Phase 2b, Randomized, Placebo-Controlled Test-of-Concept Trial to Evaluate the Safety and Efficacy of a Multiclade HIV-1 DNA Plasmid Vaccine Followed by a Multiclade HIV-1 Recombinant Adenoviral Vector Vaccine in HIV-Uninfected, Adenovirus Type 5 Neutralizing Antibody Negative, Circumcised Men and Male-to-Female (MTF) Transgender Persons, Who Have Sex With Men
Phase: PHASE2
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
Protocol 
HVTN 505 
Phase 2b, randomized, placebo-controlled test-of-
concept trial to evaluate the safety and efficacy of a 
multiclade HIV-1 DNA plasmid vaccine followed by 
a multiclade HIV-1 recombinant adenoviral vector 
vaccine in HIV-uninfected, adenovirus type 5 
neutralizing antibody negative, circumcised men 
and male-to-female (MTF) transgender persons, 
who have sex with men 
DAIDS Document ID 10753 
BB IND 13971 held by DAIDS 
Clinical trial sponsored by 
Division of AIDS (DAIDS)  
National Institute of Allergy and Infectious Diseases (NIAID)  
National Institutes of Health (NIH)  
Department of Health and Human Services (DHHS)  
Bethesda, Maryland, USA 
Vaccine provided by 
Dale and Betty Bumpers Vaccine Research Center (VRC), NIAID, NIH 
Bethesda, Maryland, USA 
July 21, 2014 
HVTN 505, Version 6.0 

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At the first planned interim analysis for efficacy futility, conducted under Version 4 of 
the protocol on April 22, 2013, the DSMB recommended that the trial be stopped for 
efficacy futility. A total of 71 HIV infections had been diagnosed in the MITT cohort (41 
among vaccine recipients, 30 among placebo recipients). Of these, 48 constituted primary 
endpoints (Week 28+ HIV infections diagnosed on or after Day 196 post-enrollment); 27 
occurred among vaccine recipients and 21 among placebo recipients. There was no 
statistically significant difference in the rate of HIV infection between treatment arms, 
either in the Week 28+ cohort (estimated hazard ratio = 1.25; 95% CI: 0.71 to 2.20; p = 
0.446) or in the MITT cohort (hazard ratio = 1.33; 95% CI: 0.83 to 2.13; p = 0.230). 
However, given that the number of HIV infections was larger in the vaccine arm, and 
given that there was a trend toward the hazard ratio increasing over time since enrollment 
(p = 0.09), the DSMB recommended, and the study team agreed, to continue to follow all 
participants beyond the Month 24 visit (the terminal visit in Version 4 of the protocol). 
Under Version 5 of the protocol, participants were followed post-unblinding to 48 
months post-enrollment. Additional interim analyses were conducted at six-month 
intervals to evaluate the HIV-1 acquisition rate in the two treatment arms, and to evaluate 
conditional power to detect an increased rate of acquisition in the vaccine arm as 
compared to the placebo arm. At the second interim analysis, conducted on March 24, 
2014 under Version 5 of the protocol, the study oversight group recommended that the 
protocol be revised to reduce the frequency of post-unblinding follow-up visits. A total of 
109 HIV infections had been diagnosed in the MITT cohort to 48 months post-enrollment 
(53 among vaccine recipients and 56 among placebo recipients). There was no 
statistically significant difference in the rate of HIV-1 infection between treatment arms, 
either including all follow-up to 48 months post-enrollment (estimated hazard ratio = 
0.92; 95% CI: 0.63 to 1.34; p = 0.65), or restricting follow-up to 24 months post-
enrollment (estimated hazard ratio = 1.09; 95% CI: 0.72 to 1.66; p = 0.68).  Given these 
data, there was very low power (< 1%) to detect an increased rate of HIV-1 infection in 
the vaccine vs. placebo arm, if the study were to continue following participants as 
specified under Version 5 of the protocol.  As described in Sections 8.2 and 8.2.1, under 
Version 6 of the protocol participants will continue to be followed to 48 months post-
enrollment, with an additional health contact at 60 months, but with study visits only 
annually following Month 24. The goal of this extended follow-up is to continue to 
monitor the rate of HIV-1 acquisition in the two treatment arms. To this end, the rate of 
study dropout will also continue to be evaluated in each treatment arm. The objectives of 
the study have been modified accordingly. Assessing the rates of study dropout and of 
HIV infection in the vaccine vs. placebo arms are now the primary objectives (see 
Section 5.2). Assessing the impact of vaccination on post-infection endpoints and on 
immunogenicity; assessing modification of vaccine effects by host immune genetic and 
other factors; and assessing immune correlates of risk are now exploratory objectives (see 
Section 5.4). 

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Contents 
1 
Ethical considerations .............................................................................................. 5 
2 
IRB/IEC review considerations ............................................................................... 7 
2.1 
Risks to participants ...................................................................................... 7 
2.2 
Risk/benefit balance ...................................................................................... 7 
2.3 
Subject selection ............................................................................................ 8 
2.4 
Informed consent ........................................................................................... 9 
2.5 
Safety monitoring .......................................................................................... 9 
2.6 
Privacy/confidentiality .................................................................................. 9 
3 
Overview ................................................................................................................ 11 
3.1 
Protocol Team ............................................................................................. 14 
4 
Background and rationale ...................................................................................... 15 
4.1 
HIV epidemic and epidemiology ................................................................. 15 
4.2 
Ad5 nAb assays ........................................................................................... 28 
4.3 
Study vaccines ............................................................................................. 28 
4.4 
Non-clinical and natural history data that provide evidence of potential 
vaccine activity ............................................................................................ 31 
4.5 
Potential benefit of VL reduction as a vaccination outcome ....................... 34 
4.6 
Experience with the VRC vaccine regimen ................................................. 37 
5 
Objectives and endpoints of the unblinded extended follow-up phase .................. 48 
5.1 
Primary objective and endpoints ................................................................. 48 
5.2 
Exploratory objectives ................................................................................. 48 
6 
Statistical considerations ........................................................................................ 50 
6.1 
Overview ..................................................................................................... 50 
6.2 
Objectives .................................................................................................... 50 
6.3 
Endpoints ..................................................................................................... 51 
6.4 
Sample size rationale ................................................................................... 52 
6.5 
Sampling design for assessing prophylactic ARV use ................................ 52 
6.6 
Statistical analysis ....................................................................................... 52 
6.7 
Monitoring of trial ....................................................................................... 55 
7 
Selection and withdrawal of participants ............................................................... 56 
7.1 
Inclusion criteria .......................................................................................... 56 
7.2 
Exclusion criteria ......................................................................................... 57 
7.3 
Co-enrollment of HVTN 505 participants ................................................... 58 
7.4 
Participant termination from the study ........................................................ 59 
8 
Clinical procedures ................................................................................................ 60 
8.1 
Informed consent ......................................................................................... 60 
8.2 
Follow-up visits for HIV-uninfected participants ....................................... 61 
8.3 
Procedures for HIV-1–infected participants ................................................ 62 
8.4 
HIV risk reduction counseling ..................................................................... 63 
8.5 
Visit windows and missed visits .................................................................. 64 
8.6 
Early termination visit ................................................................................. 64 
9 
HIV-1 infection assessment and clinical response ................................................. 65 
9.1 
HIV-1 symptom assessment ........................................................................ 65 
9.2 
HIV-1 testing during post-unblinding follow-up ......................................... 65 
9.3 
Endpoint adjudication .................................................................................. 65 
9.4 
HIV-1 infection during the study................................................................. 66 

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9.5 
Medical care for participants who become HIV-1–infected ........................ 66 
10 
Laboratory .............................................................................................................. 67 
10.1 Study site laboratory procedures ................................................................. 67 
10.2 Total blood volume ...................................................................................... 67 
10.3 VL determination ......................................................................................... 67 
10.4 Immunogenicity timepoints ......................................................................... 67 
10.5 Immunogenicity assays ............................................................................... 68 
10.6 ARV plasma drug level monitoring ............................................................. 69 
10.7 Viral sequencing .......................................................................................... 69 
10.8 Genotyping .................................................................................................. 69 
10.9 Testing for STIs ........................................................................................... 69 
10.10 Semen specimens ......................................................................................... 70 
10.11 EOS testing .................................................................................................. 70 
10.12 Ancillary studies .......................................................................................... 70 
10.13 Other use of stored specimens ..................................................................... 70 
10.14 Biohazard containment ................................................................................ 71 
11 
Safety monitoring and review ................................................................................ 72 
11.1 SAE reporting .............................................................................................. 72 
11.2 EAE reporting .............................................................................................. 72 
11.3 Review of safety data .................................................................................. 73 
12 
Protocol conduct .................................................................................................... 74 
12.1 Protocol governance .................................................................................... 74 
12.2 Overview of data collection methods .......................................................... 75 
12.3 Study site monitoring .................................................................................. 76 
12.4 Social impacts .............................................................................................. 77 
12.5 Study participant reimbursement ................................................................. 77 
12.6 Compliance with NIH guidelines for research involving products containing 
recombinant DNA ....................................................................................... 78 
12.7 Emergency communication with study participants .................................... 78 
13 
Version history ....................................................................................................... 79 
14 
Document references (other than literature citations) ............................................ 87 
15 
Acronyms and abbreviations .................................................................................. 89 
16 
Literature cited ....................................................................................................... 92 
Appendix A 
Addendum to sample informed consent form ........................................ 103 
Appendix B 
Revised tables of procedures (for Sample informed consent form 
addendum) 
 ................................................................................................................ 108 
Appendix C 
Schedule 6—Post-unblinding laboratory procedures for HIV-uninfected 
participants 
 ................................................................................................................ 109 
Appendix D 
Schedule 7—Post-unblinding laboratory procedures for HIV-infected 
participants 
 ................................................................................................................ 110 
Appendix E 
Schedule 6—Post-unblinding clinic procedures for HIV-uninfected 
participants 
 ................................................................................................................ 111 
Appendix F 
Schedule 7—Post-unblinding clinic procedures for HIV-infected 
participants 
 ................................................................................................................ 112 
 

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1 
Ethical considerations 
Multiple candidate HIV vaccines will need to be studied simultaneously in different 
populations around the world before a successful HIV preventive vaccine is found. It is 
critical that universally accepted ethical guidelines are followed at all sites involved in 
the conduct of these clinical trials. The HIV Vaccine Trials Network (HVTN) has 
addressed ethical concerns in the following ways: 
HVTN trials are designed and conducted to enhance the knowledge base necessary to 
find a preventive vaccine, using methods that are scientifically rigorous and valid, and in 
accordance with Good Clinical Practice (GCP) guidelines. 
HVTN scientists and operational staff incorporate the philosophies underlying major 
codes [1-3], declarations, and other guidance documents relevant to human subjects 
research into the design and conduct of HIV vaccine clinical trials. 
HVTN scientists and operational staff are committed to substantive community input—
into the planning, conduct, and follow-up of its research—to help ensure that locally 
appropriate cultural and linguistic needs of study populations are met. 
HVTN clinical trial staff members counsel each participant at each study visit 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. HVTN clinical trial staff members will also counsel them about reducing their 
risk of transmitting HIV to others. 
Participants who become HIV-infected during the trial are referred to medical 
practitioners to manage their HIV infection and to identify potential clinical trials they 
may want to join. 
The HVTN provides training so that all participating sites similarly ensure fair participant 
selection, protect the privacy of research participants, and obtain meaningful informed 
consent. Participants should have their privacy protected, the opportunity to withdraw, 
and their well-being monitored. 
Prior to implementation, HVTN trials are rigorously reviewed by scientists who are not 
involved in the conduct of the trials under consideration.  
HVTN trials are reviewed by local and national regulatory bodies and are conducted in 
compliance with all applicable national and local regulations. 
The HVTN designs its research to minimize risk and maximize benefit to both study 
participants and their local communities. For example, HVTN protocols provide 
enhancement of participants’ knowledge of HIV and HIV prevention, as well as 
counseling, guidance, and assistance with any social impacts that may result from 
research participation. HVTN protocols also include careful medical review of each 
research participant’s health conditions and reactions to study products while in the 
study.  

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HVTN research aims to benefit local communities by directly addressing the health HIV 
prevention needs of those communities and by strengthening the capacity of the 
communities through training, support, shared knowledge, and equipment. Researchers 
involved in HVTN trials are able to conduct other critical research in their local research 
settings. 
The HVTN recognizes the importance of institutional review and values the role of 
in-country Institutional Review Boards (IRBs) and Independent Ethics Committees 
(IECs) as custodians responsible for ensuring the ethical conduct of research in each local 
setting. 
The HVTN recognizes the importance of diversity in all research. The requirement for 
participants in this study to be circumcised may reduce participation from some ethnic or 
racial groups. While unfortunate, this is necessary in order to address the safety issues 
that were discovered from the results of the Step Study. 
As new HIV prevention strategies become available and are scientifically validated, the 
HVTN will inform participants.  

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2 
IRB/IEC review considerations 
The US Food and Drug Administration (FDA) and other US federal regulations require 
IRBs or IECs 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 procedures in this protocol 
address each of these research requirements. Each HVTN Investigator welcomes 
IRB/IEC questions or concerns regarding these items. 
2.1 
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) 
having staff properly trained in administering study procedures that may cause physical 
harm or psychological distress, such as blood draws, HIV testing and counseling, and 
HIV risk reduction counseling; (e) providing HIV risk reduction counseling; and (f) 
providing safety monitoring. 
2.2 
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 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.  
Researchers have seen different patterns of HIV risk associated with some experimental 
HIV vaccines. Researchers need more information to make sense of these patterns.  
In one study in Thailand (RV144), the vaccine lowered the risk of getting HIV by about 
31%. The study was in people at lower risk of getting HIV.  
Post hoc analyses in a previous trial (Merck V520 Protocol 023 / HVTN 502, also called 
the Step Study) of another adenovirus serotype 5 (Ad5) vector vaccine showed a potential 
increased risk of HIV infection in uncircumcised men who have sex with men (MSM) 
who had existing neutralizing antibodies (nAb) against naturally occurring Ad5 prior to 
receiving the study vaccine (see Section 4.1.3). The VRC rAd5 vaccine differs from the 
Merck-rAd5 vaccine that was used in the Step Study in the antigen content, vector 
platforms, immunization schedule, rAd5 vector construction and manufacturing substrate, 
and pattern of immune responses induced (see Section 4.3.2 for complete information). 
Also, the VRC rAd5 vaccine in this study has been administered at a lower dose than the 

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Ad5 vaccine evaluated in the Step Study. In addition, the HVTN 505 study limits 
enrollment to participants who share characteristics (circumcision and no detectable nAb 
to Ad5) with the subset of the vaccinated population in the Step Study that showed no 
increase in the rate of HIV infection compared to placebo (see Section 4.1.3 and Table 
4-2). In this way, the HVTN has minimized the risk to HVTN 505 study participants 
while continuing to develop information important to the development of T-cell based 
HIV vaccines. 
Results are now available for a second study using the same vaccine as the Step Study 
(see Section 4.1.3.6). That study, called Phambili, was conducted in South Africa and 
enrolled men and women at high risk for HIV. The Phambili study stopped further 
injections as soon as the Step study injections were stopped. The study results are 
showing more HIV infections in those who received the study vaccine. The increase in 
risk became significant about 2 ½ years after the first vaccination. In that study, men who 
were circumcised and who had never been infected with adenovirus type 5 were at 
increased risk of HIV infection like everyone else. What these results mean is not yet 
clear. Researchers are asking HVTN 503 participants to return to the clinic for more 
testing.  
The HVTN 505 study stopped study injections on April 23, 2013 due to efficacy futility. 
Data presented to the DSMB showed that, through March 22, 2013, there were 27 Week 
28+ endpoint infections in the vaccine arm and 21 in the placebo arm (HR 1.25 [95% CI 
0.71, 2.20]). In the MITT population (defined as all participants who were enrolled and 
HIV-negative at baseline), there were 41 HIV infections in the vaccine arm and 30 in the 
placebo arm. While these differences are not statistically significant (P = 0.446 for Week 
28+ infections, the primary endpoint cohort), numerically the observed infection rate is 
higher in participants who received the study vaccine.  
Since efficacy futility criteria have been met, HVTN 505 has transitioned from a proof-
of-concept efficacy trial to an observational study of the effect of the VRC DNA/rAd5 
vaccine regimen on the rate of HIV-1 acquisition compared to placebo. 
The HVTN will now monitor the participants to ascertain whether vaccine effects on the 
rate of HIV infection can be detected during an extended period of follow-up. We will 
continue with state-of-the art, individually tailored risk reduction counseling to ensure the 
safety of each study participant. 
2.3 
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. 

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2.4 
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 46.416; informed consent is 
appropriately documented as required by 45 CFR 46.417 
The protocol specifies that informed consent must be obtained before any study 
procedures are initiated and assessed throughout the trial (see Section 9.1). Each clinical 
trial site in HVTN 505 uses an Assessment of Understanding to test each participant’s 
understanding before enrollment into the study. The Assessment of Understanding 
(AOU) is a series of statements that a participant is asked to judge as “true” or “false.” 
The content of the AOU relates to some of the basic elements of informed consent, such 
as the participant’s ability to withdraw at any time without penalty. It also asks about the 
purpose of the study, whether the study vaccines can give someone HIV, the potential for 
testing vaccine-induced antibody (Ab) positive after receiving the study vaccine(s), and 
the need for a study participant to continue to reduce his or her risk of HIV while in the 
study. The HVTN 505 AOU also tests a participant’s awareness of the Step Study results. 
Study staff review the answers with the participant and participants must verbalize the 
correct response to the answers that they got wrong in order to join the trial. Although 
there is no formal schedule for assessing continued understanding during the trial, the 
protocol makes it clear that “key study concepts should be reviewed periodically with the 
participant and the review should be documented” (see Section 8.1). 
Each site is provided training in informed consent by the HVTN as part of its entering the 
HVTN. The HVTN requires a signed consent document for documentation, in addition to 
chart notes or a consent checklist. 
2.5 
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 safety monitoring in place (see Section 12). Safety is monitored 
regularly by clinical safety staff and routinely by the Protocol Safety Review Team 
(PSRT) (see Section 11.3).  
As part of the protocol conduct, each participant will receive HIV risk reduction 
counseling at each study visit (see Section 8.4). HIV risk reduction counseling training 
has been provided to key study site staff members. These trained staff members then train 
other counselors at their sites. 
2.6 
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 

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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, Sections 8 and 18). The privacy of 
participants is protected by assigning unique identifiers in place of the participant’s name 
on study data and specimens. In the United States, research participants in HVTN 
protocols are protected by a Certificate of Confidentiality from the US National Institutes 
of Health (NIH), which can prevent disclosure of study participation even when that 
information is requested by subpoena. Participants are told of the use and limits of the 
certificate in the study consent form. In addition, each staff member at each study site in 
this protocol signs a Confidentiality Agreement with the HVTN and each study site 
participating in the protocol is required to have a standard operating procedure on how 
the staff members will protect the confidentiality of study participants. 

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3 
Overview 
Title  
Phase 2b, randomized, placebo-controlled test-of-concept trial to evaluate the safety and 
efficacy of a multiclade HIV-1 DNA plasmid vaccine followed by a multiclade HIV-1 
recombinant adenoviral vector vaccine in HIV-uninfected, adenovirus type 5 neutralizing 
antibody negative, circumcised men and male-to-female (MTF) transgender persons, who 
have sex with men  
Primary objective 
 
To evaluate the rate of study dropout in vaccine and placebo recipients  
 
To evaluate the effect of the VRC DNA/rAd5 vaccine regimen on the rate of HIV-1 
acquisition compared to placebo 
Study products and routes of administration 
Note 
All study participants have received at least some of the following products. 
 
DNA vaccine: Recombinant DNA plasmid (VRC-HIVDNA016-00-VP) composed of 
6 closed, circular DNA plasmids that encode for HIV-1 Gag, Pol and Nef proteins 
(from clade B) and Env glycoproteins from clade A, clade B, and clade C. The dose 
is 4 mg, delivered intramuscularly (IM) via Biojector®. 
 
rAd5 vaccine: Recombinant adenoviral serotype 5 (rAd5) vector vaccine (VRC-
HIVADV014-00-VP) composed of 4 recombinant non-replicating adenoviral vectors 
that encode for HIV-1 Gag-Pol polyproteins (from clade B) and Env glycoproteins 
from clade A, clade B, and clade C. The dose is 1 x 1010 particle units (PU), delivered 
IM via needle and syringe. 
 
PBS: The placebo for the DNA vaccine is sterile phosphate-buffered saline (PBS), 
VRC-PBSPLA043-00-VP delivered IM via Biojector®. 
 
FFB: The placebo for the adenoviral vector vaccine is the adenoviral final 
formulation buffer (FFB), VRC-DILUENT013-DIL-VP, delivered IM via needle and 
syringe. 
Note 
Study injections were discontinued as of April 23, 2013 after site notification of the April 
22, 2013 DSMB recommendations. Subsequently, study participants have been unblinded 
to their treatment assignments (vaccine or placebo). 

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Table 3-1 Schema 
 
 
 Injection schedule in months (days) 
 
 
 Prime 
 Boost 
Group 
N* 
 0 (0) 
 1 (28) 
 2 (56) 
 6 (168) 
1 
1250  4 mg DNA 
 4 mg DNA 
 4 mg DNA 
 1010 PU rAd5 
2 
1250  PBS 
 PBS 
 PBS 
 FFB 
*Due to the randomization scheme, the numbers of vaccine and placebo recipients may differ slightly. 
Participants 
2504 healthy, HIV-uninfected, Ad5 nAb negative, circumcised US MSM and male-to-
female [MTF] transgender persons, ages 18-50 years, at risk for HIV-1 infection through 
sexual exposure. The study was fully enrolled as of March 27, 2013. 1253 participants 
were enrolled into the active vaccine arm and 1251 participants were enrolled into the 
placebo arm.  
Design 
Extended unblinded follow-up of participants enrolled in the multicenter, randomized, 
placebo-controlled, (originally) double-blinded trial  
Duration per participant 
60 months for HIV-1–uninfected participants (48 months of clinic visits plus a participant 
health contact at Month 60). 6 months for participants diagnosed with HIV infection. 
Estimated total study duration 
Enrollment spanned June 2009 to March 2013. Given 60 months of scheduled follow-up 
for the final enrolled participant and potentially 6 months of additional visits should that 
participant be diagnosed with HIV infection at Month 60, the total duration from first 
enrollment to last follow-up visit is estimated at 9.25 years. 
Investigational New Drug (IND) sponsor 
DAIDS, NIAID, NIH, DHHS (Bethesda, Maryland, USA) 
Vaccine provider 
 
All products provided by the VRC (Bethesda, Maryland, USA) 
Core operations 
HVTN Vaccine Leadership Group/Core Operations Center, Fred Hutchinson Cancer 
Research Center (FHCRC) (Seattle, Washington, USA) 
Statistical and data management center (SDMC) 
Statistical Center for HIV/AIDS Research and Prevention (SCHARP), FHCRC 

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HIV diagnostic laboratory 
University of Washington Virology Specialty Laboratory (UW/VSL) (Seattle, 
Washington, USA) 
Endpoint assay laboratories 
 
UW/VSL (Seattle, Washington, USA) 
 
Duke University Medical Center (Durham, North Carolina, USA) 
 
FHCRC/University of Washington (Seattle, Washington, USA) 
 
NIAID Vaccine Immune T-Cell and Antibody Laboratory (NVITAL) (Gaithersburg, 
Maryland, USA) 
 
University of Washington (Seattle, Washington, USA)  
 
Henry Jackson Foundation (Rockville, Maryland, USA) 
 
UW-MRL = University of Washington Molecular Retrovirology Laboratory (Seattle, 
Washington, USA) 
Study sites 
US HVTN clinical research sites (CRSs) specified in the Protocol Opening Notice and 
subsequent Site Announcement Memos.  
Safety monitoring 
HVTN 505 Protocol PSRT; Protocol Team 

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3.1 
Protocol Team 
Protocol leadership 
 
 
 
 
Chair 
Scott Hammer 
Columbia University 
212-305-7185 
smh48@mail.cumc.columbia.edu 
Protocol Team Leader 
Shelly Karuna 
HVTN Core, FHCRC 
206-667-4355 
mkaruna@fhcrc.org 
Co-chair 
Magdalena Sobieszczyk 
Columbia University 
212-305-7185; 212-342-2966 
mes52@mail.cumc.columbia.edu 
Statistician 
Peter Gilbert 
SCHARP, FHCRC 
206-667-7299 
pgilbert@scharp.org 
 
Michael Yin 
Columbia University 
212-305-7185 
mty4@mail.cumc.columbia.edu 
 
Holly Janes 
SCHARP, FHCRC 
206-667-6353 
hjanes@fhcrc.org  
 
 
Medical officer 
Elizabeth Adams 
DAIDS, NIAID 
301-803-8929 
eadams@niaid.nih.gov 
Other contributors to the protocol 
Core medical 
monitor 
Shelly Karuna 
HVTN Core, FHCRC 
DAIDS protocol 
pharmacist  
Ana Martinez 
DAIDS, NIAID  
301- 435-3734 
Vaccine 
developer 
Barney Graham 
VRC, NIH 
Statistician 
Steve Self 
SCHARP, FHCRC 
 
Mary Enama 
VRC, NIH 
Statistical research 
associate 
Doug Grove 
SCHARP, FHCRC 
 
Rick Koup 
VRC, NIH 
 
Amy Krambrink 
SCHARP, FHCRC 
 
Cynthia Hendel 
VRC, NIH 
Clinical safety specialist 
Maija Anderson 
HVTN Core, FHCRC 
Laboratory 
Program 
John Hural 
HVTN Lab Program, FHCRC 
Communications 
Jim Maynard 
HVTN Core, FHCRC 
 
Julie McElrath 
HVTN Lab Program, FHCRC 
Senior project manager 
Gina Escamilla 
SCHARP, FHCRC 
Regulatory 
affairs 
Renée Holt  
HVTN Core, FHCRC 
Project manager 
Lisa Sunner 
SCHARP, FHCRC 
 
Michelle Conan-Cibotti 
DAIDS, NIAID 
Clinical trials manager 
Shelly Ramirez 
HVTN Core, FHCRC 
Clinic 
coordinator 
Steven Chang 
Columbia University 
Protocol development 
coordinator 
Carter Bentley 
HVTN Core, FHCRC 
Community 
Advisory 
Rick Church 
Columbia University CAB 
Community engagement 
unit representative 
Gail Broder 
HVTN Core, FHCRC 
 
Rich Trevino 
Harvard University CAB 
Community 
educator/recruiter 
Coco Alinsug 
Fenway Community Health 
HVTN 
investigators 
Mike Keefer 
University of Rochester 
 
Jason Roberts 
University of Rochester  
 
Susan Buchbinder 
San Francisco Department of Public 
Health 
External relations 
Steve Wakefield 
Legacy Project, FHCRC 
 
Mark Mulligan 
Emory University 
Technical editor 
Adi Ferrara 
HVTN Core, FHCRC 
Medical officer 
Edith Swann 
DAIDS, NIAID 
 
 

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4 
Background and rationale 
4.1 
HIV epidemic and epidemiology 
In 2007 the Joint United Nations Programme on HIV/AIDS (UNAIDS) reported a lower 
estimated number of persons living with HIV/AIDS than in previous years. However, the 
difference in the estimates result from changes in methods used in formulating estimates, 
not trends in the epidemic itself. In December 2007, UNAIDS estimated that 33.2 million 
(30.6 to 36.1) million people were living with HIV/AIDS globally. The 2007 global 
incidence was estimated to be 2.5 million (1.8 to 4.1 million) new cases per year. The 
estimated number of deaths due to AIDS in 2007 was 2.1 million (1.9 to 2.4 million) 
worldwide [4]. While the estimated number of deaths due to AIDS continues to decline, the 
number of people living with HIV continues to grow due to population growth and longer 
life expectancy from improved access to antiretroviral (ARV) medications [5].  
On the basis of results from the Step Study, first reported in 2007 (see Section 4.1.3), 
HVTN 505 will enroll a study population comprising US MSM1. The current status of the 
HIV epidemic among MSM in the US, therefore, is directly relevant to HVTN 505. The US 
HIV prevalence data reported in October 2008 by the Centers for Disease Control and 
Prevention (CDC) are based on data gathered in 2006 [6]. This report estimates that 1.1 
million adults and adolescents (prevalence rate: 447.8 per 100,000 population) were living 
with diagnosed or undiagnosed HIV infection in the United States at the end of 2006. 
Nearly half of all US HIV infections (48.1%) were in MSM. These estimates are based on 
40 states that submitted data on both HIV and AIDS diagnoses, but of note several high-
morbidity areas, including California, Illinois, Maryland, and the District of Columbia, did 
not contribute data about new HIV diagnoses. The June 2007 CDC fact sheet on HIV/AIDS 
among MSM reports that MSM accounted for 71% of new HIV infections among male 
adults and adolescents in 2005 even though only an estimated 5-7% of males identify 
themselves as MSM. The number of new HIV diagnoses decreased during the 1990s but 
more recent surveillance reports indicate an increase in HIV diagnoses among MSM. 
Diagnoses of HIV/AIDS among MSM increased 11% from 2001 through 2005, although it 
is not certain if this increase is due to more testing or to actual increased incidence [7]. A 
study of young MSM indicated that 77% who tested positive for HIV did not know they 
were infected [8]. The CDC has recommended greater emphasis on voluntary testing and 
counseling with the expectation that knowledge of HIV serostatus has the potential to 
reduce risk behaviors and the transmission rate of HIV infection [9]. A study conducted in 
June 2004-April 2005 in 5 large US cities found HIV prevalence among black MSM was 
46% and among white MSM was 21% [10]. 
Given the difficulty of maintaining behaviors that prevent HIV transmission over a lifetime 
and the occurrence of non-consensual sex, the need for a safe and effective vaccine is clear. 
In 2009, results from RV 144, a large phase 3 clinical trial in Thailand, provided 
encouraging evidence that a preventive vaccine might reduce HIV acquisition [11] (see 
Section 4.1.2). In addition, models predict that even a vaccine that did not prevent infection 
but reduced VL and, therefore, reduced disease progression and transmission rates, would 
also have an impact on the HIV epidemic (see Section 4.5).  
 
