A Phase 2b Study to Evaluate the Safety and Efficacy of VRC01 Broadly Neutralizing Monoclonal Antibody in Reducing Acquisition of HIV-1 Infection in Women in Sub-Saharan Africa
Phase: PHASE2
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
PROTOCOL 
HVTN 703/HPTN 081 
A phase 2b study to evaluate the safety and efficacy of 
VRC01 broadly neutralizing monoclonal antibody in 
reducing acquisition of HIV-1 infection in women in sub-
Saharan Africa 
DAIDS DOCUMENT ID 12045 
 
 
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 
December 14, 2017 
HVTN 703/HPTN 081 
Version 4.0 

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HVTN703-HPTN081_v4.0_FINAL / Page 2 of 193 
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 ............................................................15 
2.4 
Trial design rationale ....................................................................................16 
2.5 
Combination prevention for HIV acquisition ...............................................22 
2.6 
Plans for future product development and testing ........................................25 
2.7 
Preclinical safety studies ..............................................................................26 
2.8 
Nonhuman primate (NHP) studies of VRC01 ..............................................29 
2.9 
Clinical trial experience ...............................................................................32 
2.10 Potential risks of study products and administration ...................................40 
3 Objectives and endpoints .............................................................................................42 
3.1 
Primary objectives and endpoints ................................................................42 
3.2 
Secondary objectives and endpoints ............................................................42 
3.3 
Exploratory objectives ..................................................................................43 
4 Statistical considerations ..............................................................................................44 
4.1 
Outline of the statistical considerations section ...........................................44 
4.2 
PE parameters for measuring mAb efficacy and associated primary and 
secondary hypothesis tests ...........................................................................44 
4.3 
Statistical rationale for the 3-arm design compared to a 2-arm design ........45 
4.4 
Sample size calculations for testing for overall PE (Primary objective 2) ...46 
4.5 
Power for the secondary analysis comparing HIV-1 incidence between the 
10 mg/kg mAb group versus the 30 mg/kg mAb group ...............................54 
4.6 
Sample size calculations for safety ..............................................................55 
4.7 
Monitoring of the trial ..................................................................................56 
4.8 
Assessment of PrEP use ...............................................................................61 
4.9 
Randomization .............................................................................................61 
4.10 Blinding ........................................................................................................62 
4.11 Statistical analyses ........................................................................................62 
5 Selection and withdrawal of participants .....................................................................77 
5.1 
Inclusion criteria ...........................................................................................77 
5.2 
Exclusion criteria ..........................................................................................79 
5.3 
Participant departure from infusion schedule or withdrawal .......................80 
6 Study product preparation and administration .............................................................83 
6.1 
Study product regimen .................................................................................83 
6.2 
Study product formulation ...........................................................................83 
6.3 
Preparation of study products .......................................................................85 
6.4 
Administration ..............................................................................................87 
6.5 
Acquisition of study products ......................................................................88 
6.6 
Pharmacy records .........................................................................................88 
6.7 
Final disposition of study products ..............................................................88 

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7 Clinical procedures ......................................................................................................89 
7.1 
Informed consent ..........................................................................................89 
7.2 
Pre-enrollment procedures ...........................................................................91 
7.3 
Enrollment and infusion visits ......................................................................92 
7.4 
Post-infusion visits for HIV-uninfected study participants ..........................94 
7.5 
HIV counseling and testing ..........................................................................95 
7.6 
Follow-up visits for HIV-infected participants ............................................96 
7.7 
Follow-up visits for participants who discontinue infusions for reasons other 
than HIV infection ........................................................................................97 
7.8 
Contraception status .....................................................................................98 
7.9 
Urine testing .................................................................................................98 
7.10 Assessments of reactogenicity .....................................................................99 
7.11 Visit windows and missed visits ................................................................100 
7.12 Early termination visit ................................................................................100 
7.13 Pregnancy ...................................................................................................100 
8 HIV infection assessment and clinical response ........................................................101 
8.1 
HIV symptom assessment ..........................................................................101 
8.2 
HIV screening test (prior to randomization) ..............................................101 
8.3 
HIV testing postinfusion ............................................................................101 
8.4 
Endpoint adjudication ................................................................................102 
8.5 
HIV infection during the study ...................................................................102 
8.6 
Medical care for participants who become HIV infected...........................103 
9 Laboratory ..................................................................................................................104 
9.1 
CRS laboratory procedures ........................................................................104 
9.2 
Total blood volume ....................................................................................104 
9.3 
Assay timepoints ........................................................................................104 
9.4 
VRC01 mAb levels ....................................................................................104 
9.5 
Endpoint assays: humoral ...........................................................................105 
9.6 
ARV detection ............................................................................................105 
9.7 
Host (human) genotyping ...........................................................................106 
9.8 
Lab assay algorithm ...................................................................................106 
9.9 
Possible additional studies .........................................................................106 
9.10 Other use of stored specimens ....................................................................106 
9.11 Biohazard containment ...............................................................................107 
10 Safety monitoring and safety review .........................................................................108 
10.1 Safety monitoring and oversight ................................................................108 
10.2 Safety reporting ..........................................................................................109 
10.3 Safety pause and prompt PSRT AE review................................................112 
10.4 Review of cumulative safety data ..............................................................113 
10.5 Study termination .......................................................................................114 
10.6 Social impact reporting ..............................................................................114 
11 Protocol conduct ........................................................................................................116 
11.1 Emergency communication with study participants ..................................117 
12 Ethical considerations ................................................................................................118 
13 IRB/EC/RE review considerations ............................................................................120 

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13.1 Minimized risks to participants ..................................................................120 
13.2 Reasonable risk/benefit balance .................................................................121 
13.3 Equitable subject selection .........................................................................121 
13.4 Appropriate informed consent ....................................................................121 
13.5 Adequate safety monitoring .......................................................................122 
13.6 Protect privacy/confidentiality ...................................................................122 
14 Version history ...........................................................................................................123 
15 Document references (other than literature citations) ................................................129 
16 Acronyms and abbreviations......................................................................................131 
17 Literature cited ...........................................................................................................134 
Appendix A Sample informed consent form ..................................................................148 
Appendix B Approved birth control methods (for sample informed consent form) ......168 
Appendix C Sample consent form for use of samples and information in other studies 169 
Appendix D Tables of procedures (for sample informed consent form) ........................174 
Appendix E Sample consent form for participants with HIV infection at enrollment or 
during the study ..........................................................................................177 
Appendix F Schedule 1—Laboratory procedures for HIV-uninfected participants ......181 
Appendix G Schedule 2—Laboratory procedures for HIV-1–infected participants ......183 
Appendix H Schedule 3―Laboratory procedures for participants discovered to have 
been HIV-1–infected at enrollment or who become HIV-2–infected ........185 
Appendix I Schedule 4―Laboratory procedures for participants who discontinue 
infusions for reasons other than HIV infection ..........................................187 
Appendix J Schedule 1―Procedures at CRS for HIV-uninfected participants ............188 
Appendix K Schedule 2―Procedures at CRS for HIV-1–infected participants ............190 
Appendix L Schedule 3―Procedures at CRS for participants discovered to have been 
HIV-1–infected at enrollment or who become HIV-2–infected ................191 
Appendix M Schedule 4―Procedures at CRS for participants who discontinue infusions 
for reasons other than HIV infection ..........................................................192 
Appendix N Protocol Signature Page .............................................................................193 
 

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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 in 
women in sub-Saharan Africa 
Primary objectives 
 To evaluate the safety and tolerability of VRC01 mAb administered through 
IV infusion in sub-Saharan African women 
 To determine if the VRC01 mAb prevents HIV-1 infection and to estimate the 
level of efficacy in sub-Saharan African women 
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  
634* 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
 
 
Group 
2 
VRC01  
30 mg/kg  
634* 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
 
 
Group 
3 
Control 
634* 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
 
 
 
Total:      1900 (63300 VRC01 30 mg/kg; 633 VRC01 10 mg/kg; 634 control) 
* Due to the randomization scheme, the numbers of vaccine 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. 
Participants 
1900 women in sub-Saharan Africa aged 18-40 who are at risk of HIV-1 
infection; 2:1 active:control allocation; total approximately 1268 VRC01 mAb, 
634 control 

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Design 
Multicenter, randomized, controlled, double-blind trial 
Duration per participant 
24 months of scheduled clinic visits  
Estimated total study duration 
60 months (includes enrollment and follow-up, including follow-up for HIV-
infected participants) 
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) 
 HIV Sero-Molecular Laboratory, National Institute for Communicable 
Diseases (HSML-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 Cape Town (UCT) (Cape Town, South Africa) 
 University of Colorado, Denver (UC Denver) (Denver, Colorado, USA) 
Study sites 
Clinical Research Sites (CRSs) to be specified in the Site Announcement Memo 
Safety monitoring 
HVTN 703/HPTN 081 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 
HVTN Regional 
clinical safety 
liaison for Africa 
Keitumetse Diphoko  
HCRISA 
 
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 

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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 
 
 

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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 
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/recruiter
s 
DaShawn Usher 
New York Blood 
Center, New York, 
NY, USA  
 
Jim Wick 
Bridge HIV. San 
Francisco, CA, USA  
 
Luciana Kamel 
Instituto de Pesquisa 
Clinica Evandro 
Chagas (IPEC)  
 
 
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. 

