make you feel anxious. You could feel worried if your test results show that you are 
infected with HIV. If you feel embarrassed or anxious, please tell us and we will try to 
help you. 
Risks of disclosure of your personal information: 
We will take several steps to protect your personal information. Although the risk is very 
low, it is possible that your personal information could be given to someone who should 
not have it. If that happened, you could face discrimination, stress, and embarrassment. 
We can tell you more about how we will protect your personal information if you would 
like it.  
Risks of genetic testing: 
The genetic testing could show you may be at risk for certain diseases. If others found 
out, it could lead to discrimination or other problems. However, it is almost impossible 
for you or others to know your test results from the genetic testing. The results are not 
part of your study records and are not given to you.  
U.S. Sites, include the following paragraph 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:  

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We do not know if the antibody will increase, decrease, or not change your risk of 
becoming infected with HIV if exposed. 
If we find that you were already HIV infected when you got the antibody, we do not 
know how the antibody will affect your HIV disease. We also do not know how having 
gotten it will affect your HIV-related lab results.  
If you get infected with HIV during the study, we do not know how the antibody might 
affect the course of your HIV disease. 
If you become pregnant while you still have VRC01 in your body, we don’t know if it 
could be passed to your baby. We do not know how the antibody will affect a pregnant 
participant or a developing baby.  
Benefits 
24. The study may not benefit you. 
Since we do not know if the antibody can prevent HIV infection in people, you should 
not expect any benefit from getting the antibody in this study. 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 show us that the VRC01 antibody can prevent HIV and the study results 
may also help in the search for methods to prevent HIV. However, if the VRC01 
antibody later becomes approved and sold or leads to an HIV prevention method, there 
are no plans to share any money with you.  
Your rights and responsibilities 
25. If you join the study, you have rights and responsibilities. 
You have many rights that we will respect. You also have responsibilities. We list these 
in the Participant’s Bill of Rights and Responsibilities. We will give you a copy of it. 
Leaving the study 
26. Tell us if you decide to leave the study.  
You are free to leave the study at any time and for any reason. Your care at this clinic and 
your legal rights will not be affected, but it is important for you to let us know.  
If you decide to leave the study, 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 
Sites: Do not make changes to the following section without obtaining approval from 
HVTN Regulatory Affairs at vtn.core.reg@hvtn.org. 
27. If you get sick or injured during the study, contact us immediately. 
Your health is important to us. (Sites: adjust the following 2 sentences if applicable to the 
care available at your site) We will tell you about the care that we can give here. For the 
care that we cannot provide, we will explain how we will help you get care elsewhere. 
If you become sick or injured in this study, there is a process to decide if it is related to 
the VRC01 antibody and/or study procedures. If it is, we call it a study-related injury.  
The HVTN and HPTN have limited funds to pay medical costs for study-related injuries 
that it determines are reasonable. (Sites: insert locale- appropriate medical insurance 
language in the following sentence) If the injury is not study related, then you and your 
health insurance will be responsible for treatment costs. 
Some injuries are not physical. For example, you might be harmed emotionally by being 
in an HIV prevention study. Or you might lose wages because you cannot go to work. 
However, there are no funds to pay for these kinds of injuries, even if they are study 
related. 
You may disagree with the decision about whether your injury is study related. If you 
wish, independent experts will be asked to review the decision. You always have the right 
to use the court system if you are not satisfied. 
Questions  
28. If you have questions or problems at any time during your participation in this 
study, use the following important contacts. 
If you have questions about this study, contact [name and telephone number of the 
investigator or other study staff]. 
If you have any symptoms that you think may be related to this study, contact [name and 
telephone number of the investigator or other study staff]. 
If you have questions about your rights as a research participant, or problems or concerns 
about how you are being treated in this study, contact [name/title/phone of person on IRB 
or other appropriate organization]. 
If you want to leave this study, contact [name and telephone number of the investigator or 
other study staff]. 
 Your permissions and signature  
Site: Delete this section if using a separate consent for use of samples and information in 
other studies. 

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29. In Section 14 of this form, we told you about possible other uses of your extra 
samples and limited information, outside this study. Please choose only one of the 
options below and write your initials or make your mark in the box next to it. 
Whatever you choose, the HVTN and HPTN keep track of your decision about how 
your samples and information can be used. 
 
 
I allow my extra samples combined with limited information to be used for other 
studies related to HIV prevention, the immune system, and other diseases. This may 
include genetic testing and keeping my cells growing over time.  
OR 
 
 
I agree to the option above and also to allow my extra samples combined with limited 
information to be used in genome wide studies. 
OR 
 
 
I do not allow my extra samples to be used in any other studies. This includes not 
allowing genetic testing, growing more of my cells, or genome wide studies.  
 
30. If you agree to join this study, you will need to sign or make your mark below. 
Before you sign or make your mark on this consent form, make sure of the 
following: 
 
You have read this consent form, or someone has read it to you. 
 
You feel that you understand what the study is about and what will happen to you if 
you join. You understand what the possible risks and benefits are. 
 
You have had your questions answered and know that you can ask more. 
 
You agree to join this study. 
You will not be giving up any of your rights by signing this consent form. 
 
 
 
 
 
 
 
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 consent process. 
 
 

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Appendix B 
Approved birth control methods for 
transgender men (for sample informed consent 
form) 
You should not become pregnant during the study because we do not know how the study 
antibody could affect the developing baby.  
If you were assigned female at birth and are sexually active in a way that could lead to 
pregnancy, you must agree to use effective birth control from 21 days before your first IV 
until your last scheduled clinic visit (about 2 years after your first IV). You should not 
become pregnant during the study because we do not know how the antibody could affect 
the developing baby. 
Although taking testosterone can lower the chances of becoming pregnant, it is not 
considered an effective method of birth control. Effective birth control means using any 
of the following methods every time you have sex: 
 
Drugs that are prescribed specifically for birth control and intended to prevent 
pregnancy—these include 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 have had a hysterectomy (your uterus removed); 
 
You have had an oophorectomy (your ovaries removed); or 
 
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 a tubal ligation (your “tubes tied”) or confirmed successful placement of a 
product that blocks the fallopian tubes; or 
 
You are sexually abstinent (no sex at all). 
Remember: If you are having sex, you need to use male or female condoms to protect 
yourself from HIV infection. 
If you join the study, we will test you for pregnancy at some visits, including before each 
study injection. 