1 In descriptions of the HVTN 505 study population, “MSM” is taken to include MTF transgender persons who otherwise meet the eligibility criteria (see 
sections 7.1 and 7.2). This definition of “MSM” does not necessarily apply in other contexts (eg, descriptions of previous research).  

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Implementation of a disease-modifying vaccination strategy would present unique 
challenges and would need to be part of a comprehensive multi-modality HIV-prevention 
program [12]. Multi-modality prevention is an important public health goal and current 
investigational approaches include improved strategies for testing and risk reduction 
counseling, better access to ARV treatment, circumcision, pre- and post-exposure 
prophylaxis (PrEP and PEP), development of topical microbicides that would inhibit 
transmission across mucosal surfaces, and reduction in outbreaks of concomitant sexually 
transmitted diseases that increase the risk of HIV transmission [13-15]. 
The VRC, DAIDS (NIAID, NIH), and the NIAID-funded HVTN are committed to the 
development of safe, effective vaccines to prevent HIV infection. 
4.1.1 
HIV vaccine development 
In more than 2 decades of work on development of preventive HIV vaccine, a variety of 
strategies have been tested. Early candidate vaccines were protein immunogens that 
induced antibodies (Ab), but not broadly neutralizing antibodies (nAb). With a better 
understanding of the structural and immunological factors that make induction of nAb to 
HIV-1 envelope so difficult, more sophisticated approaches are now being developed. 
However, no candidate HIV-1 vaccines with known ability to induce broadly nAb are in 
clinical trials at this time. T-cell responses are believed to be critical in controlling HIV-1 
replication and for the last several years, the development of candidate vaccines has 
emphasized T-cell immunity as well [16].  
In the absence of natural immunity to infection with HIV-1, the design of a vaccination 
strategy has been based on knowledge of viral pathogenesis, including the study of infected 
individuals who are long-term nonprogressors (LTNP) [16] and the overall immune 
response to HIV infection in relation to infection parameters [17]. Cytotoxic T lymphocyte 
(CTL) responses specific to HIV contribute to reduction in VL during acute infection 
[18,19] and may be involved in protection against HIV disease progression. High-
frequency CTL responses to HIV-1 are correlated with low VL and slow disease 
progression in chronically infected individuals [20].  
Based on the premise that LTNPs have an immune response that is superior to those who 
have progressive disease and that this may serve as a model for desirable immune 
responses in vaccine candidates, a study was undertaken to characterize the T-cell 
functional profiles of 79 HIV-infected individuals and compare these profiles to those of 9 
LTNPs. Flow cytometry was used to simultaneously evaluate 5 CD8+ T-cell functional 
markers: degranulation (CD107a), cytokine production (interferon gamma [IFN-γ]), tumor 
necrosis factor alpha (TNF-), interleukin-2 (IL-2), and chemokine production (MIP-1β). 
LTNPs had a fundamentally different profile with enhanced CD8+ T-cell functionality. 
There was a dramatic loss of 5-function CD8+ T-cells in the progressors and both the 
frequency and proportion of 5-function CD8+ T-cells correlated inversely with VL in 
progressors. Diminished T-cell function in progressors was not a result of overall 
immunosuppression as polyfunctional responses to other viral infections (eg, Epstein-Barr 
virus, cytomegalovirus, and influenza) may be retained even in the presence of high HIV 
VL. In addition, the study data suggested that the functional quality rather than the quantity 
of HIV-specific CD8+ T cells is a correlate of protection from disease progression [21]. 
The VRC candidate vaccines being evaluated in HVTN 505 were developed to induce a 
polyfunctional T-cell immune response as well as Ab to the HIV-1 envelope protein.  

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To date, only 3 candidate vaccines have advanced into efficacy studies. VaxGen (San 
Francisco, CA) completed phase 3 efficacy studies of a gp120 protein immunogen that was 
known to induce binding, but not broadly nAb; no protective efficacy was observed 
[22,23]. A large phase 3 trial in Thailand of a recombinant canary pox vector prime with a 
gp120 protein boost was completed and the primary results, indicating a modest protective 
effect, have been published [11]. The third candidate, developed by Merck & Co., Inc. 
(Whitehouse Station, NJ) was a rAd5 vector encoding for the HIV proteins Gag, Pol and 
Nef. This vaccine was designed to elicit a T-cell response and was evaluated in phase 2b 
efficacy studies, known as the Step and Phambili Studies. It was found to not prevent HIV-
1 acquisition and to not reduce the VL after HIV-1 infection [24]. An unexpected outcome 
of the Step trial was the observation of more HIV infections in the vaccine group than in 
the placebo group overall (see Section 4.1.3).  
The outcome of the Step Study is sobering and has been considered carefully in the design 
of HVTN 505. The VRC HIV vaccine regimen comprising multiple DNA primes followed 
by a single boost with recombinant E1-, E3- (partial), and E4-deleted rAd5 encoding for the 
HIV proteins EnvA, EnvB, EnvC, Gag, Pol, and Nef is also designed to induce T-cell 
mediated protection. The differences in platforms, antigenic content, preclinical data, and 
immunological characteristics in phase 1 and 2 clinical trials have been carefully reviewed 
and judged to merit additional clinical evaluation of the VRC vaccine regimen. 
4.1.2 
RV 144 and rationale for sample size increase in HVTN 505 
The efficacy of the prime-boost regimen of ALVAC-HIV (vCP1521) and AIDSVAX B/E 
for preventing HIV infection or modulating HIV viral load post-infection was examined in 
the RV 144 trial [11]. This study was conducted in two provinces in Thailand as a 
collaboration between the Thai Ministry of Public Health and the US Military HIV 
Research Program. It was designed as a multicentered, randomized, double-blind, placebo-
controlled, community-based trial and enrolled 18 to 30 year old men and women without 
regard to individual risk for HIV infection. A total of 26,676 volunteers were screened and 
16,402 were randomized. The vaccine regimen was safe and well-tolerated. After 42 
months and 52,985 person-years of follow-up, 132 individuals acquired HIV-1 infection 
(56 in the vaccine group and 76 in the placebo group). Three analyses were conducted: 
intention-to-treat (ITT), modified intention-to-treat (MITT) and per protocol. The MITT 
analysis is thought by most observers to be the most appropriate because it excludes 
persons who were infected at study entry prior to receiving the first dose of vaccine (n = 7 
in RV 144). Vaccine efficacies in the 3 analyses were 26.4% (P=0.08), 31.2% (p = 0.04) 
and 26.2% (p = 0.16), respectively, with the differences evident early post-vaccination in 
the Kaplan-Meier plots. Much debate concerning the analytic approaches and the 
interpretation of the p values took place in the scientific community but the trends were 
concordant across the analyses and consistent with a modest degree of protective efficacy 
[25]. Neither viral load nor CD4+ T-cell counts post-acquisition was different between the 
vaccine and placebo groups. 
RV 144 remains the only vaccine study to demonstrate any protective efficacy for HIV-1 
acquisition and it reignited the field. No immunologic correlate of protection was 
demonstrated on initial testing and questions concerning the mechanism of protection 
remain. AIDSVAX B/E had failed to protect when tested alone in a phase 3 trial [26] but as 
a boost to the ALVAC-HIV prime may have induced a protective effect through the 
production of binding antibodies to gp120 in this context. That the protective effect was 
mediated by antibody dependent cellular cytotoxicity (ADCC) remains one hypothesis. The 

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investigators and their collaborators are working with existing specimens and planning new 
studies to explain and replicate this result in higher risk populations. 
The results of RV 144 are relevant to HVTN 505 from a number of perspectives and 
support elevating prevention of HIV-1 acquisition to a co-primary endpoint. RV 144 once 
again demonstrates the value of later phase testing of products in humans as part of the 
discovery process. The VRC regimen being tested in HVTN 505 elicits strong binding 
antibodies to Env, comparable at least to the levels induced by the RV 144 regimen [27]. 
Although the frequency of vaccine-elicited CD4+ T-cell responses were similar between 
the 2 vaccine regimens, the VRC regimen induced a higher frequency of HIV-specific 
CD8+ T-cell responses [28]. A greater number of samples are being stored prospectively in 
HVTN 505 on an individual participant level so the Team will be in a good position to 
determine the mechanism of protection, and possibly identify a correlate, should a positive 
result be seen. Taken together with the non-human primate data detailed in Section 4.4.1, 
these results support increasing the sample size to provide the power to examine HIV-1 
acquisition in the 7-24 month post vaccination timeframe. [Note: On July 31, 2012, the 
HVTN 505 Oversight Group recommended that the study overenroll by 14% (300 
participants) to bring the total N to 2500. This action was taken to insure that the study 
maintains the power for its key objectives.] 
4.1.3 
Results of the Step Study and rationale for the HVTN 505 study population 
The Step Study (also known as Merck V520 Protocol 023 or HVTN 502) was developed as 
an efficacy trial in 3000 participants. It tested a rAd5-vector-based HIV vaccine encoding 
Gag, Pol, and Nef antigens developed by Merck & Co., Inc. (Whitehouse Station, NJ). 
While there are substantial differences between the Merck and VRC vaccine regimens (see 
Section 4.3.2), the Step Study is, to date, the largest clinical trial of an HIV-1 vaccine 
incorporating a recombinant adenoviral vector. As such, safety results from that trial have 
been considered in the development of HVTN 505. In particular, the Step Study results 
have been examined with respect to adverse reactions to vaccine, increase in risk of HIV 
infection, and potential exacerbation of HIV disease in vaccine recipients who acquire HIV 
infection [29,30]. 
In the Step Study, side effects of the vaccine were mild and similar to those reported in 
previous smaller studies of the Merck rAd5 vaccine [31]. There were no clinically 
significant differences in safety laboratory results between vaccine and placebo recipients. 
Of 40 serious adverse events (SAEs) reported by blinded study investigators, only 2 (fever, 
rigors) that were reported in the vaccine group were deemed related to study vaccine [29]. 
The comparable general safety data, showing no SAEs attributable to the VRC HIV 
vaccines and that they are generally well tolerated, are summarized in Section 4.6.1. 
For the second and third potential safety issues, the HVTN 505 protocol team has carefully 
considered the results of the Step trial. We note that there are no human data that provide a 
statistically powered comparison of the HIV acquisition or HIV disease progression 
endpoints for recipients of the VRC HIV vaccine product and an appropriate control group. 
Therefore, to inform safety issues in HVTN 505 development the relevant, publicly 
reported Step Study results based upon the HIV infections diagnosed through October 17, 
2007 [29] were considered and evaluated as supporting a conclusion that in circumcised, 
Ad5 nAb negative men, the Merck rAd5 vaccine did not elevate the rate of HIV infection. 
We note that less rAd5 vector will be administered in HVTN 505 than was the case in the 
Step Study (respectively, 1 dose of VRC rAd5 at 1 x 1010 PU determined by 
spectrophotometry compared to 3 doses of Merck-rAd5 at 3 x 1010 viral particles 

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determined by polymerase chain reaction [PCR]). An inference of vaccine safety in the 
Step Study sub-population supports a premise of vaccine safety in the HVTN 505 
population, because HVTN 505 restricts enrollment to the sub-population in the Step Study 
for whom there was no evidence of increased HIV infection risk from exposure to the 
vaccine as assessed through the statistical analysis that follows.  
At the first interim analysis in September 2007, the Step Study was found to have met the 
pre-specified futility boundaries. The study was fully enrolled and the majority of study 
vaccinations had been administered, but additional injections were stopped at that time. 
Additional exploratory analyses of the vaccine effect on HIV infection rate and on 
postinfection endpoints were conducted using all available data through October 17, 2007. 
Participants were blinded to vaccination assignment up to this date, implying that the 
amount of HIV exposure is expected to be the same in the vaccine and placebo groups. 
Because only 1 HIV infection occurred in female participants, the analyses were restricted 
to male participants. Credibility of the results is supported by the high rate of protocol 
adherence, with 94% of the vaccine and placebo groups receiving all 3 study injections, and 
by the high rate of retention, with 93.5% of vaccine recipients and 94.2% of placebo 
recipients staying in the study (participants had approximately 1 year of follow-up on 
average). 
Univariate Cox proportional hazards models were used to quantify vaccine effects for 
various Step Study participant subgroups defined by demographic and/or baseline 
behavioral risk factors. The demographic factors included baseline Ad5 nAb titer (> 18, 
 18), self-reported circumcision status (circumcised, uncircumcised), age ( 30, > 30 
years), race (White, Other), and region (North America, Other), while the behavioral risk 
factors included self-reports of the practice of unprotected receptive anal sex (URAS: yes, 
no), unprotected insertive anal sex (UIAS: yes, no), number of male sex partners (> 4,  4), 
and history of any drug use (yes, no), all in the 6 months prior to study entry. The time-to-
event variable for the Cox model analyses was defined as the time from initial vaccination 
to the midpoint between the date of the last HIV seronegative visit and the date of the first 
evidence of HIV infection, as determined by the blinded Endpoint Adjudication 
Committee. Participants who never showed any evidence of HIV infection were right-
censored on the date of their last study visit prior to October 17, 2007.  
Multivariate Cox models were used to estimate the treatment effect after adjusting for 
potential confounding variables. Candidate confounders were pre-selected on the basis of 
their plausibility to impact HIV infection risk, and included the aforementioned 
demographic and baseline behavioral risk factors, with additional specificity for some 
variables. For example, the URAS and UIAS variables were each expanded to 3 variables 
defined by the corresponding risk behavior with an HIV seropositive (HIV+), HIV Ab 
negative (HIV-), or HIV status unknown partner; likewise, the history of any drug use was 
expanded to 2 variables, use of amyl nitrates (poppers) or use of amphetamines. The 
candidate confounders were all dichotomous for simplicity, stabilizing the model fitting, 
and reducing the modeling assumptions.  
The Cox multivariate regression modeling was structured hierarchically into 4 sequential 
steps. First, separate interaction tests for each of 9 baseline variables with treatment were 
conducted. Based on the outcome of the univariate interaction tests, the multivariate base 
model 1 was defined as the model with independent variables treatment, Ad5 (> 18,  18), 
circumcision, and the interactions of treatment with Ad5 and treatment with circumcision. 
Model 2 included model 1 variables plus the candidate confounders that stayed in a 
backwards elimination model selection procedure that successively removed the variable 

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with the greatest p-value. Model 3 included model 2 variables plus any interactions of 
treatment with candidate confounders that stayed in the model after backwards elimination. 
Model 4 included model 3 variables plus the 2 interactions of circumcision with UIAS with 
an HIV+ partner and with UIAS with an HIV status unknown partner, if they stayed in the 
model after backwards elimination. The backwards elimination procedure used a Wald p-
value threshold of 0.15 for removing variables; similar results were observed using a 
threshold of 0.10. To assess consistency of results, treatment effects for relevant subgroups 
were estimated using each of the 4 models.  
Possible imbalance in HIV exposure between the vaccine and placebo groups was assessed. 
For each risk behavior variable, a generalized linear model for longitudinal binary data with 
logit link [32] was used to evaluate if and how treatment impacted the frequency of the 
reported behavior during 6-18 months after randomization. The baseline behavior status, 
age, and race were included as covariates to enhance the precision of the analysis and to 
increase compliance with standard modeling assumptions.  
Analyses were conducted on the MITT population, which consisted of all randomized 
participants who received at least 1 dose of vaccine or placebo, except those who had a 
positive HIV screening test prior to randomization. Similar results were obtained for the 
per-protocol population (all randomized participants who received the first 2 doses of either 
vaccine or placebo, except those who were either diagnosed with HIV-1 infection before or 
at week 12 (ie, 8 weeks post dose 2) and/or were identified as protocol violators based on 
predefined criteria). 
4.1.3.1 
Univariate analyses of the vaccine effect on HIV infection  
Forty-nine of the 914 male vaccine recipients became HIV infected (annual HIV incidence 
4.6%, 95% confidence interval (CI) 3.4 to 6.1) and 33 of the 922 male placebo recipients 
became HIV infected (annual incidence 3.1%, 95% CI 2.1 to 4.3). The overall treatment 
effect HR (vaccine/placebo) from the univariate Cox model was 1.5 (95% CI 0.97 to 2.3, p 
= 0.07). Because the randomization was stratified within each of 4 pre-specified baseline 
Ad5 neutralization titer strata using the Merck Laboratories Ad5 nAb assay (see Section 
4.2) (≤ 18, 19 - 200, 201 - 1000, > 1000), the vaccine effect within the Ad5 nAb negative 
stratum (Ad5 ≤ 18) and within the Ad5 seropositive stratum (Ad5 > 18) can be validly 
estimated, with the full protection of randomization from potential confounding bias. The 
vaccine effect can also be validly estimated within subgroups defined by self-reported 
circumcision status and within subgroups defined by Ad5 nAb status cross-classified with 
circumcision status, because circumcision status was measured prior to randomization and 
was independent of treatment assignment.  
For subgroups defined by either Ad5 nAb status or circumcision status, HIV incidence 
estimates during 3 semi-annual periods from the time of enrollment, separately for the 
vaccine and placebo groups, were calculated as nonparametric estimates of discrete hazard 
functions. For Ad5 nAb negative men, the estimated HIV incidence was slightly lower in 
the vaccine group than the placebo group in all 3 time intervals; the result is the same for 
circumcised men. Using all of the available follow-up information, of the 776 Ad5 nAb 
negative men, the annual HIV incidence estimates were nearly identical in the vaccine 
group (20 infections, estimated annual incidence 4.1%) and the placebo group (20 
infections, estimated annual incidence 4.0%) (Table 4-1). Similarly, of the 999 circumcised 
men, the annual HIV incidence estimates were nearly identical in the vaccine group (26 
infections, estimated annual incidence 4.1%) and the placebo group (26 infections, 
estimated annual incidence 4.2%) (Table 4-1). In the 578 men who were both Ad5 nAb 

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negative and circumcised, there were 12 infections in the vaccine group (estimated annual 
incidence 3.2%) and 18 infections in the placebo group (estimated annual incidence 4.6%) 
(Table 4-1). In this subgroup the estimated HR (vaccine/placebo) was 0.7 (95% CI 0.3 to 
1.4) (Table 4-2), indicating that within this subgroup it is unlikely the risk of infection was 
greater in the vaccine group. 
Table 4-1 HRs of HIV infection for male subgroups defined by demographic and baseline 
behavioral risk factors (univariate Cox model analyses) 
 
 
Number of HIV 
infections 
HIV infection rate 
(% per year) 
HR 
(Vaccine/Placebo) 
(95% CI) 
Interaction 
p-value1 
MITT Population 
N 
Vaccine 
Placebo 
Vaccine 
Placebo 
Demographic factors 
Ad5– (titer  18) 
776 
20 
20 
4.1 
4.0 
1.0 
(0.5 to 1.9) 
0.08 
Ad5+ (titer > 18) 
1060 
29 
13 
5.1 
2.2 
2.3 
(1.2 to 4.3) 
Circumcised 
9992 
26 
26 
4.1 
4.2 
1.0 
(0.6 to 1.7) 
0.01 
Uncircumcised 
788 
22 
6 
5.2 
1.4 
3.8 
(1.5 to 9.3) 
Whites 
907 
24 
18 
4.4 
3.2 
1.4 
(0.8 to 2.6) 
0.71 
Non-Whites 
929 
25 
15 
4.8 
2.9 
1.6 
(0.9 to 3.1) 
Age  30 yrs  
970 
28 
19 
5.0 
3.5 
1.4 
(0.8 to 2.6) 
0.81 
Age > 30 yrs 
866 
21 
14 
4.1 
2.6 
1.6 
(0.8 to 3.1) 
North America 
1171 
37 
29 
5.2 
4.0 
1.3 
(0.8 to 2.1) 
0.18 
Others 
665 
12 
4 
3.4 
1.1 
3.0 
(1.0 to 9.4) 
Behavioral risk factors3 
UIAS4: yes 
1097 
36 
25 
5.6 
3.9 
1.4 
(0.9 to 2.4) 
0.75 
UIAS: no 
739 
13 
8 
3.1 
1.8 
1.7 
(0.7 to 4.1) 
URAS5: yes 
916 
37 
25 
7.2 
4.7 
1.5 
(0.9 to 2.5) 
0.99 
URAS: no 
920 
12 
8 
2.2 
1.5 
1.5 
(0.6 to 3.7) 
Any drug use: yes 
792 
29 
19 
6.2 
4.3 
1.5 
(0.8 to 2.6) 
0.96 
Any drug use: no 
1044 
20 
14 
3.3 
2.2 
1.5 
(0.8 to 3.0) 
> 4 male sex partners 
1101 
32 
23 
5.1 
3.5 
1.5 
(0.9 to 2.5) 
0.88 
 4 male sex partners 
735 
17 
10 
3.9 
2.4 
1.6 
(0.7 to 3.5) 
 
1 2-tailed p-value for a test of difference between the HRs for the 2 subgroups, not corrected for multiplicity 
2 circumcision data unknown for 49/1836 males, including 1 infected male from each of the vaccine and placebo groups 
3 behavioral risk data are based on self-reported behavior within 6 months prior to randomization 
4 UIAS = unprotected insertive anal sex 
5 URAS = unprotected receptive anal sex 

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Table 4-2 HRs (vaccine/placebo) (95% CIs) of HIV infection using univariate and multivariate 
Cox models for subgroups defined by baseline Ad5 nAb status and/or circumcision status 
 
 
Baseline Ad5 nAb titer regardless 
of circumcision status 
Circumcision status regardless of 
baseline Ad5 nAb titer 
Analysis 
Ad5– 
Ad5+ 
Circumcised 
Uncircumcised 
Univariate 
1.0 
(0.5 to 1.9) 
2.3 
(1.2 to4.3) 
1.0 
(0.6 to 1.7) 
3.8 
(1.5 to 9.3) 
Multivariate 
 
 
 
 
Model 1 
1.0 
(0.5 to 1.8) 
2.4 
(1.2 to4.7) 
1.0 
(0.6 to 1.7) 
3.8 
(1.5 to 9.3) 
Model 2 
1.1 
(0.6 to 2.0) 
2.7 
(1.3 to 5.5) 
1.0 
(0.6 to 1.8) 
3.8 
(1.6 to 9.5) 
Model 3 
1.1 
(0.6 to 2.0) 
3.1 
(1.5 to 6.5) 
1.1 
(0.6 to 2.0) 
4.1 
(1.6 to 10.4) 
Model 4 
0.8 
(0.4 to 1.6) 
2.6 
(1.3 to 5.4) 
0.9 
(0.5 to 1.6) 
3.4 
(1.4 to 8.4) 
 
 
Circumcised 
and Ad5– 
Circumcised 
and Ad5+ 
Uncircumcised 
and Ad5– 
Uncircumcised 
and Ad5+ 
Analysis 
Univariate 
0.7 
(0.3 to 1.4) 
1.6 
(0.7 to 3.8) 
3.3 
(0.7 to 15.8) 
3.9 
(1.3 to 11.9) 
Multivariate 
 
 
 
 
Model 1 
0.8 
(0.4 to 1.6) 
1.4 
(0.6 to 3.2) 
2.5 
(0.8 to 8.0) 
4.3 
(1.7 to 11.0) 
Model 2 
0.8 
(0.4 to 1.7) 
1.7 
(0.7 to 3.8) 
2.4 
(0.8 to 7.3) 
4.8 
(1.8 to 12.6) 
Model 3 
0.6 
(0.3 to 1.2) 
1.3 
(0.6 to 3.0) 
2.0 
(0.6 to 6.3) 
4.6 
(1.8 to 12) 
Model 4 
0.6 
(0.3 to 1.2) 
1.4 
(0.6 to 3.1) 
2.1 
(0.7 to 6.6) 
4.2 
(1.6 to 11.1) 
 Ad5– and Ad5+ are baseline Ad5 nAb negative ( 18) and seropositive (> 18), respectively; 18 is the lower 
quantification limit of the Merck Laboratories Ad5 nAb titer assay; models 1-4 are of increasing complexity and 
differ in the number and type of baseline factors adjusted for in the Cox regression analysis (see Section 4.1.3). 
 