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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 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.  
 

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Figure 2-1 Neutralizing antibody epitopes on native Env timer  
As shown in Figure 2-2, several of these antibodies have shown considerable 
breadth of neutralization in in vitro testing.  

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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].  
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.  
B 
C 
A 

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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 

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doses than those suggested by SHIV challenge studies in NHP. It must also be 
recognized that the lowest challenge 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 in 1900 sexually active women in sub-Saharan 
Africa. 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.  

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The cohort for this study was selected based on regional epidemiological data. 
There were approximately 24.7 million people living with HIV in sub-Saharan 
Africa in 2013, representing over 70% of the global HIV burden. HIV prevalence 
in sub-Saharan Africa continues to be higher than anywhere else in the world. 
Women in sub-Saharan Africa are disproportionately impacted, accounting for 
nearly 60% of all people living with HIV in the region in 2013. There are 
approximately 16 million women ≥ 15 years old who are living with HIV; 80% 
live in sub-Saharan Africa. Young women 15-24 years old in sub-Saharan Africa 
are twice as likely as young men to be living with HIV, with acquisition rates 
among heterosexual women as high as 6-8% annually in some locations [60]. In 
recent clinical trials in southern Africa, annual HIV-1 incidence rates of 1.9-9.1% 
have been observed among sexually-active women [61-67]. Yet, there are 
currently no biomedical HIV prevention tools proven to protect women at high 
risk of HIV infection in sub-Saharan Africa. Fortunately there are biomedical 
tools with demonstrated HIV prevention success for men at high risk of HIV 
infection in sub-Saharan Africa (eg, medical male circumcision, oral PrEP). With 
this context in mind, and recognizing that we have limited resources for this trial 
that prevent us from addressing the HIV prevention needs of all populations, this 
trial in sub-Saharan Africa is designed to: evaluate the effectiveness of AMP, 
inform future research on AMP and related prevention approaches (eg, HIV 
vaccines), and develop a biomedical tool to reduce the disproportionate HIV 
incidence among sub-Saharan African women. Conducting the study in 
heterogeneous cohorts of overall lesser risk (eg, men as well as women in sub-
Saharan Africa), would require larger sample sizes in order to answer the study 
questions. We look forward to extending what we learn in this trial to other 
cohorts, including men at high risk of HIV infection in sub-Saharan Africa. 
We note that a parallel study assessing the safety and preventive efficacy of 
VRC01 is being conducted among 2700 men and transgender persons who have 
sex with men or transgender persons in the Americas and Europe. That study, 
designated HVTN 704/HPTN 085, will be conducted over approximately the 
same time period as HVTN 703/HPTN 081. 
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 control 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 

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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. 
 
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 

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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.  
 
 
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 [68-70]. 

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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, 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 [71]. 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 [72]. 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 among VRC01 recipients than in 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 

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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 [73] 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 4.7. Full details regarding 
implementation of monitoring for this trial are contained in a separate trial 
monitoring plan. 
2.5 
Combination prevention for HIV acquisition 
In 2013, sub-Saharan Africa bore more than 70% of the global burden of HIV 
infections and women accounted for nearly 60% of all those living with HIV in 
the region. Of all the women in the world who live with HIV, 80% live in sub-
Saharan Africa [60]. Hence it is essential that approaches to reducing HIV 
infection risk be made available to the women participating in this clinical trial.  
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 [74], free 
condoms and lubricant, counseling and referral for postexposure prophylaxis 
(PEP) when indicated, and, where appropriate, access to oral drugs for pre-
exposure prophylaxis (PrEP, see below). These activities can be expected to 
reduce HIV acquisition below historical levels. The contribution of these efforts 
will be monitored. Further details on these efforts are provided in the HVTN 
703/HPTN 081 Study Specific Procedures (SSP) and the HVTN 703/HPTN 081 
website. It should be emphasized that because the benefit of VRC01 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 [7,75-
79]. However, aside from women in HIV-discordant couples [80], comparable 
efficacy has not as consistently been demonstrated in trials evaluating topical or 
oral tenofovir (TFV)-based regimens among at-risk women in sub-Saharan 
Africa. While the CAPRISA 004 trial demonstrated a 39% reduction in HIV 
infection with pericoital application of TFV 1% vaginal gel among at-risk women 
in South Africa [65], efficacy was not seen in the larger, more recent FACTS 001 
trial conducted among young South African women [81]. In 2011 the FEM-PrEP 
trial was stopped early because of lack of efficacy of once daily oral FTC/TDF 
among at-risk women in Kenya, South Africa, and Tanzania [66]. In 2011 the 
VOICE trial, conducted in Uganda, South Africa, and Zimbabwe, reported no 
efficacy of once daily oral TDF or TFV 1% gel; in 2013, this trial reported no 
efficacy for once daily oral FTC/TDF [82]A meta-analysis of these trial results 

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shows that effectiveness correlates strongly with PrEP adherence (see Figure 
2-6)[83]; because adherence was poor in the trials that generated the largest 
number of infection events (FEM-PrEP and VOICE), overall PrEP efficacy in 
southern African trials appears particularly disappointing. However, in addition to 
adherence, other factors may also contribute to the conflicting results observed in 
women, including differences in the study populations (discordant couples versus 
uninfected individuals), differing demographic and behavioral characteristics, 
prevalent HIV subtypes, differing transmission modes (mucosal versus 
parenteral), and underlying host factors such as genital tract inflammation and/or 
copathogens [83]. In addition, pharmacokinetic studies report lower 
concentrations of PrEP drug in vaginal as compared to rectal mucosa [84], 
suggesting that efficacy mediators may differ between men and women and that 
PrEP efficacy may be more sensitive to adherence in women than in men [85]. 
Figure 2-6 Forest plot showing point estimates and 95% confidence intervals of PrEP 
effectiveness, meta-analysis estimates, and meta-analysis regression results for major PrEP 
trials in women [83] 
 
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 [86]. 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 [87]. 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 

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recommendation to include adult heterosexually active persons at substantial risk 
of HIV acquisition [88,89]. PrEP has since been incorporated into WHO 
guidelines for ARV use for HIV treatment and prevention [90,91]; a revised and 
more comprehensive WHO PrEP guideline is anticipated in 2016. Notably, the 
Republic of South Africa and Kenya approved FTC/TDF for use as PrEP in 
December 2015. 
2.5.3 
Operationalizing PrEP access in sub-Saharan Africa 
Although the WHO released updated guidance documents on universal test and 
treat and recommendations for PrEP in late 2015, most countries in this region are 
in the process of regulating antiretrovirals for prevention, and it is envisaged that 
PrEP use will be scaled up over time in the ensuing 5-10 years. Going to scale in a 
generalized heterosexual epidemic will require significant financial investment. 
For this reason, countries are currently investigating the fiscal impacts of the new 
guidelines and are in discussions to develop demonstration projects to evaluate 
mechanisms for the successful roll out of PrEP to key populations. The threshold 
for PrEP roll-out in-country will depend on: 1) the epidemiology context; 2) 
availability of resources; 3) the cost of the intervention; 4) the feasibility of 
delivering this service; and 5) demand. There are limited donor-driven 
demonstration PrEP projects in Africa and countries are working closely with 
PEPFAR and the Global Fund to design demonstration projects that are 
potentially sustainable in the long-term.  
As an example, South Africa recently registered FTC/TDF for prevention and is 
developing guidelines for its use. These guidelines stipulate that prep must be 
delivered in the service delivery setting with the main guiding principal of 
informed and voluntary choice and equitable access. There is a commitment by 
the Republic of South Africa to strategically expand the reach and coverage of the 
antiretroviral programme in such manner of it being equitable and non-
discriminatory. Although FTC/TDF is not yet available in the public sector for 
use in prevention, the South African government through the National 
Department of Health (NDOH) intends to conduct demonstration projects, in 
conjunction with key donors, in key populations such as sex workers and MSM, 
as well as in geographic locations that have a high burden of HIV. However, 
FTC/TDF for prevention is not yet on the Essential Drug List, which is a pre-
requisite for use in the public sector through which the vast majority of South 
Africans secure health care.  
Currently an investment case evaluating the new WHO guidelines is being 
undertaken by the South African government. While the investment case for 
universal test and treat is clear, and this will be rolled out as a priority, the 
investment case for PrEP is less certain and is being evaluated. Initially the 
NDOH plans to evaluate PrEP in key population groups such as sex workers and 
MSM. The roll-out of PrEP in young women is more complex and the NDOH is 
developing guidelines as to how this may occur. 

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For these reasons, the protocol team plans to work collaboratively with national 
regulatory and other government agencies to develop mechanisms for PrEP access 
that are supportive of and consistent with national priorities and strategic 
objectives in the several sub-Saharan African countries where this study is being 
implemented. 
Given the potential of FTC/TDF to prevent HIV acquisition, it could be argued 
that substantial uptake of PrEP could prevent the HVTN 703/HPTN 081 trial from 
detecting any benefit of VRC01 beyond the universal prevention package. This 
possibility is addressed in the sample size and power calculations (see Section 
4.4) and in plans for trial monitoring by the DSMB (see Section 4.7 and, 
specifically, Section 4.7.3). If the background HIV incidence rate is too low to 
support evaluation of VRC01 prevention efficacy, the DSMB will detect this and 
will make recommendations to the team accordingly. The study team will monitor 
PrEP availability and roll-out in-country; and within the protocol, evaluate 
individual use via questionnaires and blood drug levels. In support of a 
comprehensive package of prevention, PrEP will be discussed in the informed 
consent process, in risk reduction counseling sessions, and referral systems into 
demonstration projects, health service delivery settings, and the private sector will 
be developed to support those who wish to access PrEP. 
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 

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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. 
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 

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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-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]. 