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Appendix C 
Sample consent form for use of samples and 
information in other studies 
Title: A phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing 
monoclonal antibody in reducing acquisition of HIV-1 infection among men and 
transgender persons who have sex with men 
HVTN protocol number: HVTN 704/HPTN 085, The AMP Study 
Site: [Insert site name] 
When samples are no longer needed for this study, the study sponsors want to keep them 
for use in other studies by HVTN, HPTN, or other researchers. We will call these “extra 
samples.” 
This form gives you information so you can decide if you want your extra samples and 
information used in other studies. You will mark your decision at the end of the form. If 
you have any questions, please ask.  
1. Do I have to agree?  
No. You are free to say yes or no, or to change your mind after you sign this form. At 
your request, we will destroy all extra samples that we have. Your decision will not affect 
your being in this study or have any negative consequences here.  
2. Where are the samples stored?  
Extra samples are stored in a secure central place called a repository. Your samples will 
be stored in the HVTN repository in the United States.  
3. How long will the samples be stored?  
There is no limit on how long your extra samples will be stored. [Site: insert limits if your 
regulatory authority imposes them.] 
4. Will I be paid for the use of my samples?  
No. Also, a researcher may make a new scientific discovery or product based on the use 
of your samples. If this happens, there is no plan to share any money with you. The 
researcher is not likely to ever know who you are. 
5. Will I benefit from allowing my samples to be used in other studies?  
Probably not. Results from these other studies are not given to you, this clinic, or your 
doctor. They are not needed for your medical care. They are not part of your medical 
record. The studies are only being done for research purposes. 
6. Will the HVTN or HPTN sell my samples and information?  
No, but the HVTN and HPTN may share your samples with other researchers. Once we 
share your samples and information, we will not be able to get them back. 

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

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HVTN 704_HPTN 085_v3.0_FINAL.docx / Page 159 of 175 
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 stored samples and limited information for other research 
 
Government agencies that fund or monitor the research using your samples or 
information 
 
The researcher’s Institutional Review Board or Ethics Committee 
 
The people who work with the researcher  
All of these people will do their best to protect your information. The results of any new 
studies that use your extra samples or information may be published. No publication will 
use your name or identify you personally. 
Questions  
12. If you have questions or problems about allowing your samples and information to 
be used in other studies, use the following important contacts. 
If you have questions about the use of your samples or information or if you want to 
change your mind about their use, contact [name and telephone number of the 
investigator or other study staff]. 
If you think you may have been harmed because of studies using your samples or 
information, contact [name and telephone number of the investigator or other study staff]. 
If you have questions about your rights as a research participant, contact 
[name/title/phone of person on IRB or other appropriate organization]. 

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

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Appendix D 
Tables of procedures (for sample informed consent 
form) 
[Site: You may insert these tables of procedures into appropriate sections of your consent form(s) or give them to 
study volunteers/participants separately if you think they would be helpful. You are not required to do either.]  
HIV-uninfected participants 
 
 
 
 
 
Procedure 
Screening 
visit(s) 
First IV 
visit 
4 weeks 
8 weeks 
8 weeks + 
5 days 
12 weeks 
16 weeks 
20 weeks 
24 weeks 
28 weeks 
32 weeks 
36 weeks 
40 weeks 
44 weeks 
48 weeks 
52 weeks 
56 weeks 
60 weeks 
64 weeks 
68 weeks 
72 weeks 
76 weeks 
80 weeks 
88 weeks 
96 weeks 
104 weeks 
IV 
 
√ 
 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
Brief physical exam 
 
√ 
 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
 
 
 
Urine test 
√ 
 
 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
 
 
 
Blood drawn 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Pregnancy test*  
√ 
√ 
 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
 
HIV test & pretest counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Risk reduction counseling 
√ 
√ 
 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
 
 
√ 
Interview/Questionnaire 
√ 
√ 
 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
√ 
STI testing (blood, urine, and/or 
swabs) † 
 
√ 
 
 
 
 
 
 
√ 
 
 
 
 
 
√ 
 
 
 
 
 
√ 
 
 
 
 
 
Not shown in this table is a time after all study participants have completed their last scheduled visit when you can find out whether you received the study 
antibody or the placebo.  
* Persons assigned female at birth who have had their uterus or ovaries removed (a hysterectomy or oophorectomy), verified by medical records, are not 
required to have pregnancy tests. 
† And if clinically indicated. 
 
 
Participants discovered to have been HIV-1–infected at enrollment or who become HIV-2–infected 
 
Weeks after 1st 
positive HIV test 
Procedure 
4 
24 
Medical history (as needed) 
√ 
√ 
Brief physical (as needed) 
√ 
√ 
Complete physical 
 
√ 
Risk reduction counseling 
√ 
√ 
Questions/questionnaire 
√ 
√ 
Blood drawn 
√ 
√ 
 
Not shown in this table is a time after all study participants have completed their last scheduled visit when you can find out whether you received the study 
antibody or the placebo.  
 
2 years 
1 year 
6 months 
1½ years 

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Participants who become HIV-1–infected  
 
Weeks after 1st positive HIV 
test 
Procedure 
4 
6 
8 
12 
24 
Medical history (as needed) 
√ 
√ 
√ 
√ 
√ 
Brief physical (as needed) 
√ 
√ 
√ 
√ 
 
Complete physical 
 
 
 
 
√ 
Risk reduction counseling 
√ 
√ 
√ 
√ 
√ 
Questions/questionnaire 
√ 
√ 
√ 
√ 
√ 
Blood drawn 
√ 
√ 
√ 
√ 
√ 
Pregnancy test* 
 
 
 
√ 
 
 
Not shown in this table is a time after all study participants have completed their last scheduled visit when you can find out whether you received the study 
antibody or the placebo.  
Participants who become HIV-1–infected may be invited to join a separate study for follow-up visits. That study will have a separate schedule of visits and 
procedures. It will also have a separate consent form, which will be reviewed with all participants who are invited to join that study. 
* Persons who have had their uterus or ovaries removed (a hysterectomy or oophorectomy), verified by medical records, are not required to have pregnancy 
tests. 
 
