A Multicenter, Randomized, Double-blind, Placebo-controlled Phase 2b Efficacy Study of a Heterologous Prime/Boost Vaccine Regimen of Ad26.Mos4.HIV and Aluminum Phosphate-adjuvanted Clade C gp140 in Preventing HIV-1 Infection in Adult Women in Sub-Saharan Africa
Phase: PHASE2
Conditions: HIV-1
Sponsor: Janssen Vaccines & Prevention B.V.

PROTOCOL 
HVTN 705/VAC89220HPX2008 
A multicenter, randomized, double-blind, placebo-
controlled phase 2b efficacy study of a 
heterologous prime/boost vaccine regimen of 
Ad26.Mos4.HIV and aluminum phosphate-
adjuvanted Clade C gp140 in preventing HIV-1 
infection in women in sub-Saharan Africa 
DAIDS DOCUMENT ID 34567 
BB IND 016263 HELD BY JANSSEN VACCINES & PREVENTION B.V. 
CLINICAL TRIAL SPONSORED BY 
JANSSEN VACCINES & PREVENTION B.V. 
STUDY PRODUCTS PROVIDED BY 
JANSSEN VACCINES & PREVENTION B.V. 
Leiden, The Netherlands 
EDMS number: EDMS-ERI-128440423 
June 12, 2020 
FINAL 
HVTN 705/VAC89220HPX2008, Version 4.0 
NCT03060629

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Contents 
1 
Ethical considerations .............................................................................................. 5 
2 
IRB/EC review considerations ................................................................................. 7 
2.1 
Minimized risks to participants ..................................................................... 7 
2.2 
Reasonable risk/benefit balance .................................................................... 7 
2.3 
Equitable participant selection ....................................................................... 8 
2.4 
Appropriate informed consent ....................................................................... 8 
2.5 
Adequate safety monitoring ........................................................................... 8 
2.6 
Protect privacy/confidentiality ....................................................................... 8 
3 
Overview ................................................................................................................ 10 
3.1 
Protocol team ............................................................................................... 13 
4 
Background ............................................................................................................ 15 
4.1 
Rationale for trial concept ........................................................................... 15 
4.2 
Ad26.Mos4.HIV vaccine ............................................................................. 17 
4.3 
Clade C gp140 ............................................................................................. 19 
4.4 
Trial design .................................................................................................. 22 
4.5 
Combination prevention of HIV acquisition ............................................... 24 
4.6 
Plans for future product development and testing ....................................... 25 
4.7 
Nonclinical safety studies ............................................................................ 25 
4.8 
Nonclinical immunogenicity and efficacy studies ....................................... 27 
4.9 
Clinical studies ............................................................................................ 33 
4.10 Potential risks of study products and administration ................................... 40 
5 
Objectives and endpoints ....................................................................................... 42 
5.1 
Primary objectives and endpoints ................................................................ 42 
5.2 
Secondary objectives and endpoints ............................................................ 42 
5.3 
Exploratory objectives ................................................................................. 44 
6 
Statistical considerations ........................................................................................ 46 
6.1 
Study populations ........................................................................................ 46 
6.2 
Objectives .................................................................................................... 47 
6.3 
Primary analysis of vaccine efficacy ........................................................... 47 
6.4 
Accrual and sample size .............................................................................. 48 
6.5 
Trial monitoring ........................................................................................... 51 
6.6 
Assessment of PrEP use............................................................................... 57 
6.7 
Randomization of treatment assignments .................................................... 57 
6.8 
Blinding ....................................................................................................... 57 
6.9 
Statistical analysis ........................................................................................ 58 
7 
Selection and withdrawal of participants ............................................................... 62 
7.1 
Inclusion criteria .......................................................................................... 62 
7.2 
Exclusion criteria ......................................................................................... 63 
7.3 
Participant departure from vaccination schedule or withdrawal .................. 65 
8 
Study product preparation and administration ....................................................... 68 
8.1 
Vaccine regimen .......................................................................................... 68 
8.2 
Study product formulation ........................................................................... 68 
8.3 
Preparation of study products ...................................................................... 69 
8.4 
Administration ............................................................................................. 69 
8.5 
Acquisition of study products ...................................................................... 70 
8.6 
Pharmacy records......................................................................................... 70 
8.7 
Product quality complaint handling ............................................................. 70 

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8.8 
Final disposition of study products .............................................................. 70 
9 
Clinical procedures ................................................................................................ 71 
9.1 
Informed consent ......................................................................................... 71 
9.2 
Pre-enrollment procedures ........................................................................... 73 
9.3 
Enrollment and vaccination visits ................................................................ 74 
9.4 
Follow-up visits ........................................................................................... 75 
9.5 
Procedures for HIV-infected participants .................................................... 76 
9.6 
Mucosal sampling ........................................................................................ 76 
9.7 
HIV counseling and testing ......................................................................... 77 
9.8 
Pregnancy prevention assessment ................................................................ 78 
9.9 
Assessments of reactogenicity ..................................................................... 78 
9.10 Visit windows and missed visits .................................................................. 79 
9.11 Early termination visit ................................................................................. 80 
9.12 Pregnancy .................................................................................................... 80 
10 
HIV-1 infection assessment and clinical management .......................................... 81 
10.1 HIV-1 symptom assessment ........................................................................ 81 
10.2 HIV-1 screening test .................................................................................... 81 
10.3 HIV-1 testing postvaccination ..................................................................... 81 
10.4 Endpoint adjudication .................................................................................. 82 
10.5 HIV-1 infection during the study ................................................................. 82 
10.6 Medical care for participants who become HIV-1 infected ......................... 83 
11 
Laboratory .............................................................................................................. 84 
11.1 HVTN CRS laboratory procedures .............................................................. 84 
11.2 Total blood volume ...................................................................................... 84 
11.3 Immunogenicity assays ................................................................................ 84 
11.4 Endpoint assays: humoral ............................................................................ 84 
11.5 Endpoint assays: cellular ............................................................................. 85 
11.6 Innate immunity assays................................................................................ 86 
11.7 Mucosal studies ........................................................................................... 86 
11.8 Viral sequencing .......................................................................................... 86 
11.9 ARV detection ............................................................................................. 86 
11.10 Genotyping .................................................................................................. 87 
11.11 Lab assay algorithm ..................................................................................... 87 
11.12 Exploratory studies ...................................................................................... 87 
11.13 Other use of stored specimens ..................................................................... 87 
11.14 Biohazard containment ................................................................................ 88 
12 
Safety monitoring and safety review ..................................................................... 89 
12.1 Safety monitoring and oversight .................................................................. 89 
12.2 Safety reporting ........................................................................................... 90 
12.3 Safety pause and prompt PSRT AE review ................................................. 93 
12.4 Review of cumulative safety data ................................................................ 94 
12.5 Study termination......................................................................................... 95 
13 
Protocol conduct .................................................................................................... 96 
13.1 Protocol governance .................................................................................... 96 
13.2 Social impacts .............................................................................................. 97 
13.3 Compliance with NIH guidelines for research involving products containing 
recombinant DNA ....................................................................................... 98 
13.4 Emergency communication with study participants .................................... 98 
14 
Version history ....................................................................................................... 99 

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15 
Document references (other than literature citations) .......................................... 102 
16 
Acronyms and abbreviations ................................................................................ 104 
17 
Literature cited ..................................................................................................... 106 
Appendix A Sample informed consent form .................................................................. 112 
Appendix B Approved birth control methods (for sample informed consent form) ...... 131 
Appendix C Sample consent form for use of samples and information in other studies 132 
Appendix D Table of procedures (for sample informed consent form) ......................... 136 
Appendix E Schedule1: Laboratory procedures for HIV-uninfected participants ......... 138 
Appendix F Schedule 2: Laboratory procedures for HIV-infected participants ............ 141 
Appendix G Schedule 1: Procedures at HVTN CRS for HIV-uninfected participants .. 142 
Appendix H Schedule 2: Procedures at HVTN CRS for HIV-infected participants ...... 144 
Appendix I Adverse events of special interest .............................................................. 145 
Appendix J Injection Schedule for sample informed consent ....................................... 146 
 

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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. Janssen Vaccines is the Sponsor and a co-funder of the 
trial, together with NIH/NIAID/DAIDS and the Bill & Melinda Gates Foundation, and 
therefore is responsible for the oversight of the trial. The HIV Vaccine Trials Network 
(HVTN) will be primarily responsible for operational execution, as well as involved in 
other scientific and trial-related activities. Janssen fully endorses the way in which the 
HVTN addresses ethical concerns as listed below. The HVTN has addressed ethical 
concerns in the following ways: 
• 
All 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 and local in-country 
adaptations of GCP. Good Clinical Practice is an international ethical and scientific 
quality standard for designing, conducting, recording, and reporting studies that 
involve the participation of human subjects. Compliance with this standard and 
adherence to local adaptations of GCP provides public assurance that the rights, 
safety, and well-being of study participants are protected, consistent with the 
principles that originated in the Declaration of Helsinki, and that the study data are 
credible. 
• 
HVTN and Janssen scientists and operational staff incorporate the philosophies 
underlying major codes (UNAIDS, Helsinki, CIOMS) [1-3], declarations, and other 
guidance documents relevant to human subjects research into the design and conduct 
of HIV vaccine clinical trials. 
• 
HVTN and Janssen scientists and operational staff are committed to substantive 
community input—into the planning, conduct, and follow-up of its research—to help 
ensure that locally appropriate cultural and linguistic needs of study populations are 
met. Community Advisory Boards (CAB) are required by DAIDS and supported at 
all HVTN research sites to ensure community input, in accordance with Good 
Participatory Practices (GPP) and all local and national guidelines [4].  
• 
HVTN clinical trial staff counsel study participants routinely on how to reduce HIV 
risk. Participants who become HIV infected during the trial are provided referral into 
care and counseling on notifying their partners and about treatment for HIV infection 
according to local guidelines. Staff members will also counsel them about reducing 
their risk of transmitting HIV to others. 
• 
The HVTN requires that all international HVTN sites lacking national plans for 
providing antiretroviral therapy (ART) develop plans for the care and treatment of 
participants who acquire HIV infection during a trial. Each plan is developed in 
consultation with representatives of host countries, communities from which 
potential trial participants will be drawn, sponsors, and the HVTN. If a program for 
ART provision is not available at a site and ART is needed, a privately established 
fund will be used to pay for access to treatment to the fullest extent possible. 
• 
The HVTN and Janssen are committed to ensuring that all trial participants receive 
access to the highest standard of prevention, which may include, but is not limited to, 
risk reduction counseling, provision of male and female condoms, diagnostic testing 
and access to treatment for sexually transmitted infections (STIs), and appropriate 

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referrals to pre- and postexposure prophylaxis (PrEP and PEP) according to national 
and/or local guidelines. 
• 
The HVTN provides training so that all participating sites similarly ensure fair 
participant selection, protect the privacy of research participants, and obtain 
meaningful informed consent. During the study, participants will have their 
wellbeing monitored, and to the fullest extent possible, their privacy protected. 
Participants may withdraw from the study at any time. 
• 
Prior to implementation, HVTN trials are rigorously reviewed by scientists who are 
not involved in the conduct of the trials under consideration.  
• 
All trials are reviewed by local and national regulatory bodies and are conducted in 
compliance with all applicable national and local regulations. 
• 
The HVTN and Janssen design its research to minimize risk and maximize benefit to 
both study participants and their local communities. For example, the protocols 
provide enhancement of participants’ knowledge of HIV and HIV prevention, as well 
as counseling, guidance, and assistance with any social impacts that may result from 
research participation. HVTN protocols also include careful medical review of each 
research participant’s health conditions and reactions to study products while in the 
study.  
• 
HVTN research aims to benefit local communities by directly addressing the health 
and HIV prevention needs of those communities and by strengthening the capacity of 
the communities through training, support, shared knowledge, and equipment. 
Researchers involved in HVTN trials are able to conduct other critical research in 
their local research settings. 
• 
The HVTN and Janssen value the role of in-country Institutional Review Boards 
(IRBs), Ethics Committees (ECs), and other Regulatory Entities (REs) as custodians 
responsible for ensuring the ethical conduct of research in each setting. 