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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. 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 

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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 

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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. 
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. 
 

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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].  
 
 
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].  

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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. 
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. 

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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; 
 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 

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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.  
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 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]. 

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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 

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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 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 a 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. 

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 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 1, 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 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).  

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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. 
 
 
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 

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placebo/control product administration that resulted in an incomplete 
administration.  
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 injection of 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, opaque 
to translucent particles after thawing. When particles are observed, they may 
disappear after a few hours at room temperature or storage at 2°C to 8°C. For 
additional information, see the IB. 

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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 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 [106]. 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. 

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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.  
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 sub-Saharan African women 
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 sub-Saharan African women 
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 4.3 summarizes a 
statistical rationale for using a 3-arm design, which adds to the scientific rationale 
provided in Section 2.4. Section 4.4 describes sample size and power 
considerations for the primary efficacy objectives, which justify the sample size 
of the trial. Section 4.4 also provides operating characteristics of the trial design 
for addressing the primary efficacy objective. Section 4.5 describes statistical 
power available for the secondary objective that compares PE between the two 
mAb dose groups. Section 4.6 describes statistical power available for detecting 
safety problems of the mAb in terms of SAEs. Section 4.7 summarizes the 
approach to monitoring the trial including interim analysis reports provided to the 
DSMB. Sections 4.8, 4.9, and 4.10 describe ARV assessments, randomization, 
and blinding, respectively. Section 4.11 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 parameters for measuring mAb efficacy and associated primary 
and secondary hypothesis tests 
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.  
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 

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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 
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 
4.3 
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 of H1: PE > 0% is very similar between the two 
trial designs, for the same total number of study participants. By providing results 

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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 [111,112]. 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 HIV-1 susceptibility factor that is not caused by 
administration of the mAb [113-115]. 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. 
4.4 
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 [116]. 
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. 

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4.4.1 
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 
 27 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 
 4.0% annual HIV-1 incidence in the control group 
 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 4.4.6. 
We also show power calculations allowing for lower levels of HIV-1 incidence. 
In particular, we show power calculations assuming 3.3% annual HIV-1 incidence 
in the control group, which would account for lower than expected incidence rates 
due to increased PrEP usage.  
4.4.2 
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 

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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 [117], 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 total sample size 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 = 1800 total participants are needed to achieve 90% 
power to detect PE = 60%; the sample size N = 1900 total participants (~634 per 
arm) is selected to build in a provision of robustness to the control group annual 
incidence being lower than 4.0%.  
 
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% 
2.7 
10% 
7.4 
20% 
18.7 
30% 
37.0 
40% 
60.5 
50% 
82.1 
60% 
95.1 
70% 
99.4 
80% 
>99.9 
90% 
>99.9 
95% 
>99.9 

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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 of a dose-pooled VRC01 efficacy PE equal to 60%, regardless 
of whether VRC01 efficacy differs by dose group. 
4.4.3 
Additional operating characteristics of the design for assessing 
primary objective 2 
For the selected sample size (N = 1900), 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 is included in the figure. At the lower incidence of 3.3%, there is 
90.5% power to detect PE = 60%. Section 4.4.6 describes the rationale for the 
incidence assumptions in this trial. 

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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. A power curve is also shown for a lower than expected HIV-1 incidence rate. 
4.4.4 
Additional operating characteristics of the primary analysis 
accounting for the sequential monitoring 
For the selected sample size (N = 1900), 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 

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analysis to reject the null hypothesis H0: PE ≤ 0% in favor of the alternative 
hypothesis H1: PE > 0%. 
 
Figure 4-3 Probabilities of reaching each possible trial monitoring outcome, and 
unconditional power to reject the primary null hypothesis H0: PE ≤ 0% with 634 control 
recipients and 1268 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 
95.5 
4.5 
0.0 
0.0 
2.5 
87.7 
12.3 
0.0 
0.0 
2.0 
67.7 
32.3 
0.0 
0.0 
1.5 
34.3 
65.7 
0.0 
0.0 
0% 
1.0 
5.1 
92.2 
0.0 
2.7 
10% 
0.9 
2.4 
90.3 
0.0 
7.4 
20% 
0.8 
1.0 
80.3 
0.0 
18.7 
30% 
0.7 
0.3 
62.6 
0.0 
37.0 
40% 
0.6 
0.1 
39.4 
0.0 
60.5 
50% 
0.5 
0.0 
17.9 
0.0 
82.1 
60% 
0.4 
0.0 
4.9 
0.0 
95.1 
70% 
0.3 
0.0 
0.6 
2.1 
99.4 
80% 
0.2 
0.0 
0.0 
21.4 
>99.9 
90% 
0.1 
0.0 
0.0 
82.6 
>99.9 
95% 
0.0 
0.0 
0.0 
98.6 
>99.9 
N = 634:1268 Control:mAb group 
4.0% 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 

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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 alternative hypothesis scenario PE = PE10 = PE30 = 60%. Under the 
design alternative hypothesis scenario, the calculations show that 35 HIV-1 
infection endpoints are expected in the control group and 28 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 
1 
1 
0% 
52 
4 
8 
0% 
78 
10 
20 
0% 
104 
18 
35 
0% 
130 
23 
47 
0% 
156 
26 
51 
0% 
182 
26 
53 
0% 
197 
26 
54 
60% 
0 
0 
0 
60% 
26 
1 
0 
60% 
52 
4 
3 
60% 
78 
10 
8 
60% 
104 
18 
14 
60% 
130 
26 
21 
60% 
156 
31 
25 
60% 
182 
34 
28 
60% 
197 
35 
28 
4.4.5 
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. A power curve is also shown for a lower than expected HIV-1 
incidence rate. 
4.4.6 
Rationale for the HIV-1 incidence assumptions 
The assumption of 4.0% annual HIV-1 incidence for the control group is based on 
recent data directly measuring HIV-1 incidence in women at several African sites 
[6,61,64-67,81,82,118]. The overall annual incidence rate in the VOICE study 
was 5.7%, which pools over all intervention groups given the similar incidence 
rates and the lack of significant differences. The annual incidence rate of female 
control recipients in the Phambili study, at 5.1%. The Fem-Prep and ASPIRE 
studies had annual incidence rates of 5.0% and 4.5%, respectively, in the control 
groups. The FACTS-001 trial showed no efficacy and the annual incidence was 
4.0% for both study arms. 
The total sample size N=1900 builds in a conservative margin, where the smallest 
control group annual incidence under which there is at least 90% power to detect 
PE = 60% is 3.3%. Moreover, power is 81.9% to detect PE = 60% if the control 
group annual incidence is 2.56%. This scenario of 2.56% annual incidence is 
consistent with the following scenario in which many study participants choose to 
use Truvada PrEP: 60% of person-years at-risk are without PrEP use and a 4.0% 
control group annual incidence, and the other 40% of person-years at-risk are with 
PrEP use at 90% PrEP efficacy and thus a 0.4% control group annual incidence. 
In this scenario, an assumption of 75% (instead of 90%) PrEP efficacy yields the 
control-group annual incidence of 2.8% (instead of 2.56%). 
Based on a synthesis of the above-cited references using control arms or active 
arms in trials that showed no efficacy, we assume that the background annual 
incidence of HIV-1 in sub-Saharan African women in the absence of any PrEP 

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use is 5.1%. It is difficult to predict the degree of PrEP use that will occur in sub-
Saharan African women. Given that the South African Medicines Control Council 
(MCC) approved fixed-dose emtricitabine/tenofovir disoproxil fumarate 
(FTC/TDF) for use as PrEP only recently (December 2015) and the drug is not yet 
available in the public sector on which the vast majority of South Africans depend 
for health care and pharmaceuticals. While the government of South Africa is 
committed to rolling PrEP out as part of its HIV prevention efforts and is 
currently undertaking a limited number of narrowly targeted demonstration 
projects, when PrEP will be available more broadly in South Africa is unclear. 
The situation is equally uncertain in the other sub-Saharan countries in which this 
trial will be conducted. Assuming 15% of the PYRs under PrEP use with 90% 
(75%) PrEP efficacy leads to 4.4% (4.5%) control-group annual incidence. This 
protocol assumes conservatively 4.0% annual incidence in the control group. 
Higher than expected use of PrEP will be reflected in lower than expected annual 
incidence rates. As shown in Figure 4-2, however, 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. 
4.5 
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 moderately powered to detect large differences (eg, 
65.6% power to discriminate 30% vs 70% PE) but may miss moderate differences 
(eg, 37% 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. 
Table 4-4 Statistical power for comparing the 10 versus 30 mg/kg mAb groups: Power to 
select the best mAb group and power to correctly select the best mAb group 
PE10 
PE30 
Power to Select Best mAb 
Dose Group$ 
Power to Detect PE10 
Different from PE30# 
20% 
60% 
84.1 
55.2 
30% 
60% 
82.4 
37.7 
40% 
60% 
77.7 
19.0 
30% 
70% 
96.0 
65.6 
50% 
85% 
99.0 
72.5 
$ 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 that 
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) 