Participants who discontinue infusions for reasons other than HIV infection 
 
 
Weeks after enrollment 
Procedure 
8 
20 
32 
44 
56 
72 
88 
104 
Brief physical (as needed) 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Complete physical 
 
 
 
 
 
 
 
√ 
HIV testing & pretest counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Risk reduction counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Questions/questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Urine test 
√ 
 
 
 
 
 
√ 
 
Pregnancy test*  
√ 
 
√ 
 
√ 
 
√ 
 
Blood drawn 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Study participants who discontinue infusions for reasons other than HIV infection will start this visit schedule at the first visit that occurs after their last infusion. 
Not shown in this table is a time after all study participants have completed their last scheduled visit when you can find out whether you received the study 
antibody or the placebo.  
* Persons assigned female at birth who have had their uterus or ovaries removed (a hysterectomy or oophorectomy), verified by medical records, are not 
required to have pregnancy tests. 
 

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Appendix E 
Sample consent form for participants with 
HIV infection at enrollment or during the study 
Title: A phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing 
monoclonal antibody in reducing acquisition of HIV-1 infection among men and 
transgender persons who have sex with men 
Protocol number: HVTN 704/HPTN 085, The AMP Study 
Site: [Insert site name] 
Please read this consent form or ask someone to read it to you. If you decide to, 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.  
You are a participant in a study called HVTN 704/HPTN 085, The AMP Study. The rest 
of the information in the consent form that you signed earlier, about the study purpose, 
the risks and benefits of participation, your rights and responsibilities, and how your 
privacy is protected, continues to be important information for you and has not changed.  
About this form 
We tested your blood for HIV and you were found to be infected. We will help you get 
care and support. 
You became infected either prior to enrollment or during your participation in the study. 
Because of this, you cannot stay in the study for its whole length. We would like you to 
come to the clinic for a different number of visits than what is explained in the main 
study consent form.  
Depending on when you became infected, you will come to the clinic for 1-5 more visits, 
including today.  
1. If you are found to have been HIV-1 infected when you enrolled, or if you have 
HIV-2 infection: 
If you are found to have been HIV infected when you enrolled, you were already infected 
with HIV before you got the antibody or placebo. It takes a few days to complete the tests 
to see if you have HIV, so your infection was not found until after you got your first IV. 
HIV-2 is a rare kind of HIV, most often found in West Africa. In North and South 
America, there are only about a dozen cases reported each year.  
We will counsel you about your HIV infection, talk with you about ways to avoid 
transmission and about telling your partner(s).  
We are asking you to come to the clinic for 1-2 more visits (including today) within about 
6 months of your diagnosis. At these visits, we will: 
 
Ask questions about your health; 

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 
Do physical exams based on your complaints or symptoms; 
 
Ask questions about your risk of infecting others with HIV, including sexual 
behavior and drug use;  
 
Counsel you on ways to avoid transmitting HIV to other people; 
 
Collect blood samples (between 30 and 45 mL, or about 2 to 3 tablespoons, at each 
visit); and  
 
Ask questions about any personal problems or benefits you may have from 
participating in the study.  
Site: You may remove the Table of procedures 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.  
Participants discovered to have been HIV-1–infected at enrollment or who 
become HIV-2–infected 
 
Weeks after 1st 
positive HIV test 
Procedure 
4 
24 
Medical history (as needed) 
√ 
√ 
Brief physical (as needed) 
√ 
√ 
Complete physical 
 
√ 
Risk reduction counseling 
√ 
√ 
Questions/questionnaire 
√ 
√ 
Blood drawn 
√ 
√ 
 
Not shown in this table is a time after all study participants have completed their last scheduled visit when you can find 
out whether you received the study antibody or the placebo.  
2. If you got infected with HIV-1 during the study: 
If you became infected with HIV-1, we will counsel you about your HIV infection, talk 
with you about ways to avoid transmission and about telling your partner(s). You will not 
get any more IVs. We will ask you to come in for 4-5 more visits (including today) 
within about 6 months of your diagnosis. At these visits, we will: 
 
Ask questions about your health; 
 
Do physical exams based on your complaints or symptoms; 
 
Ask questions about your risk of infecting others with HIV, including sexual 
behavior and drug use;  
 
Counsel you on ways to avoid transmitting HIV to other people; 
 
Collect blood samples (between 70 mL and 130 mL, about ⅓ to ½ cup, at each visit); 
and  

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 
Ask questions about any personal problems or benefits you may have from 
participating in the study.  
Site: You may remove the Table of procedures (for addendum 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.  
HIV-1–infected participants 
 
Weeks after 1st positive HIV test  
Procedure 
4 
6 
8 
12 
24 
Medical history (as needed) 
√ 
√ 
√ 
√ 
√ 
Brief physical (as needed) 
√ 
√ 
√ 
√ 
 
Complete physical 
 
 
 
 
√ 
Risk reduction counseling 
√ 
√ 
√ 
√ 
√ 
Questions/questionnaire 
√ 
√ 
√ 
√ 
√ 
Blood drawn 
√ 
√ 
√ 
√ 
√ 
Pregnancy test* 
 
 
 
√ 
 
 
Not shown in this table is a time after all study participants have completed their last scheduled visit when you can find 
out whether you received the study antibody or the placebo.  
Participants who become HIV-1–infected may be invited to join a separate study for follow-up visits. That study will have 
a separate schedule of visits and procedures. It will also have a separate consent form, which will be reviewed with all 
participants who are invited to join that study. 
* Persons assigned female at birth who have had their uterus or ovaries removed (a hysterectomy or oophorectomy), 
verified by medical records, are not required to have pregnancy tests. 
 
Leaving the study 
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.  
Questions  
If you have questions or problems at any time during your participation in this study, use 
the following important contacts. 
If you have questions about this study, contact [name and telephone number of the 
investigator or other study staff]. 
If you have any symptoms that you think may be related to this study, contact [name and 
telephone number of the investigator or other study staff]. 