4.1.3.2 
Evaluation of effect modification by Ad5 nAb status and circumcision status 
Given that the overall HR was 1.5 (95% CI 0.97 to 2.3), which trended toward statistical 
significance (p = 0.07), it is possible that the vaccine elevated the risk of infection 
uniformly, and the apparent safety in the Ad5 nAb negative circumcised subgroup could be 
due to statistical variations of the HR estimates across subgroups. However, this possibility 
is made less likely by the following additional results. First, based on interaction tests from 
a Cox model, there was statistical evidence that the HR was higher in Ad5 seropositive men 
than Ad5 nAb negative men (HR 2.3 versus 1.0 respectively, interaction test p = 0.08), and 
was higher in uncircumcised men than circumcised men (HR = 3.8 vs. 1.0, interaction test 
p = 0.01) (Table 4-1). In addition, there was evidence that the HR increased with log10 
(Ad5) neutralization titer (univariate Cox model trend test p-value = 0.06).  
Second, the univariate results did not materially change after adjusting for other baseline 
and demographic covariates in multivariate models. This result was obtained by estimating 
HRs adjusting for the significant independent predictors of HIV infection in multivariable 
models 2, 3, and/or 4. The variables age  30, non-White race, North American, URAS 
with an HIV+ partner, and URAS with an HIV status unknown partner were significant in 
all three models 2 through 4, whereas other risk behavior variables were independent risk 

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factors in only one of the models 2 through 4. Interactions of treatment with popper use and 
with UIAS anal sex with an HIV+ partner were evident in both models 3 and 4.  
The multivariate analyses showed a consistent pattern of treatment effects by Ad5 nAb 
status and circumcision status across the 4 models, which were also similar to the univariate 
treatment effects. Furthermore, there was evidence that the HR increased with log10 (Ad5) 
neutralization titer even after adjusting for potential confounding variables (multivariate 
Cox model trend test p-value = 0.03). The covariate-adjusted treatment effect HRs for Ad5 
nAb negative men and for circumcised men ranged from 0.8 to 1.1 (see Table 4-1). The 
similarity of the univariate and multivariate results support that the randomization and 
blinding were effective in eliminating confounding from the measured baseline variables, 
and that any increased risk of infection by vaccine was restricted to Ad5 nAb positive 
and/or uncircumcised men.  
4.1.3.3 
Comparison of risk behavior data between the vaccine and placebo groups 
It is possible that, due to chance, exposure to HIV was greater in the placebo group for Ad5 
nAb negative men and/or for circumcised men. This could render the estimated HR an 
underestimate of the true HR, in which case there would be less evidence for vaccine safety 
in Ad5 nAb negative circumcised men. To address whether this chance-imbalance may 
have occurred, the risk behavioral data were compared between vaccine and placebo 
recipients through 18 months of follow-up. For Ad5 nAb negative men rates of UIAS, 
URAS with an HIV+ or HIV status unknown partner, and any drug use trended statistically 
higher in the vaccine group, when averaged over the 6-18 month time period, and other risk 
behaviors had similar frequencies in the 2 treatment groups. For circumcised men the 
frequencies of the risk behaviors were generally similar in the 2 treatment groups. These 
results support that a chance-imbalance of greater HIV exposure in the placebo group for 
Ad5 nAb negative men and/or circumcised men did not occur. In addition, the trend of 
higher risk behavior in the vaccine group for circumcised men further support an inference 
of no elevation of HIV infection risk due to vaccination in Ad5 nAb negative circumcised 
men. 
In sum, all of the Step Study analyses are consistent with a premise that the Step Study 
vaccine did not elevate the risk of HIV infection in Ad5 nAb negative circumcised men. 
4.1.3.4 
Vaccine effect on postinfection endpoints in Step Study male HIV-infected volunteers  
Postinfection follow-up of HIV infected participants ranged from 0 to 1115 days (mean = 
359 days). VL setpoints (using the pre-specified definition of the primary endpoint) were 
not materially different between vaccine and placebo recipients in the overall group of 
infected participants or within any subgroup defined by Ad5 nAb status or by circumcision 
status. Twenty-two participants initiated antiretroviral therapy (ART) (14 vaccine recipients 
and 8 placebos), all but 1 from North America. The estimated probability of initiating anti-
retroviral therapy (ART) within 1 year of diagnosis was 0.23 for infected placebo recipients 
and 0.38 for infected vaccine recipients; time to ART initiation did not differ between 
treatment groups (log-rank p = 0.38). Longitudinal pre-ART VL and CD4+ T cell 
trajectories were also similar between treatment groups (p = 0.38 and 0.43, respectively). In 
sum, the vaccine did not have a measurable impact on postinfection outcomes, supporting 
that it did not exacerbate the course of HIV-1 disease progression. These data support a 
premise that the rAd5 component of the VRC product is expected to not exacerbate HIV-1 
disease. 

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4.1.3.5 
Step Study data through December 31, 2009 
Vaccinations were stopped in the Step Study on Sept 19, 2007, after the DSMB’s first 
interim efficacy analysis. Study participants were unblinded as to treatment assignment 
beginning in November 2007. Results from these early analyses have been published and 
included data through October 17, 2007 [29]. Follow-up of study participants was 
continued in the Step Study and (subsequently) HVTN 504 until 4 years from first study 
injection or until December 31, 2009. Because few HIV infections were detected among 
women over the entire follow-up period (2 prior to unblinding and 13 post-unblinding), 
analysis has been limited to men. There were 172 infections among 1836 men during the 
entire follow-up period; 88 before 18 months and 84 afterwards. For the entire follow-up 
period, there was a higher risk of HIV infection among the male MITT (modified intent 
to treat) vaccine recipients versus placebo recipients; the covariate-adjusted HR was 1.44 
(95% CI: [1.05, 1.97], p = 0.03). Analyses of vaccine effects on HIV infection over time 
suggest that, in those subgroups that showed elevated risk associated with vaccine receipt 
(ie, Ad5 seropositive and/or uncircumcised men), the vaccine-associated risk appeared to 
be highest shortly after vaccination and to decrease after 18 months, possibly due to a 
waning vaccine effect [33,34]}. Note that circumcised men who were Ad5 seronegative 
at baseline showed no evidence of elevated infection risk at any time.  
Analysis of follow-up data through September 22, 2009 on male Step Study participants 
who became HIV-infected prior to unblinding found no differences in CD4+ T cell count, 
plasma viral load, time to initiation of ART, or time to an AIDS-defining disease between 
vaccine and placebo recipients [35]. These results are consistent with the primary 
analysis of the Step Study, conducted at the time of unblinding [29].  
4.1.3.6 
HVTN 503 (Phambili) results  
At the time vaccinations were stopped in the Step Study, enrollment was underway in 
HVTN 503 (Phambili), a phase 2b efficacy study of the same vaccine regimen in South 
Africa. 801 of a planned 3000 participants had been enrolled at that point. Vaccinations 
in HVTN 503 were stopped immediately and participants were unblinded to their 
treatment assignments. Among those assigned to the active treatment arm, 112 
participants had received 1 vaccination, 259 had received 2 vaccinations, and only 29 had 
received all three planned vaccinations. Visit schedules were revised to call for clinic 
visits every 3 months for 42 months (3.5 years). At the time HVTN 503 was unblinded, 
the few endpoint HIV infections that had accrued were relatively evenly divided between 
the vaccine and placebo arms. A subsequent analysis when Phambili participants had 
been followed for an average of ~18 months found no significant difference in infections 
between vaccine and placebo arms. However, the final analysis following 42 months of 
follow-up for all participants found that, of 100 study participants who became HIV-
infected, 63 had received the study vaccine and 37 had received placebo injections [36]. 
The increased number of infections among vaccinees was greatest among men and more 
pronounced toward the end of follow-up, that is, roughly 30 months or more following 
initial vaccination. In this study, vaccinees were more likely than placebo recipients to 
become HIV-1–infected irrespective of their circumcision status or whether they were 
Ad5 seropositive at baseline. While the difference in HIV infections between vaccinees 
and placebo recipients is statistically significant (estimated HR 1.70, 95% CI 1.13 – 2.55, 
p = 0.01), there were differences in retention between the two study arms and more than 
85% of follow-up was post-unblinding, both of which potentially introduce bias and 
make interpretation of the observed results problematic [36]. Based on these concerns, 
investigators recalled former study participants to the clinical sites for further testing 

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[37]. Of 695 participants who were HIV-1–uninfected at their final Phambili study visit, 
464 received follow-up HIV testing, including 69 of the 189 participants who had 
terminated from Phambili early. In total, 36 additional HIV infections were detected. 
Including the additional follow-up time, the adjusted HR was 1.53 (95% CI: 1.08-2.16) 
vs 1.70 (95% CI 1.13 – 2.55) seen at 3.5 years of follow-up. 
4.1.4 
iPrEx study results 
The primary analysis of iPrEx study data was reported in the 4th quarter of 2010. This 
study represents the first efficacy evaluation of systemic pre-exposure prophylaxis (PrEP) 
with once-daily oral emtricitabine/tenofovir (FTC/TDF) to prevent HIV acquisition [38]. 
The study was conducted in South America, the US, Thailand, and South Africa among 
2,499 HIV-negative male and male-to-female transgender participants who reported sex 
with a man. As part of the study, participants received HIV testing, risk reduction 
counseling, and PrEP adherence counseling every 4 weeks, and STI screening and 
treatment every 24 weeks. The median length of follow-up was 1.2 years with a 
maximum of 2.8 years. It should be noted that only 10% of the study participants were 
enrolled in US clinical sites (Boston and San Francisco). For this reason, the study was 
not powered to detect differences based on region or to determine the effect of this 
intervention on HIV-1 incidence among US MSM.  
In the analysis based on data from visits through May 1, 2010 (excluding 10 infections 
diagnosed at enrollment), 36 incident infections were identified in the FTC/TDF group 
and 64 in the placebo group, for a relative risk reduction in HIV acquisition of 44% (95% 
CI of 15% to 63%). Prespecified subgroup analyses did not reveal any significant 
differences in efficacy based on region, race/ethnicity, male circumcision status, alcohol 
use, or age. Risk behavior was assessed every 12 weeks; there were no overall differences 
in reported risk behavior between the two groups and there was no evidence of risk 
compensation during follow up. Importantly, there were no significant differences in the 
number of episodes of other sexually transmitted infections (eg, gonorrhea, syphilis) 
during follow up. 
Reduction of HIV-1 acquisition correlated with adherence to the PrEP regimen. For 
example, a 50% (95% CI, 18%-70%) reduction in HIV-1 incidence was noted at visits 
where participants had taken FTC/TDF on 50% or more of days since their last visit as 
measured by self-report and pill count/dispensing. In post hoc analyses, pill use on 90% 
or more of days was associated with an incidence reduction of 73% (95% CI, 41%–88%). 
Drug level testing [plasma and peripheral-blood mononuclear cells (PBMCs)] was 
performed for all incident HIV-1 cases and a matched subset of uninfected controls. It 
was noted that only 8% of HIV-infected and 54% of uninfected controls who were 
considered on treatment on more than 50% of days had detectable study drug in plasma 
or PBMC samples. In the FTC/TDF arm, individuals with a detectable drug level had a 
relative reduction in HIV risk of 92% (95% CI, 40-99%) compared to those with no 
detectable drug. These results indicate that most of the incident infections within the 
FTC/TDF group occurred when there was no detectable drug present in plasma or 
PBMCs. Follow-up data on infections through November 2010 indicate that the daily use 
of FTC/TDF decreased HIV acquisition by 42%, preventing an expected 35 infections in 
the FTC/TDF arm. As in the interim analysis, more consistent use of FTC/TDF correlated 
with protection from HIV acquisition [39,40].  
There were no differences in severe or life threatening laboratory events and the drug was 
generally well tolerated with some exceptions. For example, there was a trend toward 

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elevations in serum creatinine levels in the FTC/TDF group (defined as creatinine 
elevation at least 1.1 times the upper limit of normal or > 1.5 times the baseline level). 
Specifically, there were 26 instances of creatinine elevations in the FTC/TDF group and 
15 in the placebo group (p=0.08). Overall, however, this resulted in only a total of 10 
discontinuations of the study agents (7 in the active arm and 3 in the placebo group) 
which were restarted in 9 individuals. Similarly, moderate nausea and unintentional 
weight loss of 5% were reported more frequently in the FTC/TDF group compared to 
placebo. The differences were most pronounced in the beginning of the study. For 
example, nausea was more common during the first 4 weeks after enrollment (9% vs. 5%, 
p < 0.001) and thereafter decreased to comparable levels in both groups. Similarly, 
differences in weight between the groups equilibrated after week 12.  
Among those who seroconverted in the study, there were no differences in viral load 
setpoint and CD4+ T cell count between participants in the FTC/TDF and placebo group. 
Drug resistance was evaluated among the 8 individuals randomized to placebo and 2 
randomized to FTC/TDF who on subsequent testing were plasma HIV-1 RNA positive at 
enrollment. There was one case of primary or transmitted resistance detected in the 
placebo group (multidrug resistance conferred by K103N, M184V, and T215Y 
mutations). Among 2 individuals assigned to the FTC/TDF group, both had FTC 
resistance, one was confirmed as acquired during the first 4 weeks of FTC/TDF use; in 
the second individual the enrollment HIV-1 RNA level was too low to allow detection of 
drug resistance, thus it was not possible to determine if this was the case of acquired or 
primary drug resistance. These data highlight the need for a careful evaluation of at-risk 
individuals for possible acute retroviral syndrome, particularly in presence of signs or 
symptoms consistent with a viral syndrome. Importantly, there was no FTC or TDF 
resistance reported among individuals who seroconverted on-study.  
4.1.5 
Additional efficacy trials of Truvada® as PrEP 
In addition to iPrEX summarized above, four trials (Partners PrEP, TDF2, FEM PrEP and 
VOICE [MTN-003]) have evaluated the safety and efficacy of Truvada® (FTC/TDF) 
among HIV-uninfected, heterosexually active adults [41-44].  
Partners PrEP, demonstrated the efficacy of tenofovir or emtricitabine/tenofovir in 
serodiscordant heterosexual couples in sub-Saharan Africa. The study demonstrated 67% 
(95% CI 44–81%, p < 0.0001) and 75% (95% CI 55–87%, p < 0.0001) reductions in HIV 
acquisition in the tenofovir and emtricitabine/tenofovir arms, respectively; the Data and 
Safety Monitoring Board (DSMB) overseeing the trial reviewed the data and stopped the 
placebo arm early. The TDF2 trial, an extended safety trial that enrolled 1219 HIV-
negative sexually active men and women in Botswana, announced similar results. In the 
TDF2 trial, the arm assigned to daily emtricitabine/tenofovir reported 62.6% fewer HIV-
1 infections than the placebo arm (95% CI 21.5–83.4%, p = 0.0133). A second analysis 
that excluded individuals who became infected more than 30 days after the last reported 
study drug/placebo dose determined that FTC/TDF reduced HIV-1 acquisition risk by 
77.9% (95% CI 41.2–93.6%, p = 0.0053). 
The FEM-PrEP trial and the oral TDF portion of the VOICE trial conducted in high risk 
women were stopped early by their data safety monitoring boards when they concluded 
that no evidence of efficacy would be found. Although self-reported adherence to the 
medication was high in FEM-PrEP, measurements of drug levels in plasma revealed that 
adherence was <50%. 

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Primary results for the VOICE trial were announced in March 2013 [45]. The study 
found no evidence that the oral Truvada® regimen was efficacious in preventing HIV 
infection. Notably, while self-reports and pill counts pointed to high levels of adherence 
to the study drug regimen, laboratory assays found low systemic levels of study drugs, 
suggesting that adherence was, in fact, very low, especially among young women who 
were at highest risk of HIV infection. 
No serious toxicities were identified in any of the trials evaluating daily oral FTC/TDF; a 
notable exception was nausea and vomiting which occurred more commonly in those 
receiving FTC/TDF than in those receiving placebo in the first 1–2 months on 
medication.  
Based on the strength of the evidence from iPrEx and Partners PrEP, on July 16, 2012, 
the U.S. Food and Drug Administration approved Truvada (emtricitabine/tenofovir 
disoproxil fumarate) for PrEP in combination with safer sex practices to reduce the risk 
of sexually acquired HIV-infection in adults at high risk [46,47]. Specifically, once daily 
Truvada is indicated in combination with a comprehensive HIV prevention strategy 
(including condoms, HIV testing, and risk reduction counseling) among men and 
transgender women who have sex with men and women in serodiscordant relationships.  
4.1.5.1 
Monitoring for ARV use for HIV-1 prophylaxis 
The results of the iPrEx study demonstrated that combination emtricitabine and tenofovir 
taken orally every day by men and male-to-female transgender persons who have sex 
with men can provide moderate protection from HIV acquisition. This intervention was 
tested in combination with proven risk-reduction strategies such as frequent HIV testing, 
STI screening and treatment, condom use and risk reduction counseling. Many questions 
still remain about the applicability of these results to diverse communities of MSM, 
transwomen, and other groups at risk for HIV acquisition, about long-term safety of this 
regimen, and about development of resistance to FTC/TDF, which is an important 
component of the preferred initial antiretroviral regimen in the US [48].  
At present, it remains to be seen what the uptake of PrEP will be in the communities of 
men who have sex with men and transgender individuals in the US but it will likely 
depend on factors such as perception of risk, barriers to adherence, access to drug, cost, 
and perceived side effect profile [49,50]. Prior to release of iPrEx results, surveys among 
at-risk MSM from San Francisco and Boston demonstrated that knowledge about and use 
of PrEP are rare at present but that there is interest in considering its use [51,52]. A web-
based survey conducted among HVTN 505 participants (n = 376) indicated that many 
considered iPrEx results very important either to them personally or to their community 
(35% and 66%, respectively); 31% of responders would consider taking PrEP in the next 
year and only a minority indicated that taking PrEP would affect their willingness to stay 
in the study (9%), or willingness of others to enroll in HVTN 505 (16%) [53]. 
Knowledge and attitudes towards use of ARVs as prophylaxis will likely evolve as more 
data come from long-term follow up of iPrEx participants and as normative guidelines 
are issued. Likewise, as more clinical data emerge about the optimal timing and 
frequency of dosing of ART around high-risk exposure, the distinction between PrEP and 
PEP may become less clear. In this context, monitoring for use of ARVs as prophylaxis 
against HIV acquisition among 505 participants becomes crucially important.  
The availability of partially effective oral PrEP raises a number of important questions 
that are important to consider in the context of HVTN 505. For example, since HVTN 

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505 evaluates the effect of the vaccine regimen on setpoint viral load and HIV 
acquisition, ARVs used as pre or post-exposure prophylaxis may influence parameters 
such as HIV incidence. Use of PEP or PrEP may also influence post-infection disease 
course such as early virologic and immunologic marker trajectories and development of 
drug resistance. Furthermore, evaluating patterns and predictors of such ARV use may 
yield important information about their effects on study participation, risk behavior over 
time, and perception of risk, all of which are key issues for the vaccine and prevention 
fields in general.  
To evaluate these questions, prophylactic use of ARVs in HVTN 505 will be assessed 
through both FTC/TDF plasma drug level testing and self-report. 
4.2 
Ad5 nAb assays 
Merck Laboratories developed and validated an Ad5 nAb assay (hereafter termed the 
“Merck assay”) that has been used to assess Ad5 nAb titers in Merck-sponsored HIV 
vaccine trials, including the Step Study. NVITAL, in conjunction with Crucell Co., has 
also produced an assay to measure Ad5 nAb. The NVITAL assay has been used to 
monitor Ad5 nAb for clinical trials using the VRC products. The dilution range of the 
Merck assay is 1:18 to 1:4608 while the dilution range of the NVITAL assay is 1:12 to 
1:8748. Hence, a sample that tests < 18 in the Merck assay is evaluated as Ad5 nAb 
negative, whereas a value of < 12 marks a sample as Ad5 nAb negative in the NVITAL 
assay. Samples testing ≥18 (Merck) and ≥ 12 (NVITAL) are judged Ad5 nAb positive in 
the 2 assays. Because the selection of the study population for HVTN 505 has been 
guided by the results of the Step Study (see Section 4.1.3) and we want to interpret the 
results of HVTN 505 in relation to the Step Study Ad5 nAb screening cutoff, we will 
utilize the Merck assay for HVTN 505. 
4.3 
Study vaccines 
In 2001, the World Health Organization UNAIDS HIV Vaccine Advisory Committee 
recommended that candidate HIV vaccines design should be based upon the strains 
prevalent in the country in which trials are to be conducted [54]. The VRC and the World 
Health Organization-UNAIDS organized a meeting focused on the genetic diversity of 
HIV and strategies to develop vaccine candidates. A consensus was reached that 
generation of multiclade candidate vaccines was an international scientific priority [55]. 
This approach was the foundation for the design of the VRC vaccine candidates. The 
ensuing work from 2002 through 2007 was directed toward the goal of first evaluating 
safety and immunogenicity in a diverse international population and, if the vaccine 
candidates were found to be safe and immunogenic, to proceed to a global efficacy study 
in both men and women. Much work towards this goal was accomplished and a global 
study was ready to open in late September 2007. Following public release of the Step 
Study results on September 21, 2007, the plans were revised. The HVTN 505 study will 
not include women and is limited to the subset of the Step Study vaccinated population 
that did not have increased rate of HIV infection compared to placebo. There is not an 
identified cohort of high-risk women in a population with a relatively low prevalence of 
Ad5 nAb seropositivity. Although the study population for HVTN 505 is in the clade B 
region only, the multiclade vaccine is still considered to be relevant as it includes 
encoded sequences for clade B Env, Gag, Pol and Nef.  

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The regimen is comprised of 3 injections of a 6-plasmid multiclade HIV-1 
deoxyribonucleic acid (DNA) vaccine, VRC-HIVDNA016-00-VP, followed by a single 
booster injection of a multiclade HIV-1 rAd5 vector vaccine, VRC-HIVADV014-00-VP, 
and the study population includes HIV-uninfected MSM participants who are at risk for 
HIV-1 infection primarily through sexual exposure. The participants will be randomized 
in equal numbers to the vaccination regimen or to placebo injections. 
4.3.1 
DNA vaccine 
The investigational DNA vaccine, VRC-HIVDNA016-00-VP, is composed of 6 closed 
circular plasmid DNA macromolecules in a 1:1:1:1:1:1 ratio. Plasmids VRC-4401, VRC-
4409, and VRC-4404 are designed to express clade B HIV-1 Gag, Pol, or Nef, 
respectively. VRC-5736, VRC-5737, and VRC-5738 are designed to express HIV-1 Env 
glycoprotein from clade A, clade B, and clade C, respectively. The construction of these 
plasmids has been published [56] and is described in the Investigators’ Brochure. The 
VRC, NIAID, Vaccine Pilot Plant (VRC/NIAID/VPP) manufactured the vaccine DNA 
plasmids and performed the final formulation, fill and packaging. 
The dosage to be administered is based on experience with several VRC DNA vaccines, 
including specifically a dose escalation evaluation with a similar HIV DNA vaccine. A 
phase 1 study (VRC 004) of a similar 4-plasmid DNA vaccine (VRC-HIVDNA009-00-
VP) was initiated in 2002 and was conducted as a single site study at the NIH Clinical 
Center (Bethesda, MD). Dosages up to 8 mg of DNA were well-tolerated and assessed as 
safe for further evaluation [57]. The 4 mg dosage was chosen for further evaluation of the 
4-plasmid DNA vaccine alone in a multicenter US study, HVTN 052 (n = 180). With the 
goal of improving the immunogenicity of the DNA plasmid constructs, the DNA vaccine 
was redesigned using a different promoter and 3 separate plasmids for the Gag, Pol and 
Nef encoded sequences; also an additional 68 amino acids were encoded in the gag 
plasmid (reconstituting the p6 region at the carboxy terminus). This approach to 
improving immunogenicity was supported by a small bridging study, VRC 007 [58] and 
the 6-plasmid DNA was assessed as the leading candidate DNA vaccine in prime-boost 
HIV vaccine studies conducted from 2005-2007.  
4.3.2 
rAd5 vaccine 
The investigational rAd5 vaccine, VRC-HIVADV014-00-VP, is a 3:1:1:1 ratio of the 
adenoviral vectors that encode for HIV-1 Gag/Pol polyprotein from clade B and HIV-1 
Env glycoproteins from clades A, B, and C, respectively. DNA plasmids developed by 
the VRC/NIAID/NIH (Bethesda, MD) were used to construct the adenoviral vector 
clinical seed stocks used to produce the vaccine. The construction of the adenoviral 
vectors has been published [59,60] and is described in the Investigators’ Brochure. The 
dosage is specified in PU. PU are the number of viral particles, active or not, found in the 
product as determined by spectrophotometry. The adenoviral vectors were manufactured 
for the VRC by GenVec, Inc. (Gaithersburg, MD) at a contract manufacturer, Molecular 
Medicine (San Diego, CA). The FFB was custom manufactured by Cambrex 
(Walkerville, MD). Final formulation, fill, and packaging were performed by the 
VRC/NIAID/VPP, operated by SAIC-Frederick, MD.  
The 1010 PU dosage of the VRC rAd5 vaccine was selected initially based on two phase 1 
dose escalation studies. The VRC 006 study (n=36) was initiated in July 2004 at the NIH 
Clinical Center, Bethesda, MD as the first phase 1 randomized, placebo-controlled, dose-
escalation study of the rAd5 vaccine. Dosages evaluated included 109 PU (n=10), 1010 PU 