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2 
IRB/EC review considerations 
US Food and Drug Administration (FDA) and other US federal regulations require 
IRBs/ECs/REs to ensure that certain requirements are satisfied on initial and continuing 
review of research (Title 45, Code of Federal Regulations (CFR), Part 46.111(a) 1-7; 21 
CFR 56.111(a) 1-7). The following section highlights how this protocol addresses each of 
these research requirements. Each HVTN Investigator welcomes IRB/EC/RE questions 
or concerns regarding these research requirements. 
This trial is being conducted in sub-Saharan Africa, with funding from the US NIH 
among others. Due to this, the trial is subject to both US and local regulations and 
guidelines on the protection of human research subjects and ethical research conduct. 
These research regulations and guidelines are based on ethical principles of respect for 
persons, beneficence and nonmaleficence, and justice. Where there is a conflict in 
regulations or guidelines, the regulation or guideline providing the maximum protection 
of human research subjects will be followed. 
In compliance with international and local (as appropriate) Good Clinical Practice 
guidelines, each research location has a locally-based Principal Investigator (PI) who is 
qualified to conduct (and supervise the conduct of) the research. The investigators take 
responsibility for the conduct of the study and the control of the study products, including 
obtaining all appropriate regulatory and ethical reviews of the research.  
2.1 
Minimized risks to participants 
45 CFR 46.111 (a) 1 and 21 CFR 56.111 (a) 1: Risks to subjects are minimized. 
This protocol minimizes risks to participants by (a) correctly and promptly informing 
participants about risks so that they can join in partnership with the researcher in 
recognizing and reporting harms; (b) respecting local/national blood draw limits; (c) 
performing direct observation of participants postvaccination and collecting information 
regarding side effects for several days postvaccination; (d) having staff properly trained 
in administering study procedures that may cause physical harm or psychological 
distress, such as blood draws, vaccinations, HIV testing and counseling and HIV risk 
reduction counseling; (e) providing HIV risk reduction counseling and checking on 
contraception use (for women); and (f) providing safety monitoring. 
2.2 
Reasonable risk/benefit balance 
45 CFR 46.111(a) 2 and 21 CFR 56.111(a) 2: Risks to subjects are reasonable in 
relation to anticipated benefits, if any, to subjects, and the importance of the 
knowledge that may reasonably be expected to result. 
In all public health research, the risk-benefit ratio may be difficult to assess because the 
benefits to a healthy participant are not as apparent as they would be in treatment 
protocols, where a study participant may be ill and may have exhausted all conventional 
treatment options. However, this protocol is designed to minimize the risks to participants 
while maximizing the potential value of the knowledge it is designed to generate.  

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2.3 
Equitable participant selection  
45 CFR 46.111 (a) 3 and 21 CFR 56.111 (a) 3: Subject selection is equitable 
This protocol has specific inclusion and exclusion criteria for investigators to follow in 
admitting participants into the protocol. Participants are selected because of these criteria 
and not because of positions of vulnerability or privilege. Investigators are required to 
maintain screening and enrollment logs to document volunteers who screened into and 
out of the protocol and for what reasons. 
2.4 
Appropriate informed consent 
45 CFR 46.111 (a) 4 & 5 and 21 CFR 56.111 (a) 4 & 5: Informed consent is sought 
from each prospective subject or the subject’s legally authorized representative as 
required by 45 CFR 46.116 and 21 CFR Part 50; informed consent is appropriately 
documented as required by 45 CFR 46.117 and 21 CFR 50.27 
The protocol specifies that informed consent must be obtained before any study 
procedures are initiated and assessed throughout the trial (see Section 9.1). Each site is 
provided training in informed consent by the HVTN as part of its entering the HVTN. 
The HVTN requires a signed consent document for documentation, in addition to chart 
notes or a consent checklist. During a pandemic (such as COVID-19), alternative 
methods to written consent may be allowed (eg, verbal consent) as further detailed in the 
HVTN/VAC89220HPX2008 SSP. Prior to implementation, local IRB/ECs should be 
consulted to verify acceptability of alternative methods.  
2.5 
Adequate safety monitoring 
45 CFR 46.111 (a) 6 and 21 CFR 56.111 (a) 6: There is adequate provision for 
monitoring the data collected to ensure the safety of subjects. 
This protocol has extensive safety monitoring in place (see Section 12). Safety is 
monitored daily by HVTN Core, Janssen Study Responsible Physicians, and routinely by 
the HVTN 705/HPX2008 Protocol Safety Review Team (PSRT). In addition, an 
independent Data and Safety Monitoring Board (DSMB) periodically reviews study data, 
including unblinded study data if/when needed. 
2.6 
Protect privacy/confidentiality 
45 CFR 46.111 (a) 7 and 21 CFR 56.111 (a) 7: There are adequate provisions to 
protect the privacy of subjects and maintain the confidentiality of data. 
Privacy refers to an individual’s right to be free from unauthorized or unreasonable 
intrusion into his/her private life and the right to control access to individually 
identifiable information about him/her. The term “privacy” concerns research participants 
or potential research participants as individuals whereas the term “confidentiality” is used 
to refer to the treatment of information about those individuals. This protocol respects the 
privacy of participants by informing them about who will have access to their personal 
information and study data (see Appendix A). The privacy of participants is protected by 

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assigning unique identifiers in place of the participant’s name on study data and 
specimens. In addition, each staff member at each study site in this protocol signs an 
Agreement on Confidentiality and Use of Data and Specimens with the HVTN and each 
study site participating in the protocol is required to have a standard operating procedure 
on how the staff members will protect the confidentiality of study participants. 

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3 
Overview 
Title  
A multicenter, randomized, double-blind, placebo-controlled phase 2b efficacy study of a 
heterologous prime/boost vaccine regimen of Ad26.Mos4.HIV and aluminum phosphate-
adjuvanted Clade C gp140 in preventing HIV-1 infection in women in sub-Saharan 
Africa 
Primary objectives 
Primary objective 1:  
To evaluate the preventive vaccine efficacy (VE) of a heterologous prime/boost regimen 
utilizing Ad26.Mos4.HIV and aluminum-phosphate adjuvanted Clade C gp140 for the 
prevention of HIV infection in HIV-seronegative women residing in sub-Saharan Africa 
from confirmed HIV-1 infections diagnosed between the Month 7 and Month 24 visits 
Primary objective 2:  
To evaluate the safety and tolerability of a heterologous prime/boost regimen utilizing 
Ad26.Mos4.HIV and aluminum-phosphate adjuvanted Clade C gp140 for the prevention 
of HIV infection in HIV-seronegative women residing in sub-Saharan Africa  
Study products and routes of administration 
• 
Ad26.Mos4.HIV: a tetravalent adenovirus 26 vaccine containing a premixed ratio 
(1:1:1:1) of Ad26.Mos1.Gag-Pol, Ad26.Mos2.Gag-Pol, Ad26.Mos1.Env, and 
Ad26.Mos2S.Env. A dose of 5 x 1010 virus particles (vp) will be administered by 
intramuscular (IM) injection into the deltoid. 
• 
Clade C gp140: a trimeric recombinant HIV-1 Env gp140 of clade C. A dose of 250 
mcg mixed with aluminum phosphate adjuvant (0.425 mg) will be administered by 
IM injection into the deltoid. 
• 
Placebo control for Ad26.Mos4.HIV: Sodium Chloride for Injection USP, 0.9% 
administered by IM injection into the deltoid. 
• 
Placebo control for Clade C gp140: Sodium Chloride for Injection USP, 0.9% 
administered by IM injection into the deltoid. 

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Table 3-1 Schema 
Group 
N 
Month 0 
Month 3 
Month 6 
Month 12 
1 
1300 
Ad26.Mos4.HIV 
Ad26.Mos4.HIV 
Ad26.Mos4.HIV 
+ 
Clade C gp140 
(250 mcg + 
adjuvant)a 
Ad26.Mos4.HIV 
+ 
Clade C gp140 
(250 mcg + 
adjuvant)a 
2 
1300 
Placebo 
Placebo 
Placebo 
+ 
Placebo 
Placebo 
+ 
Placebo 
a 250 mcg refers to total protein content (Clade C gp140). Sterile aluminum phosphate suspension will be used as 
adjuvant. Aluminum content will be 0.425 mg/0 5 mL dose. 
Participants 
2600 healthy, HIV-1–uninfected women aged 18 to 35 years; 1300 vaccinees, 1300 
placebo control recipients 
Design 
Multinational randomized, placebo-controlled, double-blind trial 
Duration per participant 
Minimum 24, maximum 57 months per participant (including 6 months follow-up should 
a participant be diagnosed with HIV infection at their last scheduled study visit). All 
HIV-1–uninfected study participants will be followed for at least 24 months following 
enrollment unless an interim monitoring boundary is reached. Stage 1 is the calendar time 
since trial start until the last enrolled participant reaches the Month 24 visit. Stage 2 is the 
calendar time since the last enrolled participant reached the Month 24 visit until the last 
enrolled participant reaches the Month 36 visit. If the vaccine efficacy analysis in Stage 1 
supports continuation of the study through Stage 2, all HIV-1–uninfected study 
participants will be followed for at least 36 months of scheduled clinic visits. Participants 
who completed their Month 36 visit will be followed further with scheduled visits every 3 
months, until the end of the study (around July 2022, when the last Month 36 visit is 
completed). Participants who become HIV-1–infected during the study will be followed 
for approximately 6 months after confirmation of diagnosis. 
Estimated total study duration 
About 57 months (includes enrollment and follow-up). 
Regulatory sponsor 
Janssen Vaccines & Prevention B.V. (Leiden, The Netherlands) 
Study product providers 
• 
Ad26.Mos4.HIV: Janssen Vaccines & Prevention B.V. (Leiden, The Netherlands) 
• 
Clade C gp140 and aluminum phosphate: Janssen Vaccines & Prevention B.V. 
(Leiden, The Netherlands) 

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HVTN Core operations 
HVTN Vaccine Leadership Group/Core Operations Center, Fred Hutchinson Cancer 
Research Center (FHCRC) (Seattle, Washington, USA) 
Janssen Operations 
Janssen Pharmaceutica NV, Global Clinical Development Operations (Beerse, Belgium) 
Statistical and data management center (SDMC) 
Statistical Center for HIV/AIDS Research and Prevention (SCHARP), FHCRC (Seattle, 
Washington, USA) 
HIV diagnostic laboratory 
HIV Sero-Molecular Laboratory, National Institute for Communicable Diseases (HSML-
NICD) (Johannesburg, South Africa) 
University of Washington Virology Specialty Laboratory (UW-VSL) (Seattle, 
Washington, USA) 
Endpoint assay laboratories 
• 
South Africa Immunology Laboratory and National Institute for Communicable 
Diseases (SAIL-NICD) (Johannesburg, South Africa) 
• 
HIV Sero-Molecular Laboratory, National Institute for Communicable Diseases 
(HSML-NICD) (Johannesburg, South Africa) 
• 
Cape Town HVTN Immunology Laboratory (CHIL) (Cape Town, South Africa) 
• 
Duke University Medical Center (Durham, North Carolina, USA) 
• 
FHCRC/University of Washington (Seattle, Washington, USA)  
• 
Janssen Vaccines & Prevention B.V. (Leiden, The Netherlands) 
• 
University of Cape Town (UCT) (Cape Town, South Africa) 
• 
University of Colorado Denver (UC Denver) (Aurora, Colorado, USA) 
Study sites 
HVTN Clinical Research Sites (HVTN CRSs), in Southern Africa where clade C 
predominates, to be specified in the Site Announcement Memo 
Safety monitoring 
HVTN 705/HPX2008 PSRT; NIAID Data Safety Monitoring Board (DSMB) 

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3.1 
Protocol team 
Protocol leadership 
Chair 
 Chris 
Hani Baragwanath Hospital, Soweto; 
, 
South African Medical Research Council 
 
 
Statisticians 
 
SCHARP, FHCRC 
 
 
 
SCHARP, FHCRC 
 
 
 
Janssen Vaccines & 
Prevention, B
 
 
Cochairs 
 
Aurum Institute 
 
 
Medical 
officers 
 
DAIDS, NIAID 
 
 
 
DAIDS, NIAID 
 
 
 
 
San Francisco Department of Public Health 
 
 
 
 
Janssen Research & Development 
Janssen Vaccines & Prevention, B.V.  
 