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HVTN 704_HPTN 085_v3.0_FINAL.docx / Page 166 of 175 
If you have questions about your rights as a research participant, or problems or concerns 
about how you are being treated in this study, contact [name/title/phone of person on IRB 
or other appropriate organization]. 
If you want to leave this study, contact [name and telephone number of the investigator or 
other study staff]. 
Your permissions and signature  
If you agree to continue in this study with this new visit schedule, 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 the changes to the visit schedule and what will happen 
to you. You understand that the possible risks and benefits of participation have not 
changed. 
 
You have had your questions answered and know that you can ask more at any time. 
 
You agree to continue in 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 
 
 
 
 
 
 
 
 
Study staff conducting consent 
discussion (print) 
 
Study staff signature 
 
Date 
 
Time 
 
For participants who are unable to read or write, also complete the signature block below: 
 
 
 
 
 
 
 
 
 
Witness’s name (print)# 
 
Witness’s signature 
 
Date 
 
Time 
# Witness is impartial and was present for the consent process. 

HVTN 704/HPTN 085 Version 3.0 / June 15, 2017 
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Appendix F 
Schedule 1—Laboratory procedures for HIV-uninfected participants 
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Day:
D0
D28
D56
D61
D84
D112
D140
D168
D196
D224
D252
D280
D308
D336
D364
D392
D420
D448
D476
D504
D532
D560
D616
D672
D728
Week:
W0
W4
W8
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
W52
W56
W60
W64
W68
W72
W76
W80
W88
W96
W104
Inf#1
Inf#2
Inf#3
Inf#4
Inf#5
Inf#6
Inf#7
Inf#8
Inf#9
Inf#10
Procedure
Ship to1
Assay location2
Tube 
Type4
Tube size
(vol. 
capacity)4
Total
BLOOD COLLECTION
Screening/Diagnostic
Screening HIV test
Local lab
Local lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
HIV diagnostics 7
UW-VSL /
Peru CTU Laboratory /
CADIG-Immunodiagnostic 
Lab (INI-FIOCRUZ)
UW-VSL /
Peru CTU Laboratory /
CADIG-Immunodiagnostic 
Lab (INI-FIOCRUZ)
EDTA
10mL
—
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
207
260
Safety labs
CBC/ Differential
Local lab
Local lab
EDTA
5mL
5
5
—
5
—
—
5
—
5
—
5
—
5
—
5
—
5
—
5
—
5
—
—
—
—
—
55
ALT, Creatinine
Local lab
Local lab
SST
5mL
5
5
—
5
—
—
5
—
5
—
5
—
5
—
5
—
5
—
5
—
5
—
—
—
—
—
55
STI Serology
Syphilis11
Local lab
Local lab
SST
5mL
—
513
—
—
—
—
—
—
513
—
—
—
—
—
513
—
—
—
—
—
513
—
—
—
—
—
20
Drug Levels/Detection
VRC01 Ab levels
CSR
NVITAL
SST
8.5mL
—
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
0
ARV detection by serum or plasma9, 10
CSR
JHU
SST
8.5mL
—
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
0
ARV detection by dried blood spots 10
CSR
HVTN Labs
EDTA
2mL
—
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
50
Immunogenicity & Virologic Assays
Host genetics 5
CSR
HVTN Labs
ACD
8.5mL
—
z
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
0
Anti-VRC01 Ab levels
CSR
VRC / NVITAL
SST
8.5mL
—
y
—
—
—
—
—
—
—
—
—
y
—
—
—
—
—
—
—
—
—
y
—
—
—
—
0
Functional humoral assays 8
CSR
HVTN Labs /
VRC / NVITAL
SST
8.5mL
—
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
0
Viral isolation/sequencing9
CSR
TBD
EDTA
10mL
—
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
250
STORAGE
Serum storage
CSR
—
SST
8.5mL
—
76.5
51
51
42.5
51
42.5
42.5
42.5
42.5
42.5
51
42.5
42.5
42.5
42.5
42.5
42.5
42.5
42.5
42.5
51
42.5
42.5
42.5
42.5
1139
PBMC storage
CSR
—
ACD
8.5mL
—
51
—
—
—
—
—
—
—
—
—
—
34
—
—
—
—
—
—
—
34
—
—
—
—
34
153
Visit total16
15
168
76
86
68
76
78
68
83
68
78
76
112
68
83
68
78
68
78
68
117
76
68
68
68
112
2062
56-Day total
 
15
183
259
345
230
306
307
221
228
218
228
221
265
255
262
218
228
213
223
213
262
260
260
135
135
179
URINE COLLECTION
Urine dipstick15
Local lab
Local lab
X
—
—
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
X
—
—
—
Pregnancy Test6
Local lab
Local lab
X
X
—
X
—
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
—
—
Chlamydia/Gonorrhea12
Local lab
Local lab
—
X13
—
—
—
—
—
—
X13
—
—
—
—
—
X13
—
—
—
—
—
X13
—
—
—
—
—
RECTAL SWAB COLLECTION
Chlamydia/Gonorrhea12
Local lab
Local lab
—
X13
—
—
—
—
—
—
X13
—
—
—
—
—
X13
—
—
—
—
—
X13
—
—
—
—
—
OROPHARYNGEAL SWAB COLLECTION
Gonorrhea12
Local lab
Local lab
—
X14
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
Screening 
visit3
 