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4.6 
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 = 634) versus the control group 
(Group 3 with n = 634). 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 = 
634 (or the combined mAb groups n2 = 1268) and a control group of size 
n0 = 634. 
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 = 634) 
Observed event 
rate in single 
mAb group 
(n1 = 634) 
Observed event 
rate in 
combined mAb 
groups 
(n1 = 1268) 
Rate 
difference 
(mAb group 
– control) 
95 % CI 
(n1 = 634) 
95% CI 
(n1 = 1268) 
0% 
 2% 
 2% 
2% 
(0.0116, 0.0341) 
(0.0136, 0.0293) 
4% 
4% 
4% 
(0.0273, 0.0582) 
(0.0305, 0.0523) 
10% 
10% 
10% 
(0.0790,  0.1258) 
 (0.0847,  0.1177) 
20% 
20% 
20% 
(0.1707,  0.2329) 
(0.1789,  0.2229) 
 
 
 
 
 
 
2% 
 2% 
 2% 
0% 
(-0.0164,  0.0164) 
(-0.0155,  0.0126) 
4% 
4% 
2% 
(0.0013, 0.0403) 
(0.0032,  0.0351) 
10% 
10% 
8% 
(0.0553, 0.1075) 
(0.0598, 0.1000) 
20% 
20% 
18% 
 (0.1482, 0.2114) 
(0.1554, 0.2049) 
 
 
 
 
 
 
4% 
 2% 
 2% 
-2 % 
(-0.0403,  -0.0013) 
(-0.0394, -0.0044) 
4% 
4% 
0% 
(-0.0222,  0.0222) 
(-0.0205,   0.0177) 
10% 
10% 
6% 
(0.0325, 0.0891) 
(0.0365,  0.0822) 
20% 
20% 
16% 
(0.1261, 0.1957) 
( 0.1327, 0.1867) 
*95% CIs are computed using the method of Miettinen and Nurminen [119]. Entries are bolded where 
significantly more events are observed among mAb recipients than among control recipients based on the 
95% CI. 
Figure 4-5 shows the power to detect an elevated SAE rate as a function of the 
true rate in the mAb group under consideration. 

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Figure 4-5 Power to detect a greater SAE rate in a mAb group versus the control group 
given a 4% SAE rate in the control group (2-sided 0.05-level test) 
Figure 4-5 shows that there is 80% power to detect a higher SAE rate in a mAb 
arm if the true SAE rate is 7.8% and 90% power if the true rate is 8.5%. 
4.7 
Monitoring of the trial 
4.7.1 
Role of the Data and 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.  

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4.7.1.1 
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 4-6. 
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. 

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Figure 4-6 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 
[73]).  
4.7.2 
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. 
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. 
4.7.3 
Monitoring for futility to assess PE 
The objective of monitoring the trial for futility to assess PE is to monitor 
progress toward the minimal needed target number of treatment arm-pooled HIV-

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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 50% 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 57 and 21, 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 50% 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 November 2017, 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 ≥ 57 
(target 1) with 95% credible intervals, 
c. the estimated probability that the total number of HIV-1 infections is ≥ 21 
(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: 
 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 

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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 = 0% (the null hypothesis). 
The reason for conducting the estimation procedure twice is that the purpose of 
the results for the 57 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 
21 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 at least 57 total 
infections is less than 25%, the Oversight Committee 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 at least 21 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%.  

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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 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. 
4.8 
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 TFV (see Section 9.6),  using a 
calendar based selection of visits that will ensure representative sampling of 
participants across the entire visit schedule at all sites throughout the study. 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. 
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. 
4.9 
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).  

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4.10 
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 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 703/HPTN 081 PSRT should be consulted before emergency 
unblinding occurs. 
4.11 
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. 
4.11.1 
Analysis variables 
The analysis variables consist of baseline participant characteristics, safety, 
efficacy, and markers of mAb characteristics for primary- and secondary-
objective analyses. 
4.11.2 
Baseline comparability 
Treatment arms will be compared for baseline participant characteristics using 
descriptive statistics. 

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4.11.3 
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. 
4.11.3.1 
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. 
4.11.3.2 
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.  
4.11.3.3 
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. 

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4.11.3.4 
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. 
4.11.4 
Efficacy analysis 
4.11.4.1 
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 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 PE 
using Cox proportional hazards models with score tests stratified by VRC01 dose 
group for testing whether PE 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 

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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 VRC01 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].  
4.11.5 
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.  
4.11.6 
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 (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. 
4.11.7 
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  

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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. 
4.11.7.1 
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 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-

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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. 
4.11.7.2 
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 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. 
4.11.7.3 
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 

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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 or 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. 
4.11.7.4 
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 that is mostly exposed to subtype C HIV-1, Figure 4-7 shows a logo 
plot of the VRC01 antibody footprint motifs comprising 35 amino acid sites [19] 
based on 444 subtype C sub-Saharan African sequences deposited in the Los 
Alamos National Laboratory (LANL) sequence database between 2006 and 2014.  
 

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Figure 4-7 Logo plot of the VRC01 antibody footprints that occur in 444 subtype C sub-
Saharan African 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.  
4.11.7.5 
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. 

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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 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 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 4-8 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 

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needed. For the scenario that this extra variability reduces rho to 0.7, there is 
about 80% 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. 
Power to Discriminate (Lo, Med, Hi) PE = (15%, 60%, 85%) [Overall PE = 60%] 
30% with Lo and 30% with Hi Marker Response 
 
Figure 4-8 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 1900 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 4-9 shows the same power analysis as Figure 4-8, 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. 

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Power to Discriminate (Lo, Med, Hi) PE = (15%, 60%, 85%) [Overall PE = 60%; rho = 0.9] 
 
 
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 = 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 1900 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. 
4.11.7.6 
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 C 
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 

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escape mutations and a PE of 0% against HIV-1s with >2 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 [128]. Figure 4-10 illustrates a genotypic and 
phenotypic sieve analysis. 
 
Figure 4-10 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. 

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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. 
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).  
4.11.7.7 
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 she received the mAb with IC50 value of x to the exposing virus. 
Figure 4-11 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 
4-11, power = 0.793). 

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Figure 4-11 Power calculations for comparing IC50 distributions between mAb group 
breakthrough HIV-1s and control group breakthrough HIV-1s, with difference equivalently 
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 4-11. 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. 

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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 4-11 
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 information available at the time of 
enrollment, including 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 40 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 

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8. Willingness to discuss HIV infection risks and amenable to HIV risk reduction 
counseling  
9. Persons born Female (assigned female sex at birth) and identifying as female, 
who, in the 6 months prior to randomization, has had vaginal and/or anal 
intercourse with a male partner 
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  
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 703/HPTN 081 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 703/HPTN 081 
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 

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 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, 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 tissue (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 

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 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 703/HPTN 081 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 
703/HPTN 081 PSRT will be consulted to determine whether the participant 
may resume infusions or whether infusions should be permanently 
discontinued.  
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 703/HPTN 081 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 703/HPTN 081 PSRT is 
required prior to subsequent infusion following any hypersensitivity 
reaction associated with study product; or 

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 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 
 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 [Note – participants randomized under Version 1.0 were enrolled in 
this same treatment but under the assignment “Treatment 4(T4)”] 
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 IV at Weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, and 72. 
Group 2 [Note – participants randomized under Version 1.0 were enrolled in 
this same treatment but under the assignment “Treatment 5(T5)”] 
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 IV at Weeks 0, 8, 16, 24, 32, 40, 48, 56, 64, and 72. 
Group 3 [Note – participants randomized under Version 1.0 were enrolled in 
this same treatment (control) but under the assignment “Control 
6(C6)”] 
Control 3 (C3): Control for VRC01 (Sodium Chloride for Injection USP, 
0.9% ) to be prepared as a final total volume of 150 mL IV at Weeks 0, 8, 
16, 24, 32, 40, 48, 56, 64, and 72. 
For all participants originally enrolled under Version 1.0, a new prescription 
must be written and sent to the pharmacy once the participant has consented 
under Version 2.0 with the appropriate 4-digit CODE written on the 
prescription as well as a way for the pharmacist to verify that the participant 
has consented under Version 2.  
6.2 
Study product formulation  
VRC-HIVMAB060-00-AB [VRC01, Labeled as VRC01 HIV MAb Drug 
Product VRC-HIVMAB060-00-AB] 

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VRC01 will be provided as a sterile clear, colorless to yellow isotonic solution, 
essentially free of visible particles; some white, opaque 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. 
VRC01 is a highly concentrated protein solution and may develop white, opaque 
to translucent particles after thawing. When particles are observed, they may 
disappear after a few hours at room temperature or storage at 2°C to 8°C (36°F to 
46°F).  
Prior to preparation, vials containing VRC01 must be removed from the freezer 
and thawed for a minimum of 1 hour at controlled room temperature (maximum 
27°C). Following this 1 hour thaw, the unopened vials of VRC01 may be stored 
for up to 24 hours at controlled room temperature (maximum 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. 
Prior to preparation, vials should be swirled for 30 seconds with sufficient force to 
resuspend any visible particles, yet avoiding foaming. DO NOT SHAKE THE 
VIALS. 
If particles are observed, return the vials to 2°C to 8°C storage. 
If the particles re-dissolve within the maximum storage time of up to 4 weeks at 
2°C to 8°C, the vials may be used for product preparation.  Refrigerated product 
in the vial must be equilibrated at controlled room temperature (maximum 27°C) 
for a minimum of 30 minutes before preparation and must be used within 8 hours 
of removal from the refrigerator. 
If particles continue to be observed after 4 weeks at 2°C to 8°C, do not use 
the vialed product for IV bag preparation.  These vials must be quarantined 
until they are returned to the NIAID Clinical Research Products Management 
Center (CRPMC) or to the 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. 