 
Laboratory 
leads 
 
HVTN Laboratory 
Program 
 
 
 
HVTN Laboratory  
 
 
 
Janssen Vaccines & 
Prevention, B.V.  
  
 
HVTN 
Protocol 
Team 
leader 
and Core 
medical 
monitor 
 
HVTN Core, FHCRC 
 
 
Janssen 
Protocol 
Team 
Leader and 
Study 
Responsible 
Physician 
 
Janssen Research & 
Development 
Janssen Vaccines & 
Prevention, B.V.  
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Other contributors to the protocol 
Janssen Medical 
Safety Officer 
 
Janssen Vaccines & 
Prevention, B.V. 
Senior Clinical Data 
managers 
 
SCHARP, FHCRC 
 
Janssen Vaccines & 
Prevention, B.V.  
Laboratory center 
representatives 
 
 
HVTN Laboratory 
Program, FHCRC 
Clinical trials manager 
 
HVTN Core, FHCRC 
 
Janssen Vaccines & 
Prevention, B.V. 
Regulatory affairs 
 
 
HVTN Core, FHCRC 
 
Janssen Vaccines & 
Prevention, B.V. 
Clinical safety 
specialist  
 
HVTN Core, FHCRC 
Community 
Advisory Board 
(CAB) members 
 
Seke South 
 
CAPRISA 
Clinic coordinators 
 
Aurum Institute 
 
Perinatal HIV 
Research Unit 
HVTN Regional 
medical liaison 
Southern Africa 
 
HVTN Core, FHCRC 
Protocol development 
managers 
 
HVTN Core, FHCRC 
Statistical research 
associates 
 
SCHARP, FHCRC 
 
Janssen Vaccines & 
Prevention, B.V 
Laboratory 
Representative 
 
HVTN, FHCRC 
 
Janssen Vaccines & 
Prevention, B.V. 
IPCAVD 
representative  
 
Harvard Medical 
School; Ragon Institute  
Community 
engagement unit 
representative 
 
HVTN Core, FHCRC 
 
 
Community 
educators/recruiters 
 
Seke South 
 
CAPRISA 
 
 
Technical editor 
 
HVTN Core, FHCRC 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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4 
Background 
4.1 
Rationale for trial concept 
A safe and effective HIV vaccine is presently the elusive cornerstone of HIV prevention 
despite advances in other preventive measures [5]. Optimally, researchers believe that 
both a robust CD4+ and CD8+ T-cell response and a potent humoral response with 
multiple effector functions should be induced by a vaccine. A successful global 
prophylactic HIV vaccine will likely need to protect against the diverse strains and clades 
of HIV-1 as present in different geographic regions. Current strategies are targeting clade 
specific vaccine approaches, aimed at specific populations. We aim to develop a single 
global vaccine which offers important scientific and logistic advantages over multiple 
clade-specific vaccines. Optimizing the magnitude and breadth of epitope coverage is 
thought to be key to development of a successful antibody and T-cell based preventive 
HIV vaccine.  
Strategies to accomplish this include the use of vaccines containing immunogens from a 
number of prevalent clades and/or using mosaic sequences, ie, proteins assembled from 
natural sequences of the different clades [6]. Mosaic antigens could potentially increase 
the breadth of humoral and cellular immune responses for improved immunologic 
coverage of diverse clades. This approach has been demonstrated in nonhuman primates 
showing that mosaic antigens elicit increased cellular immune breadth and depth, and 
augmented antibody responses, compared with naturally occurring sequences and 
consensus or conserved antigens [7-9]. This will be the first time to evaluate the efficacy 
of mosaic HIV-1 antigens and their impact on protection.  
There is a paucity of vaccine regimens that have advanced into late-stage clinical 
development. Only 4 vaccine strategies have proceeded to efficacy studies, and only 1 
has demonstrated modest efficacy [10-15]. The RV144 trial in Thailand demonstrated 
that a heterologous prime-boost regimen using a canarypox vector ALVAC (vCP1521) 
expressing env, gag, and pol genes with a boost of a bivalent gp120 env glycoprotein, 
AIDSVAX B/E could provide protection against acquisition. Recently, study HVTN 702 
or Uhambo, a Phase 2b/3 evaluating the efficacy of an investigational heterologous 
vaccine regimen (ie, ALVAC-HIV [vCP2438] + Bivalent Subtype C gp120/MF59) based 
on the regimen evaluated in the RV144 clinical study but adapted to HIV-1 Clade C 
which is most common in southern Africa, was stopped early because the pre-established 
criteria for non-efficacy had been met [56, 57]. 
Janssen Vaccines and its partners are currently evaluating a novel strategy that involves 
the use of adenovirus serotype 26 (Ad26) vectors as a prime, and a combination of Ad26 
vectors and adjuvanted recombinant glycoproteins as a boost. Although the clinical 
studies with Ad5 failed to demonstrate protection against HIV infection, the rationale to 
advance clinical development of Ad26 vector-based vaccines for HIV-1 is based on data 
[16] showing that (1) Ad26 is biologically substantially different than Ad5; (2) Ad26-
based vaccines afford superior protective efficacy compared with Ad5-based vaccines 
against stringent SIVmac251 challenges in rhesus monkeys; and (3) Ad26 did not 
increase the number or activation status of total or vector-specific CD4+ T lymphocytes 
at mucosal surfaces in humans in a randomized, double-blind, placebo-controlled clinical 
study (IPCAVD 003) [44]. 

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The following candidate HIV vaccine components are being evaluated in clinical studies: 
Ad26.Mos.HIV (a trivalent Ad26), Modified Vaccinia Ankara (MVA)-Mosaic and Clade 
C glycoprotein 140 (Clade C gp140). Several prime boost vaccine regimens, either 
heterologous or homologous, are currently being studied (the APPROACH study, HIV-
V-A004) in Southern and East Africa, Thailand, and the US. In addition, Janssen 
Vaccines has optimized the design of the Ad26 component by adding a fourth vector, 
encoding a second mosaic Env antigen (Ad26.Mos2S.Env), to the trimeric 
Ad26.Mos.HIV (generating the tetravalent Ad26.Mos4.HIV) that demonstrated increased 
breadth of immune response in preclinical studies. This tetravalent Ad26.Mos4.HIV is 
currently also being evaluated in a clinical study. 
The vaccine components chosen for this efficacy study are Ad26.Mos4.HIV and 
aluminum phosphate-adjuvanted Clade C gp140 (Table 4-1). A heterologous prime-boost 
regimen will be administered, consisting of an Ad26 mosaic component, followed by the 
co-administration of the Ad26 mosaic with a Clade C gp140, adjuvanted with aluminum 
phosphate. The immune response is expected to be active cross clades as animal studies 
have shown that there is cross clade immunogenicity after administration of Clade C 
gp140 as a boost in animals primed with the Ad26 mosaic component. Data from this 
study will guide future development of the vaccine. The study will enroll female 
participants from populations at high risk of acquiring HIV infection in southern African 
settings with overall moderate to high HIV incidence, predominantly with clade C. 
Women in these settings have among the highest HIV infection rates globally, making 
them one of the populations in greatest need of effective prevention interventions. Should 
this trial demonstrate efficacy of this regimen, it is likely that additional efficacy studies 
will include men in these same settings. Other vaccine trials have adopted this staged 
strategy based on gender (eg, HPV). 
In an international adenovirus seroprevalence study [45], Ad5 seroprevalence was 87.9-
89.5% in several cohorts of adults in South Africa (N=1,551). The majority of individuals 
also exhibited moderate Ad5 nAb titers >200 (61.1-63.5%), and a substantial fraction had 
high Ad5 nAb titers >1000 (25.1-27.9%). In contrast, Ad26 seroprevalence was lower at 
43.1-53.2%. Fewer individuals demonstrated moderate Ad26 nAb titers >200 (5.4-7.6%), 
and only rare individuals had high Ad26 nAb titers >1000 (0.0-0.9%). In the 
IPCAVD004 clinical trial (N=217) [41], we observed that the baseline Ad26 nAb titers 
observed in South and East Africa did not impact the humoral or cellular immune 
responses elicited by the prototype Ad26.ENVA.01 vaccine. Therefore, participants will 
be enrolled regardless of baseline Ad26 positivity. 
Table 4-1 Vaccine Components 
Vaccine  
JNJ Number 
Dose/IM Injection 
Ad26.Mos4.HIV: 
NA 
5x1010 vp (1:1:1:1) 
 Ad26.Mos1.Gag-Pol* 
JNJ-55471494-AAA 
- 
 Ad26.Mos2.Gag-Pol* 
JNJ-55471520-AAA 
- 
 Ad26.Mos1.Env* 
JNJ-55471468-AAA 
- 
 Ad26.Mos2S.Env 
JNJ-64219324-AAA 
- 
Clade C gp140/aluminum 
phosphate 
JNJ-55471585-AAA 
250 mcg Clade C gp140, mixed 
with aluminum phosphate 
adjuvant (0.425 mg aluminum) 
Placebo 
NA 
0.9% saline 
gp, glycoprotein; IM, intramuscular; NA, not applicable; vp, virus particles 
* These are the components of the trivalent Ad26.Mos.HIV 