1 CSR = central specimen repository; UW-VSL = University of Washington Virology Specialty Laboratory (Seattle, Washington, USA); Peru CTU Laboratory (Lima, Peru); CADIG - Immunodiagnostic Lab (INI-FIOCRUZ) (Rio de Janeiro, Brazil). 
2 HVTN Laboratories include: Cape Town HVTN Immunology Laboratory (CHIL, Cape Town, South Africa); South African Immunology Laboratory–National Institute for Communicable Diseases (SAIL-NICD, Johannesburg, South Africa); Fred 
Hutchinson Cancer Research Center (Seattle, Washington, USA); Duke University Medical Center (Durham, North Carolina, USA); University of Cape Town (Cape Town, South Africa); University of Colorado Denver (Aurora, Colorado, USA). 
 Non-HVTN laboratories: NVITAL = NIAID Vaccine Immune T-Cell Antibody Laboratory (Gaithersburg, Maryland, USA); VRC = Vaccine Research Center (Bethesda, Maryland, USA); JHU = Johns Hopkins University, HPTN Laboratory Center 
(Baltimore, Maryland, USA). 
 TBD = Laboratories to be determined by HVTN Laboratory Program. 
3 Screening may occur over the course of several contacts/visits up to and including day 0 prior to infusion.  
4 Local labs may assign appropriate alternative tube types for locally performed tests. 
5 Genotyping may be performed on enrolled participants using cryopreserved PBMC collected at baseline. 
6 For persons capable of becoming pregnant, pregnancy test must be performed on urine or blood specimens on the day of infusion with negative results received prior to infusion. 
7 At an early termination visit for a withdrawn or terminated participant (see Section 7.12), blood should be drawn for HIV diagnostic testing, as shown for visit 26 above. 
8 Functional humoral assays include nAb, ADCC, virion capture, and phagocytosis assays. 
9 EDTA blood collected for plasma may also be used for ARV detection assay, if necessary. 
10 Testing plan for ARV detection to be determined. 
11 Syphilis testing will be done by serology. 
12 Nucleic acid amplification testing (NAAT) for chlamydia and gonorrhea will be performed on urine and on rectal and oropharyngeal swabs.  
13 Syphilis testing, and chlamydia/gonorrhea testing by urine and rectal swab, will be performed at visits 2, 9, 15 and 21; in addition, testing may occur at any visit if clinically indicated.  
14 Gonorrhea testing by oropharyngeal swab will be performed at visit 2; in addition, testing may occur at any visit if clinically indicated. A combination gonorrhea/chlamydia oropharyngeal test is allowable (see the SSP for results reporting). 
15 And microscopy if needed. 
16 A 3mL volume is included in the visit totals for drawing a non-additive discard tube to prevent blood tube additive cross-contamination. This is not applicable to the screening visit. Refer to the Specimen Collection SSP for more information. 
y = SST blood collected for serum storage will also cover specimen needs for the VRC01 drug level, ARV detection, and functional humoral assays; no separate blood draw is needed. 
z = ACD blood collected for PBMC storage will also cover specimen needs for host genetics assay; no separate blood draw is needed. 

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Appendix G 
Schedule 2—Laboratory procedures for HIV-1–infected participants 
Visit:
#.X5
Visit:
31
32
33
34
35
Days:
D28
D42
D56
D84
D168
Weeks after 
diagnosis 7:
W4
W6
W8
W12
W24
Procedure
Ship to1
Assay location2
Tube 
Type3
Tube size        
(vol. capacity)3
Total
BLOOD COLLECTION
Screening or diagnostic assays
        HIV diagnostics
UW-VSL /
Peru CTU Laboratory /
CADIG-Immunodiagnostic 
Lab (INI-FIOCRUZ)
UW-VSL /
Peru CTU Laboratory /
CADIG-Immunodiagnostic 
Lab (INI-FIOCRUZ)
EDTA
10mL
20
—
—
—
—
—
20
        HIV PCR viral load
UW-VSL /
Peru CTU Laboratory /
CADIG-Immunodiagnostic 
Lab (INI-FIOCRUZ)
UW-VSL /
Peru CTU Laboratory /
CADIG-Immunodiagnostic 
Lab (INI-FIOCRUZ)
EDTA
10mL
—
10
10
10
10
10
50
        CD4+T cell count
Local Lab
Local Lab
EDTA
5mL
5
5
5
5
5
5
30
Safety lab
        Hemoglobin
Local Lab
Local Lab
EDTA
5mL
—
—
—
5
5
—
10
Drug levels
        VRC01 Ab levels
CSR
NVITAL
SST
8.5mL
8.5
8.5
8.5
8.5
8.5
8.5
51
Immunogenicity & Virologic Assays
        Functional humoral assays 6
CSR
HVTN Labs /
VRC / NVITAL
SST
8.5mL
17
17
17
17
17
17
102
        Viral isolation/sequencing
CSR
TBD
EDTA
10mL
10
10
10
10
10
10
60
Storage
Serum
CSR
SST
8.5mL
25.5
17
17
17
17
17
110.5
Plasma
CSR
EDTA
5mL
5
5
5
5
5
5
30
PBMC
CSR
ACD
8.5mL
34
—
—
—
34
34
102
Visit total8
128
75.5
75.5
80.5
114.5
109.5
584
56-Day total
128
204
279
360
346
109.5
URINE COLLECTION
Pregnancy Test4
Local Lab
Local Lab
X
—
—
—
X
—
 
1 CSR = central specimen repository; UW-VSL = University of Washington Virology Specialty Laboratory (Seattle, Washington, USA); Peru CTU Laboratory (Lima, Peru); CADIG - Immunodiagnostic Lab (INI-FIOCRUZ) (Rio de Janeiro, Brazil). 
2 HVTN Laboratories include: South African Immunology, Laboratory-National Institute for Communicable Diseases (SAIL-NICD, Johannesburg, South Africa); Duke University Medical Center (Durham, North Carolina, USA). 
  Non-HVTN laboratories: NVITAL = NIAID Vaccine Immune T-Cell Antibody Laboratory (Gaithersburg, Maryland, USA; VRC = Vaccine Research Center (Bethesda, Maryland, USA) 
  TBD = Laboratories to be determined by HVTN Laboratory Program. 
3 Local labs may assign appropriate alternative tube types for locally performed tests. 
4 For persons capable of becoming pregnant, pregnancy test may be performed on urine or blood specimens. 
5 Visit #.X indicates a Redraw visit where # is a Schedule 1 visit number. Confirmatory draw for HIV diagnostics will be collected at the Redraw visit, in addition to the other indicated specimens. The Redraw visit should occur as soon as possible after the 
clinic receives a Redraw Request from the HIV diagnostics laboratory. Multiple subsequent Redraw visits may be necessary; only the EDTA blood specimens for HIV diagnostics, viral isolation/sequencing, and plasma storage will be collected at the 
subsequent Redraw visits. Refer to the HIV Testing SSP for more information. 
6 Functional humoral assays include nAb, ADCC, virion capture, and phagocytosis assays. 
7 Date of diagnosis = date of the initial specimen draw that led to the first Redraw Request. 
8 A 3mL volume is included in the visit totals for drawing a non-additive discard tube to prevent blood tube additive cross-contamination. Refer to the Specimen Collection SSP for more information. 