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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 27ºC) 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.  
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 

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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 the 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 27ºC) 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.  
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) 
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. 

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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 (Groups 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 (see 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 

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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.  
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.  

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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. 
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 

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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 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.  
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); 

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 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 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 procedures 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). 
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);  
 Pregnancy prevention assessment (as described in Section 7.2 and 7.6);  

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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);  
 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 or cervical/vaginal swab, 
 Trichomonas by cervical/vaginal 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 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:  
 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) 

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 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;  
 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 population enrolled in this trial.  
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 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 

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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 and Appendix H); 
 Blood collection for CD4+ T cell counts; 

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 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. 
7.7 
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, CBC/differential, ALT, creatinine, VRC01 
Ab levels, functional assays, and sample storage (see Appendix I and 
Appendix M); 
 Urine dipstick (see Section 7.9);  

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 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 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 

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detail). If a follow-up dipstick is abnormal due to infection, document this issue in 
the participant’s chart 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 each infusion 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), 
Corrected Version 2.1, dated July 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 either the 
appropriate 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 
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 assessments include assessments of specific systemic and local 
signs and symptoms and IV infusion-related  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.  
For more detailed information and instructions on reactogenicity assessments, see 
the SSP. 
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 
IV infusion-related site reactions may include redness/erythema and 
induration/swelling. The maximum horizontal and maximum vertical 
measurements for IV infusion-related site redness/erythema and 
induration/swelling are recorded. 

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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 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. 
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 

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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. 
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 703/HPTN 
081 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.  

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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.  
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 I. 
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 

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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. 
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 [129-131] 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 [82,132,133]. 
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 [134,135]. 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 [75]. Samples are 
collected and stored on regularly scheduled calendar days throughout the study 
and testing will be performed periodically on batched samples. In addition, both 
serum and plasma samples are collected from all participants at all timepoints. 
This will allow additional assessment of PrEP use by selected participants if 
warranted by the results of the dried blood spot assay. Individual test results will 
not be returned to study sites or study participants. 

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9.7 
Host (human) genotyping 
Various markers, such as genes associated with host immune functions or HIV 
disease progression may also be assessed.  
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 

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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 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 703/HPTN 081 PSRT 
The HVTN 703/HPTN 081 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 703/HPTN 081 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 703/HPTN 081 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 4.7.1.1, and may give advice to 
the HVTN 703/HPTN 081 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 
703/HPTN 081 PSRT and NIAID DSMB. 

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The roles and responsibilities of the HVTN CSS or HVTN Core designee in 
relation to safety monitoring include: 
 Daily monitoring of clinical data for events that meet the safety pause and 
HVTN 703/HPTN 081 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 703/HPTN 081 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, Corrected Version 2.1. dated July 2017, available on the RSC 
website at http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-
grading-tables, except 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 

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 Uterine bleeding secondary to contraception 
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 
703/HPTN 081.  
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 HVTN703/HPTN 081 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, South Africa Standard Time, or Central Africa 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).  

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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), 
 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 

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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. 
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 703/HPTN 081 
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 703/HPTN 081 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 703/HPTN 
081 PSRT notification 
SAE, related 
Grade 3 
E-mail and submit forms 
immediately 
Prompt HVTN 703/HPTN 081 
PSRT AE review to consider 
pause 
AEc, related 
Grade 4 
or 3 
Email and submit forms 
immediately 
Prompt HVTN 703/HPTN 081 
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/hvtn703/HPTN081). 
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 703/HPTN 081 PSRT, 
HVTN Regulatory Affairs, DAIDS Pharmaceutical Affairs Branch (PAB), 
DAIDS Regulatory Affairs Branch (RAB), DAIDS Safety and Pharmacovigilance 

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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 703/HPTN 081 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 703/HPTN 081 PSRT 
assessment, DAIDS RAB notifies the FDA as needed. 
If an immediate HVTN 703/HPTN 081 PSRT notification or prompt HVTN 
703/HPTN 081 PSRT AE review is triggered, HVTN Core notifies the HVTN 
703/HPTN 081 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 703/HPTN 081 PSRT AE review cannot be 
completed within 72 hours of notification (excluding weekends and US federal 
holidays), an automatic safety pause occurs. 
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 703/HPTN 081 
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 703/HPTN 081 PSRT AE review criteria. 
10.4.2 
Twice monthly review 
During the infusion phase of the trial, the HVTN 703/HPTN 081 PSRT reviews 
clinical safety reports twice each month and conducts calls to review the data as 

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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 703/HPTN 081 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 
4.7.1. 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. 
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 

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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 [136-138], 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 [139].  
 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 

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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. 
 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 Africa, 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; 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. 

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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 703/HPTN 081 PSRT. In addition, a DSMB periodically reviews study 
data. 
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 
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 703/HPTN 081 are 
described below. 
Protocol history and modifications 
Date: December 14, 2017 
Protocol version: Version 4.0 
Protocol modification: Full Protocol Amendment 3 
Item 1 Sample size increased from 1500 to 1900  
Item 2 
Added in Appendices A and C: Broad regulatory agency access to 
participant study records 
Date: August 25, 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 Revised in Section 2.4.5, Trial monitoring: Feasibility assessment 
Item 4 Updated in Sections 2.9, 2.9.3, 2.9.4, 2.10, and Appendix A: VRC01 clinical 
experience in HVTN 104 
Item 5 Updated in Section 2.9.5, Particle formation, and Section 6.2, Study product 
formulation: Product description and formulation/preparation instructions 
Item 6 Revised in Section 4.7.3: Monitoring for futility to assess PE 
Item 7 Clarified in Section 5: Eligibility determination 
Item 8 Clarified in Section 5.2, Exclusion criteria: Tissue or organ transplantation 
exclusion criterion 
Item 9 Clarified in Section 6.4, Administration: IV bag label weight and IV tubing 
flushing 
Item 10 Clarified in Section 7.3, Enrollment and infusion visits: Timing of HIV 
infection assessment and HIV testing 
Item 11 Updated in Section 7.10, Assessments of reactogenicity, Section 10.2.2, AE 
reporting, and Section 15, Document references (other than literature 
citations): DAIDS AE grading table version and exceptions 
Item 12 Updated in Sections 10.2: URLs for referenced documents 

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Item 13 Updated in Section 10.2.3: Expedited reporting of adverse events to DAIDS 
Item 14 Updated in Section 14: Version history 
Item 15 Updated in Section 15, Document references (other than literature citations): 
Documents and URLs 
Item 16 Updated in Section 16: Acronyms and abbreviations 
Item 17 Updated in Appendix A, Sample informed consent form: Minimum infusion 
time 
Item 18 Corrected in Appendix A, Sample informed consent form: Blood draw 
volumes 
Item 19 Clarified in Appendix A, Sample informed consent form: Early termination 
Item 20 Revised in Appendix B, Approved birth control methods (for sample 
informed consent form): Approved contraception methods 
Item 21 Corrected in Appendix D, Tables of procedures (for sample informed consent 
form): Procedure timepoint 
Item 22 Clarified in Appendix F: DBS allowance applies to Visit and 56-day blood 
draw totals 
Item 23 Updated in Appendices F through I: Assay locations and HVTN laboratory 
listings 
Item 24 Revised in Appendices G, H, K, and L: Table format and Schedule 3 blood 
draws at Visit #.X 
Item 25 Clarified in Appendices J and M: Provision of HIV test results 
Item 26 Added as Appendix N: Protocol signature page 
Item 27 Updated in Sections 6.2 through 6.4 per Clarification Memo 1 to protocol 
Version 2.0: Study product description, storage, and administration 
instructions 
Item 28 Corrected: Minor typographical, grammatical, and formatting errors 
Date: March 8, 2017 
Protocol version: Version 2.0 
Protocol modification: Clarification Memo 1 
Item 1 Updated in Section 6.2, Study product formulation: VRC01 description and 
storage temperature 
Item 2 Revised in Sections 6.3 and 6.4: Holding times for study products after 
preparation 
Item 3 Updated in Section 6.4, Administration: Minimum infusion time period 
Item 4 Added in Section 6.4, Administration: In-line filter set requirement 
Item 5 Clarified in Sections 6.3.1 and 6.3.2: VRC01 vials with visible particles not 
to be used 