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4.2 
Ad26.Mos4.HIV vaccine 
Ad26.Mos4.HIV is a tetravalent recombinant, replication-incompetent Adenovirus 26-
based vaccine. Replication-incompetent Ad26.Mos4.HIV vectors are derived from wild-
type human adenovirus 26. Wild-type human adenoviruses are common pathogens and 
endemic to all countries. Adenoviral infections in humans are usually mild and self-
limiting. Ad26.Mos4.HIV vectors do not replicate in unmodified human cells and do not 
produce any toxins. Therefore, no adverse effects would be expected for healthy 
individuals who inadvertently come into contact with it. 
The Ad26 vectors have been made replication-incompetent by deletion of the E1 region 
of the adenovirus type 26 genome, which is required for replication. A large portion of 
the E3 region, which promotes persistence within the host cell, has also been removed to 
create sufficient space in the viral genome for insertion of foreign antigens. For 
productive infection and replication during manufacturing the E1 defect is supplemented 
by engineered E1 (from Ad5) complementing cell lines (HEK293, PER.C6®). In 
unmodified human cells the Ad26.Mos4.HIV vectors cannot replicate. The absence of E1 
and presence of the transgene expression cassette is confirmed by identity PCR and 
sequencing at several stages of vector production. Additionally, replication-incompetence 
is confirmed by a functional test for replication competent Adenovirus (RCA). The 
absence of any DNA sequence overlap between the Ad26 vector and the PER.C6® cell 
line prevents the formation of RCA.  
Ad26.Mos4.HIV contains the following 4 active pharmaceutical ingredients (APIs) in a 
1:1:1:1virus particle (vp) ratio: 
• 
Ad26.Mos1.Env: recombinant, replication incompetent adenovirus serotype 26 
expressing a mosaic 1 HIV-1 Env protein, manufactured in PER.C6 Cells. 
• 
Ad26.Mos2S.Env: recombinant, replication incompetent adenovirus serotype 26 
expressing a mosaic 2S HIV-1 Env protein, manufactured in PER.C6 Cells. 
• 
Ad26.Mos1.Gag-Pol: recombinant, replication incompetent adenovirus serotype 26 
expressing mosaic 1 HIV-1 Gag and Pol proteins, manufactured in PER.C6 Cells.  
• 
Ad26.Mos2.Gag-Pol: recombinant, replication incompetent adenovirus serotype 26 
expressing mosaic 2 HIV-1 Gag and Pol proteins, manufactured in PER.C6 Cells.  
4.2.1 
Construct 
Ad26.Mos4.HIV is comprised of 4 replication-incompetent, Early region 1/Early region 3 
(E1/E3)-deleted Adenovirus 26 vectors engineered to express mosaic Gag-Pol and Env 
sequences. This set of mosaic proteins was assembled in silico from fragments derived 
from natural sequences via a computational optimization method [6]. The dataset used for 
generating the fragments was restricted to include only full length proteins and only 1 
sequence per patient. Ad26.Mos4.HIV consists of Ad26.Mos1.Gag-Pol, 
Ad26.Mos2.Gag-Pol, Ad26.Mos1.Env, and Ad26.Mos2S.Env. A schematic 
representation of these 4 vectors of Ad26.Mos4.HIV is shown in Figure 4-1. 

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Figure 4-1 Schematic representation of the 4 vectors comprising Ad26.Mos4.HIV 
 
4.2.2 
Formulation characteristics 
Ad26. Mos4.HIV will be provided in single dose vials for IM injection at a concentration 
of 1 × 1011 vp/mL. The dose to be administered is 5 × 1010 vp (per 0.5 mL dose). The 
quantitative composition of Ad26.Mos4.HIV Drug Product (DP) is shown in Table 4-2. 
Table 4-2 Targeted composition and concentration of Ad26.Mos4.HIV DP, pH 6.2 
Ingredient 
Grade 
Concentration 
Function 
Ad26.Mos1.Gag-Pol 
NA 
2.5  1010 vp/mL 
Active 
Ad26.Mos2.Gag-Pol 
NA 
2.5  1010 vp/mL 
Active 
Ad26.Mos1.Env 
NA 
2.5  1010 vp/mL 
Active 
Ad26.Mos2S.Env 
NA 
2.5  1010 vp/mL 
Active 
NaCl 
Ph. Eur. / USP 
75 mM 
Tonicity agent 
Citric acid monohydrate  
Ph. Eur. / USP 
15 mM 
Buffer 
PS-80 
Ph. Eur. 
0.03% w/w 
Stabilizer 
HBCD 
Ph. Eur. / USP 
5 % w/w 
Stabilizer 
Ethanol 
Ph. Eur. / USP 
0.4% w/w 
Stabilizer 
NaOH 
Ph. Eur. / USP 
q.s. 
pH modifier 
WFI 
Ph. Eur. 
q.s. 
Solvent 
PS-80, Polysorbate 80; HBCD, 2-hydroxypropyl--cyclodextrin; WFI, Water for Injection; USP, 
United States Pharmacopeia; q.s., sufficient quantity 
4.2.3 
Manufacturing 
Ad26.Mos4.HIV active ingredients are produced in PER.C6 cells by Janssen Vaccines & 
Prevention B.V., Leiden, The Netherlands. The PER.C6 cells have been qualified in line 
with current US Guidance for Industry, International Conference on Harmonization 
(ICH) guidelines and the European Pharmacopeia. Formulation and filling of the 
Ad26.Mos4.HIV DP is performed at a qualified current Good Manufacturing Practice 

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(cGMP) fill and finish contract manufacturer. Manufacturing and release are performed 
according to cGMP and the facilities involved are in possession of the relevant licenses. 
4.3 
Clade C gp140 
4.3.1 
Construct 
Clade C gp140 drug substance (DS) = trimeric, recombinant HIV-1 Env gp140 of clade 
C, produced on a PER.C6 cell line. Aluminum phosphate suspension is used as adjuvant 
(JNJ-55471585-AAA: Clade C gp140 + aluminum phosphate adjuvant). A schematic 
representation of the foldon (Fd)-stabilized trimeric gp140 is shown in Figure 4-2. 
The clade C antigen is derived from a clade C isolate CZA97012 [17]. 
 
 
Figure 4-2 Schematic of the Fd-stabilized HIV-1 trimeric gp140. gp140-Fd represents the 
uncleaved ectodomain of gp160 with a T4-fibritin foldon trimerization tag. Segments of gp120 and 
gp41 are designated as follows: C1-C5, conserved regions 1-5; V1-V5, variable regions 1-5; F, 
fusion peptide; HR1, heptad repeat 1; C-C loop, the immunodominant loop with a conserved 
disulfide bond; HR2, heptad repeat 2; MPER, membrane proximal external region; TM., 
transmembrane; CT, cytoplasmic tail; Fd, foldon trimerization motif.  
4.3.2 
Formulation characteristics 
Clade C gp140 and aluminum phosphate adjuvant will either be co-formulated or 
supplied in separate vials. 
4.3.2.1 
Co-formulation of Clade C gp140 and adjuvant 
The phase 2 DP is being developed as a co-formulated sterile liquid, adjuvanted protein 
with 250 mcg Clade C gp140 dosage strength, with 425 mcg aluminum phosphate 

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adjuvant at a fill volume of 0.7mL (extractable volume ≥ 0.5 mL) in a single vial. The 
target composition and concentration of the co-formulation is shown in Table 4-3. 
Table 4-3 Target composition and concentration of the co- formulation of Clade C gp140 and 
Adjuvant 
Component 
Grade 
Clade C gp140, 250mcg 
Aluminum Phosphate, 425 
mcg 
Function 
Clade C gp140 
N/A 
0.5 mg/mL 
Active 
Aluminum 
phosphate Adjuvant 
N/A 
0.85 mg Al/mL 
Adjuvant 
L-Histidine 
USP/EP/JP 
1.15 mg/mL 
Buffer 
L-Histidine 
monohydrochloride 
monohydrate 
EP/JP 
0.54 mg/mL 
Buffer 
Polysorbate 20 
NF/EP/JP 
0.02% w/v 
Surfactant 
Sorbitol 
NF/EP/JP 
5% w/v 
Stabilizer/Tonicifier 
Volume of WFI 
EP 
q.s. 
Solvent 
 
N/A, not applicable; EP, European Pharmacopoeia; NF, National Formulary; USP, United States 
Pharmacopeia; JP, Japan Pharmacopoeia; WFI, water for injection; q.s., sufficient quantity 
4.3.2.2 
Clade C gp140 and separate aluminum phosphate adjuvant drug product 
Clade C gp140 and aluminum phosphate adjuvant drug product will be supplied in 
separate vials, to be mixed at the site pharmacy prior to administration, with a resulting 
250 mcg Clade C gp140 dosage strength and a 425 mcg aluminum phosphate adjuvant 
dosage strength, with a nominal fill volume of 0.5 mL. The target composition and 
concentration of Clade C gp140 drug product (HEPES buffer) and Clade C gp140 drug 
product (L-Histidine buffer) is shown in Table 4-4 and Table 4-5, respectively. The target 
composition and concentration of the aluminum phosphate adjuvant drug product is 
shown in Table 4-6. 
Table 4-4 Target composition and concentration of Clade C gp140 Drug Product (HEPES 
Buffer) 
Component 
Grade 
Clade C 
gp140 250mcg 
Function 
Clade C gp140 
N/A 
1.0 mg/mL 
Active 
NaCl 
USP/EP 
90 mM 
Tonicity agent 
HEPES 
Exipient grade 
20 mM 
Buffer 
Polysorbate 80 
EP 
0.02% w/v 
Surfactant 
Sucrose 
NF/EP 
4% w/v 
Stabilizer 
Volume of WFI 
USP/EP 
q.s. 
Solvent 
N/A, not applicable; EP, European Pharmacopoeia; NF, National Formulary; USP, United States 
Pharmacopeia; WFI, water for injection; q.s., sufficient quantity 
 

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Table 4-5 Targeted composition and concentration of Clade C gp140 Drug Product (L-
Histidine buffer) 
Component 
Grade 
Clade C gp140 250 mcg 
Function 
Clade C gp140 
N/A 
1.0 mg/mL 
Active 
L-Histidine 
USP/EP/JP 
1.15 mg/mL 
Buffer 
L-Histidine 
monohydrochloride 
monohydrate 
EP/JP 
0.54 mg/mL 
Buffer 
Sorbitol  
NF/EP/JP 
50 mg/mL 
Stabilizer/ 
Tonicifier 
Polysorbate 20 
NF/EP/JP 
0.02% w/v 
Surfactant 
Volume of WFI 
USP/EP 
q.s. 
Solvent 
N/A, not applicable; EP, European Pharmacopoeia; NF, National Formulary; USP, United States 
Pharmacopeia; JP, Japan Pharmacopeia; WFI, water for injection; q.s., sufficient quantity 
 
Table 4-6 Target composition and concentration of Aluminum Phosphate Adjuvant 
Component 
Grade 
Aluminum 
phosphate, 
425 mcg 
Function 
Aluminum 
phosphate 
adjuvant 
N/A 
1.7 mg Al/mL 
Adjuvant 
NaCl 
USP/EP 
90 mM 
Tonicity agent 
HEPES 
Exipient grade 
20 mM 
Buffer 
Polysorbate 80 
EP 
0.02% w/v 
Surfactant 
Sucrose 
NF/EP 
4% w/v 
Stabilizer 
Volume of WFI 
USP/EP 
q.s. 
Solvent 
N/A, not applicable; EP, European Pharmacopoeia; NF, National Formulary; USP, United States 
Pharmacopeia; WFI, water for injection; q.s., sufficient quantity 
4.3.3 
Manufacturing 
4.3.3.1 
Co-formulation of Clade C gp140 and adjuvant 
Clade C gp140 DS is produced in PER.C6 cells by Janssen Biotech, Inc. at the contract 
manufacturing organization Cook Pharmica LLC, Bloomington, IN, USA (or 
manufactured at another qualified manufacturing site). The Clade C gp140 co-formulated 
DP is manufactured at Janssen Vaccine Corporation, South Korea (or manufactured at 
another qualified manufacturing site). All manufacturing is performed according to 
cGMP requirements and the facilities are in possession of the relevant licenses. 
4.3.3.2 
Clade C gp140 and separate aluminum phosphate adjuvant drug product 
Clade C gp140 DS (HEPES buffer) is produced at Patheon Biologics (formerly Gallus 
Biopharmaceuticals, LLC) Princeton, NJ, USA (or manufactured at another qualified 
manufacturing site). For Clade C gp140 the DP manufacturing site is Patheon Biologics 
(formerly Gallus Biopharmaceuticals, LLC) Princeton, NJ, USA (or manufactured at 
another qualified manufacturing site).  
Clade C gp140 DS (L-Histidine buffer) is produced at Cook Pharmica LLC, 
Bloomington, US. For Clade C gp140 (L-Histidine buffer) the DP manufacturing site is 