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Appendix H 
Schedule 3―Laboratory procedures for participants discovered to have been 
HIV-1–infected at enrollment or who become HIV-2–infected 
Visit:
#.X5
Visit:
47
48
Days:
D28
D168
Weeks after 
diagnosis 7:
W4
W24
Procedure
Ship to1
Assay location2
Tube 
Type3
Tube size        
(vol. capacity)3
Total
BLOOD COLLECTION
Screening or diagnostic assays
        HIV diagnostics
UW-VSL /
Peru CTU Laboratory /
CADIG-Immunodiagnostic 
Lab (INI-FIOCRUZ)
UW-VSL /
Peru CTU Laboratory /
CADIG-Immunodiagnostic 
Lab (INI-FIOCRUZ)
EDTA
10mL
20
—
—
20
        HIV PCR viral load
UW-VSL /
Peru CTU Laboratory /
CADIG-Immunodiagnostic 
Lab (INI-FIOCRUZ)
UW-VSL /
Peru CTU Laboratory /
CADIG-Immunodiagnostic 
Lab (INI-FIOCRUZ)
EDTA
10mL
—
10
10
20
        CD4+T cell count
Local Lab
Local Lab
EDTA
5mL
5
5
5
15
Drug levels
        VRC01 Ab levels
CSR
NVITAL
SST
8.5mL
8.5
—
—
8.5
Immunogenicity & Virologic Assays
        Functional humoral assays 6
CSR
HVTN Labs /
VRC / NVITAL
SST
8.5mL
17
—
—
17
        Viral isolation/sequencing
CSR
TBD
EDTA
10mL
10
—
—
10
Storage
Serum
CSR
SST
8.5mL
25.5
17
17
59.5
Plasma
CSR
EDTA
5mL
5
—
—
5
PBMC
CSR
ACD
8.5mL
34
—
—
34
Visit total8
128
35
35
198
56-Day total
128
163
35
URINE COLLECTION
Pregnancy Test4
Local Lab
Local Lab
X
—
—
 
1 CSR = central specimen repository; UW-VSL = University of Washington Virology Specialty Laboratory (Seattle, Washington, USA); Peru CTU Laboratory (Lima, Peru); CADIG - Immunodiagnostic Lab (INI-FIOCRUZ) (Rio de Janeiro, Brazil). 
2 HVTN Laboratories include: South African Immunology Laboratory–National Institute for Communicable Diseases (SAIL-NICD, Johannesburg, South Africa); Duke University Medical Center (Durham, North Carolina, USA); University of Colorado 
Denver (Denver, Colorado, USA). 
Non-HVTN laboratories: NVITAL = NIAID Vaccine Immune T-Cell Antibody Laboratory (Gaithersburg, Maryland, USA); VRC = Vaccine Research Center (Bethesda, Maryland, USA). 
TBD = Laboratories to be determined by HVTN Laboratory Program. 
3 Local labs may assign appropriate alternative tube types for locally performed tests. 
4 For persons capable of becoming pregnant, pregnancy test may be performed on urine or blood specimens. 
5 Visit #.X indicates a Redraw visit where # is a Schedule 1 visit number. Confirmatory draw for HIV diagnostics will be collected at the Redraw visit, in addition to the other indicated specimens. The Redraw visit should occur as soon as possible after the 
clinic receives a Redraw Request from the HIV diagnostics laboratory. Multiple subsequent Redraw visits may be necessary; only the EDTA blood specimens for HIV diagnostics, viral isolation/sequencing, and plasma storage will be collected at the 
subsequent Redraw visits. Refer to the HIV Testing SSP for more information. 
6 Functional humoral assays include nAb, ADCC, virion capture, and phagocytosis assays. 
7 Date of diagnosis = date of the initial specimen draw that led to the first Redraw Request. 
8 A 3mL volume is included in the visit totals for drawing a non-additive discard tube to prevent blood tube additive cross-contamination. Refer to the Specimen Collection SSP for more information. 

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Appendix I 
Schedule 4―Laboratory procedures for participants who discontinue infusions 
for reasons other than HIV infection 
Visit:
71
72
73
74
75
76
77
78
Days after enrollment:
D56
D140
D224
D308
D392
D504
D616
D728
Weeks after enrollment:
W8
W20
W32
W44
W56
W72
W88
W104
Procedure
Ship to1
Assay location2
Tube Type3
Tube size
(vol. capacity)3
Total
BLOOD COLLECTION
Screening or diagnostic assays
HIV diagnostics5
UW-VSL /
Peru CTU Laboratory /
CADIG-Immunodiagnostic 
Lab (INI-FIOCRUZ)
UW-VSL /
Peru CTU Laboratory /
CADIG-Immunodiagnostic 
Lab (INI-FIOCRUZ)
EDTA
10mL
10
10
10
10
10
10
10
205
90
Safety labs
CBC/ Differential
Local lab
Local lab
EDTA
5mL
5
—
5
—
5
—
—
—
15
ALT, Creatinine
Local lab
Local lab
SST
5mL
5
—
5
—
5
—
—
—
15
Drug Levels/Detection
VRC01 Ab levels
CSR
NVITAL
SST
8.5mL
y
y
y
y
y
y
y
y
0
ARV detection by serum or plasma8,
CSR
JHU
SST
8.5mL
y
y
y
y
y
y
y
y
0
ARV detection by dried blood spots 9
CSR
HVTN Labs
EDTA
2mL
2
2
2
2
2
2
2
2
16
Immunogenicity & Virologic Assays
Functional humoral assays 6
CSR
HVTN Labs /
VRC / NVITAL
SST
8.5mL
y
y
y
y
y
y
y
y
0
Viral isolation/sequencing8
CSR
TBD
EDTA
10mL
10
10
10
10
10
10
10
10
80
STORAGE
Serum storage
CSR
—
SST
8.5mL
51
42.5
42.5
42.5
42.5
42.5
42.5
42.5
349
PBMC storage
CSR
—
ACD
8.5mL
—
—
—
—
—
—
—
34
34
Visit total10
86
68
78
68
78
68
68
112
623
56-Day total
 