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(n=10) and 1011 PU (n=10), with the 1010 PU dosage evaluated as offering good 
immunogenicity with less reactogenicity [61].  
The HVTN 054 study (n=48; 40 vaccinees and 8 placebo recipients) was initiated in 
April 2005 in multiple US sites as the second phase 1 study of the rAd5 vaccine in 
uninfected, Ad5 nAb negative adult study participants. The HVTN 054 safety and 
immunogenicity data also supported the selection of 1010 PU for the VRC rAd5 vaccine 
[62].  
Given the concern about all Ad5 vaccines that was raised by the observation of more HIV 
infections in the vaccine group in the Step Study, it is important to note that the VRC 
rAd5 vaccine differs from the Merck-rAd5 vaccine that was used in the Step Study in the 
antigen content, vector platforms, immunization schedule, rAd5 vector construction, and 
manufacturing substrate [59,60,63], and pattern of immune responses induced [31,61]. 
The character of immunity generated by DNA prime/rAd5 boost differs from consecutive 
injections of homologous rAd5 vaccine [64,65]. Emerging data from studies in mice, 
nonhuman primates (NHP), and humans suggest that high doses of rAd5 vaccine vectors 
generate a population of effector T-cells which are predominantly differentiated with low 
proliferative capacity. In contrast, lower rAd5 doses, or rAd5 given after a primary 
immunization with a heterologous vaccine vector, generates CD4+ T cell help and 
diversification of the CD4+ T-cell responses, which results in more balanced CD4+ and 
potent CD8+ T cell effector responses [66-69]. Studies of the VRC DNA and rAd5 
vectors in preclinical and phase 1 and 2 studies are consistent with these findings. 
Compared to rAd5 alone, DNA/rAd5 elicits a higher magnitude of CD4+ and CD8+ T-
cell responses (see Section 4.6.2.2) and a higher proportion of multi-functional cells 
comprising the total cytokine response [70]. While the biological significance of these 
differences in humans is unknown, in vivo animal model systems show that such 
qualitative immunological differences can affect vaccine-elicited protection [71,72]. 
The VRC rAd5 and Merck-rAd5 vaccines express different antigens. The VRC DNA and 
rAd5 vectors express clades A, B, and C Env antigens that elicit both T and B cell 
responses. The Merck-rAd5 vaccine expressed Gag, Pol and Nef, but not Env. The VRC 
vaccine also includes Gag and Pol; T-cell responses to Gag have a slightly lower 
magnitude than those to Env while Pol-specific responses are much lower. Nef is 
included in the DNA, but not in the rAd5. Thus, the predominant immune responses 
induced by the Merck vaccine are to Gag and Pol, while the VRC vaccine elicits 
predominant responses to Gag and Env. Since circulating HIV-1 strains in North America 
are largely clade B, it is reasonable to expect that the Gag and Env responses will 
recognize some epitopes in many or most circulating strains. While the vaccine-induced 
immune responses have not been evaluated side-by-side, the total magnitude of the IFN- 
enzyme-linked immunospot (ELISpot) responses to the 2 vaccines is similar, but the 
specificity of the responses is different [62].  
Vector construction of the Merck and VRC rAd5 vaccines is different. The VRC rAd5 
vector includes deletions of the Ad5 E1 and E4 regions with partial deletion of E3 region, 
while the Merck rAd5 vector has an E1 deletion, but intact E3 and E4 regions [59,60,63]. 
Studies of the VRC rAd5 vector show that the E4 gene deletion results in markedly 
reduced expression of Ad5 structural and non-structural proteins, while expression of the 
HIV-1 gene inserts is maintained. Compared to the Merck rAd5 3 injection regimen, the 
VRC DNA prime- rAd5 boost vaccine regimen should generate a more favorable ratio of 
immunity to the encoded HIV antigen versus immunity to the Ad5 vector, and the 

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heterologous prime-boost approach compared to homologous boosting has theoretical 
advantages for T-cell function, based on nonclinical studies [65,67]. 
4.3.3 
Placebos 
In this study the placebo for the DNA vaccine is designated VRC-PBSPLA043-00-VP 
and composed of PBS and the placebo for rAd5 vaccine is designated VRC-
DILUENT013-DIL-VP and composed of the FFB. Both types of placebo were filled and 
packaged by the VRC/NIAID/VPP, operated by SAIC-Frederick, MD. 
4.4 
Non-clinical and natural history data that provide evidence of potential 
vaccine activity 
The following section provides a summary of findings from non-clinical studies that are 
pertinent to study vaccine activity endpoints. “Vaccine activity” is defined in the context 
of this section as the ability to modulate HIV-1 acquisition and VL post-acquisition (see 
primary objectives 1 and 2, Section 5.1). Refer to Investigators’ Brochure (IB) for a more 
extensive summary of non-clinical studies that provide more information about the safety 
and immunogenicity of the vaccination regimen. Section 4.5 provides a summary of 
human natural history data that suggest desirable immunological characteristics of a 
preventive HIV-1 vaccine regimen. 
4.4.1 
Non-clinical data  
Over 2 decades of work on HIV vaccine concepts has led to the prevailing belief that 
control of the AIDS epidemic through a vaccination strategy would require the 
development of a vaccination regimen against HIV-1 that elicits potent cellular and 
humoral immune responses which recognize divergent viral strains. The vaccine regimen 
in this protocol is a multiclade DNA vaccine prime followed by a multiclade adenoviral 
vector vaccine boost. Earlier prime-boost vaccination regimens developed by others 
showed promise in NHP models of HIV infection with the potential for raising high 
levels of immune responses [73-75]. In these studies, attenuation of a pathogenic simian 
human immunodeficiency virus (SHIV) infection in rhesus macaques was attributed to 
the generation of a CD8+ CTL response. Compelling evidence of an antiviral effect of 
CD8+ T cells was demonstrated in controlled studies in macaques, in which CD8+ cells 
were depleted in vivo using a monoclonal Ab. The VLs in these animals increased or 
decreased as the CD8+ T cells were depleted or reappeared, respectively [76,77]. 
Therefore, induction of a CTL response specific to the viral proteins may represent a 
desirable response in an HIV-1 vaccine. 
More recently, studies have been conducted in NHP using vaccines modeled on the VRC 
vaccine candidates, which encode a simian immunodeficiency virus (SIV) Gag-Pol-Nef 
or SIV Gag-Pol polyprotein in combination with either a single HIV-1 Env or a mixture 
of clade A, clade B and clade C HIV-1 Env. Monkeys receiving multiclade Env 
immunization developed robust cellular and humoral immune responses to all vaccine 
antigens and a greater breadth of Env recognition than monkeys immunized with a single 
Env immunogen. After challenge with a pathogenic SHIV strain (SHIV-89.6P), all 
groups of vaccinated monkeys demonstrated a lower setpoint VL than control monkeys. 
The monkey data indicate that a multiclade vaccination regimen can generate broad Env-
specific T-lymphocyte and Ab responses without antigenic interference from the presence 
of multiple immunogens [78]. 

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The NHP studies have also attempted to evaluate whether a DNA prime-rAd5 boost 
vaccination strategy against HIV-1 offers a survival advantage over placebo in a SIV 
challenge model. The data suggest that even if the HIV vaccination regimen offers 
transient reduction in VL, there could be a more prolonged survival advantage in subjects 
infected with HIV despite vaccination [73,74]. In the monkey model, the vaccine regimen 
induced broad CD4+ and CD8+ T-cell responses and antibodies that neutralized the 
primary isolate of SIV used in the challenge model [74]. Although the regimen did not 
prevent the SIV infection, vaccinated animals had prolonged survival compared to 
control animals [68]. The NHP studies demonstrated that the best predictor of survival of 
vaccinated animals after exposure to SIV was preservation of the central memory CD4+ 
T lymphocytes [68,69]. In theses studies the VRC DNA/rAd5 vaccine platform 
demonstrated a beneficial virologic and clinical effect in the SIVmac251 challenge model 
using Mamu A*01 negative animals. Compared to controls, vaccinated animals had a 30-
fold decrease in peak VL and a statistically significant increase in AIDS-free survival. 
The Merck rAd5 SIV Gag vaccine did not demonstrate these effects in Mamu A*01 
negative animals. Improved AIDS-free survival is a key goal of vaccination. We do not 
know how these SIV data will translate to heterologous virus protection or to protection 
against HIV-1 in humans. Nor do we know if high-dose intravenous SIV challenge 
resulting in AIDS in a median of 1 year is a predictive model for the low-dose mucosal 
exposure more common in humans. 
In follow-up to the above noted studies, an NHP study in a larger number of animals was 
initiated to expand upon and further characterize these observations. Mamu-A*01 
animals were excluded. Four groups of 13 monkeys each were included with the 
following types of DNA prime-rAd5 boost vaccine constructs administered: (1) gag/pol 
SIVmac239; (2) env SIVmac239; (3) gag/pol + env SIVmac239; and, (4) sham DNA with empty 
vector Ad5. Preliminary data (also excluding the few Mamu-B*17 and B*08 animals in 
the study) on the peak (14 days post challenge with SIVmac251 IV) VLs by group are 
available (Figure 4-1), along with VL data in the semen in the groups receiving the 
gag/pol immunogens (not shown). The following conclusions have been drawn from 
these preliminary data: while the groups receiving either Env alone or Gag/Pol alone 
have some effect on peak VL, the group receiving all the immunogens had the maximal 
effect on peak plasma VL (see Figure 4-1). This effect was not mediated by nAb, as no 
neutralizing activity was detected by week 20 post challenge in a pseudo-virion 
neutralization assay. There was significant decrease in the VL with statistical significance 
in the first 80 days post challenge. Since much transmission of HIV is believed to occur 
during the high viremia of acute infection, reduction in peak VL in the plasma and in the 
semen during this acute period may result in decreased transmission, providing an 
indirect public health benefit from vaccination. The study continues and effects on VL at 
setpoint will be evaluated, as well as T-cell responses. In addition, plans to conduct a 
study to evaluate the potential of the prime-boost regimen to impact acquisition of SIV 
infection in a repeated low-dose mucosal challenge model are planned.  

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Figure 4-1 DNA prime/rAd5 boost effect on VL after SIV challenge 
The NHP data support the hypothesis that the VRC prime-boost vaccination regimen may 
be able to induce an immune response that is associated with an improved outcome if 
HIV-1 infection should occur compared to what would be expected in the absence of 
vaccine-induced immunity.  
To address the question of whether the DNA/rAd5 regimen expressing SIVmac239 env 
and gag-pol genes could prevent acquisition when macaques were subjected to repeated 
rectal challenge, a model system was developed using either SIVmac251 or heterologous 
SIVsmE660 stocks titrated to infect about 50% of animals following each exposure. 
Rhesus macaques challenged weekly for 12 weeks intra-rectally are uniformly infected. 
Studies were performed in 129 animals stratified by MHC alleles. 20 vaccinees and 20 
sham vaccinated Mamu A*01- animals were challenged intrarectally with SIVmac251 
and 25 vaccinees and 25 sham vaccinated Mamu A*01- animals were challenged 
intrarectally with SIVsmE660. An additional 20 vaccinees and 19 placebo recipients that 
were Mamu A*01+ were also challenged intra-rectally with SIVsmE660. In the 
SIVmac251 challenged animals there was no protection from acquisition, but as had been 
noted in prior IV challenge experiments, there was a significantly lower peak VL in 
vaccinees post-challenge (p = 0.001, Wilcoxon rank-sum test). In Mamu A*01- animals 
challenged with SIVsmE660 there was a 50% reduction in acquisition (p=0.001, Logrank 
test) but no effect on peak VL. However, in Mamu A*01+ animals both a 50% reduction 
in acquisition (p = 0.009) and a reduced peak VL (p = 0.07) were seen in vaccinees. 
When the 45 vaccinees and 44 placebo recipients with all MHC phenotypes that were 
challenged with SIVsmE660 were combined, the vaccine conferred a statistically 
significant effect on both acquisition and VL (Figure 4-2) 

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Figure 4-2 DNA prime/rAd5 boost effect on acquisition and VL following heterologous SIV 
challenge 
These data indicate that the VRC DNA/rAd5 regimen has the capacity to prevent 
acquisition from a mucosal heterologous lentivirus challenge, and can induce CD8+ T 
cells (particularly in subjects with certain MHC 1 alleles) that can reduce VL in 
lentivirus-infected vaccinees. Although protection was not achieved against SIVmac251, 
50% of vaccinated monkeys were protected from infection with SIVsmE660 [79].  
4.5 
Potential benefit of VL reduction as a vaccination outcome 
There are substantial data to suggest that, even in the absence of sterilizing immunity, a 
vaccine capable of reducing VL in vaccinated participants would provide clinical benefit 
to the individual (ie, delay the time to the onset of AIDS or initiation of antiretroviral 
therapy) and be a valuable public health intervention (ie, decrease the risk of 
transmission). However, it is unclear at this time whether the predictive value of a 
vaccine-induced reduction in VL is comparable to that seen in natural infection. 
Data generated from large natural history cohort studies suggest that plasma VL is 
strongly predictive of the risk of HIV disease progression. For example, in the 
Multicenter AIDS Cohort Study (MACS), levels of plasma VL, even those measured 
early after infection, discriminated risk at all levels of CD4+ T lymphocyte counts and 
predicted their subsequent rate of decline, risk of progression to AIDS (Figure 4-3), and 
death from AIDS [80,81]. Other cohort studies have demonstrated a similar association 
[82]. 

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Figure 4-3 Likelihood of developing AIDS within 3 years in the MACS cohort [80] 
Similarly, multiple analyses have shown a statistically significant dose-response type 
association between decreases in plasma viremia in a number of antiretroviral treatment 
trials and improved clinical outcome [83].  
Based on the data described above, a vaccine effect resulting in a sustained reduction in 
VL could be predicted to translate into a clinically significant delay in the time to 
progress to AIDS or initiation of antiretroviral therapy. 
A vaccine capable of reducing VL in vaccinated recipients would be expected to decrease 
the risk of secondary transmission. Support for this comes from a community-based study 
in a rural district of Uganda where each log10 increment in the VL of an infected 
individual was associated with a 2.45-fold increase in the risk of secondary transmission 
(Figure 4-4) [81]. 

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Figure 4-4 Mean (+SE) rate of heterosexual transmission of HIV-1 among 415 discordant 
couples, according to the sex and the serum HIV-1 RNA level of the HIV-1–positive partner 
[84] [Copyright ©2000 Massachusetts Medical Society. All rights reserved.] 
Formal demonstration of an effect on secondary transmission will require large studies of 
long duration. However, mathematical models and natural history data suggest that 
observing a difference in VL could have substantial public health benefit. 
Modjarrad, et al. [85] recently completed a systematic review of studies that evaluated 
associations between small differences in VL changes and rates of heterosexual HIV 
transmission, and also between VL and progression to AIDS or death. Based on these 
studies, the authors estimated the relative risks (RR) of HIV transmission and disease 
progression associated with 0.3, 0.5, and 1.0 log10 differences in VL. The calculations 
indicate that every 0.3 log10 increase in VL increases the likelihood of transmitting HIV-1 
(heterosexually) by 20% and increases the risk of progression to AIDS or death by 25%; 
For every 1.0 log10 increase in VL, the relative risk of HIV heterosexual transmission was 
2.0 and progression to an AIDS-defining event was 2.13 (see Table 4-3, adapted from 
Modjarrad, et al. [85]). Comparable published data for MSM transmission of HIV-1 are 
not available. 

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Table 4-3 RR of HIV transmission and disease progression per 1.0 log10 increase in plasma 
HIV RNA 
RR of heterosexual transmission of HIV between serodiscordant couples 
per 1.0 log10 increment of plasma HIV RNA concentration 
Reference 
 
Risk ratio per 1.0 log10 Δ HIV RNA 
Quinn et al., 2000 [84] 
 
2.45 (1.85, 3.26) 
Fideli et al., 2001 [86] 
 
 
 
Female-to-male 
 
2.5 (1.5, 4.0) 
 
Male-to-female 
 
1.8 (1.2, 2.8) 
Hisada et al., 2000 [87] 
 
1.31 (0.94, 1.84) 
Tovanabutra et al., 2002 [88] 
 
1.81 (1.33, 2.48) 
Weighted mean 
 
2.0 (1.4, 2.8) 
 
 
 
RR of progression to an AIDS-defining event or AIDS-related death per 
1.0 log10 increment of plasma HIV RNA concentration. 
Reference 
 
Risk ratio per 1.0 log10 Δ HIV RNA 
Welles et al., 1996 [68] 
 
2.79 (1.44, 5.38) 
Coombs et al., 1996 [89] 
 
2.26 (1.10, 5.13) 
Sterling et al., 2001 [90] 
 
1.55 (0.95, 2.52) 
Phillips et al., 2004 [91] 
 
2.03 (1.68, 2.46) 
Lavreys et al., 2006 [92] 
 
2.28 (1.36, 3.59) 
Weighted mean 
 
2.13 (1.33, 3.62) 
This review supports the conclusion that even modest reductions in VL contribute to 
reducing the risk of transmission and disease progression 
4.6 
Experience with the VRC vaccine regimen 
A series of phase 1 and 2 clinical trials sponsored in collaboration with DAIDS, NIAID, 
NIH have been conducted by several clinical trials research groups, including the VRC, 
HVTN, International AIDS Vaccine Initiative (IAVI), and US Military HIV Research 
Program (USMHRP). These clinical trials have included 1 of 2 similar multiclade DNA 
vaccines and/or the rAd5 vaccine in single agent and combination vaccination regimens. 
Table 4-4 shows the clinical trials with these vaccines conducted through 5 INDs for 
which HIV prevention was the intended indication. All studies in this table are closed to 
accrual and have completed subject clinical follow-up although several studies are 
proceeding with long-term follow-up contacts. 

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Table 4-4 Clinical trials with VRC multiclade HIV vaccines for uninfected participants 
 
IND 
Product 
Protocol 
Number 
Total 
Accrual 
BB10681 
VRC-HIVDNA009-00-VP 
(4 plasmid DNA) 
VRC 004 
50 
RV 156 
31 
HVTN 052 
180 
BB11661 
VRC-HIVADV014-00-VP 
(Adenoviral vector) 
VRC 006 
36 
HVTN 054 
48 
VRC 015 
31 
BB11750 
VRC-HIVDNA016-00-VP 
(6 plasmid DNA) 
VRC 007 
15 
BB11894 
VRC-HIVDNA009-00-VP 
VRC-HIVADV014-00-VP 
HVTN 057 
70 
VRC 009 
10 
HVTN 068 
66 
HVTN 069 
90 
RV156A 
18 
BB12326 
VRC-HIVDNA016-00-VP 
VRC-HIVADV014-00-VP 
VRC 008 
40 
VRC 010 
4 
VRC 011 
60 
IAVI V001 
114 
RV 172 
326 
HVTN 204 
480 
The VRC studies were conducted at the National Institutes of Health, Bethesda, MD. 
HVTN 204 was an international study in the Americas and South Africa; other HVTN 
studies were multicenter studies with all or the majority of participants at US sites. 
USMHRP (RV) studies and the IAVI V001 study are in Eastern Africa. The last 3 studies 
listed (IAVI V001, RV 172, and HVTN 204) are known as the “Triad” studies and were 
designed to provide an international phase 1 and 2 experience among partner organization 
with the intention of conducting a large, international phase 2b efficacy study with safety, 
HIV acquisition, and early VL as endpoints. Following the announcement of Step Study 
results in 2007, plans for a large international efficacy study were canceled. With 
consideration given to input from a number of advisory groups, including a public NIAID 
summit [93], development of HVTN 505 then ensued with a focus on the subject 
population from the Step Study in whom there is equipoise for evaluating an rAd5 vector-
containing vaccine regimen despite the increased risk of HIV acquisition among Step 
vaccinees as a whole. The eligible study population (circumcised MSM who are Ad5 nAb 
negative) was not at increased risk of HIV acquisition in the Step Study [29]. As 
originally designed, vaccine safety and the potential effect of vaccine on the VL setpoint 
were the primary endpoints in HVTN 505 when it opened to accrual in June 2009. As 
discussed in Section 4.1.2, subsequent information and events provide support for 
expansion of the trial to test as a co-primary objective the ability of the vaccine regimen 
to prevent HIV-1 acquisition. 
BB-IND 12326 includes the same regimen as HVTN 505. Prior to the opening of HVTN 
505, studies in this IND provided more than 700 person years of safety data on the prime-

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boost regimen in the phase 1 and 2 Triad studies with the VRC vaccine. Across the 3 
INDs (BB IND 11661, BB IND 11750, and BB IND 12326) in which the 2 specific 
vaccine products in HVTN 505 have been previously evaluated, cumulatively 1121 
participants have participated in phase 1 and phase 2 studies thus far with 699 receiving 
vaccine and 422 receiving placebo. As of May 2013, there have been 5 HIV-1 infections 
in vaccinees and 4 in placebo recipients who received the complete vaccine regimen 
specified for HVTN 505. Given the very small numbers of infections and that these 
studies were not designed to determine efficacy, conclusions about the vaccines’ effect 
on the risk of acquiring HIV cannot be made from long-term follow-up. 
Because of the concerns raised in the Step trial about the possibility that Ad5 immunity 
may predispose to infection in individuals receiving the Merck vaccine and because this 
risk was highest in those who were not circumcised, HVTN 505 includes eligibility 
criteria that restrict enrollment to circumcised men with no nAb to Ad5. This trial design 
provides equipoise related to the imputed safety concern observed with the Merck 
vaccine. 
4.6.1 
Safety of the 6-plasmid DNA and rAd5 vaccines alone and in prime-boost regimens 
The vaccination regimen in HVTN 505 will be 3 priming doses of DNA vaccine at 4 mg 
each with 1 dose of rAd5 vaccine boost at 1010 PU. The safety summary emphasizes 
experience as of October 2008 for this regimen; there have been no other new studies of 
the regimen completed since that time and no new risks or serious adverse events 
attributed to vaccine from smaller ongoing studies with the VRC regimen. 
The VRC DNA vaccinations will be administered IM by the needle-free injection device, 
Biojector 2000 Needle-Free Injection Management SystemTM, manufactured by Bioject 
(Tualatin, OR). In the VRC 008 study, which compared needle to Biojector injection of 
vaccine, the close, prospective scrutiny of the vaccination sites revealed that a small skin 
lesion, described as a papule, was commonly observed after DNA injection by Biojector® 
(38/60 [63.3%]), but was not observed after DNA injection by standard needle. These 
papules or scabs are infrequently recorded on diary cards completed by study participants 
and resolve without treatment. Although the Biojector® is associated with pain, redness, 
swelling and/or bruising at the injection site [94], as well as some self-limited, small skin 
lesions, this method of administration is well tolerated, and offers the advantage of 
eliminating needle stick accidents in the clinic. This system has FDA clearance for 
delivering IM injections of vaccine.  
The VRC rAd5 vaccine will be administered IM by needle injection. Several studies have 
safety data for the rAd5 vaccine alone and as a booster vaccine at both 1010 and 1011 PU. 
There is greater frequency and severity of symptoms as dosage is increased. Systemic 
symptoms typically start 12-16 hours after rAd5 vaccination and diminish in severity 
within hours. When an acute fever occurs in association with rAd5 vaccination it 
typically resolves within a few hours. Headache and malaise are the most common 
symptoms and may persist for a few days, but respond quickly to treatment with 
acetaminophen or nonsteroidal anti-inflammatory medications. Local reactogenicity 
(pain, redness, swelling) is usually mild and often begins within 24 hours after 
vaccination, but in some individuals onset of local injection site reactions may be delayed 
until 3-5 days after vaccination and may reach moderate severity before resolving 
spontaneously. The VRC 008 study included both 1010 (n=19) and 1011 PU (n=20) 
booster vaccinations of the rAd5 vaccine, with an equal number of participants with low 
and high Ad5 nAb titers at screening randomized to each dosage. Three cases of 

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moderate (> 9 x 9 cm) erythema and/or induration in the injected arm had onset 
postvaccination days 3-5, peaked about days 5-6, and resolved at days 7-9. A large 
erythema reaction was observed in 1 participant in the VRC 009 study and in 1 subject in 
HVTN 068 with a similar pattern of onset and resolution. The onset is after the period of 
solicited reactogenicity in the HVTN, IAVI, and USMHRP studies that have used 3 days 
reactogenicity collection. The subjects observed to have these reactions in the VRC 
studies with 5 day solicited reactogenicity have not been alarmed by the reaction and may 
not have reported it if it had not been solicited; therefore, the incidence is not well 
defined. This is the basis for including a longer period of solicited local reactogenicity 
data collection following the booster rAd5 injection in the HVTN 505 study.  
The Triad Studies (HVTN 204 [28], RV 172 [95], and IAVI V001 [96]) were designed to 
provide an international Phase 1 and 2 safety and immunogenicity evaluation of the VRC 
regimen towards the original goal of conducting an international efficacy study. The 
individual results from each of these studies are available [28,92,93]. Prior to initiating 
the HVTN 505 study, a cross-study summary of the unblinded safety data was completed 
and is shown in Table 4-5 for the participants randomized to the vaccine and placebo 
arms for the regimen that will be administered in HVTN 505. This is why the numbers 
shown add up to N=746 (383 vaccine and 363 placebo recipients) rather than the 918 
total for the 3 studies shown in Table 4-4. The summary in Table 4-5 shows incidence for 
the unsolicited adverse events (AEs) that were reported in >1% of vaccinees for which 
the incidence was equal to or higher than that in placebo recipients; a statistical analysis 
has not been applied. There were no SAEs attributable to either the DNA vaccine or the 
rAd5 vaccine alone or in the combination regimen.  

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Table 4-5 Triad studies AEs in >1% of vaccine recipients for which there was equal or 
greater frequency in the vaccine than in the placebo groups, sorted by descending 
frequency 
MedDRA Preferred Term 
Vaccine (n=383) 
n (%) 
Placebo (N=363) 
n (%) 
Number with one or more AE 
346 (90.3) 
321 (88.4) 
Headache 
66 (17.2) 
53 (14.6) 
Neutropenia 
48 (12.5) 
40 (11) 
Malaria 
40 (10.4) 
27 (7.4) 
Nasopharyngitis 
40 (10.4) 
34 (9.4) 
Alanine aminotransferase (ALT) increased 
34 (8.9) 
30 (8.3) 
Neutrophil count decreased 
24 (6.3) 
18 (5) 
Back pain 
22 (5.7) 
19 (5.2) 
Gastroenteritis 
20 (5.2) 
15 (4.1) 
Viral upper respiratory tract infection 
19 (5) 
16 (4.4) 
Arthralgia 
16 (4.2) 
14 (3.9) 
Diarrhea 
13 (3.4) 
10 (2.8) 
Lymphadenopathy 
13 (3.4) 
11 (3) 
Toothache 
13 (3.4) 
9 (2.5) 
Influenza 
12 (3.1) 
11 (3) 
Pharyngitis 
12 (3.1) 
9 (2.5) 
Vomiting 
12 (3.1) 
6 (1.7) 
Weight decreased 
12 (3.1) 
6 (1.7) 
Anemia 
11 (2.9) 
9 (2.5) 
Blood creatinine increased 
11 (2.9) 
8 (2.2) 
Cough 
11 (2.9) 
4 (1.1) 
Dyspepsia 
11 (2.9) 
8 (2.2) 
Influenza like illness 
9 (2.3) 
7 (1.9) 
Dental caries 
8 (2.1) 
6 (1.7) 
Gastritis 
8 (2.1) 
7 (1.9) 
Pharyngolaryngeal pain 
8 (2.1) 
6 (1.7) 
Abdominal discomfort 
7 (1.8) 
1 (0.3) 
Contusion 
7 (1.8) 
4 (1.1) 
Epistaxis 
7 (1.8) 
4 (1.1) 
Furuncle 
7 (1.8) 
2 (0.6) 
Urticaria 
7 (1.8) 
4 (1.1) 
Dermatitis 
6 (1.6) 
4 (1.1) 
Injection site pruritus 
6 (1.6) 
0 (0) 
Leukopenia 
6 (1.8) 
3 (0.8) 
Menorrhagia 
6 (1.6) 
3 (0.8) 
Oral herpes 
6 (1.6) 
3 (0.8) 
Pelvic inflammatory disease 
6 (1.6) 
4 (1.1) 
Soft tissue injury 
6 (1.6) 
3 (0.8) 
Viral infection 
6 (1.6) 
4 (1.1) 
Depression 
5 (1.3) 
3 (0.8) 
Dysmenorrhea 
5 (1.3) 
2 (0.6) 
Excoriation 
5 (1.3) 
2 (0.6) 
Hemorrhoids 
5 (1.3) 
2 (0.6) 
Metrorrhagia 
5 (1.3) 
2 (0.6) 
Otitis media 
5 (1.3) 
4 (1.1) 
Pyrexia 
5 (1.3) 
2 (0.6) 
Sexually transmitted disease 
5 (1.3) 
0 (0) 
Subcutaneous abscess 
5 (1.3) 
2 (0.6) 
Tinea versicolor 
5 (1.3) 
3 (0.8) 
Figure 4-5 shows the worst severity local and systemic reactogenicity across up to 3 
DNA primes and following a single 1010 PU rAd5 boost for the VRC prime-boost 
regimen cumulatively across the Triad studies. Among the local reactogenicity 
parameters, pain and/or tenderness is the most frequently reported symptom for both the 

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DNA and rAd5 vaccine. The most frequently reported systemic symptoms were headache 
and malaise/fatigue. Across the diverse population in the Triad studies reactogenicity is 
reported as none to mild in severity in 70-90% of all vaccine recipients.  
 