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Patheon Ferentino, Ferentino, Italy (or manufactured at another qualified manufacturing 
site). 
For aluminum phosphate adjuvant the DP manufacturing site is IDT Biologika 
Corporation (formerly Aeras) Rockville, MD, USA (or manufactured at another qualified 
manufacturing site). 
4.3.4 
Aluminum phosphate adjuvant 
4.3.4.1 
Co-formulation of Clade C gp140 and adjuvant 
For the co-formulated product, the aluminum phosphate adjuvant material is sourced 
from Pfizer Ireland Pharmaceuticals, Ireland. The DS will be thawed, pooled and mixed. 
The adjuvant will be mixed with sterile filtered formulation buffer. The drug substance is 
filtered through a bioburden reduction filter and a 0.22 m sterilizing filter prior to 
mixing with adjuvant. The mixed adjuvant and Clade C gp140 protein will be aseptically 
filled into Type I glass vials. The glass vials are fitted with a grey butyl rubber FluroTec 
Film Coated stopper. 
4.3.4.2 
Clade C gp140 and separate aluminum phosphate adjuvant drug product 
For the Clade C gp140 with separate aluminum phosphate adjuvant, the aluminum 
phosphate adjuvant material is sourced from BRENNTAG BIOSECTOR A/S, Denmark 
(or manufactured at another qualified manufacturing site). Formulation buffer is mixed 
aseptically with aluminum phosphate adjuvant. Vials are filled, stoppered, and capped at 
the manufacturing site IDT Biologika Corporation (formerly Aeras) Rockville, MD, USA 
(or manufactured at another qualified manufacturing site). 
4.4 
Trial design 
4.4.1 
Dose (amount and number) 
Ad26.Mos4.HIV will be administered at a dose of 5 x 1010 vp by IM injection into the 
deltoid. This dose has been chosen based on 3 previous phase 1 studies of the related 
Ad26.ENVA.01 vaccine (see Section 4.9). In these studies Ad26.ENVA.01, at doses over 
the range of 109 to 1011 vp, induced Env-specific humoral and cell-mediated responses 
when given up to 3 times to more than 200 healthy participants in the United States and 
Africa. The dose of 5 x 1010 vp was found to provide the optimal balance of 
immunogenicity and reactogenicity. The same dose has been used in the NHP 
13-19/15-06 study (Section 4.8.4) and is also being used in the ongoing clinical Phase 
1/2a studies HIV-V-A004 (Section 4.9.2.2) and HPX2004 (Section 4.9.2.4). 
Based on the final results of HIV-V-A003 and the results of the primary analysis (Week 
28) of HIV-V-A004, a dose of 250 mcg Clade C gp140, adjuvanted with aluminum 
phosphate, has been selected for use in the current study (see Section 4.9).  
4.4.2 
Schedule 
The choice of schedule is based on observations from a variety of pre-clinical and clinical 
studies using different adenovirus vectors with a variety of inserts, as well as 
immunogenicity generated in RV144 (which demonstrated the probable benefit of a late 

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boost) (see Sections 4.8 and 4.9). Given that RV144 demonstrated modest efficacy, we 
have built on the vector prime, protein boost concept, choosing a similar schedule but 
adding a late boost in an attempt to compensate for the waning effect of RV144 after the 
first year. 
This schedule was used in NHP study 13-19/15-06, which demonstrated encouraging 
immunogenicity and protection against challenge (see Section 4.8.4). 
4.4.3 
Prime-boost regimen 
The prime-boost strategy consists of Ad26.Mos4.HIV primes with Ad26.Mos4.HIV plus 
Clade C gp140 boosts.  
In rhesus macaque SIV challenge models, heterologous boost immunizations with a SIV 
model vaccine potently expanded cellular and humoral immune parameters that 
correlated with protection against viral challenge [18]. These results were confirmed for 
the clinically applied mosaic/recombinant protein HIV vaccine concept in rhesus 
macaque SHIV challenge models [19,20]. 
The concept of priming with 1 HIV vaccine component followed by boosting with 
another heterologous HIV vaccine component emerged in the 1990s as a strategy to 
enhance vaccine immunogenicity and, potentially, vaccine efficacy. While Env 
glycoproteins elicit strong humoral responses, they have not been associated with potent 
cellular immunity or efficacy when administered alone as in the first efficacy trials of 
AIDSVAX [11,14]. On the other hand, although viral vector constructs, including Ad26, 
often elicit both antibody and cell-mediated responses, it was observed that the 
magnitude of antibody responses could be increased significantly by subsequent 
administration of Env glycoproteins. In addition, prime-boost vaccine regimens were 
explored as means of increasing the breadth of HIV strains to which vaccination might 
induce responses. Response breadth and the capacity to induce both potent cytotoxic T 
lymphocyte and potent antibody responses is a combination believed to be important in 
conferring protective immunity against HIV infection [21,22]. These desirable immune 
response characteristics were often observed in early phase clinical trials using a variety 
of prime-boost vaccine regimens [22-32]. 
The use of a prime-boost regimen is currently being evaluated in the clinical studies HIV-
V-A004 (Section 4.9.2.2) and HPX2004 (Section 4.9.2.4). 
4.4.4 
Choice of control 
The placebo control for Ad26.Mos4.HIV and Clade C gp140 is sodium chloride for 
injection, 0.9%. 
4.4.5 
HIV-1 incidence estimates from previous clinical trials among at-risk study 
populations in Southern Africa  
The high rates of HIV acquisition amongst young women in Southern Africa highlight 
the need for biomedical interventions that are female controlled. Recent longitudinal 
studies evaluating various interventions indicate HIV incidence rates of between 4-11% 
and are summarized below: 
Vaccine efficacy studies 

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• 
The HVTN 503 (Phambili) HIV vaccine study (2007), in which HIV-1 incidence 
among placebo recipients, 18-35 years of age was estimated at 3.7 per 100 person-
years (5.86 for females and 1.93 for males) [33]. 
Topical and Systemic Pre-Exposure Prophylaxis Studies 
• 
The FACTS 001 vaginal microbicide study (2011-2014), in which HIV-1 incidence 
was estimated at 4.0 per 100 person-years in women age 18-30 [34]. 
• 
The VOICE study of vaginal microbicide and systemic prophylactic antiretroviral 
drugs (2009-2013), in which overall HIV-1 incidence was 5.7% and incidence in the 
3 placebo arms of the trial varied from 4.2 to 6.8 per 100 person-years, while the 
annual incidence in single women in South Africa aged 25 or younger was up to 10% 
[35]. 
• 
The MTN-020-ASPIRE dapivirine vaginal ring study (2012-2015), in which HIV-1 
incidence was estimated at 4.5 per 100 person-years in female placebo recipients 
aged 18-45 in Malawi, South Africa, Uganda, and Zimbabwe [36]. 
• 
The RING study (IPM-027), a vaginal ring study (2012-2015), in which HIV-1 
incidence was estimated at 6.1 per 100 person-years in female placebo recipients 
aged 18-45 [37]. 
• 
The Fem-PrEP, a study of PrEP effectiveness in HIV-negative women in Kenya, 
South Africa, and Tanzania (2009-2012), in which HIV-1 incidence was estimated at 
5.0 per 100 person-years overall and ranged from 3.4–6 per 100 person-years in 
South African female placebo recipients aged 18-35 [38]. 
Based on a synthesis of the above references the estimated annual incidence rate of HIV-
1 in Sub-Saharan women is 5.0% (total HIV acquisition events divided by total person 
years at risk). Under an assumed 90% PrEP efficacy during PrEP use, a conservative 
estimate of 4.2% annual HIV incidence can tolerate up to 15 out of 100 person years at 
risk during PrEP use. 
A conservative estimate of the background HIV-1 incidence is 4.2 per 100 person-years, 
and this level of incidence is expected for the duration of our study. Self-reported risk has 
been shown to decline over time in HIV prevention studies, attributed to risk reduction 
counseling and the provision of other interventions provided to study participants as part 
of a package of prevention. While incidence of HIV infection may be expected to 
decrease over time in trial populations due to the provision of HIV prevention packages, 
as well as the heterogeneity in risk for HIV-1, the increasing access to pre-exposure 
prophylaxis at a country level may impact HIV incidence more profoundly. 
4.5 
Combination prevention of HIV acquisition 
HVTN 705 embraces the highest South African standards of prevention for all 
participants. Participants will be provided with a comprehensive HIV prevention 
package. This package includes evidence-based behavioral risk reduction counseling 
[39], advocacy and referral of partner for medical male circumcision as appropriate, free 
condoms and lubricant (where available), regular testing as well as treatment or 
appropriate referral for sexually transmitted infections (STIs), counseling and referral for 
postexposure prophylaxis (PEP) when indicated, and, where appropriate, access to oral 
drugs for pre-exposure prophylaxis (PrEP). Participants will be informed as new 
prevention modalities are proven effective and become available. These activities can be 

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expected to reduce HIV acquisition below historical levels. The contribution of these 
efforts will be monitored. Further details on these efforts are provided in the HVTN 705 
Study Specific Procedures (SSP) and the HVTN 705 website. 
4.6 
Plans for future product development and testing 
Upon confirmation of the safety and immunogenicity of Ad26.Mos4.HIV in HVTN 
117/HPX2004 (see Section4.9.2.4), HVTN 705/VAC89220HPX2008 will be initiated in 
southern Africa utilizing a regimen of Ad26.Mos4.HIV and Clade C gp140. 
Upon confirmation of the safety and immunogenicity of the combination of Clade C 
gp140 and Mosaic gp140, with Ad26.Mos4.HIV in HVTN 118/HPX2003 (see Section 
4.9.2.5), a phase 3 global efficacy trial will be performed to determine if this regimen can 
sufficiently prevent infection globally with HIV-1 of multiple clades. 
4.7 
Nonclinical safety studies 
Table 4-7 Summary of nonclinical safety studies 
Study 
number 
Product 
Type of 
study 
Animal 
N 
Route 
Schedule 
TOX10872 
Control 
Clade C gp140 
Clade C gp140 + 
Aluminum Phosphate 
Double 
dose 
Toxicity 
NZW1 
Rabbits 
30m/30f 
IM 
day 0, 21 
TOX10873 
Control 
Ad26.Mos.HIV 
MVA Mosaic 
Clade C gp140 + 
Aluminum Phosphate 
4 Cycle 
Toxicity 
NZW Rabbits 
60m/60f 
IM 
day 0, 21, 
42, 63 
NZW, New Zealand white; IM, intramuscular; m, male; f, female 
4.7.1 
Double dose IM toxicity study of Clade C gp140 in New Zealand White rabbits 
(TOX10872) 
This study assessed potential toxicity and local tolerance of Clade C gp140 and Clade C 
gp140/aluminum phosphate administered IM to male and female NZW rabbits (see Table 
4-7). Animals were injected with 250 mcg of Clade C gp140 +/- 425 mcg of aluminum 
phosphate (the proposed clinical dose) 3 weeks apart and any adverse effects were 
monitored during a 21 day recovery period.  
The vaccine was well tolerated when administered 2 times with an interval of 3 weeks 
between injections. An immune response was triggered, as shown by the IgG levels 
measured in both groups. Increases in C-reactive protein (CRP) were seen in both groups 
(but more consistently in the adjuvant group) and had resolved by the end of the recovery 
period. These CRP increases are typical for a mild immune and/or inflammatory response 
related to vaccine administration. Mild reactions were seen at the injection sites, which 
largely recovered 3 weeks after the last dose administration. For additional information 
please see the Investigator's Brochure. 