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Date: June 24, 2016 
Protocol version: Version 2.0 
Protocol modification: Full Protocol Amendment 1 
Item 1 Study population limited to women in sub-Saharan Africa at risk of acquiring 
HIV through sexual transmission 
Item 2 Added in Section 1, Overview: Note regarding enrollment numbers 
Item 3 Revised in Section 1, Overview, and Section 5.1, Inclusion criteria: 
Participant age range 
Item 4 Updated in Section 1.1, Protocol Team: Membership and affiliations 
Item 5 Clarified in Section 2.1, Rationale for trial concept: Worldwide HIV 
infections and licensure status of VRC01 
Item 6 Updated: Section 2.4.5, Trial monitoring 
Item 7 Updated: Section 2.6, Plans for future product development and testing 
Item 8 Added in Section 2.8.1, Protection against challenge in NHP models: Non-
neutralizing mechanisms of bnAb protection in NHP challenge studies 
Item 9 Added in Section 2.9.2, VRC 602: Information on serum neutralizing activity 
and anti-VRC01 antibodies 
Item 10 Updated in Sections 2.9.3 and 2.9.4: Phase 1 clinical trial experience and 
VRC01 safety summary 
Item 11 Added in Section 2.9.3: VRC01 pharmacokinetics in HVTN 104 
Item 12 Revised in Sections 3.3, 4.8, and 9.6 and Appendix F: PrEP use monitoring 
Item 13 Revised: Section 4, Statistical considerations 
Item 14 Clarified in Section 5.1, Inclusion criteria: Urine protein measures 
Item 15 Revisions in Section 5.2: Exclusion criteria 
Item 16 Clarified in Section 5.3.3, Discontinuing infusions for a participant: 
Participants for whom infusions are stopped for reasons other than HIV 
infection 
Item 17 Updated in Section 6, Study product preparation and administration: Study 
product regimen, formulation, storage, preparation, and administration 
instructions 
Item 18 Removed in Section 7.2, Pre-enrollment procedures: Required recording of 
generic names for concomitant medications 
Item 19 Clarified in Section 7.3, Enrollment and infusion visits: Urine dipstick and 
instructions for infusion observation and reactogenicity assessment 
Item 20 Corrected in Section 7.4: Post-infusion visits for HIV-uninfected study 
participants 
Item 21 Corrected in Section 7.5, HIV counseling and testing: PrEP information 
source 

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Item 22 Clarified in Section 7.5.1, Study product-related seroreactivity: Serum 
concentrations tested and reference to HIV testing only 
Item 23 Added as (new) Section 7.6: Follow-up visits for HIV-infected participants 
Item 24 Added as (new) Section 7.7 and Appendices I and M: Follow-up for study 
participants for whom infusions have been stopped for reasons other than 
HIV infection 
Item 25 Corrected in Section 7.8, Contraception status: Where to find details 
regarding contraception requirements 
Item 26 Clarified in Section 7.9 and Appendices F, I, J, and M: Urine testing 
Item 27 Clarified in Sections 7.10, Assessments of reactogenicity: Systemic and local 
signs and symptoms and infusion sites reactions 
Item 28 Revised in Section 7.11, Visit windows and missed visits: Visits for 
performance of safety assessments and local safety labs 
Item 29 Corrected in Section 8.5, HIV infection during the study: Visit schedules for 
HIV-infected study participants 
Item 30 Revised in Section 9.5.1, Anti-VRC01 antibody assay: Assay description 
Item 31 Clarified in Section 9.5.2, Neutralizing antibody assay: Range of 
applicability 
Item 32 Clarified in Section 10.1.1, HVTN 703/HPTN 081 PSRT: Protocol safety 
review team membership 
Item 33 Removed in Section 10.1.3, Roles and responsibilities in safety monitoring: 
Reference to planned holds 
Item 34 Added in Section 10.2.2, AE reporting: Uterine bleeding secondary to 
contraception 
Item 35 Added in Section 10.2.2, AE reporting: African working hours 
Item 36 Updated in Section 10.2.3, Expedited reporting of adverse events to DAIDS: 
DAERS support email address 
Item 37 Corrected in Section 10.4.2: PSRT review timing 
Item 38 Clarified in Section 10.4.3: Cumulative safety data reports to DSMB 
Item 39 Removed in Section 10.6, Social impact reporting: Reference to Study 
Specific Procedures (SSP) 
Item 40 Updated in Section 15: URL for DAIDS source documentation requirements 
Item 41 Updated and clarified: Appendix A, Sample informed consent form 
Item 42 Added in Appendix A and (optional) Appendix E: Consent for HIV-infected 
study participants 
Item 43 Clarified in Appendix A and C consent forms: Potential genetic testing 
Item 44 Added in Appendix A, C, and E consent forms: MCC contact information 

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Item 45 Added in Appendix B, Approved birth control methods: Injectable 
contraceptives 
Item 46 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 47 Clarified in footnotes to Appendix F and J: Pregnancy testing 
Item 48 Clarified in Appendices F, G, and I: HVTN and non-HVTN endpoint 
laboratories 
Item 49 Added in Appendix F: VRC lab for anti-VRC01 antibody levels 
Item 50 Corrected in Appendices G, H, K, and L: Appendix titles, visit schedules, 
visit numbering, and procedures 
Item 51 Added in Appendices G and H: Whole blood samples for confirmatory HIV 
testing 
Item 52 Clarified in Appendix J, Schedule 1—Procedures at CRS for HIV-uninfected 
participants: No participant questionnaire at Visit 0 (screening visit) 
Item 53 Added to Appendices K and L: Local lab assessments 
Item 54 Updated and corrected throughout the protocol document: Acronyms, 
abbreviations, numbering of figures, tables, and appendices, cross-references, 
and grammatical errors 
Date: April 15, 2016 
Protocol version: Version 1.0 
Protocol modification: Clarification Memo 2 
Item 1 Clarified in Appendix I, Schedule 1―Procedures at CRS for HIV-uninfected 
participants: No participant questionnaire during screening 
Date: February 22, 2016 
Protocol version: Version 1.0 
Protocol modification: Clarification Memo 1 
Item 1 Corrected in Appendices G, H, J, and K: Visit numbering 
[Note: Clarification Memo 1 dated February 22, 2016 replaces Clarification Memo 1 dated 
September 4, 2015 and Letter of Amendment 1 dated September 28, 2015.] 
Date: September 28, 2015 
Protocol version: Version 1.0 
Protocol modification: Letter of Amendment 1 
Item 1 Corrected in Appendices G, H, J, and K: Visit schedules 
Item 2 Clarified in Appendices J and K: Assessment of HIV/AIDS-related conditions 
applies to both complete and abbreviated physical exams 

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Item 3 Removed in Appendices J and K: Social impact assessment questionnaire 
Date: September 4, 2015 
Protocol version: Version 1.0 
Protocol modification: Clarification Memo 1 
Item 1 Corrected in Appendices G, H, J, and K: Visit numbering 
Item 2 Corrected: Titles of Appendices J and K 
Date: August 11, 2015 
Protocol version: 
1.0 
Protocol modification: 
NA 
 

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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 July 2017. Available at http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
 The Manual for Expedited Reporting of Adverse Events to DAIDS. Version 
2.0, January 2010. Available at http://rsc.tech-res.com/clinical-research-
sites/safety-reporting/manual 
 HVTN Certificate of Confidentiality. Accessible through the HVTN website. 
 HVTN 703/HPTN 081 Special Instructions. Accessible through the HVTN 
protocol-specific website. 
 HVTN 703/HPTN 081 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. 

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HVTN703-HPTN081_v4.0_FINAL / Page 130 of 193 
Available at http://www.ich.org/products/guidelines/efficacy/article/efficacy-
guidelines.html 
 HVTN 703/HPTN 081 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/Cl
inicalSite.aspx 
 Title 21, Code of Federal Regulations, Part 50. Available at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFR
Part=50 
 Title 45, Code of Federal Regulations, Part 46. Available at 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html 
See Section 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 
 

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HIPAA 
Health Insurance Portability and Accountability Act 
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 
NDOH 
(South Africa) National Department of Health 
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 

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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 
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 in 
women in sub-Saharan Africa 
Protocol number: HVTN 703/HPTN 081, 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 1900 people will take part in this study at multiple sites in Africa. 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 2700 men and transgender people 
who have sex with men and transgender people in the North America, South 
America, and Switzerland. 
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? 

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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. 
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 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: 

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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.  
 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. 

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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 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 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 

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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 1 visit every 4 weeks 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] 
Site: Insert any costs to participants (eg, birth control costs for participants who 
could become pregnant). 
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. 

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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, also 
known as a drip. 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 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. 
6 months 
1 year 

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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. 
Site: Insert the first 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. 
We will be looking for side effects.  
About every six months we will do a blood test for syphilis and will test your 
urine or a cervical/vaginal swab for gonorrhea and chlamydia. At these times we 
will also test you for Trichomonas using a cervical/vaginal swab. 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 and 
South Africa. The samples will be tested to: 

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 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 
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 South 
Africa.  

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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.  
If you become HIV infected, the researchers may look at all of the genes of the 
virus found in your samples. The researchers will use this information to learn 
more about HIV and the study product(s).  
In some cases, researchers may take cells from your samples and grow more of 
them over time, so that they can continue to contribute to this study.  