86
68
78
68
78
68
68
112
URINE COLLECTION
Urine dipstick7
Local lab
Local lab
X
—
—
—
—
—
X
—
Pregnancy Test4
Local lab
Local lab
X
—
X
—
X
—
X
—
 
1 CSR = central specimen repository; UW-VSL = University of Washington Virology Specialty Laboratory (Seattle, Washington, USA); Peru CTU Laboratory (Lima, Peru); CADIG - Immunodiagnostic Lab (INI-FIOCRUZ) (Rio de Janeiro, Brazil). 
2 HVTN Laboratories include: South African Immunology Laboratory–National Institute for Communicable Diseases (SAIL-NICD, Johannesburg, South Africa); Duke University Medical Center (Durham, North Carolina, USA),; University of Colorado 
Denver (Denver, Colorado, USA). 
 Non-HVTN laboratories: NVITAL = NIAID Vaccine Immune T-Cell Antibody Laboratory (Gaithersburg, Maryland, USA); VRC = Vaccine Research Center (Bethesda, Maryland, USA); JHU = Johns Hopkins University, HPTN Laboratory Center 
(Baltimore, Maryland, USA). 
TBD = Laboratories to be determined by HVTN Laboratory Program. 
3 Local labs may assign appropriate alternative tube types for locally performed tests. 
4 For participants capable of becoming pregnant; pregnancy test may be performed on urine or blood specimens. 
5 At an early termination visit for a withdrawn or terminated participant (see Section 7.12), blood should be drawn for HIV diagnostic testing, as shown for visit 78 above. 
6 Functional humoral assays include nAb, ADCC, virion capture, and phagocytosis assays. 
7 And microscopy if needed. 
8 EDTA blood collected for plasma may also be used for ARV detection assay, if necessary. 
9 Testing plan for ARV detection to be determined. 
10 A 3mL volume is included in the visit totals for drawing a non-additive discard tube to prevent blood tube additive cross-contamination. Refer to the Specimen Collection SSP for more information. 
y = SST blood collected for serum storage will also cover specimen needs for the VRC01 drug level and functional humoral assays; no separate blood draw is needed. 

HVTN 704/HPTN 085 Version 3.0 / June 15, 2017 
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Appendix J 
Schedule 1―Procedures at CRS for HIV-uninfected participants 
Visit:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Post
Day:
D0
D28 D56 D61 D84 D112 D140 D168 D196 D224 D252 D280 D308 D336 D364 D392 D420 D448 D476 D504 D532 D560 D616 D672 D728
Week:
W0
W4
W8
W12 W16 W20 W24
W28
W32
W36
W40
W44
W48
W52
W56
W60
W64
W68
W72
W76
W80
W88
W96 W104
Procedure
Scr.
Inf#1
Inf#2
Inf#3
Inf#4
Inf#5
Inf#6
Inf#7
Inf#8
Inf#9
Inf#10
Study procedures2
    Signed screening consent (if used)
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
    Assessment of understanding
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
    Signed protocol consent 
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
    Medical history
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
    Complete physical exam
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
X
—
    Abbreviated  physical exam
—
X
—
X
—
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
—
—
—
—
—
    Risk reduction counseling
X
X
—
X
—
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
—
—
—
X
—
    Pregnancy prevention assessment3
X
X
—
X
—
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
—
—
—
X
—
    Confirm eligibility, obtain demographics, randomize
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
    Social impact assessment
—
X
—
X
—
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
—
—
—
X
—
    Participant Questionnaire
—
X
—
X
—
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
—
—
—
X
—
    Concomitant medications
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
—
    HIV infection assessment4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
—
    Confirm HIV test results provided to participant12
—
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
—
Local lab assessment
    Screening HIV test
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
    Urine dipstick11
X
—
—
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
X
—
—
—
—
    Pregnancy (urine or serum HCG)5
X
X
—
X
—
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
—
—
—
    CBC, differential
X
X
—
X
—
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
—
—
—
—
—
    ALT, Creatinine
X
X
—
X
—
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
—
—
—
—
—
    Syphilis 6
—
X7
—
—
—
—
—
—
X7
—
—
—
—
—
X7
—
—
—
—
—
X7
—
—
—
—
—
—
    Chlamydia, Gonorrhea 8
—
X7
—
—
—
—
—
—
X7
—
—
—
—
—
X7
—
—
—
—
—
X7
—
—
—
—
—
—
Study product administration procedures
    IV infusion9
—
X
—
X
—
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
—
—
—
—
—
    Reactogenicity assessment10
—
X
—
X
—
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
—
—
—
—
—
Poststudy
    Unblind participant
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
X
Screening 
visit1
 
1 Screening may occur over the course of several contacts/visits up to and including day 0 prior to infusion. 
2 For specimen collection requirements, see Appendix F. 
3 Pregnancy prevention assessments are required only for participants who are capable of becoming pregnant. 
4 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. 
5 For a participant capable of becoming pregnant, pregnancy test must be performed on the day of infusion prior to infusion. Pregnancy test to determine eligibility may be performed at screening, but must also be done on Day 0 prior to infusion. Persons who 
are NOT capable of becoming pregnant 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. 
6 Syphilis testing will be done by serology. 
7 Syphilis and Chlamydia/Gonorrhea testing will be performed at visits 2, 9 15, and 21; in addition, testing may occur at any visit or if clinically indicated. 
8 Chlamydia/Gonorrhea testing will be done with urine and rectal swabs; oropharyngeal swabs will be collected for gonorrhea testing at visit 2; in addition, testing may occur at any visit if clinically indicated. A combination gonorrhea/chlamydia 
oropharyngeal test is allowable (see the SSP for results reporting). 
9 Blood draws required at infusion 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 must be drawn within 
the 3 days prior to infusion. 
10 Reactogenicity assessments performed for 3 days postinfusion (see Section 7.10). 
11 And microscopy if needed. 
12 If HIV test results are not available at the visit indicated, provide test results at next available opportunity. 