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4.7.2 
Four-cycle IM toxicity study with prime-boost combinations of Ad26.Mos.HIV, MVA-
Mosaic, and Clade C gp140 in New Zealand White rabbits (TOX10873)  
This study assessed potential toxicity and local tolerance of prime-boost combinations of 
Ad26.Mos.HIV, MVA-Mosaic, and Clade C gp140/aluminum phosphate administered 
once every 3 weeks for up to 4 injections (see Table 4-7). Ad26.Mos.HIV was 
administered at a dose of 5 × 1010 vp (the proposed clinical dose) and Clade C 
gp140/aluminum phosphate was administered at a dose of 250 mcg/425 mcg (the 
proposed clinical dose).  
The different dose regimens were well tolerated when administered once every 3 weeks 
for up to 9 weeks (ie, 4 injections). All tested vaccine regimens were immunogenic and 
induced Clade C gp140-specific serum IgG levels. The observed increases in CRP, 
fibrinogen, globulin and body temperature and the transient decrease in food 
consumption are considered to reflect a normal, non-adverse response to the vaccine 
administration. Non-adverse test article-related findings were seen in iliac lymph nodes, 
in the spleen, and at the injection sites. Injection-site lesions showed ongoing recovery at 
the 3 weeks recovery interval while the findings in lymph nodes and spleen (ie, 
immunogenic response) were still present after recovery. 
For additional information please see the Investigator’s Brochure. 
4.7.3 
Nonclinical assessment of Ad26.Mos4.HIV and formulation buffer changes 
No repeated dose GLP toxicity study has been performed with Ad26.Mos4.HIV (ie. 
containing the Ad26.Mos2S.HIV vector). There is significant nonclinical experience with 
Ad26 vectored vaccines using various HIV and non-HIV gene-inserts, showing that these 
vaccines are safe and well tolerated. At least 7 GLP toxicity studies have been performed 
in rabbits testing the nonclinical safety of various prime-boost regimens with Ad26 
vectored HIV and non-HIV vaccines at full human doses of up to 1.2x1011 vp. All effects 
observed in these studies were considered to be reflective of a physiological 
inflammatory/immune response to the vaccines administered and seem to be independent 
of the specific gene-insert used in the Ad26 vector. This indicates that differences in the 
expressed inserts do not pose a significant safety concern, when using the same vector 
backbone and vector (vp) dose.  
Ad26.Mos4.HIV (including the new Ad26.Mos2S.Env vector) vaccine was tested in a 
non-GLP immunogenicity study in rabbits (See Section 4.8.5). Two full human doses 
(5x1010 vp per dose) were administered via IM injection to the animals with a 6-week 
interval. The animals were observed daily for signs of toxicity and body weights were 
measured monthly. No test article-related adverse effects were observed. 
The Ad26.Mos2S.Env construct is produced using the same production platform as was 
used for the Ad26.Mos1.Env, Ad26.Mos1.Gag-Pol and Ad26.Mos2.Gag-Pol constructs 
that were part of Ad26.Mos.HIV and which was toxicologically assessed previously 
(TOX10873). 
Ad26.Mos4.HIV will be formulated in a different formulation buffer as used for 
Ad26.Mos.HIV that was toxicologically assessed in TOX10873. This change in the 
formulation buffer does not raise a safety concern, as the excipients in the post-change 
formulation buffer are either used in the pre-change formulation buffer or are accepted 
excipients for parenteral use. In addition, the new formulation buffer (without vaccine) 

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has been tested in a supportive single dose intramuscular local tolerability and tissue 
reaction study in rabbits (1 mL injection volume), not showing any adverse local effects 
(TOX11521). 
Based on these considerations it was not deemed necessary to perform an additional GLP 
toxicity study including Ad26.Mos4.HIV. This has been agreed with the US FDA in a 
pre-IND meeting on September 24, 2015, as well as in a Type C meeting on January 21, 
2016. 
The co-formulated Clade C gp140 + aluminum phosphate will be using a different 
formulation buffer than the buffer used for the Clade C gp140 + aluminum phosphate mix 
that will be prepared at the pharmacy and which was used in the HIV-V-A003 and HIV-
V-A004 clinical trials (See Section 4.9), as well as in the available GLP toxicity studies 
TOX10872 and TOX10873. For the co-formulated product, this initial (sucrose-based) 
buffer will be replaced by a buffer composed of histidine, sorbitol, and PS-20. This buffer 
change is not considered to impact on the safety profile of the co-formulated Clade C 
gp140 DP, as the excipients are used in licensed vaccines (with histidine also being a 
component of the current Ad26.Mos4.HIV formulation buffer) and are listed as approved 
excipients for parenteral use. Based on this rationale it was not deemed necessary to 
perform an additional GLP toxicity study with the post-change Clade C gp140 DP. This 
approach has been agreed with the US FDA through a Type C meeting briefing document 
in a Type C meeting on January 21, 2016. A rabbit immunogenicity study has been 
performed to evaluate potential influence of the formulation change on immunogenicity 
(Section 4.8.6). In this study, visual inspection of the injection sites was performed to 
assess possible local (skin) effects. No safety signals were observed in this study. 
4.8 
Nonclinical immunogenicity and efficacy studies 
4.8.1 
Nonclinical models 
The nonclinical data presented here is primarily based on data from 2 rhesus macaque 
challenge models, using simian immunodeficiency virus (SIV) or simian-human 
immunodeficiency virus (SHIV) [18-20]. 
In the SIV model, NHP were immunized with vaccines carrying SIV antigens (analogues 
of HIV) and then challenged with neutralization-resistant SIVmac251. This model was 
used to evaluate potential viral vectors and inserts capable of inducing cellular and 
humoral immune responses with broad specificity and high magnitude. In the SHIV 
model, the mosaic HIV-1 vectors were used to immunize NHP prior to challenge with 
neutralization-resistant SHIV SF162P3. SHIV is an engineered virus comprising the 
genetic backbone of SIVmac239 with the envelope of HIV-1 and accessory genes. The 
clade B-derived challenge virus SF162P3 is fully heterologous in relation to all used 
vaccine antigens (Clade C gp140, Mos1 and Mos2/Mos2S).To mimic natural exposure to 
HIV-1, multiple low doses of SIV or SHIV were delivered intra-rectally, and 
neutralization-resistant challenge strains were used.  
In addition, a rabbit immunogenicity model was used. This species is able to generate 
antibodies with long CDR H3 loops, which is a function-related characteristic of most 
neutralizing antibodies isolated from HIV-1 infected humans. 

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4.8.2 
Immunogenicity and protective efficacy of vectors encoding mosaic antigens in 
rhesus macaques 
A proof-of-concept study in rhesus macaques demonstrated that adenoviral heterologous 
Ad26/Ad35 vaccine regimens encoding bivalent HIV-1 Mosaic Env/Gag/Pol antigens 
afforded partial protection against acquisition of infection following repetitive, 
heterologous, intrarectal challenges with the difficult-to-neutralize SHIV-SF162P3 (tier 
2; Clade B; HIV-1 Env and SIV Gag/Pol) [19]. This corresponded to a per exposure risk 
reduction of 87%, although absolute protection against the full challenge series was low.  
Protection against acquisition of infection correlated with (1) binding antibody titers 
against the homologous Mosaic 1 Env antigen, (2) vaccine-elicited neutralizing 
antibodies against SF162 (tier 1; Clade B), a neutralization sensitive virus that is related 
to the challenge virus SHIV-SF162P3, and (3) functional antibody-dependent cellular 
phagocytosis responses (ADCP) which are usually dependent on neutralizing and non-
neutralizing binding antibodies. Taken together, the identified correlates of protection 
suggest that the coordinated activity of multiple antibody functions may contribute to 
protective efficacy. 
4.8.3 
Immunogenicity and protective efficacy of Ad26 vectors followed by a boost with 
Clade C gp140 in rhesus macaques 
Clade C gp140 protein was selected as protein boost component of the proposed 
investigational vaccine regimen in order to maximize the humoral immune response, to 
increase the chances of eliciting HIV-1 specific functional antibodies [17,40].  
A study was conducted in rhesus macaques to assess the effect of boosting with Env 
gp140 protein after priming with Ad26 [20]. In the SIV model, boosting with adjuvanted 
SIVmac32H gp140 protein afforded 50% protection from infection in animals that were 
primed with an Ad26 vector expressing the SIVsmE543 Env/Gag/Pol antigens. This 
protection was significantly higher than in animals that received prime and boost 
vaccinations with adenoviral vectors (17% protection). This suggests that recombinant 
Env gp140 is an important component of an efficacious vaccine regimen. Antibody Env 
binding capacity and Env specific antibody functionality significantly correlated with 
protection against SIV challenge. Env gp140 boosting primarily expanded Env-specific 
IFN-γ CD4+ T-lymphocyte responses in the Ad26/gp140 group [20].  
In addition to the protective advantage of a boost immunization with gp140, an 
adenovirus-based prime immunization was demonstrated to be an important factor in 
mediating protection from infection. Prime immunization with adenoviral vectors Ad26 
and Ad5 coding for HIV-1 antigens followed by an HIV-1 Clade C gp140 protein boost 
(with AS01B as adjuvant), was able to partly protect rhesus macaques against stringent 
heterologous SHIV-SF162P3 challenge while repeated immunization with the similarly 
adjuvanted Clade C gp140 alone mediated a lower level of protection. Forty percent (8 of 
20) of Ad/Env-vaccinated animals were completely protected against the series of 6 
challenges. Binding antibody titers and ADCP responses correlated with protection 
against acquisition of infection [20].  
Taken together, these data indicate that Ad26 priming followed by Env gp140 protein 
boosting is the most advantageous regimen of those examined and warrants further 
testing as an efficacious prototype HIV-1 vaccine. 

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4.8.4 
Immunogenicity and protective efficacy of Ad26.Mos.HIV and Clade C gp140 in 
rhesus macaques 
An NHP study (Study 13-19/15-06) was performed to test, among other compounds, the 
combination of Ad26.Mos.HIV priming and Clade C gp140 boost, using comparable 
regimens, starting materials and manufacturing processes as those being used in clinical 
studies. Briefly, 6 cohorts of 12 rhesus macaques were primed in Month 0 and Month 3 
with trivalent Ad26.Mos.HIV, followed by heterologous boosts with vector-based 
vaccine components or Clade C gp140 with aluminum phosphate adjuvant or a 
combination thereof in Month 6 and Month 12. 
Immunogenicity data from this study (Figure 4-3, Panels A-C) showed that group 
geometric mean binding antibody titers were highest in all groups boosted with Clade C 
gp140 protein. Boosting with Clade C gp140 also increased the Env-specific cellular 
response, measured by ELISpot. HIV-1 pseudovirus neutralization data overall followed 
the trend of humoral responses; however, substantial neutralization was only observed for 
easy-to-neutralize Tier 1 Env pseudotyped viruses (data not shown). 
Viral load data were determined after each challenge of a series of 6 IR weekly 
challenges with SHIV-SF162P3 (Figure 4-3, Panel D). The 3 most protective regimens 
contained Clade C gp140 as a boost vaccine component. The regimen boosted with a 
combination of Ad26.Mos.HIV and Clade C gp140 led to the highest level of protection 
in this study (8 out of 12 monkeys protected after the full course of challenges). 
Statistical analysis of the data showed that this group had a 94% per exposure risk 
reduction, which was associated with a 66% complete protection after the full series of 6 
challenges (Table 4-8). 
 