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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 
 Any regulatory agency that reviews clinical trials 
 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. The current text reflects the situation in the Republic of South 
Africa.] These methods may include not having sex, using condoms, or other 
behavior changes. We will talk about new methods of HIV prevention as they 
become available. These methods may include the use of anti-HIV drugs taken 
every day to prevent HIV. This is called pre-exposure prophylaxis or PrEP. In the 

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past few months a combination of two anti-HIV drugs (TDF/FTC) has been 
licensed in South Africa and Kenya for use to prevent HIV infection in people at 
high risk. Studies in women have shown this drug combination can reduce the risk 
of getting HIV when it is taken every day. The drug combination is not always 
effective and HIV infections may happen, especially if the medicine is not taken 
every day. This drug combination is available in the private health sector by 
prescription from a doctor. The Ministry of Health in South Africa is starting 
several programs called “demonstration projects” that provide this drug 
combination to people free of charge. We can refer you to the nearest of these 
programs if you are interested. 
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 2-5 more visits. 
We will tell you more about what will happen at these visits in another form.  
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.  
We will counsel you about your HIV infection, talk with you about ways to avoid 
transmission and about telling your partner(s).  
We will ask you to come to the clinic for 2 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 symptoms; 

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 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  
 Do pregnancy tests if you could become pregnant;  
 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 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 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  
 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.  
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 

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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;  
 Collect urine samples; 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. 
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. 

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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. 
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, 
 Any regulatory agency that reviews clinical trials 
 [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] 
The results of this study may be published. No publication will use your name or 
identify you personally. 
We may share information from the study with other researchers. We will not 
share your name or information that can identify you. 
A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov. This website will not include information that can 
identify you. At most, the website will include a summary of the results. You can 
search this website at any time. 
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, 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 

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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.  
Unknown risks:  
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.  

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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.  
Next paragraph for all sites except in Zimbabwe.  
(Sites: adjust the language in this paragraph so it is applicable to your site. Note: 
Insurance is purchased for all African countries except Zimbabwe. The ABPI 
guidelines may only apply to South Africa and Mozambique.)  
In this study, our clinic has insurance to cover your medical treatment in the case 
of a study-related injury. The insurance will follow the Association of the British 
Pharmaceutical Industry guidelines for payment of study-related injury. We can 
give you a copy of these guidelines. In rare cases, the insurance funds may not be 
enough. If needed, the HVTN and HPTN have limited funds to pay medical costs 
for study-related injuries that they determine 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]. 

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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]. 
South African sites: Include the following: 
If you have questions about this trial you should first discuss them with your doctor or the ethics 
committee (contact details as provided on this form). After you have consulted your doctor or the 
ethics committee and if they have not provided you with answers to your satisfaction, you should 
write to the South African Medicines Control Council (MCC) at: 
The Registrar of Medicines 
Medicines Control Council 
Department of Health 
Private Bag X828 
PRETORIA 
0001 
 
Fax: (012) 395 9201 
 
e-mail: gouwsj@health.gov.za 
 Your permissions and signature  
Site: Delete this section if using a separate consent for use of samples and 
information in other studies. 
29. In Section 14 of this form, we told you about 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. 
 

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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: 
 
 
 
 
 
 
 
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 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 born female and are sexually active in a way that could lead you to 
get pregnant, 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.  
Effective birth control means using any of the following methods: 
 Birth control drugs that prevent pregnancy—given by pills, patches, vaginal 
rings, injectables, or implant under the skin; or 
 Intrauterine device (IUD). 
You do not have to use birth control if: 
 You have been diagnosed with early menopause, with no menstrual periods 
for one year; 
 You have had a hysterectomy (your uterus removed); 
 You have had your ovaries removed; 
 You have a tubal ligation (your “tubes tied”) or confirmed successful 
placement of a product that blocks the fallopian tubes. 
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 IV. 

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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 in 
women in sub-Saharan Africa 
HVTN protocol number: HVTN 703/HPTN 081, 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 South Africa.  
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. 

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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. 
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. 

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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.  
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 
 Any regulatory agency that reviews clinical trials 
 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]. 
South African sites: Include the following: 
If you have questions about this trial you should first discuss them with your 
doctor or the ethics committee (contact details as provided on this form). After 
you have consulted your doctor or the ethics committee and if they have not 

HVTN 703/HPTN 081 Version 4.0 / December 14, 2017 
HVTN703-HPTN081_v4.0_FINAL / Page 172 of 193 
provided you with answers to your satisfaction, you should write to the South 
African Medicines Control Council (MCC) at: 
The Registrar of Medicines 
Medicines Control Council 
Department of Health 
Private Bag X828 
PRETORIA 
0001 
 
Fax: (012) 395 9201 
 
e-mail: mogobm@health.gov.za 
13. Please choose only one of the options below and write your initials or make 
your mark in the box next to it. Whatever you choose, the HVTN 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: 

HVTN 703/HPTN 081 Version 4.0 / December 14, 2017 
HVTN703-HPTN081_v4.0_FINAL / Page 173 of 193 
 
 
 
 
 
 
 
Witness’s name (print) 
 
Witness’s signature  
 
Date 
 
Time 
*Witness is impartial and was present for the consent process. 

HVTN 703/HPTN 081 Version 4.0 / December 14, 2017 
HVTN703-HPTN081_v4.0_FINAL / Page 174 of 193 
6 months 
1½ years 
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 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. 
 
 
2 years 
1 year 

HVTN 703/HPTN 081 Version 4.0 / December 14, 2017 
HVTN703-HPTN081_v4.0_FINAL / Page 175 of 193 
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.  
 
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. 
 

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HVTN703-HPTN081_v4.0_FINAL / Page 176 of 193 
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 who have had their uterus or ovaries removed (a hysterectomy or oophorectomy), verified by medical records, are not required to have pregnancy tests. 

HVTN 703/HPTN 081 Version 4.0 / December 14, 2017 
HVTN703-HPTN081_v4.0_FINAL / Page 177 of 193 
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 in 
women in sub-Saharan Africa 
Protocol number: HVTN 703/HPTN 081, 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 703/HPTN 081, 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.  
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: 

HVTN 703/HPTN 081 Version 4.0 / December 14, 2017 
HVTN703-HPTN081_v4.0_FINAL / Page 178 of 193 
 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 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.] 
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  
 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.] 
 

HVTN 703/HPTN 081 Version 4.0 / December 14, 2017 
HVTN703-HPTN081_v4.0_FINAL / Page 179 of 193 
Leaving the study 
3. 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]. 
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]. 
South African sites: Include the following: 
If you have questions about this trial you should first discuss them with your 
doctor or the ethics committee (contact details as provided on this form). After 
you have consulted your doctor or the ethics committee and if they have not 
provided you with answers to your satisfaction, you should write to the South 
African Medicines Control Council (MCC) at: 
The Registrar of Medicines 
Medicines Control Council 
Department of Health 
Private Bag X828 
PRETORIA 
0001 
 
Fax: (012) 395 9201 
 
e-mail: mogobm@health.gov.za 
 

HVTN 703/HPTN 081 Version 4.0 / December 14, 2017 
HVTN703-HPTN081_v4.0_FINAL / Page 180 of 193 
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 703/HPTN 081 Version 4.0 / December 14, 2017 
HVTN703-HPTN081_v4.0_FINAL / Page 181 of 193 
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 location1,2
Tube 
Type4
Tube size
(vol. 
capacity)4
Total
BLOOD COLLECTION
Screening/Diagnostic
Screening HIV test
Local lab
Local lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
HIV diagnostics7
HSML-NICD / 
UW-VSL
HSML-NICD /
UW-VSL
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 plasma10
CSR
JHU
SST
8.5mL
—
y
—
y
—
—
y
—
y
—
y
—
y
—
y
—
y
—
y
—
y
—
y
—
y
—
0
ARV detection by dried blood spots16
CSR
HVTN Labs
EDTA
2mL
—
0
Immunogenicity & Virologic Assays
Host genetics5
CSR
HVTN Labs
ACD
8.5mL
—
z
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
0
Anti-VRC01 Ab levels
CSR
VRC/NVITAL
SST
8.5mL
—
y
—
—
—
—
—
—
—
—
—
y
—
—
—
—
—
—
—
—
—
y
—
—
—
—
0
Functional humoral assays8
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
HVTN Labs
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 total17
15
165
73
83
65
73
75
65
80
65
75
73
109
65
80
65
75
65
75
65
114
73
65
65
65
109
1987
56-Day total17
 
15
180
253
336
221
294
295
212
219
209
219
212
256
246
253
209
219
204
214
204
253
251
251
129
129
173
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
—
—
—
CERVICAL/VAGINAL SWAB COLLECTION
Trichomonas vaginalis
Local lab
Local lab
—
X14
—
—
—
—
—
—
X14
—
—
—
—
—
X14
—
—
—
—
—
X14
—
—
—
—
—
EITHER URINE OR CERVICAL/VAGINAL SWAB COLLECTION 
Urine - Chlamydia/Gonorrhea12
Local lab
Local lab
—
X13
—
—
—
—
—
—
X13
—
—
—
—
—
X13
—
—
—
—
—
X13
—
—
—
—
—
Cervical/Vaginal Swab - 
Chlamydia/Gonorrhea12
Local lab
Local lab
—
X13
—
—
—
—
—
—
X13
—
—
—
—
—
X13
—
—
—
—
—
X13
—
—
—
—
—
Screening 
visit3
See footnote 16
 
1 CSR = central specimen repository; HSML-NICD = HIV Sero-Molecular Laboratory, National Institute for Communicable Diseases (Johannesburg, South Africa); UW-VSL = University of 
Washington Virology Specialty Laboratory (Seattle, Washington, USA) 
2 HVTN Laboratories include: Cape Town HVTN Immunology Laboratory (CHIL, Cape Town, 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). 
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. 