Figure 4-5 Maximal severity reactogenicity symptoms in the Triad studies (HVTN 505 
vaccine/control regimen only) 
4.6.1.1 
Safety of the 6-plasmid DNA prime, rAd5 boost regimen in HVTN 204 
The HVTN’s contribution to the Triad studies was HVTN 204, a randomized, placebo-
controlled phase 2a study examining the identical vaccine regimen that is being proposed 
for HVTN 505. The study enrolled 480 participants without regard to their pre-existing 
Ad5 nAb titer. The study was stratified so that half (N=240) were enrolled at HVTN sites 
in the Americas (US, Haiti, Jamaica and Brazil) and half (N=240) were enrolled at 
HVTN sites in South Africa. The stratum enrolled in the Americas was further divided 
into 180 subjects enrolled at US sites and 60 at non-US sites. In each stratum, an equal 
number of participants received the candidate vaccines and control preparations. The 
cohort in the US was enrolled between September 22, 2005 and April 7, 2006, whereas 
the cohort in South Africa was enrolled between July 17, 2006 and December 18, 2006, 
and the non-US Americas cohort was enrolled between August 11, 2006 and March 20, 
2007. Study participants were followed for local and systemic reactogenicity for 3 days 
after each vaccination and AEs were recorded for the 12 months duration of the study.  
Pre-existing Ad5 nAb (titer > 12 in the NVITAL assay) were found in 118 of 171 (69%) 
of participants enrolled in the US (9 missing values), 53 of 60 (88%) enrolled at the non-
US sites in the Americas and 230 of 238 (97%) enrolled in South Africa (2 missing 
values). Of the 180 participants enrolled in the US, 27 (15%) were MSM or bisexual, and 
of these 11 of 25 (44%) were Ad5 nAb negative (2 missing values). Data on circumcision 
status was not collected in HVTN 204. 
A table of AEs constructed similar to Table 4-5 was prepared for US participants only. 
Although some AEs (eg, malaria) do not appear on a comparable table for US 

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participants, there were no AE types reported for US participants in HVTN 204 that 
would suggest any difference in the general safety of the vaccines in this population. The 
overall reactogenicity profile of participants enrolled in all strata in HVTN 204 was not 
appreciably different than that seen in the Triad studies as a whole.  
The VRC DNA and rAd5 candidate vaccines were also well-tolerated by participants 
enrolled at US sites, in spite of having lower median Ad5 nAb titers on study entry. Local 
reactions of mild and moderate intensity were reported by more participants after the 
DNA candidate vaccines than the Ad5 vaccine (92% vs 60%), while the frequency and 
intensity of systemic reactions was similar in both groups (57% vs 50%). Only 3 of the 
180 study participants in the US reported severe reactions, 1 with severe local pain and 
tenderness after receiving each DNA vaccine injection, another with severe elevated 
temperature after the second DNA vaccine injection, and 1 with severe systemic malaise 
and/or fatigue after receiving the rAd5 boost. In all cases, the reactions diminished within 
24 hours and completely resolved by day 5. In addition, AEs reported in US vaccine 
recipients did not differ significantly from those reported by placebo recipients.  
 
Figure 4-6 Maximum severity reactogenicity symptoms in HVTN 204 (US only) 
In addition, there were no important differences in AEs reported by US recipients of the 
DNA+ rAd5 or placebo preparations in HVTN 204.  

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4.6.1.2 
Potential risks of study products and administration 
Table 4-6 Summary of potential risks of study products and administration 
Known risks associated with the VRC DNA prime-rAd5 boost regimen 
Common 
 
Mild to moderate injection site pain, tenderness, erythema, or 
swelling/induration/edema 
 
Malaise/fatigue, myalgia, or headache in the first few days following 
injection  
 
A vaccine-induced positive HIV Ab test result 
Less common or 
uncommon 
 
Severe injection site pain or tenderness 
 
Fever, chills, flu-like syndrome, arthralgia, rash, nausea, or dizziness in 
the first few days following injection  
 
Vasovagal reaction/lightheadedness/dizziness related to the injection 
procedure 
 
Transient changes in clinical laboratory values 
 
Injection site hematoma, bruising/ecchymosis, laceration, or bleeding 
related to the injection procedure 
 
Papule or scab formation at or near the site of Biojector® injection 
 
Painless induration and erythema inferior to site of the Ad5 vector 
injection 
Potential or theoretical risks of HIV vaccines in general 
General rare risks of 
vaccination 
 
Severe localized injection site reaction, such as sterile abscess or 
secondary bacterial infection  
 
Allergic reaction, including rash, urticaria, angioedema, bronchospasm, 
or anaphylaxis 
Unknown frequency 
or theoretical risks 
 
Muscle damage at the injection site 
 
Autoimmune disease or cancer  
 
Effects on a participant’s response to an approved HIV vaccine 
administered in the future 
 
Effects on susceptibility to HIV, if the participant is exposed to HIV  
 
Effects on the course of HIV infection/disease, if the participant is 
infected with HIV 
 
Effects on the fetus and on pregnancy 
4.6.2 
Immunogenicity of DNA vaccine and rAd5 vaccine alone and in combination 
The VRC, through evaluations performed by the Immunology Core Laboratory, as well 
as the NVITAL, HVTN, and IAVI laboratories, has accumulated phase 1 and 2 data 
indicating that the study vaccines show cellular and humoral immunogenicity comparable 
to or greater than other investigational HIV vaccines to date [28,62,70,95,96].  
4.6.2.1 
T-cell immune responses 
The VRC plasmid DNA and rAd5 vectors are immunogenic as individual vectors in 
humans [57,58,61]. DNA delivery by a needle-free Biojector® device results in improved 
ELISpot and CD8+ T-cell responses compared with when the DNA prime is delivered by 
needle and syringe [97]. rAd5 boosting after DNA prime also results in a greater 
proportion of CD4+ and CD8+ T cells secreting multiple cytokines that include IL-2 than 
after rAd5 alone. Phase 2 evaluation was performed in collaboration with the HVTN, 

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USMHRP, and IAVI. These studies enrolled a total of 920 participants. T-cell responses 
were evaluated by VRC and in laboratories from each of the 3 network partners. All 
laboratories showed T-cell response rates in the range of 70% or higher. Over 50% of 
participants produced antigen-specific CD8 T-cell responses, and these responses were in 
volunteers with varied Ad5 nAb titers. The proposed HVTN 505 study would include 
only Ad5 nAb negative volunteers, a population that would be optimal for induction of 
immune responses to the vaccine.  
4.6.2.2 
T-cell immune responses in HVTN 204 
The primary HVTN immunogenicity readout in HVTN 204 was IFN-γ ELISpot 
stimulated by global potential T-cell epitope (PTE-g) peptide pools (ie, pools including 
all peptides found in 15%+ of sequences in the Los Alamos database [98]) from 
cryopreserved peripheral blood mononuclear cells (PBMCs) collected 6 weeks after the 
Ad5-HIV boost. In addition, intracellular cytokine staining (ICS) examining CD4+ vs 
CD8+ T cell phenotypes and IFN-γ, IL-2, and TNF-α cytokine production in response to 
global PTE-g was performed using PBMCs collected at that time. 
IFN-γ ELISpot responses to any HIV antigen were detected in 55/74 (74.3% [CI 63.3, 
82.9]) of vaccine recipients in the US stratum, 15/21 (71.4%; CI 50.0, 86.2]) of vaccine 
recipients in the non-US Americas stratum and 64/93 (68.8%; CI 58.8, 77.3]) of vaccine 
recipients in the South African stratum. As shown in Figure 4-7, these responses were 
primarily directed at Env and Gag peptide pools and positive responders had a mean of 
100-250 spot-forming cells (SFC)/106 PBMCs for all HIV antigens. In addition, the 
frequency and intensity of ELISpot responses did not differ significantly between the 
geographic regions. 
 
Figure 4-7 IFN-γ ELISpot responses in HVTN 204 by antigen and region 
ICS assays were also performed on PBMCs from this timepoint. CD4+ T-cell responses 
to any HIV antigen were detected in 26/57 (45.6 %; CI 33.4, 58.4) of vaccinees in the US 
stratum and in 5/24 (20.8%; CI 9.2, 40.5) of vaccines in the South African stratum. CD8+ 

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T-cell responses were seen in 30/56 (53.6%; CI 40.7, 66.0) and 16/38 (42.1%; CI 27.9, 
57.8) in the US and South African groups, respectively. CD4+ T-cell responses were 
most frequently directed at Gag (in 32.4% of vaccine recipients) with a mean of 
approximately 0.2% cells producing IFN-γ and/or IL-2 (Figure 4-8). CD8+ T-cell 
responses were most frequently directed at Env (in 31.9% of vaccine recipients) with a 
mean of approximately 0.2% cells producing IFN-γ and/or IL-2 (Figure 4-9). Of note, 
CD4+ and CD8+ responses did not differ significantly among vaccine recipients who had 
pre-existing Ad5 nAb or not. 
 
Figure 4-8 CD4+ T-cell cytokine responses by antigen 
 
 
Figure 4-9 CD8+ T-cell cytokine responses by antigen  

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4.6.2.3 
Humoral immunity 
Ab responses have been measured by a research enzyme-linked immunosorbent assay 
(ELISA) that involves use of vaccine-specific purified protein bound to the solid phase. 
All vaccinees who completed 3 DNA primes and an rAd5 boost evaluated to date from 
the VRC phase 1 studies, as well as the preliminary Triad sample set, have had vaccine-
specific Ab responses. The rAd5 vaccine boosts the Ab response even in the presence of 
pre-existing Ad5 nAb. The neutralizing activity of the vaccine-induced Ab response is 
type-specific and limited to laboratory-adapted HIV-1 isolates. An occasional participant 
sample will neutralize selected primary HIV-1 isolates such as SF162, which are 
considered relatively neutralization-sensitive, but none of the sera evaluated to date is 
broadly neutralizing.  
4.6.2.4 
Immunogenicity evaluations in HVTN 505 
Evaluation of HIV-1–specific immunogenicity of the VRC DNA/rAd5 vaccine regimen 
is currently in process using samples collected pre-unblinding.  
 

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5 
Objectives and endpoints of the unblinded 
extended follow-up phase  
5.1 
Primary objective and endpoints 
Primary objective: 
To evaluate the rate of study dropout in vaccine and placebo recipients  
Primary endpoint:  
Study dropout through the Month 48 visit 
Primary objective: 
To evaluate the effect of the VRC DNA/rAd5 vaccine regimen on the rate of HIV-1 
acquisition compared to placebo 
Primary endpoints:  
HIV-1 infection diagnosed after Day 0 through the Month 24 visit 
HIV-1 infection diagnosed after Day 0 including all available follow up through the 
maximum Month 48 visit  
Note 
Evaluation of differences in safety parameters between vaccine and placebo recipients, 
Primary objective 3 in previous versions of HVTN 505, remains as a primary objective 
for data obtained prior to protocol unblinding. During post-unblinding follow-up, HIV-1–
uninfected participants will be monitored for SAEs and safety reports will be generated 
routinely by the SDMC and will be reviewed by the HVTN 505 PSRT (see Section 11). 
5.2 
Exploratory objectives 
Version 6.0: Scientific priorities and resources will determine which of the following 
exploratory objectives will be pursued. 
Exploratory objectives: 
To evaluate the effect of the VRC DNA/rAd5 vaccine regimen on VL at the time of 
HIV-1 infection diagnosis 
To evaluate the effect of the VRC DNA/rAd5 vaccine regimen on CD4+ T cell count 
and disease progression course 

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To evaluate HIV-1-specific and Ad5 vector-specific immune responses induced by 
the vaccine regimen  
To evaluate the impact of viral genetic variation, host genetic factors, prophylactic 
ARV use, and other participant covariates including self-reported risk behavior on 
vaccine effects on study endpoints 
To describe the prevalence of drug (TDF and FTC) resistance mutations after HIV-1 
seroconversion among vaccine and placebo recipients reporting prophylactic ARV 
use 
To evaluate immune correlates of risk of HIV-1 infection among vaccine recipients 
and (possibly) placebo recipients 

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6 
Statistical considerations 
6.1 
Overview 
This study consists of extended unblinded follow-up of participants enrolled in the 
multicenter, randomized, placebo-controlled, double-blinded trial described under 
protocol versions 1 through 4. The primary analysis will evaluate and compare the rate of 
study dropout and HIV-1 acquisition in the vaccine and placebo groups. 
6.2 
Objectives 
At the first planned interim analysis for efficacy futility under Version 4 of the protocol, 
on April 22, 2013, the DSMB recommended that the trial be stopped for efficacy futility. 
A total of 71 HIV infections had been diagnosed in the MITT cohort (41 among vaccine 
recipients, 30 among placebo recipients). Of these, 48 constituted primary endpoints 
(Week 28+ HIV infections diagnosed on or after Day 196 post-enrollment); 27 occurred 
among vaccine recipients and 21 among placebo recipients. There was no statistically 
significant difference in the rate of HIV infection between treatment arms, either in the 
Week 28+ cohort (estimated hazard ratio = 1.25; 95% CI: 0.71 to 2.20; p = 0.446) or in 
the MITT cohort (hazard ratio = 1.33; 95% CI: 0.83 to 2.13; p = 0.230). However, given 
that the number of HIV infections was larger in the vaccine arm, and given that there was 
a trend toward the hazard ratio increasing over time since enrollment (p = 0.09), the 
DSMB recommended, and the study team agreed, to continue to follow all participants 
beyond the Month 24 visit [the terminal visit in Version 4 of the protocol]. Under Version 
5 of the protocol, participants were followed post-unblinding to 48 months post-
enrollment. Six-monthly interim analyses were conducted to evaluate the HIV-1 
acquisition rate in the two treatment arms, and to evaluate conditional power to detect an 
increased rate of acquisition in the vaccine arm as compared to the placebo arm.  At the 
second interim analysis under Version 5 of the protocol, on March 24, 2014, the study 
oversight group recommended that the protocol be revised to reduce the frequency of 
post-unblinding follow-up visits. A total of 109 HIV infections had been diagnosed in the 
MITT cohort to 48 months post-enrollment (53 among vaccine recipients and 56 among 
placebo recipients). There was no statistically significant difference in the rate of HIV-1 
infection between treatment arms, either including all follow-up to 48 months post-
enrollment (estimated hazard ratio = 0.92; 95% CI: 0.63 to 1.34; p = 0.65), or restricting 
to follow-up to 24 months post-enrollment (estimated hazard ratio = 1.09; 95% CI: 0.72 
to 1.66; p = 0.68).   
As described in Sections 8.2 and 8.2.1, under Version 6 of the protocol participants will 
continue to be followed to 48 months post-enrollment, with an additional health contact 
at 60 months, but with study visits only annually following Month 24. The goal of this 
extended follow-up is to continue to monitor the rate of HIV-1 acquisition in the two 
treatment arms. To this end, the rate of study dropout will also continue to be evaluated in 
each treatment arm.  . The objectives of the study have been modified accordingly. 
Assessing the rates of study dropout and of HIV infection in vaccine vs. placebo arms are 
now the primary objectives (see Section 5.1). Assessing the impact of vaccination on 
post-infection endpoints and on immunogenicity; assessing modification of vaccine 

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effects by host immune genetic and other factors; and assessing immune correlates of risk 
are now exploratory objectives (see Section 5.2). 
6.3 
Endpoints 
The first primary endpoint is study dropout during the follow-up of the trial. Participants 
who terminate from the study will be considered to be “dropouts” at the date of their last 
visit.   
The second primary endpoint is diagnosis of HIV-1 infection during the follow-up of the 
trial. The occurrence of HIV-1 infection will be detected through HIV-1 tests 
administered at timepoints specified in Appendix C or at interim visits. Participants found 
to be HIV-1–infected will have additional testing to confirm the diagnosis of HIV-1 
infection. The vaccine-induced immune responses may lead to positive HIV-1 tests and 
difficulty in interpretation. Therefore, the study will continue to use a specialized HIV-1 
diagnostic testing algorithm to confirm diagnoses of HIV-1 infection. 
Primary analyses of the HIV-1 infection endpoint will include infections diagnosed after 
enrollment; we refer to these as “MITT infections”. The set of all enrolled participants 
who are HIV-1 negative at Day 0 is referred to as the “MITT population”. Versions 1 
through 4 of the protocol restrict attention to “Week 28+” infections, defined as those 
diagnosed on or after Day 196 post-enrollment through the Month 24 visit, for primary 
analyses. By Day 196, all participants would have been expected to have had their fourth 
study injection and most would have had time to develop a complete vaccine-induced 
immune response. This restriction will no longer be applied for primary analyses because 
of a primary interest in all HIV-1 infections and because a subset of participants had not 
reached the fourth injection visit when study injections were discontinued on April 23, 
2013. In supportive analyses the HIV-1 infection endpoint will be assessed in various 
subgroups of the MITT population. 
We will continue to define the date of diagnosis of HIV-1 infection to be the draw date of 
the first sample that leads to a positive result by the diagnostic algorithm. The final 
analysis will take place after the last enrolled participant has reached the end of the 
Month 48 visit window; we refer to this as the final evaluation time (FET).  
6.3.1 
Primary endpoints 
The primary dropout endpoint is study dropout through the Month 48 visit. 
The primary HIV-1 acquisition endpoints are HIV-1 infection diagnosed after Day 0 
through the Month 24 visit, and HIV-1 infection diagnosed after Day 0 including all 
follow-up through the Month 48 visit. Corresponding to these primary endpoints, primary 
analyses will conduct estimation and inference on the parameter VEMITT(24), the 
multiplicative reduction in the hazard rate of HIV infection (vaccine versus placebo) by 
the Month 24 visit, and on the parameter VEMITT(t), the multiplicative reduction by time t 
post-enrollment for all times through to the Month 48 study visit. 
6.3.2 
Exploratory endpoints 
 
VL obtained from samples drawn at the visit at which a study participant is 
diagnosed with HIV-1 infection  

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 
Post-infection CD4+ T cell count, initiation of ART, clinical events 
 
Immune responses measured by HIV-1 specific and Ad5-specific multiparameter 
flow cytometry, epitope mapping, and Ab assays (binding and neutralization)  
 
Host genetic factors measured in HIV-1 infected participants and a random sample of 
uninfected participants 
 
Full-genome HIV-1 sequences measured from each HIV-1 infected subject 
 
Resistance mutations identified using viral genome sequencing of HIV-1 strains at 
the first evidence of infection  
 
Participant risk behavior and prophylactic ARV use as measured by behavioral risk 
factor and prophylactic ARV use questionnaire as well as plasma ARV drug level 
testing 
 
Selected immune response biomarkers measured at baseline and at selected post-
baseline visits at which participants test HIV-1 negative  
 
Social impacts 
6.4 
Sample size rationale 
The size of the study is fixed; all participants enrolled under versions 1 through 4 of the 
protocol will continue to be followed. In addition, participants brought back into the 
study under version 5 of the protocol will continue to be followed. This choice ensures 
that the primary endpoints are estimated with maximal precision.  
6.5 
Sampling design for assessing prophylactic ARV use 
For all participants and at all ARV assessment visits, questionnaires will capture 
information on prophylactic ARV use. Plasma drug levels may be measured on samples 
from selected timepoints and subjects, where decisions on which samples to run will be 
made retrospectively taking into account the questionnaire data and HIV-1 diagnostic 
data. This sampling strategy was implemented in Version 3.0 of the protocol, as 
questionnaire data and stored plasma samples were lacking for study participants enrolled 
previously. 
Details of sampling and analysis plans for assessing prophylactic ARV use will be 
provided in a statistical analysis plan (SAP). 
6.6 
Statistical analysis 
All primary analyses of study dropout will be performed in the MITT population.  
Analyses will right-censor HIV-1-uninfected participants at the time of their Month 48 
visit (or the end of the Month 48 visit window, should that visit be missed).  
All primary analyses of HIV-1 acquisition will be performed in the MITT population. 
Analyses of VEMITT(24) will right-censor HIV-1-uninfected participants at the time of last 
HIV test result in Months 0-24, Analyses of VE through time t post-entry, VE(t), will 
right-censor participants at the time of the last HIV test result prior to t. Secondary 

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analyses of the HIV-1 acquisition endpoint will consider defined subgroups of the MITT 
population (see Section 6.6.3.3). 
6.6.1 
Analysis variables 
The analysis variables consist of baseline variables, vaccine activity variables, 
immunogenicity variables, and social impact variables. 
6.6.2 
Baseline comparability 
Treatment groups will be compared on baseline characteristics using descriptive 
statistics. Variables examined will include potential risk factors such as age, 
race/ethnicity, and self-reported risk behavior, as well as other demographic 
characteristics. 
6.6.3 
Primary analyses 
6.6.3.1 
Primary analysis: Study dropout 
To evaluate the primary endpoint of study dropout, the incidence of study dropout in each 
treatment arm will be estimated by dividing the number of dropouts by the amount of 
person-time “at risk”, and exact methods will be used to calculate 95% confidence 
intervals.  The dropout incidence will be compared between treatment arms using a two-
sided score test assuming a Cox proportional hazards model.  Dropout incidence will also 
be assessed over study time (pooling treatment arms), both pre- and post-study 
unblinding, using methods described in the SAP.  Goodness-of-fit tests will be 
performed, including the Grambsch and Therneau [99] test based on Schoenfeld 
residuals, to assess the proportional hazards assumption of the Cox model.  Cumulative 
probabilities of dropout over time will also be estimated in each treatment arm.   
6.6.3.2 
Primary analysis: HIV-1 acquisition 
To evaluate the primary endpoint of HIV-1 acquisition, the incidence of acquired HIV-1 
infections (“events”) in the vaccine arm will be compared to the incidence in the placebo 
arm. The vaccine effect will be assessed using a Cox proportional hazards model. Given 
that vaccine and placebo arms will be compared over a time period when participants are 
unblinded as to treatment assignment, the potential for confounding will be carefully 
considered.  Specifically, in addition to estimating the marginal HR associated with 
vaccine assignment, the HR adjusted for potential confounding factors will also be 
estimated. First, the extent to which baseline participant characteristics and baseline 
behavioral risk score are predictive of HIV-1 infection risk will be assessed. Variables 
that, when considered univariately and pooled over treatment arms, predict infection risk 
with significance p < 0.10 based on two-sided score tests in the Cox model will be added 
to the Cox model relating treatment assignment to HIV-1 infection risk. The baseline 
variables considered will be age, baseline behavioral risk score, race/ethnicity, HSV-2 
serostatus, and BMI. BMI is included in this set because it may predict infection risk 
among vaccine recipients if it modifies the vaccine effect on HIV-1 acquisition; some 
biomedical interventions have efficacy that differs by subject BMI [100,101]. Note that 
HSV-2 serostatus will not be considered if fewer than 95% of participants have 
measurements; this assay is specified as optional in the protocol. The behavioral risk 
score has been calculated using baseline data as of April 22, 2013 and is a function of 
variables measured by the behavioral risk questionnaire, which queries participants about 

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risk behavior over the last 3 months. The score is a function of an indicator that the 
number of male sexual partners is greater than three and an indicator of unprotected 
receptive anal sex. Both unadjusted HRs for vaccination (without adjustment for the 
baseline covariates) and adjusted HRs (with adjustment for baseline covariates) will be 
reported.  
The method of Lu and Tsiatis [102] will be used for more efficient estimation or standard 
partial likelihood estimation will be used depending on certain criteria specified in the 
statistical analysis plan (SAP). Two-sided 0.05-level Wald tests will be used for 
inference. Goodness-of-fit tests will be performed [including the Grambsch and Therneau 
[99] test based on Schoenfeld residuals] to assess the proportional hazards assumption of 
the Cox model. 
An additional analysis, especially relevant if the goodness-of-fit diagnostics support 
violation of the proportional hazards assumption of the Cox model, is estimation of 
cumulative probabilities of HIV-1 infection over time in each treatment arm, adjusted for 
potential confounders, and estimation of the additive difference and the ratio of these 
cumulative probabilities for the vaccine versus placebo group. In addition to the point 
estimates, 95% confidence intervals about the cumulative probabilities of HIV-1 
infection over time for each treatment arm will be computed, as well as 95% confidence 
intervals about the additive difference and ratios over time. The Cox collaborative 
targeted maximum likelihood estimation method [103] will be used, which in addition to 
allowing confounding adjustment can correct for potential bias due to covariate-
dependent censoring.  
If the goodness-of-fit diagnostics support failure of the proportional hazards assumption, 
then additional Cox regression modeling analyses will be performed that include time-
dependent interactions between the natural logarithm of failure time and treatment arm. 
In addition, the nonparametric smoothing method of Durham et al. [104] based on 
Schoenfeld residuals may be used. These analyses will adjust for covariates in the same 
manner as the Cox model analysis that does not include the time-dependent interactions.  
The SAP will specify the details of the methods that will be applied, and will be 
developed independent of any data collected after April 22, 2013. 
6.6.3.3 
Secondary analyses of dropout 
Secondary analyses of study dropout will restrict attention to follow-up to Month 24 post-
enrollment. These analyses will inform the validity of vaccine efficacy analyses restricted 
to Month 0-24 follow-up. 