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Figure 4-3 Immunogenicity and protective efficacy of various Ad26.Mos.HIV/Clade C gp140 
prime-boost regimens in rhesus macaques. Results of NHP Study 13-19/15-06. Clade C gp140 
(A) and Mosaic gp140 (B) Binding Antibody Responses Generated in Rhesus Macaques in Week 
56 Post First Immunization (4 Weeks Post Final Immunization), (C) ELISpot Responses Against 
PTE (Potential T-cell Epitopes From Worldwide Circulating HIV-1 Strains) Peptides in Week 54 
Post First Immunization. All Animals Were Primed in Month 0 and Month 3 With Trivalent 
Ad26.Mos.HIV, Followed by Heterologous Boosts in Month 6 and 12 as Indicated in the Graphs 
and in Table 2. (D) Number of Challenges Required for Acquisition of Infection Displayed as 
Kaplan-Meier Plots. Ad - Ad26.Mos.HIV; Env – Clade C gp140; MVA – MVA-Mosaic. 

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Table 4-8 Statistical analysis of NHP study 13-19/15-06 
Regimen 
Hazard Ratio 
(95% CI) 
Per-exposure 
risk reduction 
p-value versus 
sham 
Complete 
protection 
Ad 
Ad 
0.647 
(0.205-2.039) 
35% 
1.000 
 
0% 
Ad 
Env 
0.161 
(0.050-0.516) 
84% 
0.011 
 
33% 
Ad 
Ad + Env 
0.055 
(0.014-0.215) 
94% 
0.001 
 
66% 
Ad 
MVA 
0.288 
(0.094-0.879) 
71% 
0.144 
 
8% 
Ad26 
MVA + Env 
0.130 
(0.040-0.430) 
87% 
0.004 
 
42% 
Sham 
1 (reference) 
N/A 
N/A 
0% 
1 Cox proportional hazard model 
p-values were adjusted with a 5-fold Bonferroni correction for multiple comparisons 
Ad, Ad26.Mos.HIV; Env, Clade C gp140; MVA, MVA-Mosaic 
4.8.5 
Immunogenicity of Ad26.Mos4.HIV with Clade C gp140 in rabbits  
The immunogenicity and antigenicity of Ad26.Mos4.HIV compared to Ad26.Mos.HIV 
was tested in rabbits (study 0095-14). Six rabbits per group were immunized with 2 
prime immunizations with Ad26.Mos.HIV or Ad26.Mos4.HIV, each at doses of 5x109 or 
5x1010 vp, and 2 aluminum phosphate-adjuvanted Clade C gp140 protein boost 
immunizations. 
The neutralization capacity of immune sera collected after the second, third and fourth 
immunization was determined against easy to neutralize Tier 1 pseudoviruses (Figure 
4-4). For the clade C pseudovirus MW965, the Ad26.Mos4.HIV vaccine (Groups 3+4, 
Panels A+B, Figure 4-4) elicited significantly increased neutralization capacity in 
comparison to the Ad26.Mos.HIV combination (Groups 1+2, Panels A+B, Figure 4-4). 
For the clade B pseudovirus SF162, the neutralization capacity elicited by 
Ad26.Mos4.HIV did not significantly differ from the neutralization capacity elicited by 
Ad26.Mos.HIV (data not shown). This demonstrates that the proposed combination of 
Ad26.Mos4.HIV and Clade C gp140 shows improved clade C pseudovirus recognition in 
the absence of negative effects on clade B pseudovirus recognition. 

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HIV-V-A004. Readout parameters included antigen-specific antibody binding (ELISA or 
comparable assay) and viral neutralization assays. Data were analyzed using a non-
inferiority testing method comparing pre-change and postchange formulations across 
dose levels based on antigen-specific serum antibody binding data determined by ELISA. 
This study demonstrated non-inferiority of the co-formulation compared with the 
pharmacy mixture of Clade C gp140 and aluminum phosphate adjuvant. 
4.9 
Clinical studies 
4.9.1 
Clinical studies with related Adenovirus 26 vaccine, Ad26.ENVA.01 
In Ad26.ENVA.01 a gene insert was used that coded for a clade A env protein, while 
Ad26.Mos4.HIV is a tetravalent vaccine containing 4 Ad26 vectors encoding mosaic 
antigens. These mosaic antigens were shown in pre-clinical NHP studies to increase the 
breadth of induced immune responses in comparison to antigens derived from circulation 
viruses or consensus virus sequences [7]. Ad26.Mos4.HIV consists of 2 Env antigen-
encoding vectors (Ad26.Mos1.Env, Ad26.Mos2S.Env) and 2 Gag-Pol antigen-encoding 
vectors (Ad26.Mos1.GagPol, Ad26.Mos2.GagPol). Thus, each antigen is encoded by 2 
complementary mosaic sequences that were designed with the aim of providing maximal 
coverage of globally circulating HIV-1 strains [6].  
In 3 phase 1 studies (IPCAVD 001, IPCAVD 003, and IPCAVD 004 [41-44]), 
Ad26.ENVA.01, at IM doses over the range 109 to 1011 vp, was found to induce Env-
specific humoral and cell-mediated responses when given on up to 3 occasions to more 
than 200 healthy participants. Ad26.ENVA.01 was generally well tolerated in these 
studies. An IM dose of 5x1010 vp was found to provide the optimal balance of 
immunogenicity and reactogenicity. Therefore, this Ad26.Mos4.HIV vaccine will be 
administered in a 1:1:1:1 ratio totaling 5x1010 vp for evaluation in the current 
HVTN705/VAC89220HPX2008 study. 
In IPCAVD 003, 24 HIV-1 negative participants were randomized 3:1 to receive a single 
vaccination with Ad26.ENVA.01 or placebo. Eight of the participants were Ad26 
seropositive at screening. The T-cell responses by IFNγ ELISpot assays were slightly 
lower in the baseline Ad26 seropositive participants; ICS and enzyme-linked 
immunosorbent assay responses proved comparable between participants who were Ad26 
seropositive and Ad26 seronegative at baseline, both in peripheral blood and in colorectal 
mucosa. In addition, systemic and mucosal responses persisted for at least 1 year in the 
majority of participants after a single IM vaccine dose. These data suggest that the impact 
of baseline Ad26 nAbs, at the titers observed in that study, on the immunogenicity of this 
Ad26 vaccine is modest. Additionally, there were no consistent increases in Ad26-
specific CD4+ T lymphocyte responses at mucosal surfaces following vaccination in 
either Ad26-seronegative or Ad26 seropositive participants. 
In the IPCAVD 004 clinical trial (N=217) [41], the safety and immunogenicity of IM 
doses of Ad26.ENVA.01 and Ad35.ENV (5x1010vp), administered in heterologous and 
homologous prime-boost regimens at 3- versus 6-month intervals, were evaluated. We 
observed that the baseline Ad26 nAb titers observed in South and East Africa did not 
impact the humoral or cellular immune responses elicited by the prototype 
Ad26.ENVA.01 vaccine. See Investigator’s Brochure for additional information. 

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There were no SAEs, and none of the participants discontinued due to AEs. 
Vaccine-induced binding antibody responses were investigated using ELISA performed 
at the Beth Israel and Deaconess Medical Center, Boston, MA, USA. Antibodies were 
mainly detected at 4 weeks after the boost injection (when tested at baseline, Day 29, and 
Day 57 [4 weeks after the 2nd injection]). Although the limited number of participants 
precludes a formal comparison, the highest response was observed in the high dose (HD) 
with adjuvant (250 mcg Clade C gp140/AP) group. See the Investigator’s Brochure for 
more details. 
Table 4-9 HIV-V-A003 Schema 
Group 
N 
Dose 
Month 0 
Month 1 (day 29) 
1 
10 
50 mcg 
Clade C gp140 
Clade C gp140 
2 
10 
50 mcg 
Clade C gp140/AP* 
Clade C gp140/AP 
3 
5 
0 
Placebo for 50 mcg 
Placebo for 50 mcg 
4 
10 
250 mcg 
Clade C gp140 
Clade C gp140 
5 
10 
250 mcg 
Clade C gp140/AP 
Clade C gp140/AP 
6 
5 
0 
Placebo for 250 
mcg 
Placebo for 250 mcg 
* AP, aluminum phosphate adjuvant, 425 mcg 
4.9.2.2 
HIV-V-A004 
HIV-V-A004 is a multi-center, randomized, parallel-group, placebo-controlled, double-
blind phase 1/2a study to evaluate safety/tolerability, and immunogenicity of various 
prime/boost regimens containing Ad26.Mos.HIV, MVA-Mosaic, and/or Clade C gp140 
(with aluminum phosphate adjuvant) components in approximately 400 healthy HIV-
uninfected adult participants in the US, Uganda, Rwanda, South Africa, and Thailand. 
The schema is depicted in Table 4-10.  
Table 4-10 HIV-V-A004 Schema 
Group 
N 
Prime 
Month 0, Month 3 
Boost 
Month 6, Month 12 
1 
50 
Ad26.Mos.HIV 
Ad26.Mos.HIV + 250 mcg Clade C gp140/AP* 
2 
50 
Ad26.Mos.HIV 
Ad26.Mos.HIV + 50 mcg Clade C gp140/AP 
3 
50 
Ad26.Mos.HIV 
Ad26.Mos.HIV + Placebo 
4 
50 
Ad26.Mos.HIV 
MVA-Mosaic + 250 mcg Clade C gp140/AP 
5 
50 
Ad26.Mos.HIV 
MVA-Mosaic +50 mcg Clade C gp140/AP 
6 
50 
Ad26.Mos.HIV 
MVA-Mosaic + Placebo 
7 
50 
Ad26.Mos.HIV 
250 mcg Clade C gp140 +Placebo 
8 
50 
Placebo 
Placebo + Placebo 
*AP, aluminum phosphate adjuvant, 425 mcg 

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The study is currently ongoing and is still blinded for subjects and sites. At the time of 
the primary analysis (Week 28), results of which are described below, all subjects had 
received their 3rd vaccination or discontinued earlier. For more details, see the 
Investigator’s Brochure. 
The results from the primary analysis (Week 28) showed that all vaccine regimens were 
found to be well tolerated.  
Solicited events, both local and systemic, were overall mild to moderate in severity. 
Injection site pain, headache and fatigue were the most frequent reported solicited events 
overall.  
Most solicited systemic AE were reported after the first dose. The frequency of grade 3 
related solicited systemic AEs was low, with headache and fatigue most frequently 
reported. Only one serious adverse event was assessed as related to the study products by 
the investigator, ie, severe allergic reaction/hypersensitivity: 
A 50 years-old male subject reported a severe allergic reaction/hypersensitivity 
having started 12 hours after first vaccine administration. Symptoms and signs 
mentioned by the subject included facial swelling, blurred vision, difficulty 
swallowing, and generalized rash of the face, extremities, and chest tightness. The 
subject was brought to the emergency room per ambulance. Clinical observations by 
the emergency room physician noted an alert and oriented person, with symptoms of, 
but with no clinical signs of allergic reaction (no rash, no 
lip/tongue/oropharyngeal/uvular swelling, normal findings of cardiovascular and 
respiratory system). Diphenhydramine was administered; no hospitalization or 
administration of corticosteroids occurred. The reaction was resolved within 1 day of 
onset. Concurrent medical conditions included 
 (not 
disclosed by the subject to the investigator) with hallucinatory decompensation and 
chest pain 1 week after the severe allergic reaction. The subject was withdrawn from 
the study due to non-compliance (history of 
 and non-reported 
 
). 
Three on-study HIV infections occurred. For all 3 subjects, factors known to increase 
the risk for HIV infection were present.  
No deaths were reported.  
All active vaccine regimens were immunogenic as most groups showed 100% of subjects 
having a detectable antibody response post the third vaccination. The ELISA utilizing the 
same ELISA antigen as used for protein boost immunization showed a clear increase in 
antibodies upon the Clade C gp140 boost (irrespective of vector boost) (Figure 4-5): for 
HIV Env Clade C C97ZA.012 the geometric mean ratio of the Ad26/Ad26+gp140HD 
group versus the Ad26/Ad26 group was 5.5 (with a 95% CI between 3.5 and 8.6). In 
addition, the ELISA showed a clear increase in antibodies upon boost with a high dose of 
the Clade C gp140 in the boost compared to the low dose, and inclusion of a vector in the 
boost with the Clade C gp140 in comparison to Clade C gp140 alone. Up to 100% cross 
clade antibody responses to clade A, B and C were detected in most vaccine groups. The 
Ad26/Ad26+gp140HD group showed highest humoral responses overall. Clear IgG3, 
ADCP and neutralizing antibody responses were detected. IgG subclass responses to the 
vaccine protein were of the IgG1 and IgG3 subtype, with little to no IgG2 and IgG4 
detected in most vaccine groups. 
PPD
PPD
PPD

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Figure 4-5 IgG gp140 ENV ELISA Clade C (C97ZA.012) (HIV-V-A004, Week 28 Analysis) 
High numbers of responders were identified by ELISPOT (Figure 4-6), with some of the 
highest numbers of responders in the groups boosted with Ad26+gp140HD as well as 
MVA in the boost, with the highest median responses in the groups with MVA in the 
boost. Responses for CD4 and CD8 T cells producing IFNγ and/or IL2 were detected by 
Intracellular Cytokine Staining (ICS). A clear contribution of both the vector and the 
protein to boosting of both humoral and cellular immune responses was observed. 