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HVTN703-HPTN081_v4.0_FINAL / Page 182 of 193 
6 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 Chlamydia/Gonorrhea testing will be done with EITHER urine OR cervical/vaginal swab. Either specimen is acceptable, and clinics will determine which specimen will be collected and 
tested. 
13 Syphilis testing, and chlamydia/gonorrhea testing by either urine or cervical/vaginal swab, will be performed at visits 2, 9, 15, and 21; in addition, testing may occur at any visit if clinically 
indicated. 
14 Cervical/vaginal swab will be collected for Trichomonas testing at visits 2, 9, 15, and 21; in addition, testing may occur at any visit if clinically indicated. 
15 And microscopy if needed. 
16 EDTA blood for dried blood spots will be collected on regularly scheduled calendar days throughout the study. Refer to the Specimen Collection SSP for more information. 
17 The total 56-day blood collection includes 2mL EDTA blood collection for dried blood spots. It is highly improbable that the 2mL EDTA blood collection will occur at every possible 
timepoint, but it is reflected in the blood draw totals for every visit to account for this extreme possibility. 
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 location1,2
Tube 
Type3
Tube size        
(vol. capacity)3
Total
BLOOD COLLECTION
Screening or diagnostic assays
        HIV diagnostics
HSML-NICD /
UW-VSL
HSML-NICD /
UW-VSL
EDTA
10mL
20
—
—
—
—
—
20
        HIV PCR viral load
HSML-NICD
HSML-NICD
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 assays6
CSR
HVTN Labs /
VRC / NVITAL
SST
8.5mL
17
17
17
17
17
17
102
        Viral isolation/sequencing
CSR
HVTN Labs
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 total
125
72.5
72.5
77.5
111.5
106.5
566
56-Day total
125
198
270
348
334
106.5
URINE COLLECTION
Pregnancy Test4
Local Lab
Local Lab
X
—
—
—
X
—
 
1 CSR = central specimen repository; HSML-NICD = HIV Sero-Molecular Laboratory-National Institute for Communicable Diseases (Johannesburg, South Africa); UW-VSL = University of 
Washington Virology Specialty Laboratory (Seattle, Washington, USA) 
2 HVTN Laboratories include: South African Immunology Laboratory-National Institute for Communicable Diseases (SAIL-NICD, Johannesburg, South Africa); Duke University Medical 
Center (Durham, North Carolina, USA); University of Cape Town (Cape Town, South Africa)  
Non-HVTN laboratories: NVITAL = NIAID Vaccine Immune T-Cell Antibody Laboratory (Gaithersburg, Maryland, USA); VRC = Vaccine Research Center (Bethesda, Maryland, USA) 

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3 Local labs may assign appropriate alternative tube types for locally performed tests. 
4 Pregnancy test may be performed on 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. 

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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 location1,2
Tube 
Type3
Tube size        
(vol. capacity)3
Total
BLOOD COLLECTION
Screening or diagnostic assays
        HIV diagnostics
HSML-NICD /
UW-VSL
HSML-NICD /
UW-VSL
EDTA
10mL
20
—
—
20
        HIV PCR viral load
HSML-NICD
HSML-NICD
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 assays6
CSR
HVTN Labs /
VRC / NVITAL
SST
8.5mL
17
—
—
17
        Viral isolation/sequencing
CSR
HVTN Labs
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 total
125
32
32
189
56-Day total
125
157
32
URINE COLLECTION
Pregnancy Test4
Local Lab
Local Lab
X
—
—
 
1 CSR = central specimen repository; HSML-NICD = HIV Sero-Molecular Laboratory-National Institute for Communicable Diseases (Johannesburg, South Africa); UW-VSL = University of 
Washington Virology Specialty Laboratory (Seattle, Washington, USA). 
2 HVTN Laboratories include: South African Immunology Laboratory–National Institute for Communicable Diseases (SAIL-NICD, Johannesburg, South Africa); Duke University Medical 
Center (Durham, North Carolina, USA) ; University of Cape Town (Cape Town, South Africa). 
Non-HVTN laboratories: NVITAL = NIAID Vaccine Immune T-Cell Antibody Laboratory (Gaithersburg, Maryland, USA); VRC = Vaccine Research Center (Bethesda, Maryland, USA). 
3 Local labs may assign appropriate alternative tube types for locally performed tests. 

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4 Pregnancy test may be performed on 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. 

HVTN 703/HPTN 081 Version 4.0 / December 14, 2017 
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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 location1,2
Tube Type3
Tube size
(vol. capacity)3
Total
BLOOD COLLECTION
Screening or diagnostic assays
HIV diagnostics5
HSML-NICD / 
UW-VSL
HSML-NICD /
UW-VSL
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
VRC01 Ab levels
CSR
NVITAL
SST
8.5mL
y
y
y
y
y
y
y
y
0
Immunogenicity & Virologic Assays
Functional humoral assays6
CSR
HVTN Labs /
VRC / NVITAL
SST
8.5mL
y
y
y
y
y
y
y
y
0
   Viral isolation/sequencing
CSR
HVTN Labs
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 total
81
63
73
63
73
63
63
107
583
56-Day total
 
81
63
73
63
73
63
63
107
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; HSML-NICD = HIV Sero-Molecular Laboratory-National Institute for Communicable Diseases (Johannesburg, South Africa) ; UW-VSL = University of 
Washington Virology Specialty Laboratory (Seattle, Washington, USA) 
2 HVTN Laboratories include: South African Immunology, Laboratory-National Institute for Communicable Diseases (SAIL-NICD Johannesburg, South Africa); Duke = Duke University 
Medical Center (Durham, North Carolina, USA); University of Cape Town (Cape Town, South Africa) 
   Non-HVTN laboratory: NVITAL = NIAID Vaccine Immune T-Cell Antibody Laboratory (Gaithersburg, Maryland, USA); VRC = Vaccine Research Center (Bethesda, Maryland, USA). 
3 Local labs may assign appropriate alternative tube types for locally performed tests. 
4 Pregnancy test may be performed on 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. 
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 703/HPTN 081 Version 4.0 / December 14, 2017 
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Appendix J 
Schedule 1―Procedures at CRS for HIV-uninfected participants  
 
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. 
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 participant13
—
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
Local lab assessment
    Screening HIV test
X
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
    Urine dipstick12
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
—
—
—
—
—
—
    Syphilis6
—
X7
—
—
—
—
—
—
X7
—
—
—
—
—
X7
—
—
—
—
—
X7
—
—
—
—
—
—
    Chlamydia, Gonorrhea8
—
X7
—
—
—
—
—
—
X7
—
—
—
—
—
X7
—
—
—
—
—
X7
—
—
—
—
—
—
    Trichomonas vaginalis (cervical/vaginal swab)
—
X9
—
—
—
—
—
—
X9
—
—
—
—
—
X9
—
—
—
—
—
X9
—
—
—
—
—
—
Study product administration procedures
  IV infusion10
—
X
—
X
—
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
—
—
—
—
—
  Reactogenicity assessment11
—
X
—
X
—
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
X
—
—
—
—
—
—
Poststudy
    Unblind participant
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
X
Screening 
visit1

HVTN 703/HPTN 081 Version 4.0 / December 14, 2017 
HVTN703-HPTN081_v4.0_FINAL / Page 189 of 193 
5 Pregnancy test must be performed on the day of infusion with negative results received 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 may be performed at additional timepoints if clinically indicated. 
8 Chlamydia/Gonorrhea testing will be done by urine or cervical/vaginal swab. 
9 Cervical/vaginal swab may be collected for Trichomonas testing at additional timepoints if clinically indicated. 
10 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. 
11 Reactogenicity assessments performed for 3 days postinfusion (see Section 7.10). 
12 And microscopy if needed. 
13 If HIV test results are not available at the visit indicated, provide test results at the next available opportunity. 

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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 assessment 
 
 
 
 
 
 
 
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. 

HVTN 703/HPTN 081 Version 4.0 / December 14, 2017 
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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 assessment 
 
 
 
 
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. 

HVTN 703/HPTN 081 Version 4.0 / December 14, 2017 
HVTN703-HPTN081_v4.0_FINAL / Page 192 of 193 
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 
Post 
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 
X 
Behavioral risk assessment questionnaire 
— 
X 
— 
X 
— 
X 
— 
X 
— 
Social impact assessment 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Local lab assessment 
 
 
 
 
 
 
 
 
 
Urine dipstick4 
X 
— 
— 
— 
— 
— 
X 
— 
— 
Pregnancy test5 
X 
— 
X 
— 
X 
— 
X 
— 
— 
Poststudy 
 
 
 
 
 
 
 
 
 
Unblind participant 
— 
— 
— 
— 
— 
— 
— 
— 
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. 

HVTN 703/HPTN 081 Version 4.0 / December 14, 2017 
HVTN703-HPTN081_v4.0_FINAL / Page 193 of 193 
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 in 
women in sub-Saharan Africa 
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 703/HPTN 081 
DAIDS Protocol Version: Version 4.0 
Protocol Date: December 14, 2017