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6.6.3.4 
Secondary vaccine efficacy analyses: HIV-1 acquisition 
Secondary analyses of vaccine efficacy will consider four subgroups of the MITT 
population:  
(1) The Week 28+ population, those on-study on Day 196 and HIV-negative (ie, not yet 
diagnosed as infected) prior to that;  
(2) The Week 28+ population who received rAd5/FFB;  
(3) The Week 28+ population who did not receive rAd5/FFB; and  
(4) (Per-protocol) the Week 28+ population who received all four immunizations with 
correct product administration and within visit windows.  
For each subgroup analysis, both VE(24) and VE over all available follow-up time will 
be evaluated. The subgroups will help to address whether and how vaccine efficacy 
depends on the rAd5 vaccination. 
Additional secondary analyses will assess the possibility of confounding by time-
dependent variables as specified in the SAP. 
6.7 
Monitoring of trial 
The study will be monitored, potentially leading to modification or termination of the 
study. Interim analyses will occur every 6 months, with the first analysis scheduled for 
approximately September, 2014. The results of the interim analyses will be shared in a 
report to the Oversight Group (see Section 12.1.3) that will keep the results confidential.  
Interim analysis reports will include point estimates, 95% confidence intervals, and 2-
sided p-values testing H0: VE = 0% for VEMITT(24), VEMITT(t) for the latest available time 
point t, and for these parameters defined for the subgroups defined in Section 6.6.3.3. 
Point estimates and 95% confidence intervals will also be reported for dropout rates by 
treatment arm, over study time, and in pre- and post-unblinding follow-up periods.   

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7 
Selection and withdrawal of participants 
At the time that the DSMB determined that HVTN 505 had met pre-set criteria for 
efficacy futility and recommended stopping all further study vaccinations (April 22, 
2013), the study was fully enrolled. 
At enrollment, participants were healthy, HIV-1–uninfected (Ad5 nAb negative) adults 
who comprehended the purpose of the study and provided written informed consent. 
Volunteers were determined to be eligible based on the inclusion and exclusion criteria 
(see Sections 7.1 and 7.2). Final eligibility determination depended on results of 
laboratory tests, medical history, physical examinations, and answers to self-administered 
and/or interview questions. 
In addition, investigators used clinical judgment in considering a volunteer’s overall 
fitness for trial participation. 
7.1 
Inclusion criteria 
1. Male1, age 18 to 50 years, who is fully circumcised (as documented at screening 
examination) and who, in the 6 months prior to randomization, experienced 1 or both of 
the following HIV risk criteria: 
 
unprotected anal intercourse with 1 or more male or MTF transgender partner(s); 
or 
 
anal intercourse with 2 or more male or MTF transgender partners. 
Note: Volunteers who have been in a monogamous relationship with an HIV-1 
seronegative partner for > 1 year are excluded. 
2. Negative HIV-1 and -2 blood test (FDA-approved enzyme immunoassay [EIA]) 
3. Ad5 nAb titer < 1:18 
4. ALT ≤ 2.5 upper limit of normal 
5. Within reach of a participating study site and willing to be followed for the planned 
duration of the study, including long-term safety surveillance contact for 5 years after 
enrollment 
6. Able and willing to provide informed consent 
7. Assessment of understanding: demonstrates understanding of this study and the Step 
Study results; completes a questionnaire prior to first vaccination with verbal 
demonstration of understanding of all questionnaire items answered incorrectly 
 
1 Male-to-female transgender volunteers who have undergone gender reassignment surgery (GRS) are allowed to participate if they provide documentation from 
a healthcare provider confirming that they were fully circumcised prior to GRS. Male-to-female transgender volunteers who have not undergone GRS are 
also eligible to participate if they meet all enrollment criteria. Receipt of hormonal therapy does not make a transgender volunteer ineligible. 

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8. Willing to receive HIV test results 
9. Willing to discuss HIV infection risks and amenable to risk reduction counseling 
10. Good general health as shown by medical history, physical exam, and screening 
laboratory tests 
11. Agrees not to enroll in another study of an investigational research agent prior to 
unblinding of the HVTN 505 study  
7.2 
Exclusion criteria 
1. Volunteer has received any of the following: 
 
HIV vaccine(s) received in a prior HIV vaccine trial. For potential participants 
who have received control/placebo in an HIV vaccine trial, the HVTN 505 PSRT 
will determine eligibility on a case-by-case basis. 
 
Immunosuppressive medications received within 168 days before first 
vaccination. (Not excluded: [1] corticosteroid nasal spray for allergic rhinitis; [2] 
topical corticosteroids for mild, uncomplicated dermatitis; or [3] oral/parenteral 
corticosteroids given for non-chronic conditions not expected to recur [length of 
therapy 10 days or less with completion at least 30 days prior to enrollment].) 
 
Blood products within 90 days before first vaccination 
 
Immunoglobulin within 90 days before first vaccination 
 
Live attenuated vaccines other than influenza vaccine within 30 days before first 
vaccination or scheduled within 14 days after injection (eg, measles, mumps, and 
rubella [MMR]; oral polio vaccine [OPV]; varicella; yellow fever) 
 
Influenza vaccine or any vaccines that are not live attenuated vaccines within 14 
days before first vaccination (eg, tetanus, pneumococcal, Hepatitis A or B) 
 
Allergy treatment with antigen injections within 30 days before first vaccination 
or that are scheduled within 14 days after first vaccination 
 
Investigational research agents within 90 days before first vaccination 
2. Volunteer has used antiretroviral drugs (ARVs) for the purpose of HIV-1 
prophylaxis ≥ 50% of days during the 3 months prior to first vaccination, or for 30 
consecutive days within the 60 days prior to first vaccination 
3. Volunteer has been circumcised within 90 days prior to first vaccination or displays 
evidence that surgical site is not fully healed 
4. History of serious adverse reactions to vaccines including anaphylaxis and related 
symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain. (Not 

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excluded: a participant who had a nonanaphylactic adverse reaction to pertussis vaccine 
as a child.) 
5. Current anti-tuberculosis prophylaxis or therapy 
6. Clinically significant medical condition, physical examination findings, clinically 
significant abnormal laboratory results, or past medical history that, in the judgment of 
the investigator, has clinically significant implications for current health.  
7. Any medical, psychiatric, or occupational or other condition that, in the judgment of the 
investigator, would interfere with, or serve as a contraindication to, protocol adherence, 
assessment of safety or reactogenicity, or a participant’s ability to give informed consent 
8. 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. 
9. Autoimmune disease (Not excluded: Volunteer with mild, stable and uncomplicated 
autoimmune disease that does not require 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.) 
10. Immunodeficiency 
11. Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or platelet 
disorder requiring special precautions). [This exclusion also applies to therapeutic 
anticoagulation that results in a prolonged prothrombin time/international normalized 
ratio (PT/INR) or partial thromboplastin time (PTT).] 
12. History of malignancy (Not excluded: a participant with a surgical excision and 
subsequent observation period that in the investigator’s estimation has a reasonable 
assurance of sustained cure or is unlikely to recur during the period of the study.) 
13. Seizure disorder (Not excluded: a participant with a history of seizures who has had no 
seizures within the past 3 years.) 
14. Asthma other than mild, well-controlled asthma  
15. Hereditary Angioedema (HAE), Acquired Angioedema (AAE), or idiopathic 
angioedema 
7.3 
Co-enrollment of HVTN 505 participants 
Co-enrollment of HVTN 505 participants is allowed. If co-enrollment (including co-
enrollment in trials that do not utilize investigational agents) may pose safety risks to the 
participant (eg, where blood draw limits may be exceeded), the HVTN 505 PSRT should 
be consulted. Any additional questions regarding co-enrollment should be directed to the 
HVTN 505 PSRT. Instances of co-enrollment should be recorded and reported to the 
SDMC on the appropriate case report form (CRF). 

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7.4 
Participant termination from the study 
Under certain circumstances, an individual participant may be terminated from 
participation in this study. Specific events that will result in early termination include: 
 
Participant refuses further participation, 
 
Participant relocates and remote follow-up or transfer to another HVTN CRS is not 
possible, 
 
HVTN CRS determines that the participant is lost to follow-up, or  
 
Investigator decides, in consultation with Protocol Team leadership, to terminate 
participation (eg, if participant exhibits inappropriate behavior toward clinic staff). 

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8 
Clinical procedures 
The schedules of clinic procedures are shown in Appendix E and Appendix F. 
8.1 
Informed consent 
Informed consent is the process of ensuring that participants fully understand what will 
and may happen to them while participating in a research study. The HVTN informed 
consent form documents that a participant (1) has been informed about the potential risks, 
benefits, and alternatives to participation, and (2) is willing to participate in an HVTN 
study. Informed consent encompasses all written or verbal study information HVTN site 
staff members provide to the participant, before and during the trial. Study site staff will 
obtain informed consent of participants according to HVTN policies and procedures. 
The informed consent process continues throughout the study. Key study concepts should 
be reviewed periodically with the participant and the review should be documented. At 
each study visit, site 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 study site may employ recruitment efforts prior to the participant consenting. For 
example, some HVTN CRSs use a telephone script to prescreen people before they come 
to the clinic for a full screening visit. Participants must sign a screening or protocol-
specific consent before any procedures are performed to determine eligibility. Study sites 
must submit recruitment and prescreening materials to IRBs/IECs for human subjects 
protection review and approval. 
8.1.1 
Protocol-specific consent form 
The protocol-specific consent form describes the study products to be used and all 
aspects of protocol participation, including screening and enrollment procedures.  
Each study site is responsible for developing a protocol-specific consent form for local 
use, based on the sample protocol-specific consent form in . The consent form must be 
developed in accordance with local IRB/IEC requirements and the principles of informed 
consent as described in Title 45, CFR Part 46 and Title 21 CFR, Part 50, and in 
International Conference on Harmonisation (ICH) E6 (R1), Guideline for Good Clinical 
Practice: Section 4.8, Informed consent of trial subjects. It must be approved by all 
responsible ethical review bodies before any participants can be deemed to have 
consented for the study. 
Study sites are strongly encouraged to have their local CABs review the sites’ protocol-
specific consent form. 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 interspersed instructions for developing 
specific content. 

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An addendum to the sample protocol-specific consent form is located in Appendix A. 
This form reviews key study information, provides new information, and describes 
changes to the protocol in Version 6. Each study site is responsible for developing an 
addendum to the consent form for local use, based on the sample addendum in Appendix 
A. Informed consent must be obtained prior to performing laboratory and clinic 
procedures in Version 5.0. 
The DAIDS Support Center (RSC) Protocol Registration Office will review all site-
specific informed consent forms and approve them for use according to DAIDS policies. 
The study cannot be initiated at a site until the site is fully registered with the DAIDS 
RSC Protocol Registration Office and has received written notification of protocol 
activation from HVTN Regulatory Affairs. 
8.2 
Follow-up visits for HIV-uninfected participants 
The following procedures will be performed at all scheduled clinic visits through Month 
48 (see Appendix E): 
 
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; 
 
Risk reduction counseling; 
 
Behavioral risk, prophylactic ARV use, and demographics questionnaire; 
 
HIV infection assessment, including pre-test information and assessment of signs and 
symptoms of acute HIV infection. A subsequent follow-up contact is conducted after 
testing 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 appropriated; 
 
Assessment of new or unresolved SAEs; 
 
Social impact assessment; 
 
Administration of the social impact assessment questionnaire (types of impacts 
assessed involve personal relationships, medical insurance, life insurance, 
educational or employment opportunities, housing, immigration, or travel); 
 
Assessment of ARV use for purposes of PrEP or PEP [Note: If and only if a 
participant reports having used ARVs for PrEP or PEP since the last clinic visit, draw 
blood sample for plasma as indicated in Appendix C]; 
 
Testing for Neisseria gonorrhea (GC), Chlamydia trachomatis (CT), and Syphilis (see 
Appendix C and Appendix E). 
 
Specimen collection (see Appendix C). 
8.2.1 
Month 60 health contact 
As indicated in Appendix E, a clinic visit is not required at Month 60. This contact is for 
purposes of assessing participant vital status and safety surveillance. At this contact, CRS 
staff will collect the information listed below. Except as noted, clinic visits are not 
required. 

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 
Confirmation of vital status; if deceased, attempt to learn cause of death 
 
If participant is alive, record the participant’s responses to questions regarding any 
occurrence of the following events since the last HVTN study contact: 
o Life-threatening adverse experiences; 
o Persistent or significant disability/incapacity;  
o Hospitalizations and reasons; 
o Other important medical events that may jeopardize the participant or may 
require intervention to prevent 1 of the other outcomes listed above;  
o New chronic conditions requiring medical intervention of more than 30 days;  
o Change in HIV status; and  
o Newly diagnosed or treated STIs. 
All such events will be recorded and assessed for relationship to study product except for 
change in HIV status. HIV infections will be recorded in the database without a 
relationship assessment. Any participant reporting that they have become HIV-infected 
will be asked to come to the clinic so that HIV status can be confirmed. If HIV-1 
infection is confirmed, the infected participant will be followed under Schedule 7 (see 
Section 8.3, Appendix D, and Appendix F). 
During the window for this contact, an interim clinic visit for purposes of HIV testing 
may take place at the participant’s request. 
8.2.2 
Unblinding and evaluation of vaccine-induced seroreactivity (EOS) testing  
The study has been unblinded and study participants have been informed of their 
treatment assignments. EOS testing among vaccinees is currently underway (see Section 
10.11) and results are being provided to participants as soon as they become available. 
EOS testing will be repeated on samples obtained from study participants at their Month 
48 visits. 
8.3 
Procedures for HIV-1–infected participants  
The following procedures will be performed at all scheduled clinic visits (see Appendix 
F): 
 
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; 
 
ART assessment; 
 
Transmission risk reduction counseling;  
 
Notation of HIV-associated events;  
 
Social impact assessment; and  
 
Specimen collection (see Appendix D). 
The following procedures will be performed at designated clinic visits (see Appendix F): 

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 
Counseling on HIV testing/diagnosis; and 
 
Administration of the social impact assessment questionnaire (types of impacts 
assessed involve personal relationships, medical insurance, life insurance, 
educational or employment opportunities, housing, immigration, or travel). 
8.4 
HIV risk reduction counseling  
HIV counseling will be performed in compliance with the CDC’s guidelines and other 
local guidelines for HIV counseling, testing, and referral. Information on PEP and PrEP 
should be included, including information about HIV testing and risk reduction 
counseling for individuals taking ARVs for HIV-1 prophylaxis.. Participants will be 
counseled at all scheduled visits during the trial on the avoidance of HIV infection. 
Vaccine recipients will be counseled on the potential negative social impacts of testing 
Ab positive due to the vaccine. They will also be counseled on the risks of HIV Ab 
testing outside of the study sites during any period of vaccine-induced positive serology. 
Study staff will take particular care to inform vaccine recipients of the likelihood of 
routine HIV testing being offered or performed outside the study site at emergency 
rooms, clinics, and medical offices. Such testing has become more likely due to the 
CDC’s revised guidelines for HIV counseling and testing, as well as policy changes in 
many countries to make HIV testing more frequent and routine. Site staff should inform 
vaccine recipients of their right to opt out of HIV testing outside the study site. Site staff 
should inform study participants if local and/or state policies and regulations permit 
medical providers to perform HIV testing without first informing patients. If this is the 
case, then site staff should advise study vaccine recipients that they may decline testing 
preemptively. Site staff should provide vaccine recipients with site contact information 
and should encourage participants to ask medical providers to contact the site. The site 
can verify that the vaccinee is a participant in an HIV vaccine clinical trial and should 
only be tested at the study site. 
As part of risk reduction counseling, study participants should be informed of and 
educated about clinical trial results pertaining to HIV-1 prophylaxis (eg, prophylactic 
ARV use in iPrEx [38]. Participants should be informed of the Food and Drug 
Administration’s approval on July 16, 2012 of the fixed-dose combination of 
emtricitabine-tenofovir disoproxil fumarate (FTC-TDF; trade name Truvada®) for the 
prevention of HIV infection in persons at high risk of sexual acquisition of HIV (PrEP), 
and of the CDC’s release, on May 14, 2014, of  “Preexposure Prophylaxis for the 
Prevention of HIV Infection in the United States -2014: A Clinical Practice Guideline”. 
The CDC guidelines provide comprehensive information for the use of daily oral 
antiretroviral pre-exposure prophylaxis (PrEP) to reduce the risk of acquiring HIV 
infection in adults. HIV risk reduction counseling by a clinician may help a participant 
determine what measures are appropriate for that individual’s personal circumstances. 
These may include abstinence, condom use, systemic or topical prophylactic ARV use, 
behavior modification, etc. As needed or desired by a participant, referrals will be made 
to appropriate services. A participant interested in PrEP will receive information on 
where to access this intervention, including, where appropriate, referrals to providers who 
may prescribe PrEP.  

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8.5 
Visit windows and missed visits  
Visit windows are defined in HVTN 505 Study Specific Procedures. For a visit not 
performed within the window period, a Missed Visit form is completed. If the missed 
visit is one that required safety assessments or local safety labs, site staff should attempt 
to bring the participant in for an interim visit as soon as possible. 
Procedures performed at an interim visit are limited to toxicity/safety assessments 
(including local safety labs) and HIV testing. With the exception of HIV testing, these 
procedures are performed only if they were required at the missed visit or if clinically 
indicated. HIV testing may be performed as deemed appropriate by the study staff. Blood 
samples for immunogenicity assays are not typically collected at interim visits. 
8.6 
Early termination visit 
In the event of early participant termination, site staff should consider if the following 
safety assessments are appropriate: a final physical examination, social impact 
assessment, and HIV test. 

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9 
HIV-1 infection assessment and clinical response 
9.1 
HIV-1 symptom assessment 
At each visit 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-1 
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-1 infection. Presence of 
signs/symptoms suggestive of acute HIV-1 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 to determine HIV infection. 
9.2 
HIV-1 testing during post-unblinding follow-up 
HIV testing at surveillance visits will be performed using the HVTN HIV testing 
algorithm (as described in the HVTN Laboratory Manual of Operations), which is able to 
distinguish vaccine-induced antibody responses from actual HIV infections. Samples to 
be stored for future immunogenicity or virology studies will also be collected at this time 
(see Appendix C). 
A ‘case’ will be defined as a participant with confirmed detectable HIV-1 nucleic acid 
PCR on 2 different specimen collection dates. The nucleic acid test will most commonly 
be the HIV-1 RNA VL PCR test. Confirmation of HIV-1 infection will be determined 
through use of the protocol-specific HIV testing algorithm (available on the HVTN  
website). Before issuing an HIV-1 infection report for a participant diagnosed with HIV-
1 infection, all testing results will be reviewed by a blinded, independent Endpoint 
Adjudicator or designee (see Section 9.3). 
If a participant is confirmed to have become HIV-1–infected following the initial 
injection of study product, plasma HIV-1 viral RNA will be measured on archived 
samples prior to the first positive screening test and at subsequent timepoints indicated in 
Appendix D. 
If a participant had completed scheduled clinic visits and, while in Schedule 3 (Annual 
health contacts), reports having been diagnosed with HIV-1 infection, the participant will 
be asked to come to the CRS for confirmatory HIV testing. 
The HVTN Laboratory Program is responsible for all in-study diagnostic testing. 
9.3 
Endpoint adjudication 
The diagnostic criteria for HIV-1 infection outside the setting of a vaccine trial are well 
accepted. However, definitive diagnosis of HIV-1 infection in the context of having 
received a vaccine that is even partially effective may be more difficult. Specifically, if 
the immune responses elicited by vaccination are capable of completely suppressing viral 
replication, or if vaccination alters the normal serological response upon exposure to 

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HIV-1, standard diagnostic tests may be more difficult to assess. For example, CDC 
guidelines define a positive HIV-1 Western blot as one having reactivity to at least 2 of 
the following antigens: p24, gp41, gp120/160. However, the HIV vaccines may elicit 
antibodies to p24 in many participants, so reactivity to this antigen could be due to either 
vaccination or infection. Therefore, the HVTN will have an endpoint adjudication 
process to assess all serological and virological testing, in a blinded manner, on each 
participant in the trial who tests positive per the HVTN 505 HIV-1 diagnostic testing 
algorithm. The assessment of the Endpoint Adjudicator or designee will be reported to 
the SDMC and to the HIV diagnostics laboratory. 
The Endpoint Adjudicator and/or designee must notify the SDMC within 1 working day 
of any confirmed HIV-1 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 will be an 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. 
9.4 
HIV-1 infection during the study 
Participants who develop HIV-1 infection following the initial injection of study product 
will be asked to remain in the study for follow-up. Participants who become HIV-1–
infected following enrollment will be monitored as indicated in Appendix D and 
Appendix F. 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-1 infection.  
9.5 
Medical care for participants who become HIV-1–infected 
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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10 
Laboratory 
10.1 
Study site laboratory procedures 
The cross-protocol HVTN Laboratory Manual of Operations provides further guidelines 
for operational issues concerning the clinical laboratories and phlebotomy. The 
procedures include general specimen collection guidelines, special considerations for 
blood collection, HIV testing guidelines, guidelines for processing whole blood, and 
labeling guidelines. 
Tube types for blood collection post-unblinding are listed in Appendix C and Appendix 
D. 
In specific situations, the blood collection tubes will be redirected to another laboratory 
or will require study-specific processing techniques. In these cases, laboratory special 
instructions will be posted on the protocol-specific section of the HVTN website. 
10.2 
Total blood volume 
Total blood draw volumes per visit for post-unblinding Schedules 6 and 7 are listed in 
Appendix C and Appendix D. Not shown is any additional blood volume that would be 
required if HIV testing needs to be repeated. The total blood volume drawn for each 
participant does not exceed 500 mL in any 56-day (8-week) period. 
10.3 
VL determination 
VL assessments will be conducted in accordance with the HIV diagnostic algorithm 
implemented for this study. Details can be found in the document entitled HVTN 505 
HIV-1 Diagnostic Testing. 
10.4 
Immunogenicity timepoints 
The primary immunogenicity timepoint in this study is at visit 7 (Day 196), 4 weeks 
following the final vaccination. Endpoint assays for humoral and cellular responses will 
be performed on approximately 8% of participants at baseline (humoral only) and at the 
primary immunogenicity timepoint. Depending on the number of responders observed, 
assays for humoral and cellular responses may be performed on additional participants 
and at other timepoints. 

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10.5 
Immunogenicity assays 
10.5.1 
Humoral assays 
10.5.1.1 
Binding antibodies by HIV-1 multiplex Ab assay 
HIV-specific binding antibodies against Env may be assessed on plasma/serum samples 
from study participants taken at the primary immunogenicity timepoint and baseline. 
10.5.1.2 
HIV-1 nAb assay 
HIV-1–specific nAb assays may be performed on serum samples from study participants 
taken at baseline and at the primary immunogenicity timepoint. The assays will initially 
test neutralization of HIV-1 MN and SF162.LS strains. Because this is an artificial 
Envelope immunogen, no corresponding full-length functional gp-160 gene is available 
for use as a pseudovirus in the assessment of nAb in this clinical trial. 
Additionally, the HVTN Laboratory Program may examine nAb responses against a 
panel of heterologous primary isolates using cross-sectional serum samples. If nAb are 
detected, a subset of samples with the best neutralization activity will be screened at a 
single serum dilution for neutralization activity against a panel of heterologous strains. 
10.5.1.3 
Rectal secretion assays 
Frozen rectal secretion samples may be used to identify HIV-specific mucosal antibodies. 
Env-specific IgG and IgA may be assessed by binding antibody multiplex assay 
(BAMA). In addition, soluble cytokines and other immunological markers may be 
assessed by multiplex bead array. 
10.5.2 
Cellular assays 
10.5.2.1 
Flow cytometry 
Flow cytometry will be used to examine HIV-specific CD4+ and CD8+ T-cell responses 
using IL-2 and IFN-γ ICS of PBMC following stimulation with vaccine-match peptide 
sets or PTE-g synthetic HIV peptides sets that span the proteins encoded by the vaccine 
construct. Data will be reported as percentages of CD4+ or CD8+ T cells recognizing a 
specific peptide pool. Response rates will be determined using validated positivity criteria 
for this assay. 
As an exploratory assay, other markers included in the flow cytometry assay above may 
be analyzed (eg, TNF-α, perforin, granzyme B, and CD57). Some of these markers may 
be validated by the time these assays are performed. 
Additionally, the HVTN Laboratory Program may assay PBMCs using a panel of cell 
surface markers that can distinguish HIV-specific central and effector memory T-cell 
subsets. These assays will be performed if positive HIV-specific cellular responses are 
detected at the primary immunogenicity timepoint. Additional cell surface markers or 
functional markers may also be analyzed. 
Multiparameter flow cytometry for Ad5-specific responses will be conducted using the 
HVTN method, including currently validated markers (IL-2 and IFN-γ). Ad5 empty 
vectors will be used for antigen stimulation in these assays. 

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10.5.2.2 
T cell viral suppression assay 
T cell suppression assays that measure the ability of CTLs to suppress the replication of 
HIV-1 may be conducted on PBMC specimens at the primary immunogenicity and other 
timepoints. 
10.6 
ARV plasma drug level monitoring 
Extracellular levels of ARV drugs may be measured from stored plasma samples. The 
sampling selection will be based on the prophylactic ARV-use questionnaires completed 
by the participants, the statistical sampling plan, and the HIV-1 diagnostic data.  
10.7 
Viral sequencing 
Viral sequencing may be conducted on the earliest available plasma and semen 
specimens with positive HIV-1 RNA PCR tests from study participants who are 
diagnosed with HIV-1 infection.  
10.7.1 
Testing for HIV-1 drug resistance mutations 
Drug resistance genotyping and phenotyping may be conducted on stored plasma and/or 
semen specimens of select participants with positive HIV-1 RNA PCR tests at select time 
points. 
10.8 
Genotyping 
Molecular human leukocyte antigen (HLA) typing may be performed on enrolled 
participants using cryopreserved PBMC collected at baseline or another timepoint. HLA 
typing may be performed on specimens from participants who demonstrate vaccine-
induced T-cell responses at postvaccination timepoints. In addition, HLA typing may be 
performed on HIV-infected participants regardless of whether they demonstrate vaccine-
induced T-cell responses. Other participants (including control recipients) may be HLA-
typed to support future studies of immunological interest at the discretion of the protocol 
chair and the HVTN Laboratory Program. Other markers, such as genes associated with 
immune responses or HIV-1 may also be tested. 
10.9 
Testing for STIs 
Post-unblinding, testing for Neisseria gonorrhea (GC) and Chlamydia trachomatis (CT) 
by nucleic acid amplification testing (NAAT) or culture on urine samples and serum 
testing for syphilis will be conducted on all HIV-uninfected participants (see Appendix C 
and Appendix E). 
Cryopreserved specimens may be used to test for the presence of sexually transmitted 
infections (eg, herpes simplex virus type 2 [HSV-2]) at baseline and postvaccination 
timepoints. 