HVTN 704/HPTN 085 Version 3.0 / June 15, 2017 
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Appendix K 
Schedule 2―Procedures at CRS for HIV-1–infected participants  
 
Visit Number: #.X1 
 
31 
32 
33 
34 
35 
 
Days after 
diagnosis2 D28 D42 
D56 
D84 D168 
 
Weeks after 
diagnosis 
4 
6 
8 
12 
24 
Study procedures3 
 
 
 
 
 
 
 
Counseling on HIV-1 testing/diagnosis 
X 
 
X 
— 
— 
— 
— 
Abbreviated physical exam4 
X 
 
X 
X 
X 
X 
— 
Complete physical exam4 
— 
 
— 
— 
— 
— 
X 
ART assessment 
X 
 
X 
X 
X 
X 
X 
Concomitant medications 
— 
 
X 
X 
X 
X 
X 
Intercurrent illness/adverse experience 
— 
 
X 
X 
X 
X 
X 
Transmission risk reduction counseling 
X 
 
X 
X 
X 
X 
X 
Behavioral risk assessment questionnaire 
— 
 
— 
— 
— 
— 
X 
Social impact assessment 
X 
 
X 
X 
X 
X 
X 
Local lab assessment3 
 
 
 
 
 
 
 
Pregnancy test5 
X 
 
— 
— 
— 
X 
— 
CD4+ T cell count 
X 
 
X 
X 
X 
X 
X 
Hemoglobin 
 
 
 
 
X 
X 
 
 
1 Visit #.X indicates a Redraw visit where # is a Schedule 1 visit number. Confirmatory draw for HIV diagnostics will be collected at the Redraw visit. The Redraw visit should occur as soon as possible after the clinic receives a Redraw Request from the HIV 
diagnostics laboratory. Multiple Redraw visits may be necessary; only the blood specimen indicated in Appendix G will be collected at the subsequent Redraw visits. 
2 Date of diagnosis = date of the initial specimen draw that led to the first Redraw Request 
3 For specimen collection requirements, see Appendix G. 
4 Includes assessment of HIV/AIDS-related conditions. 
5 For participants capable of becoming pregnant, pregnancy test may be performed on urine or blood specimens. 

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Appendix L 
Schedule 3―Procedures at CRS for participants discovered to have been HIV-1–
infected at enrollment or who become HIV-2–infected 
Visit Number #.X1 
 
47 
48 
 
Days after 
diagnosis2 
D28 D168 
 
Weeks after 
diagnosis 
4 
24 
Study procedures3 
 
 
 
 
Counseling on HIV-1 testing/diagnosis 
X 
 
X 
— 
Abbreviated physical exam4 
X 
 
X 
— 
Complete physical exam4 
— 
 
— 
X 
ART assessment 
X 
 
X 
X 
Concomitant medications 
— 
 
X 
X 
Intercurrent illness/adverse experience 
— 
 
X 
X 
Transmission risk reduction counseling 
X 
 
X 
X 
Behavioral risk assessment questionnaire 
— 
 
— 
X 
Social impact assessment 
X 
 
X 
X 
Local lab assessment3 
 
 
 
 
Pregnancy test5 
X 
 
— 
— 
CD4+ T cell count 
X 
 
X 
X 
  1 Visit #.X indicates a Redraw visit where # is a Schedule 1 visit number. Confirmatory draw for HIV diagnostics will be collected at the Redraw visit. The Redraw visit should occur as soon as possible after the clinic receives a Redraw Request from the 
HIV diagnostics laboratory. Multiple Redraw visits may be necessary; only the blood specimens indicated in Appendix H will be collected at the subsequent Redraw visits. 
2 Date of diagnosis = date of the initial specimen draw that led to the first Redraw Request 
3 For specimen collection requirements, see Appendix H. 
4 Includes assessment of HIV/AIDS-related conditions. 
5 For participants capable of becoming pregnant, pregnancy test may be performed on urine or blood specimens. 

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Appendix M 
Schedule 4―Procedures at CRS for participants who discontinue infusions for 
reasons other than HIV infection 
 
Visit Number: 
71 
72 
73 
74 
75 
76 
77 
78 
Days after enrollment: 
56 
140 
224 
308 
392 
504 
616 
728 
Weeks after enrollment: 
8 
20 
32 
44 
56 
72 
88 
104 
Study procedures1 
 
 
 
 
 
 
 
 
Abbreviated physical exam 
X 
X 
X 
X 
X 
X 
X 
— 
Complete physical exam 
— 
— 
— 
— 
— 
— 
— 
X 
Risk reduction counseling 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Intercurrent illness/adverse experience 
X 
X 
X 
X 
X 
X 
X 
X 
HIV infection assessment2 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm HIV test results provided to participant3 
X 
X 
X 
X 
X 
X 
X 
X 
Behavioral risk assessment questionnaire 
— 
X 
— 
X 
— 
X 
— 
X 
Social impact assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Local lab assessment1 
 
 
 
 
 
 
 
 
Urine dipstick4 
X 
— 
— 
— 
— 
— 
X 
— 
Pregnancy test5 
X 
— 
X 
— 
X 
— 
X 
— 
 
1 For specimen collection requirements, see Appendix I. 
2 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. 
3 If HIV test results are not available at the visit indicated, provide test results at next available opportunity. 
4 And microscopy if needed. 
5 For participants capable of becoming pregnant, pregnancy test may be performed on urine or blood specimens. 

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Appendix N 
Protocol Signature Page 
 
A phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing 
monoclonal antibody in reducing acquisition of HIV-1 infection among men and 
transgender persons who have sex with men 
I will conduct the study in accordance with the provisions of this protocol and all 
applicable protocol-related documents. I agree to conduct this study in compliance with 
United States (US) Health and Human Service regulations (45 CFR 46); applicable U.S. 
Food and Drug Administration regulations; standards of the International Conference on 
Harmonization Guideline for Good Clinical Practice (E6); Institutional Review 
Board/Ethics Committee determinations; all applicable in-country, state, and local laws 
and regulations; and other applicable requirements (e.g., US National Institutes of Health, 
Division of AIDS) and institutional policies 
 
 
 
 
 
 
 
 
 
Investigator of Record Name (print) 
 
Investigator of Record Signature 
 
Date 
 
 
DAIDS Protocol Number: HVTN 704/HPTN 085 
DAIDS Protocol Version: Version 3.0 
Protocol Date: June 15, 2017