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10.10 
Semen specimens 
Semen specimens collected from a subset of HIV-1–uninfected study participants may be 
used to examine vaccine-induced antibodies and other immunomodulatory factors such as 
cytokines. Env-specific IgG and IgA may be assessed by binding antibody multiplex 
assay (BAMA). In addition, soluble cytokines and other immunological markers may be 
assessed by multiplex bead array. 
10.11 
EOS testing 
Following study unblinding on April 23, 2013, EOS testing was undertaken on samples 
from HIV-1–uninfected vaccinees for whom this testing had not yet been performed. For 
HIV-uninfected vaccinees, this testing is repeated at Month 48 (see Section 8.2.2 and 
Appendix C).  
All participants who have positive or indeterminate HIV-1 serology at the last clinic visit 
(as measured by standard anti-HIV Ab screening tests) may obtain follow-up HIV-1 
diagnostic testing periodically and free of charge as medically/socially indicated 
(approximately every 6 months). This testing will be available until the HIV diagnostic 
test(s) no longer yields positive or indeterminate results or until HIV infection is 
confirmed. It may be noted that vaccine induced positive serology may last many years 
(see the HVTN Laboratory Manual of Operations).  
10.12 
Ancillary studies 
Cryopreserved samples may be used to perform additional assays to further HIV or 
vaccine research.  
10.13 
Other use of stored specimens 
The HVTN and VRC aim not only to test vaccine candidates but also to continue to 
explore the correlates of immunity to HIV. In order to do so, specimens from participants 
will be stored. These samples may be used for other testing and research to the extent 
authorized in each study site’s informed consent form, or as otherwise authorized under 
applicable law. Other testing on specimens will only occur, at a minimum, after review 
and approval by the HVTN and the IRB of the researcher requesting the specimens.  
The protocol sample informed consent form is written so that the participant either 
explicitly allows or does not allow sample storage for other research when signing the 
form. Participants who initially agree to other use of their samples may rescind their 
approval once they enter the study; such participants will still remain in this study. If a 
participant rescinds approval for other use, the study site investigator or designee must 
notify HVTN Regulatory Affairs in writing. In either case, after study analyses are 
complete, the HVTN Laboratory Program will request that the repository destroy all 
specimens with the participant identification numbers of all participants who do not agree 
to other use of their samples. HVTN Core will report the destruction of relevant 
specimens to the participants’ site PIs.  

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Study sites must notify HVTN Regulatory Affairs if institutional or local governmental 
requirements pose a conflict with or impose restrictions on the use of stored specimens. 
10.14 
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 
locally appropriate agencies. 
All dangerous goods materials, including Biological Substances, Category A or Category 
B, must be transported according to instructions detailed in the International Air 
Transport Association Dangerous Goods Regulations. 

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11 
Safety monitoring and review 
11.1 
SAE reporting 
Through Month 48 during post-unblinding follow-up for HIV-1–uninfected study 
participants (see Section 8.2 and Appendix E), SAEs regardless of relatedness to study 
products (per ICH guideline E2A) will be recorded on the appropriate CRF and reported 
to the SDMC according to procedures listed in the Safety monitoring section of the HVTN 
505 Study Specific Procedures. SAEs that are deemed related are subject to expedited 
reporting via DAERS (see Section 11.2). Grade 1 through 4 AEs that are not SAEs 
should not be reported. 
All SAEs are graded according to The Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December, 
2004 (Clarification dated August 2009) (available at http://rsc.tech-
res.com/safetyandpharmacovigilance). 
11.2 
EAE reporting 
Requirements, definitions, and methods for expedited reporting of AEs are outlined in 
Version 2.0 of “The Manual for Expedited Reporting of Adverse Events to DAIDS” 
(DAIDS EAE Manual), which is available on the RSC website at http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
The internet-based DAIDS Adverse Event Reporting System (DAERS) must be used for 
expedited AE reporting to DAIDS. In the event of system outages or technical 
difficulties, expedited AE reports may be submitted via the DAIDS EAE Form. For 
questions about DAERS, please contact DAIDS-ES at DAIDS-ESSupport@niaid.nih.gov 
or from within the DAERS application itself.  
Sites where DAERS has not been implemented will submit expedited AE reports by 
documenting the information on the current DAIDS EAE Form. This form is available on 
the RSC website: http://rsc.tech-res.com/safetyandpharmacovigilance/. For questions 
about expedited AE reporting, please contact the RSC (DAIDSRSCSafetyOffice@tech-
res.com).  
11.2.1 
EAE reporting periods 
Through Month 48 in Schedule 6 (see Section 8.2, Appendix C, and Appendix E), report 
SAEs deemed related to study product. 
Following the Month 48 visit in Schedule 6 and for the Month 60 participant health 
contact (see Section 8.2.1, Appendix C, and Appendix E) report Serious, Unexpected 
Suspected Adverse Reactions (SUSARs), as defined in Version 2.0 of the DAIDS EAE 
manual. 

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11.2.2 
Study products for expedited reporting to DAIDS 
The study products that must be considered in determining relationships of AEs requiring 
expedited reporting to DAIDS are recombinant DNA plasmid (VRC-HIVDNA016-00-
VP), rAd5 vector vaccine (VRC-HIVADV014-00-VP), placebo for the DNA vaccine 
(VRC-PBSPLA043-00-VP), and placebo for the rAd5 vector vaccine (VRC-
DILUENT013-DIL-VP).  
11.3 
Review of safety data 
Reviews proceed from a standardized set of protocol-specific safety data reports. These 
reports are produced by the SDMC and include queries to the HVTN CRSs. Events are 
tracked by internal reports until resolution. Reports will be reviewed periodically by 
Clinical safety specialist(s) and by the PSRT. 
11.3.1 
Protocol team review of cumulative safety data 
The Protocol Chair or DAIDS Medical Officer may periodically request cumulative 
summary reports of safety data, which will be made available on a secure website for 
PSRT review. 

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12 
Protocol conduct 
The protocol will be conducted in compliance with the principles of GCP and according 
to standard DAIDS and HVTN policies and procedures, including procedures for the 
following: 
 
Protocol registration, activation, and implementation; 
 
Informed consent, screening, and enrollment; 
 
Clinical and safety assessments; 
 
Safety monitoring and reporting; 
 
Data collection and documentation; 
 
Study follow-up and close-out; 
 
Unblinding of staff and participants; 
 
Quality control; 
 
Protocol monitoring and compliance; 
 
Advocacy and assistance through local and governmental activities to participants 
regarding social impacts associated with the vaccine trial; 
 
Risk reduction counseling; and 
 
Specimen collection, processing, and analysis. 
Any policies or procedures that vary from DAIDS and HVTN standards or require 
additional instructions will be described in the HVTN 505 Study Specific Procedures (eg, 
instructions for randomization specific to this study). 
12.1 
Protocol governance 
12.1.1 
Protocol Team 
The Protocol Team will be responsible for administrative oversight of the study, provides 
the overall operational direction for the trial, and is responsible for the conduct of the trial 
according to the highest scientific and ethical standards, as well as approving revisions 
and amendments to the protocol.  
12.1.2 
PSRT 
The PSRT will review all safety data during the course of the study. 
The HVTN 505 PSRT is composed of the following members: 
 
Protocol chair and co-chair* 
 
Core medical monitor* 
 
Clinical safety specialist 
 
DAIDS medical officer* 

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 
Vaccine developer representative 
* The clinician members of the PSRT, who are responsible for the review of the clinical 
safety reports, and decisions regarding cancellation of scheduled safety calls. 
The protocol team clinic coordinator, project manager, and others may also be included at 
the request of the HVTN 505 PSRT. 
12.1.3 
Oversight Group 
The Oversight Group is a high-level committee co-chaired by the Director of DAIDS, 
HVTN PI, and VRC Director along with the Chair and Co-chairs of the Protocol Team. 
The Oversight Group provides the overall scientific direction for the trial. The Oversight 
Group must approve all scientific reports concerning the main findings of the trial. 
12.2 
Overview of data collection methods 
Clinical research data will be collected in a secure electronic data management system by 
the assigned SDMC. Data will be extracted and provided to the protocol statistician for 
statistical analysis. 
12.2.1 
Source documents and data entry at sites 
Standard GCP will be followed to ensure accurate, reliable, and consistent data 
collection. Each participating site will maintain appropriate medical and research records 
for this trial, in compliance with ICH, GCP, regulatory, network, and institutional 
requirements for the protection of confidentiality of participants.  
HVTN sites will follow the DAIDS Standard Operating Procedure on Source 
Documentation, Version 2 or any later version in managing source documentation for the 
trial. Source document information may include but is not limited to: 
 
Signed informed consent documents; 
 
Dates of visits, including dates of study injections; 
 
Documentation of the study eligibility evaluation; 
 
Reported laboratory results; 
 
SAE evaluations; 
 
Participant reported concomitant medications; and 
CRFs and laboratory reports will be reviewed by the site clinical team responsible for 
ensuring that they are accurate and complete. Many HVTN CRFs are designed to be used 
as source documents. HVTN CRSs complete a source documentation table to indicate 
which CRFs the site will use as source documents for the trial. 
12.2.2 
Participant confidentiality 
Documentation, data, and all other information generated for a participant will be held in 
strict confidence. No identifying participant information concerning the study or the data 

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will be released to any unauthorized third party without prior written approval of the 
participant except as necessary for monitoring by the IRB/IEC, the FDA (if applicable), 
the study sponsor, the OHRP, and the pharmaceutical supporter(s) (if applicable). 
Information about a study participant also may be released when required by law. 
Participants must be made aware in the informed consent document of the occasions 
when information may be released without their consent. In addition, if information is 
released, either by accident or deliberately without a participant’s consent, the site must 
attempt to notify the participant of the release, complete a Protocol Event Form (see 
Section 12.3.2), and notify their IRB/IEC. 
US study sites that are at institutions regarded as covered entities under the Health 
Information Portability and Accountability Act (HIPAA) are expected to take appropriate 
action to remain in compliance with the legislation. 
US sites are covered by an NIH Certificate of Confidentiality (see Section 2.6). 
The study database assembled by the SDMC will identify study participants only by a 
study identification number and will not contain identifying information such as name, 
address, national identification number (eg, social security number), medical record 
number, or personal contact information. 
12.2.3 
Lab data transfer 
Data generated at central and regional laboratories will be transferred directly from the 
laboratory to the SDMC by secure means and with procedures that ensure the integrity of 
the data.  
12.2.4 
Storage of source documents and completed CRFs 
All study data must be verifiable to the source documentation. A file containing all the 
source documents will be maintained for each study participant at the study site. Source 
documentation will be available for review to ensure that the collected data are consistent 
with the CRFs. 
CRFs, source documents, and other supporting documents will be kept in a secure 
location. 
12.3 
Study site monitoring 
To ensure protection of study participants, compliance with the protocol, and accuracy 
and completeness of records, site monitors under contract to NIAID may visit 
participating CRSs to review the individual subject records, including consent forms, 
CRFs, supporting data, laboratory specimen records, and medical records (physicians’ 
progress notes, nurses’ notes, and individuals’ hospital charts). The monitors will inspect 
sites’ regulatory files to ensure that regulatory requirements are being followed and may 
also inspect sites’ pharmacies to review product management and storage. 
12.3.1 
Access to source documents 
Because this study is sponsored by NIAID, each site must permit authorized 
representatives of NIAID and regulatory agencies to examine (and, when required by 

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applicable law, to copy) clinical records for the purposes of quality assurance reviews, 
audits, and evaluation of the study’s safety and progress. 
Additionally, each site must permit representatives of the HVTN, SDMC, and related 
contractors to examine clinical records for the purposes of quality assurance reviews, 
audits, and evaluation of the study’s safety and progress. 
12.3.2 
Protocol events 
A protocol event is defined as an individual incident or omission in study conduct that 
results in significant added risk to the participant, or nonadherence to significant protocol 
requirements, or nonadherence to the International Conference on Harmonisation E6: 
Guideline for Good Clinical Practice.  
The nonadherence may be either on the part of a participant, the investigator, or the study 
site staff.  
It is the responsibility of the site to identify and report protocol events according to the 
guidelines of the IND sponsor and the local IRB/IEC per their guidelines. The site must 
also report protocol events to the HVTN using the Protocol Event Form. The site PI and 
study staff are responsible for knowing and adhering to their IRB requirements. 
In response to noted protocol events, site personnel are to implement corrective actions 
promptly. 
12.4 
Social impacts 
Participants in this study risk experiencing discrimination or other personal problems as a 
result of being in the study or developing a vaccine-induced positive HIV Ab response. 
The HVTN CRS is obliged to provide advocacy for and assistance to participants 
regarding negative social impacts associated with the vaccine trial. If HVTN CRS staff 
have questions regarding how to assist a participant dealing with a social impact, a 
designated NIAID representative can be contacted.  
Social harms are tabulated by the SDMC and subjected to descriptive analysis with a 
view toward reducing their incidence and enhancing the ability of study staff to mitigate 
them when possible. 
Summary tables of social impact events will be generated weekly and made available for 
review by the protocol chairs, Protocol Team leader, and the designated NIAID 
representative. 
12.5 
Study participant reimbursement 
Reimbursement of study participants for attendance at study visits is at the discretion of 
each study site. Reimbursement should be comparable to the reimbursement offered for 
similar research in the local community, if possible. The study site is encouraged to 
confer with its local CAB in deciding appropriate reimbursement.  

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The study consent submitted to the site IRB/IEC will state the plan for reimbursement (if 
any). The HVTN relies upon local IRBs/IECs to determine whether the proposed plan for 
reimbursement meets ethical requirements in the local context. The exact amounts may 
be modified during the course of the study in consideration of changes in costs such as 
bus fares, exchange rates, child care, or other factors that affect the ability of a participant 
to comply with study visit requirements. Reviewing IRBs/IECs must be made aware of 
the changes in reimbursement before they occur. Study participants will not be charged 
for study injections, research clinic visits, research-related examinations, or research-
related laboratory tests. 
The HVTN does not allow reimbursement that induces a study participant to remain in 
the study against his or her will. A lump sum reimbursement at trial completion or a 
reimbursement plan that starts with low reimbursement that increases at later study visits 
solely to encourage retention is unacceptable. 
12.6 
Compliance with NIH guidelines for research involving products 
containing recombinant DNA 
Because this study is evaluating products containing recombinant DNA, per NIH 
Guidelines for Research Involving Recombinant DNA Molecules the study must be 
submitted to site Institutional Biosafety Committees (IBC) and must be approved before 
participants are enrolled at each respective institution. Investigators at each site are 
responsible for obtaining IBC approval and periodic review of the research per NIH 
guidelines Section IV-B07-b-(6) and Section IV-B-2-b. IBC review and approval must be 
documented by the investigator and submitted as part of initial protocol registration for 
this trial. 
12.7 
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 in order to report study findings that may otherwise concern 
their health or welfare.  
In communicating with the trial participants emergently, the clinical trial site will request 
that its IRB/IEC expedite review of the message. However, if IRB/IEC review cannot be 
completed in a timeframe consistent with the urgency of communication with study 
participants, the clinical trial site will contact the participant and then notify the IRB/IEC 
as soon as possible during normal business hours. 
 

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13 
Version history 
The Protocol Team may modify the original version of the protocol. Modifications are 
made to HVTN protocols via clarification memos, letters of amendment, or full protocol 
amendments.  
The table below describes the version history of, and modifications to, Protocol HVTN 
505. 
Protocol history and modifications 
Date: July 21, 2014 
Protocol version: Version 6.0 
Protocol modification: Full Protocol Amendment 5 
Item 1 
Boxed text added following title page: Summary of extended follow-up 
results, Version 6 study redesign 
Item 2 
Revised in Section 5: Study objectives and endpoints 
Item 3 
Revised in Section 8 and Appendices C, D, E, and F: Visit schedules for HIV-
1–uninfected and for HIV-1–infected study participants 
Item 4 
HVTN 503 (Phambili) results updated in Section 4.1.3.6 
Item 5 
Revised in Section 6, Statistical considerations: Objectives, endpoints, sample 
size rationale, analysis plans, and study monitoring 
Item 6 
Deleted: Section 8.1.2, VISP registry consent form and former Appendix C: 
HVTN VISP registry consent 
Item 7 
Clinic procedures revised in Section 8.2, Follow-up visits for HIV-uninfected 
participants 
Item 8 
Deleted: (former) Section 8.4, Procedures for participants who became HIV-
1–infected during annual health contacts 
Item 9 
Section 8.4, HIV risk reduction counseling updated to reference CDC PrEP 
clinical practice guidelines 
Item 10 
Description of HVTN HIV testing algorithm updated in Section 9.2, HIV-1 
testing during post-unblinding follow-up and in Section 10.11, EOS testing 
Item 11 
May 2014 CDC PrEP clinical practice guidelines added to Section 14, 
Document references (other than literature citations) 
Item 12 
Job titles and institutional affiliations updated in Section 3.1, Protocol team, 
Section 11.3, Review of safety data, and Section 12.1.2, PSRT 
Item 13 
Updated in Section 13, Version history: Protocol history and modifications 
Item 14 
Updated: Appendix A, Addendum to sample informed consent form 
Item 15 
Updated in Appendix B, Tables of procedures (for Sample informed consent 
form addendum) 

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Item 16 
Visit schedule revised in Appendix C: Schedule 6–Post-unblinding laboratory 
procedures for HIV-uninfected participants and Appendix E, Schedule 6—
Post-unblinding clinic procedures for HIV-uninfected participants 
Item 17 
Visit schedule revised in Appendix D: Schedule 7–Post-unblinding laboratory 
procedures for HIV-infected participants and Appendix F, Schedule 6—Post-
unblinding clinic procedures for HIV-infected participants 
Item 18 
Minor errors in grammar, typography, and cross-references have been 
corrected throughout the protocol document 
Date: March 11, 2014 
Protocol version: Version 5.0 
Protocol modification: Clarification Memo 1 
Item 1 
Clarified: Safety monitoring functions transition to HVTN Core Clinical 
Safety Specialists 
Item 2 
Clarified: Current HVTN laboratory algorithms for HIV diagnostic testing and 
evaluation of vaccine-induced seroreactivity 
Date: July 12, 2013 
Protocol version: Version 5.0 
Protocol modification: Full Protocol Amendment 4 
Item 1 
Boxed text added following title page: Vaccinations stopped, treatment 
assignments unblinded, and study redesigned 
Item 2 
Revised in Section 5: Study hypothesis, objectives, and endpoints 
Item 3 
Revised in Section 8 and Appendices D and G: Visit schedule for HIV-1–
uninfected participants extended to 48 months of clinic visits with Month 60 
participant health contact 
Item 4 
Revised in Section 8 and Appendices E, F, H, and I: Visit schedules for HIV-
1–infected study participants 
Item 5 
Revised in Section 3, Overview: Primary objective, participants, design, 
duration per participant, estimated total study duration, safety monitoring 
Item 6 
Updated in Section 4, Background and rationale: HVTN 503 (Phambili) and 
VOICE study results, PrEP uptake, and HIV-1 infections in HVTN 204 
Item 7 
Revised in Section 6, Statistical considerations: Objectives, endpoints, sample 
size rationale, analysis plans, and study monitoring 
Item 8 
Updated and modified in Section 7, Selection and withdrawal of participants: 
Introductory text, co-enrollment, participant departure from vaccination 
schedule or withdrawal 
Item 9 
Deleted: (Former) Section 8, Study product preparation and administration 
Item 10 
Deleted in Section 8, Clinical procedures: Screening consent form and 
assessment of understanding 
Item 11 
Deleted in Section 8, Clinical procedures: Subsections concerning pre-
enrollment procedures and procedures at enrollment and vaccination visits, 
procedures for participants discovered to be HIV-infected at enrollment, and 
reactogenicity assessment 

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Item 12 
Revised in Section 8.2 and Appendices D and G: Clinic and laboratory 
procedures for HIV-1–uninfected study participants 
Item 13 
Revised in Sections 8.3 and 8.4 and Appendices E, F, H, and I: Procedures for 
HIV-1–infected study participants 
Item 14 
Revised in Section 8.2.2: Unblinding and evaluation of vaccine-induced 
seroreactivity (EOS) testing 
Item 15 
Revised in Section 8.5, Risk reduction counseling: Counseling regarding 
outside testing limited to vaccine recipients 
Item 16 
Removed in Section 8.7, Visit windows and missed visits: Reference to 
missed vaccination visits 
Item 17 
Revised in Section 9: HIV-1 infection and clinical response 
Item 18 
Revised in Section 10¸ Laboratory: Specimens, blood volumes, and assays 
Item 19 
Revised in Section 11, Safety monitoring and review: Safety reporting and 
safety monitoring 
Item 20 
Revised in Section 12, Protocol conduct: DSMB oversight and Protocol Team 
blinding removed, Oversight Committee membership updated, 
Item 21 
Updated in Section 13, Version history: Protocol history and modifications 
Item 22 
Added in Section 14, Document references (other than literature citations): 
ICH E2(A) 
Item 23 
Literature references updated in Section 16 
Item 24 
Deleted: (Former) Appendix A, Sample informed consent form 
Item 25 
Deleted: (Former) Appendix B, Tables of procedures (for sample informed 
consent form) 
Item 26 
Added as (new) Appendix A: Addendum to sample informed consent form 
Item 27 
Added as Appendix B: Tables of procedures (for Sample informed consent 
form addendum) 
Item 28 
Renumbered as Appendix C: HVTN VISP registry consent 
Item 29 
Deleted: (former) Appendix E, Rationale for the primary VL endpoint 
definition 
Item 30 
Deleted: (former) Appendix J, Annual health contacts for HIV-uninfected 
participants 
Item 31 
Deleted: (former) Appendix M, Sample consent form for rectal fluid and 
semen collection 
Item 32 
Updated in Section 3.1: Protocol Team members and contact information 
Item 33 
Cross-references updated and minor errors corrected 

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Date: March 5, 2013 
Protocol version: Version 4.0 
Protocol modification: Clarification Memo 1 
Item 1  
Clarified in Section 9.4.2, Annual health contacts for HIV-uninfected 
participants and Section 12.4.4, DSMB review of cumulative safety data: 
Safety reviews during annual health contact period  
Item 2  
Formatting error corrected in Section 12.3, EAE reporting 
Date: September 12, 2012 
Protocol version: Version 4.0 
Protocol modification: Full Protocol Amendment 3 
Item 1 
Sample size increased to 2500 
Item 2 
Information on use of Truvada® for HIV prevention updated 
Item 3 
Endpoints and analysis plans corrected in Section 5.3, 6.3.3.4, and 6.6.4.7 
Item 4 
Extended follow-up for HIV-infected study participants clarified via Letter of 
Amendment 1 to Version 3.0 
Item 5 
Optional rectal secretion and semen sampling for HIV-uninfected study 
participants added via Letter of Amendment 1 to Version 3.0 
Item 6 
Syphilis testing methods clarified via Clarification Memo 1 to Version 3.0 
Date: April 27, 2012 
Protocol version: Version 3.0 
Protocol modification: Clarification Memo 2 
Item 1 
Clarified in Sections 9.4.3 and 9.4.4 and in footnotes to Appendices F and H: 
Mucosal sampling timepoints 
Date: April 2, 2012 
Protocol version: Version 3.0 
Protocol modification: Clarification Memo 1 
Item 1 
Clarified in Sections 9.4.3, Rectal secretion sampling and 9.4.4, Semen 
sampling: Sampling timepoints 
Item 2 
Clarified in Section 11.10, STD testing and footnote to Appendix F, Schedule 
1—Laboratory procedures for HIV-uninfected participants: Syphilis testing 
Date: January 23, 2012 
Protocol version: Version 3.0 
Protocol modification: Full Protocol Amendment 2 
Item 1 
Title revised 
Item 2 
Enrollment expanded to 2200 
Item 3 
HIV acquisition elevated to primary endpoint 
Item 4 
Duration per participant and total study duration revised 
Item 5 
Eligibility age limit raised from 45 to 50 years 

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Item 6 
Protocol leadership and other contributors to the original protocol revised in 
Section 3.1, Protocol team 
Item 7 
HIV epidemiology updated in Section 4.1 
Item 8 
Description of VRC candidate vaccines revised in Section 4.1.1 
Item 9 
Information on RV 144 and rationale for sample size increase added as new 
Section 4.1.2 
Item 10 
Summary update of Step Study results added as Section 4.1.3.5 
Item 11 
Added in Sections 4, 5, 6, 7, 9, 11, and Appendices: iPrEx study results and 
monitoring of ARV use for HIV-1 prophylaxis 
Item 12 
NHP SIV challenge data added to Section 4.4.1 
Item 13 
Human experience with VRC vaccine regimen updated in Section 4.6 
Item 14 
Viral load objectives/endpoints modified in Sections 5.2 and 5.3 
Item 15 
Exploratory objectives added in Section 5.4 
Item 16 
Statistical considerations revised in Section 6 
Item 17 
Exclusion criteria clarified in Section 7.2 
Item 18 
Co-enrollment of participants in other clinical trials addressed in new Section 
7.3 
Item 19 
Sections 7.4.2, 9.4.2, 12.2.1, 12.3, and Appendix I revised for consistency 
with version 2.0 of DAIDS EAE manual 
Item 20 
VISP Registry consent form added in Section 9.1.3 and new Appendix D 
Item 21 
Unblinding, VISP testing, and provision of VISP test results revised in 
Sections 9.4.1 and 11.12 
Item 22 
Annual health contact language updated in Section 9.4.2 and Appendix J 
Item 23 
STI testing referrals added to risk reduction counseling in Section 9.6 
Item 24 
References to DAIDS AE grading table updated in Sections 9.7, 12.1, and 15 
Item 25 
IBC review requirements clarified in Section 13.6 
Item 26 
Version history table updated in Section 14 
Item 27 
Reference to DAIDS EAE Manual updated in Section 15 
Item 28 
Acronyms and abbreviations updated in Section 16 
Item 29 
Appendix A, Sample informed consent form, revised 
Item 30 
Visit schedule revised in Appendix B 
Item 31 
Consent for other uses of study samples revised in Appendix C 
Item 32 
Laboratory and clinic procedures schedules revised in Appendices F and H 
Item 33 
Blood samples for viral isolation/sequencing and semen sampling clarified in 
footnotes to Appendix G 
Item 34 
Annual health contacts table revised in Appendix J 
Item 35 
Reference numbers and cross-references to protocol sections and appendices 
have been updated throughout the document 

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Item 36 
Typographical errors, duplicate references, and deviations from HVTN 
protocol style conventions have been corrected throughout the document 
Date: September 29, 2010 
Protocol version: Version 2.0 
Protocol modification: Letter of Amendment 4 (new version-specific numbering system) 
Item 1 
Revised in Sections 3, Overview and 7.1, Inclusion criteria: Upper age limit 
raised from 45 to 50 years 
Date: June 7, 2010 
Protocol version: Version 2.0 
Protocol modification: Letter of Amendment 3 (new version-specific numbering system) 
Item 1 
Revised for consistency with version 2.0 of DAIDS EAE manual: Sections 
7.3.2, 9.4.2, 12.2.1, 12.3, and Appendix I 
Item 2 
Updated in Sections 9.7, 12.1, and 15: References to DAIDS AE grading table 
Date: March 12, 2010 
Protocol version: Version 2.0 
Protocol modification: Letter of Amendment 4 
Item 1 
Replaced in title and text: “Transgender women” by “male-to-female (MTF) 
transgender persons” 
Item 2 
Added as new section 4.1.2.5: Summary update of Step Study results 
Item 3 
Revised and reorganized in Appendix A, Sample informed consent form: 
Sections 5 – 8, including update to “Step Study” language 
Item 4 
Revised in Section 7.2, Exclusion criteria: Autoimmune disease exclusion 
criterion 
Date: January 28, 2010 
Protocol version: Version 2.0 
Protocol modification: Letter of Amendment 3 
Item 1 
Revised in Appendix A, Sample informed consent form: Section 5 title 
Date: December 29, 2009 
Protocol version: Version 2.0 
Protocol modification: Full Protocol Amendment 1 
Item 1 
Title, objectives, and participants clarified: MSM and MTF transgender 
persons included 
Item 2 
HVTN 505 assigned BB-IND 13971 
Item 3 
Revised throughout protocol: “Post-week 28 infection” replaces WITT 
Item 4 
Updated in section 3.1: Protocol Team 
Item 5 
Updated in section 4.1.1: Reference to the Thai trial 
Item 6 
Clarified throughout: Study transition points and estimated study duration 

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Item 7 
Clarified in section 6: Primary analysis population and MITT infections, 
alternative VL setpoint, and trial monitoring 
Item 8 
Revised in section 7.1: Behavioral risk criteria, circumcision status, and 
transgender eligibility 
Item 9 
Revised in section 7, Selection and withdrawal of participants: Influenza 
vaccine exclusion/delay windows, therapeutic anticoagulation exclusion, and 
co-enrollment restrictions 
Item 10 
Deleted in sections 8.3.3, 8.3.4, and 8.4.2: 5 mL syringe option 
Item 11 
Added to sections 9, 10, Appendix A and Appendix B: Provision for 
participants discovered to have been HIV-infected at enrollment 
Item 12 
Clarified in section 9: Clinical procedures timing 
Item 13 
Clarified in section 11: Samples assayed for secondary and exploratory 
endpoint data, applicability of VISP testing, and other uses of stored 
specimens 
Item 14 
Clarified in section 12: AE/EAE reporting and immediate notification 
Item 15 
Clarified in section 13: DSMB monitoring for operational futility 
Item 16 
Corrected in section 15: Document listings 
Item 17 
Clarified and corrected in Appendix A: Follow-up for HIV-infected 
participants, participants confirmed to be HIV-infected at enrollment 
circumcision, semen samples, blood volumes, and minor errors 
Item 18 
Clarified in Appendix B: Outside testing counseling and follow-up for HIV-
infected participants 
Item 19 
Revised in Appendix C: Genetic testing added and “leftover” deleted 
Item 20 
Corrected in Appendix E: Sampling volumes, timepoints, lab listings 
Item 21 
Revised in Appendix F: Ship to and assay location added for semen samples, 
new lab added, and footnote revised 
Item 22 
Revised in Appendix G: Final Schedule 1 visit designation, outside testing 
counseling, and behavior risk assessment timing 
Item 23 
Revised in Appendix I: Timepoints, contact numbers, and footnote 
Item 24 
Corrected: Minor errors 
Date: October 16, 2009 
Protocol version: Version 1.0 
Protocol modification: Letter of Amendment 2 
Item 1 
Added: Provision for participants discovered to have been HIV-infected at 
enrollment 
Item 2 
Revised in sections 7.2, Exclusion criteria and 7.3.1, Delaying vaccinations 
for a participant: Influenza vaccine exclusion/delay windows 

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Date: April 22, 2009 
Protocol version: Version 1.0 
Protocol modification: Letter of Amendment 1 
Item 1 
HVTN 505 assigned BB-IND 13971 
Item 2 
Clarified in section 7.1, Inclusion criteria and Appendix A, Sample informed 
consent form: Circumcision status 
Item 3 
Corrected in section 9, Clinical procedures and Appendix G, Schedule 1—
Clinic procedures for HIV-uninfected participants: Timing of initial 
administration of behavioral risk assessment questionnaire 
Item 4 
Replaced in sections 9.3.3, 9.4, Appendix B, and Appendix G: Outside testing 
questionnaire by outside testing counseling 
Item 5 
Clarified in section 12.2, AE reporting: AE reporting periods for participants 
who miss the third or fourth vaccination 
Item 6 
Revised in Appendix E, Schedule 1—Laboratory procedures for HIV-
uninfected participants: Blood draws added for viral sequencing and 
ELISpot/ICS volume increased at visit 5 
Date: February 25, 2009 
Protocol version: Version 1.0 
Protocol modification: Original protocol 
 

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14 
Document references (other than literature citations) 
Other documents referred to in this protocol, and containing information relevant to the 
conduct of this study, include: 
 
Assessment of Understanding. Accessible through the HVTN protocol-specific 
website. 
 
Current CDC Guidelines. Revised Recommendations for HIV Testing of Adults, 
Adolescents, and Pregnant Women in Health-Care Settings. Available at 
http://www.cdc.gov/mmwr/PDF/rr/rr5514.pdf.  
 
Division of AIDS (DAIDS) Clinical Research Policies and Standard Procedures 
Documents. Available at 
http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/ 
 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 1.0, December 2004 (Clarification dated August 2009). Available at 
http://rsc.tech-res.com/safetyandpharmacovigilance. 
 
The Manual for Expedited Reporting of Adverse Events to DAIDS. Version 2.0, 
January 2010. Available at http://rsc.tech-res.com/safetyandpharmacovigilance.  
 
HVTN 505 HIV-1 Diagnostic Testing. Available through the HVTN protocol-specific 
website. 
 
HVTN 505 Special Instructions. Accessible through the HVTN protocol-specific 
website. 
 
HVTN 505 Study Specific Procedures. Accessible through the HVTN protocol-
specific website. 
 
HVTN Laboratory Manual of Operations. Accessible through the HVTN website. 
 
HVTN Manual of Operations. Accessible through the HVTN website. 
 
International Conference on Harmonisation (ICH) E2 (A), Clinical Safety Data 
Management, section 3B, Serious Adverse Event or Adverse Drug Reaction. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
2A/Step4/E2A_Guideline.pdf. 
 
International Conference on Harmonisation (ICH) E6 (R1), Guideline for Good 
Clinical Practice: section 4.8, Informed consent of trial subjects. Available at 
http://www.emea.europa.eu/pdfs/human/ich/013595en.pdf. 
 
NIH Guidelines for Research Involving Recombinant DNA Molecules. Available at 
http://www4.od.nih.gov/oba/rac/guidelines/guidelines.html. 
 
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.  
 
Protocol Registration Policy and Procedure Manual. Accessible through the HVTN 
website. 

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 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials. Available at 
http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/ClinicalSite.htm 
 
Title 21, Code of Federal Regulations, Part 50. Available at 
http://www.access.gpo.gov/nara/cfr/waisidx_08/21cfrv1_08.html. 
 
Title 45, Code of Federal Regulations, Part 46. Available at 
http://www.access.gpo.gov/nara/cfr/waisidx_07/45cfrv1_07.html. 
 
Preexposure Prophylaxis for the Prevention of HIV Infection in the United States – 
2014 Clinical Practice Guideline. Available at 
http://www.cdc.gov/hiv/prevention/research/prep/. 
See section 16 for literature cited in the background and statistics sections of this 
protocol. 

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15 
Acronyms and abbreviations 
Ab 
antibody 
Ad5 
adenovirus serotype 5 
AE   
adverse event 
ALT  
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
AOU 
assessment of understanding 
ART  
(post-HIV diagnosis) antiretroviral therapy 
ARV 
antiretroviral (drug) 
BOI 
burden-of-illness 
CAB 
Community Advisory Board 
CDC 
US Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI  
confidence intervals 
CRF  
case report form 
CRPMC  
NIAID Clinical Research Products Management Center 
CRS* 
clinical research site 
CTL 
cytotoxic T lymphocyte 
DAIDS  
Division of AIDS (US NIH) 
DHHS  
US Department of Health and Human Services 
DSMB 
NIAID Data and Safety Monitoring Board 
EAE  
expedited adverse event 
EIA 
enzyme immunoassay 
ELISA 
enzyme-linked immunosorbent assay 
ELISpot  
enzyme-linked immunospot 
EOS 
evaluation of vaccine-induced seroreactivity 
FDA 
US Food and Drug Administration 
FET 
final evaluation time 
FFB 
final formulation buffer 
FHCRC  
Fred Hutchinson Cancer Research Center 
FTC 
emtricitabine  
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HLA 
human leukocyte antigen 
HR 
hazard ratio 
HSV-2 
Herpes simplex virus type 2 
HVTN  
HIV Vaccine Trials Network 
IAVI 
International AIDS Vaccine Initiative 
IB  
Investigator’s Brochure 
IBC 
Institutional Biosafety Committee 

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ICH  
International Conference on Harmonisation 
ICS  
intracellular cytokine staining 
IEC  
Independent Ethics Committee 
IFN-γ  
interferon gamma 
IL-2 
interleukin 2 
IND 
Investigational New Drug 
IRB  
Institutional Review Board 
IV 
intravenous 
LTNP 
long-term nonprogressors 
MAR 
missing at random 
MIP1-β 
macrophage inflammatory protein 1 beta 
MOP 
manual of operations 
MITT 
modified intent-to-treat 
MSM 
men who have sex with men 
MTF 
male-to-female 
nAb 
neutralizing antibody 
NHP 
nonhuman primate 
NIAID  
National Institute of Allergy and Infectious Diseases (US NIH) 
NIH  
US National Institutes of Health 
NVITAL 
NIAID Vaccine Immune T-Cell and Antibody Laboratory 
PBMC  
peripheral blood mononuclear cell 
PBS 
phosphate-buffered saline 
PCR 
polymerase chain reaction 
PD 
post [HIV-infection] diagnosis 
PEP 
post-exposure prophylaxis 
PET 
Primary Evaluation Time 
PI  
Principal Investigator 
PrEP 
pre-exposure prophylaxis 
PSRT  
HVTN Protocol Safety Review Team 
PTE-g 
global potential T-cell epitope 
PT/INR 
prothrombin time/international normalized ratio 
PTT 
partial thromboplastin time 
rAd5 
recombinant adenovirus serotype 5 
RCC  
DAIDS Regulatory Compliance Center 
RR 
relative risk 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCHARP  Statistical Center for HIV/AIDS Research and Prevention 
sd 
standard deviation 
SDMC  
statistical and data management center 
SFC  
spot-forming cell 
SIV 
simian immunodeficiency virus 

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SUSAR 
sudden unexpected serious adverse reaction 
TDF 
tenofovir disoproxil fumarate  
TNF- 
tumor necrosis factor alpha 
UIAS 
unprotected insertive anal sex 
UNAIDS 
Joint United Nations Programme on HIV/AIDS 
URAS 
unprotected receptive anal sex 
USMHRP US Military HIV Research Program 
UW-VSL University of Washington Virology Specialty Laboratory 
VISP 
vaccine-induced seropositivity 
VL 
viral load 
VPP 
Vaccine Pilot Plant 
VRC 
Vaccine Research Center (NIAID) 
 
* CRSs were formerly referred to as HIV Vaccine Trial Units (HVTUs). Conversion to 
use of the term CRS is in process, and some HVTN documents may still refer to HVTUs. 

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16 
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plasma HIV-1 RNA levels and progression to AIDS in women and men. N Engl J 
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Appendix A 
Addendum to sample informed consent form 
Protocol HVTN 505, Version 5.01: Phase 2b, randomized, placebo-controlled test-of-
concept trial to evaluate the safety and efficacy of a multiclade HIV-1 DNA plasmid vaccine 
followed by a multiclade HIV-1 recombinant adenoviral vector vaccine in HIV-uninfected, 
adenovirus type 5 neutralizing antibody negative, circumcised men and male-to-female 
(MTF) transgender persons, who have sex with men 
Short title of study: HVTN 505 
Please review this form carefully. The study staff will talk with you about the information 
in it. You may also ask to review the information in the original study consent form. You 
are free to ask questions at any time. 
To show that you have received and understand this information, we will ask you to sign 
this form. You will get a copy to keep. 
Review of study information 
You are a participant in a study called HVTN 505. This is a study of an experimental 
HIV vaccine regimen that used a DNA vaccine and an adenoviral vector vaccine. 
This study was designed to look at two main questions:  
 
Does this study vaccine regimen prevent HIV infection?  
 
Does this study vaccine regimen reduce the amount of HIV in a person’s body (the 
HIV viral load) in those who got the vaccine and later developed HIV infection? 
The study opened on June 5, 2009. By March 31, 2013 the study was fully enrolled with 
2504 participants. 1253 participants received the study vaccines and 1251 received the 
placebo.  
In April 2013, injections in HVTN 505 were stopped after an interim analysis showed 
that the study vaccines did not prevent HIV infection. This analysis also showed that the 
study vaccines did not reduce the amount of virus (viral load) in people who later became 
infected with HIV. 
At that time, we asked HVTN 505 participants to stay in the study so we could monitor 
their health and follow participants who later became infected with HIV. We also wanted 
to make sure that people who got the study vaccines were not more likely to get infected 
with HIV. 
New information  
Since then we have collected more information. This information confirmed the earlier 
analysis that the study vaccines did not prevent HIV infection or reduce viral load.  

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This information also showed that people who got the study vaccines did not have more 
HIV infections than people who got the placebo.  
Thanks to our study volunteers, these important questions about the HVTN 505 study 
vaccines have been answered.  
Ongoing laboratory studies of samples collected in HVTN 505 continue to provide 
information about immune system responses to the vaccines, about factors affecting 
whether HIV vaccines work or not, and about other factors that make a person more or 
less likely to get infected with HIV. 
Changes to HVTN 505  
Even though many questions have been answered, there is still more to learn from HVTN 
505. Additional information gathered in this study may help us improve the design of 
future studies. For this reason, we are asking HVTN 505 study participants to continue in 
the study.  
We want to continue to check on your health and to track any new HIV infections. It is 
also important to learn whether people will stay enrolled in a study, especially after they 
have learned whether they received the study vaccines or placebo.  
This new information may change how you feel about staying in the study. If you decide 
to stay in the study, we will ask you to continue visits to the study clinic. 
For participants who are HIV-negative, we will ask you to come to the clinic for 
annual visits. These clinic visits will be scheduled 3 years and 4 years after your first 
vaccination.  
At these annual clinic visits, we will: 
 
Do regular HIV testing, as well as counseling on your results; 
 
Perform brief physical exams; 
 
Collect blood samples; 
 
Collect urine samples;  
 
Ask questions about your health; 
 
Counsel you on avoiding HIV infection; 
 
Ask about any personal problems or benefits you may have from being in this study; 
 
Ask questions about any antiretroviral (ARV) drugs you may be taking; and 
 
Give you a computer questionnaire about ARV drugs, behaviors that could put you at 
risk for HIV infection, and some aspects of your life situation. 

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We will use some blood and urine samples to test you for chlamydia, gonorrhea, and 
syphilis. If you have one of these infections, we will refer you for care and treatment. 
After your clinic visits have ended, we will contact you once more to check on your 
health. This contact will be about 5 years after your first vaccination. This may just be a 
phone call. If you have had a positive HIV test since your last clinic visit, we will ask you 
to come to the clinic for testing to confirm your HIV infection. 
If you become HIV-infected before completing your scheduled clinic visits, we will 
ask you to come to the clinic 3 more times over a 6-month period. At these visits, we 
will: 
 
Ask questions about your health; 
 
Perform brief physical exams; 
 
Ask about any antiretroviral treatments (ART) you may be taking; 
 
Collect blood samples; 
 
Counsel you on how to avoid giving HIV to other people; and 
 
Ask about any personal problems or benefits you may have from being in this study. 
We will tell you where to get support, medical care, and HIV treatment if you do not 
already have these in place.  
After your time in this study ends, we may invite you to join another study to follow your 
health and to see how your body controls your HIV infection. For this separate study 
there will be a new consent form that we will review with you. 
PrEP in HVTN 505 
In July 2012, the US FDA approved the use of the antiretroviral medicine Truvada for 
prevention of HIV infection. This is called pre-exposure prophylaxis (PrEP). 
In May 2014, the US Centers for Disease Control and Prevention (CDC) published 
guidelines for doctors to follow when prescribing PrEP. These guidelines recommend 
that PrEP be considered as a method of HIV prevention for people who are HIV-negative 
and at increased risk for HIV infection.  
The HVTN, the Division of AIDS, and Gilead Sciences, Inc. (the maker of Truvada) have 
reached an agreement to provide Truvada as PrEP to study participants in HVTN 505. If 
you are interested, clinic staff can give you more information about this program and can 
refer you to providers who can prescribe PrEP. 
What if I choose to leave this study? 
You can leave this study at any time. If you leave this study, you will not lose any 
benefits or rights you would normally have. 

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If you decide to leave this study, please tell the clinic staff. We will ask you to come back 
to the clinic at least one last time, to check your health and your immune response. 
  
Who should I call if I have questions or problems? 
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]. 
Other information 
The rest of the information in the consent forms 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. Additional copies of the consent form are available from the clinic staff and we 
encourage you to read it again.  
In addition, other consent forms you have signed previously remain in place. These other 
forms are for other uses of your study samples and your inclusion in the VISP registry. 
We will provide copies of these consent forms if you would like them. [Site: Modify this 
paragraph as appropriate to reflect local practice and IRB requirements.] 
I agree to continue in this study. 
 
 
 
 
 
Initial_____ 
I do not want to continue in this study. 
 
 
 
 
Initial_____ 
If you have read this addendum to the consent form (or had it explained to you) and 
understand it, please sign your name below. 

HVTN 505, Version 6.0 / July 21, 2014 
HVTN505_v6.0_FINAL.docx / Page 107 of 112 
 
 
 
 
 
 
 
 
 
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. 

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Appendix B 
Revised tables of procedures (for Sample 
informed consent form addendum) 
 
HIV-negative participants 
 
 
Months after first study injection 
Procedure 
6 
9 
12 
15 
18 
21 
24 
36 
48 
60 
Brief physical exam 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Blood drawn 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
HIV testing/counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Questions/questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√* 
Risk reduction counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Testing for syphilis, gonorrhea, and 
chlamydia 
√ 
 
√ 
 
√ 
 
√ 
√ 
√ 
 
Shaded area indicates visits previously completed by all study participants. 
* Clinic visit not required. 
Participants who become HIV-infected  
 
 
 
Weeks after first 
HVTN test showing 
HIV infection 
Procedure 
0* 
2 
4 
24 
HIV testing/counseling 
√ 
√ 
√ 
 
Brief physical (as needed) 
√ 
√ 
√ 
√ 
Risk reduction counseling 
√ 
√ 
√ 
√ 
Questions/questionnaire 
√ 
√ 
√ 
√ 
Blood drawn 
√ 
√ 
√ 
√ 
* If there has been a positive HIV test outside the HVTN, participant comes to site for HIV confirmatory 
testing. 
 
 

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Appendix C 
Schedule 6—Post-unblinding laboratory procedures for HIV-uninfected 
participants 
Vis it:
10 1
10 2
10 3
10 4
10 5
10 6
10 7
10 8
10 9
110
111
112
113
114
115
Day:
D168
D273
D364
D455
D546
D637
D728
D819
D909
D1000
D1091
D1182
D1273
D1454
D1818
M o nth
6
9
12
15
18
21
24
27
30
33
36
39
42
48
60
P ro cedure
Ship to 1,2
As s ay lo catio n2
Tube 3
To ta l
Blo o d Co llectio n
      HIV diagno s tic tes t
UW/VSL
UW/VSL
EDTA
10
10
10
10
10
10
10
—
—
—
10
—
—
20
—
10 0
Syphilis
Lo cal Lab
Lo cal lab
SST
—
—
10
—
—
—
10
—
—
—
10
—
—
10
—
4 0
P las ma 4
CSR
UNC
EDTA
5
5
5
5
5
5
5
—
—
—
5
—
—
5
—
4 5
     Specimen s to rage
Serum
CSR
SST
—
—
17
—
—
—
17
—
—
—
—
—
—
—
—
3 4
Vis it To ta l
15
15
4 2
15
15
15
4 2
0
0
0
2 5
0
0
3 5
0
2 19
5 6 -D a y to ta l
15
15
4 2
15
15
15
4 2
0
0
0
2 5
0
0
3 5
0
URINE COLLECTION
STI Tes ting
GC/Chlamydia by NAAT o r culture
Lo cal Lab
Lo cal Lab
X
—
X
—
X
—
X
—
—
—
X
—
—
X
 
Shaded visits not required. 
1 CSR = central specimen repository 
2 HVTN Laboratory Program includes endpoint laboratories at UW-VSL. UW-VSL = University of Washington Virology Specialty Laboratory (Seattle, Washington, USA). Non-
HVTN Laboratories include UNC. UNC = University of North Carolina - Chapel Hill (Chapel Hill, North Carolina, USA). 
3 Local labs may assign appropriate alternative tube types for locally performed tests. 
4 Draw plasma at specified visit only if participant reports having used ARVs for PrEP or PEP since the last clinic visit. 
 

HVTN 505, Version 6.0 / July 21, 2014 
HVTN505_v6.0_FINAL.docx / Page 110 of 112 
Appendix D 
Schedule 7—Post-unblinding laboratory procedures for HIV-infected 
participants 
Vis it
# .X 1
2 0 1
2 0 2
2 0 3
2 0 4
W2
W4
W8
W12
W24
P ro cedure
Ship to 2,3
As s ay lo catio n3
Tube 4
To ta l
Blo o d Co llectio n
     Screening o r diagno s tic as s ays
          HIV diagno s tic EIA/WB/P CR
UW/VSL
UW/VSL
EDTA
15
—
—
—
—
15
          HIV P CR viral lo ad
UW/VSL
UW/VSL
EDTA
—
—
—
—
—
0
          CD4+T cell co unt
Lo cal Lab
Lo cal Lab
EDTA
5
—
—
—
—
5
     Sto rage
          Serum
CSR
SST
—
8.5
—
—
8.5
17
To ta l
2 0
8 .5
—
—
8 .5
3 7
5 6 -D a y to ta l
2 0
2 9
—
—
8 .5
Weeks  after Diagno s is
 
Shaded visits not required. 
1 Visit #.X = interim visit for the purpose of drawing samples for confirmatory HIV testing 
2 CSR = central specimen repository 
3 HVTN Laboratory Program includes endpoint laboratories at UW-VSL. UW-VSL = University of Washington Virology Specialty Laboratory (Seattle, Washington, USA) 
4 Local labs may assign appropriate alternative tube types for locally performed tests. 

HVTN 505, Version 6.0 / July 21, 2014 
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Appendix E 
Schedule 6—Post-unblinding clinic procedures for HIV-uninfected participants 
Visit: 
101 
102 
103 
104 
105 
106 
107 
108 
109 
110 
111 
112 
113 
114 
115a 
Day: 
D168 
D273 
D364 
D455 
D546 
D637 
D728 
D819 
D909 
D1000 
D1091 
D1182 
D1273 
D1454 
D1818 
Month: 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
39 
42 
48 
60 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study proceduresb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated physical exam 
X 
X 
X 
X 
X 
X 
X 
— 
— 
— 
X 
— 
— 
X 
— 
Risk reduction counseling 
X 
X 
X 
X 
X 
X 
X 
— 
— 
— 
X 
— 
— 
X 
— 
Behavioral risk, prophylactic ARV use, demographics questionnaire 
X 
X 
X 
X 
X 
X 
X 
— 
— 
— 
X 
— 
— 
X 
— 
Social impact assessment 
X 
X 
X 
X 
X 
X 
X 
— 
— 
— 
X 
— 
— 
X 
— 
Social impact assessment questionnaire 
— 
— 
X 
— 
X 
— 
X 
— 
— 
— 
X 
— 
— 
X 
— 
PEP/PrEP assessmentc 
X 
X 
X 
X 
X 
X 
X 
— 
— 
— 
X 
— 
— 
X 
— 
SAE assessmentd 
X 
X 
X 
X 
X 
X 
X 
— 
— 
— 
X 
— 
— 
X 
— 
Vital status & safety surveillance 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Xe f 
HIV infection assessmentg 
X 
X 
X 
X 
X 
X 
X 
— 
— 
— 
X 
— 
— 
X 
— 
Confirm HIV test results provided to participant 
X 
X 
X 
X 
X 
X 
X 
— 
— 
— 
X 
— 
— 
X 
— 
Local lab assessment 
 
 
 
 
 
 
 
— 
— 
— 
 
— 
— 
 
— 
GC/CT test by NAAT or cultureh 
X 
— 
X 
— 
X 
— 
X 
— 
— 
— 
X 
— 
— 
X 
— 
Syphilis test 
— 
— 
X 
— 
— 
— 
X 
— 
— 
— 
X 
— 
— 
X 
— 
 
Shaded visits not required. 
a Clinic visit not required (see Section 8.2.1). 
b For specimen collection requirements, see Appendix C. 
c If and only if participant reports having used ARVs for PrEP or PEP since the last clinic visit, draw blood sample for plasma as indicated in Appendix C. 
d Report SAEs only. Do not report Grade 1 through 4 AEs unless they are also SAEs (see Section 11.1. 
e Any participant reporting that they have become HIV-infected will be asked to come to the clinic so that HIV status can be confirmed. 
f Report SUSARs only. 
g Includes pre-test information and assessment of signs and symptoms of acute HIV infection. A subsequent follow-up contact is conducted to provide post-test counseling and to provide test results to 
the participant. 
h Urine test (see Appendix C). 

HVTN 505, Version 6.0 / July 21, 2014 
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Appendix F 
Schedule 7—Post-unblinding clinic procedures for HIV-infected participantsa 
 
Visit Number:
#.Xb 
201 
202 
203 
204 
Weeks after diagnosis:
2 
4 
8 
12 
24 
Study proceduresc 
 
 
 
 
 
Counseling on HIV-1 testing/diagnosis  
X 
X 
— 
Abbreviated physical exam 
X 
X 
X 
ART assessment 
X 
X 
X 
HIV-associated events 
X 
X 
X 
Transmission risk reduction counseling 
X 
X 
X 
Social impact assessment 
X 
X 
X 
Social impact assessment questionnaire 
— 
— 
X 
 
 
Shaded visits not required. 
a At completion of Schedule 7, HIV-infected participants may be invited to enroll in a separate follow-up protocol. 
b Visit #.X = interim visit for the purpose of drawing samples for confirmatory HIV testing 
c For specimen collection requirements, see Appendix D.