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Figure 4-6 IFNγ ELISPOT ENV PTE peptide pool (HIV-V-A004, Week 28 Analysis) 
4.9.2.3 
HPX1002 
VAC89220HPX1002 is a single-center, randomized, parallel-group, placebo-controlled, 
double-blind phase 1 clinical study in healthy HIV-uninfected adults to evaluate the 
safety, tolerability, and immunogenicity of different regimen durations (24 or 48 weeks) 
and different number of dose administrations with Ad26.Mos.HIV (3 or 4 dose 
administrations) and Clade C gp140 (2 or 3 dose administrations). The study is fully 
enrolled. Participants will be followed up until Week 72. 

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Table 4-11 HPX1002 study design  
Group 
Subgroup 
N 
Week 0  
Week 8 
Week 12 
Week 24 
Week 48 
1 
A 
10 
Ad26.Mos.HIV 
 
Ad26.Mos.HIV 
Ad26.Mos.HIV 
+ 
Clade C gp140 
(250 mcg + 
adjuvant)a 
Ad26.Mos.HIV 
+ 
Clade C gp140 
(250 mcg + 
adjuvant)a 
B 
2 
Placebo 
 
Placebo 
Placebo 
+ 
Placebo 
Placebo 
+ 
Placebo 
2 
A 
10 
Ad26.Mos.HIV 
+ 
Clade C gp140 
(250 mcg + 
adjuvant)a 
 
Ad26.Mos.HIV 
+ 
Clade C gp140 
(250 mcg + 
adjuvant)a 
Ad26.Mos.HIV 
+ 
Clade C gp140 
(250 mcg + 
adjuvant)a 
 
B 
2 
Placebo 
+ 
Placebo 
 
Placebo 
+ 
Placebo 
Placebo 
+ 
Placebo 
 
3 
A 
10 
Ad26.Mos.HIV 
Ad26.Mos.HIV 
+ 
Clade C gp140 
(250 mcg + 
adjuvant)a 
 
Ad26.Mos.HIV 
+ 
Clade C gp140 
(250 mcg + 
adjuvant)a 
 
B 
2 
Placebo 
Placebo 
+ 
Placebo 
 
Placebo 
+ 
Placebo 
 
a Sterile aluminum phosphate suspension is used as adjuvant. Aluminum content is 0.425 mg/0.5 mL dose.  
4.9.2.4 
HPX2004 (HVTN117)  
VAC89220HPX2004 (HVTN117) is a randomized, parallel-group, placebo-controlled, 
double-blind phase 1/2a study to evaluate the safety/tolerability and immunogenicity of 
priming with trivalent Ad26.Mos.HIV and boosting with trivalent Ad26.Mos.HIV plus 
Clade C gp140 (with aluminum phosphate adjuvant), or priming with tetravalent 
Ad26.Mos4.HIV and boosting with Ad26.Mos4.HIV plus Clade C gp140 (with 
aluminum phosphate adjuvant). Approximately 198 participants will be enrolled in the 
study. Better Clade C responses are to be expected with the tetravalent Ad26.Mos4.HIV 
compared to the trivalent Ad26.Mos.HIV. A Data Review Committee (DRC) will review 
blinded safety data (4 weeks of follow-up) after 15% of participants have received their 
first injection (Ad26.Mos.HIV/Ad26.Mos4.HIV/placebo). Administration of the first 
dose of Ad26.Mos4.HIV (first injection) in VAC89220HPX2003 (see below), will be 
allowed only if no significant safety concerns are identified. Interim safety results on 
Ad26.Mos4.HIV are expected to be available before dosing of this vaccine component in 
the current HVTN705/VAC89220HPX2008 study. 

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Table 4-12 HPX2004 (HVTN117) schema 
Group 
N 
Prime 
Month 0, Month 3 
Boost 
Month 6, Month 12 
1A 
55 
Ad26.Mos.HIV 
Ad26.Mos.HIV + 250 mcg Clade C gp140/AP* 
1B 
11 
Placebo 
Placebo + Placebo 
2A 
110 
Ad26.Mos4.HIV 
Ad26.Mos4.HIV + 250 mcg Clade C gp140/AP* 
2B 
22 
Placebo 
Placebo + Placebo 
Total 198 (165 vaccine/33 placebo) 
*Aluminum Phosphate 
4.9.2.5 
HPX2003 (HVTN 118) 
VAC89220HPX2003 (HVTN 118) will be a randomized, parallel-group, placebo-
controlled, double-blind phase 1/2a study in healthy HIV-uninfected adults to evaluate 
safety/tolerability and immunogenicity of different regimens of tetravalent 
Ad26.Mos4.HIV together with either Clade C gp140 or a combination of Mosaic and 
Clade C gp140 (with aluminum phosphate adjuvant). Approximately 150 participants 
will be enrolled in the study. 
Table 4-13 HPX2003 (HVTN118) schema 
Group 
N 
Prime 
Month 0, Month 3 
Boost 
Month 6, Month 12 
1 
25 
Ad26.Mos4.HIV 
Ad26.Mos4.HIV + 250 mcg Clade C gp140/AP* 
2 
100 
Ad26.Mos4.HIV 
Ad26.Mos4.HIV + 125 mcg Clade C gp140/AP + 
125 mcg Mosaic gp140/AP 
3 
25 
Placebo 
Placebo + Placebo 
Total 150 (125 vaccine/ 25 placebo) 
*Aluminum Phosphate 
4.10 
Potential risks of study products and administration 
4.10.1 
Risks related to vaccines 
Subjects may exhibit general signs and symptoms associated with administration of a 
vaccine, or vaccination with placebo, including fever, chills, rash, aches and pains, 
nausea, headache, dizziness and fatigue. These side effects will be monitored, but are 
generally short-term and do not require treatment. 
Vasovagal reactions, lightheadedness or dizziness, mostly related to injections 
procedures, have also been observed, and therefore the vaccine should be administered 
while subjects are sitting or lying down and precautions must be taken to avoid falls 
potentially due to those events. All subjects will be observed in the clinic for 25-60 
minutes after each vaccination. 
Subjects may have an allergic reaction to the vaccination. An allergic reaction may cause 
a rash, hives or even difficulty breathing. Severe reactions are rare. Medications must be 
available in the clinic to treat serious allergic reactions. The effect of this vaccine on a 

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fetus or nursing baby is unknown so female subjects of child bearing potential will be 
required to agree to use birth control for sexual intercourse beginning prior to the first 
vaccination and through 3 months after the last vaccination. Women who are pregnant or 
nursing will be excluded from the study.  
Risks related to VISP are discussed in Section 9.7.2. 
4.10.2 
Risks from blood draws 
Blood drawing may cause pain, bruising, and, rarely, infection at the site where the blood 
is taken. Large volume blood draws can cause transient anemia. 
4.10.3 
Risks from HLA testing 
Tests results can be used to provide information about how susceptible subjects are to 
certain diseases. Used inappropriately, this information could be discriminatory (for 
example, by insurance companies). Human Leukocyte Antigen typing can also be used to 
determine paternity. However, the blood samples donated will not be used for this 
purpose; they will be used only to provide study investigators information about the 
immune system. The results will be coded to protect subject identity. 
4.10.4 
Unknown risks 
There may be other serious risks that are not known. Subjects may believe that this 
vaccine provides protection against acquiring HIV infection, and therefore practice 
riskier behavior. They will receive extensive counseling throughout the study to address 
this potential problem. It is not known if the study vaccines increase or decrease the 
chance of becoming HIV infected when exposed, or if upon becoming HIV infected, the 
person’s disease course progresses faster or slower to AIDS. In previous HIV-efficacy 
studies utilizing Ad5, an increase in HIV-1 infections was observed in male vaccine 
recipients as compared with placebo recipients. Adenovirus serotype 26 is biologically 
substantially different than Ad5 and Ad26-based vaccines afford superior protective 
efficacy compared with Ad5-based vaccines against SIVMAC251 challenges in rhesus 
monkeys [16]. Further, Ad26 did not increase the number or activation status of total or 
vector-specific CD4+ T-lymphocytes at mucosal surfaces in humans following 
vaccination in a randomized, double-blind, placebo-controlled clinical study [44]. 

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5 
Objectives and endpoints 
5.1 
Primary objectives and endpoints 
Primary objective 1:  
To evaluate the preventive vaccine efficacy (VE) of a heterologous prime/boost regimen 
utilizing Ad26.Mos4.HIV and aluminum-phosphate adjuvanted Clade C gp140 for the 
prevention of HIV infection in HIV-seronegative women residing in sub-Saharan Africa 
from confirmed HIV-1 infections diagnosed between the Month 7 and Month 24 visits 
Primary endpoint 1:  
Vaccine efficacy as derived from confirmed HIV-1 infections diagnosed between the 
Month 7 and Month 24 visits 
Primary objective 2:  
To evaluate the safety and tolerability of a heterologous prime/boost regimen utilizing 
Ad26.Mos4.HIV and aluminum-phosphate adjuvanted Clade C gp140 for the prevention 
of HIV infection in HIV-seronegative women residing in sub-Saharan Africa 
Primary endpoint 2: 
Local and systemic reactogenicity signs and symptoms for 3 days after each vaccination, 
adverse events for 30 days after each vaccination, and serious adverse events, AESIs, and 
adverse events leading to early participant withdrawal or early discontinuation of study 
product(s) administration for the entire duration of the study. 
5.2 
Secondary objectives and endpoints 
Secondary objective 1: 
To evaluate vaccine efficacy from enrollment through 24 months 
Secondary endpoint 1: 
HIV-1 infection diagnosed after enrollment through 24 months post enrollment  
Secondary objective 2: 
To evaluate vaccine efficacy from enrollment through the end of the study if Stage 2 
occurs 
Secondary endpoint 2: 
HIV-1 infection diagnosed after enrollment through the end of the study 

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Secondary objective 3: 
To evaluate vaccine efficacy from month 12 through month 24 
Secondary endpoint 3: 
HIV-1 infection diagnosed after month 12 through 24 months post enrollment 
Secondary objective 4: 
To evaluate vaccine efficacy from month 12 through the end of the study if Stage 2 
occurs 
Secondary endpoint 4: 
HIV-1 infection diagnosed after month 12 through the end of the study post enrollment 
Secondary objective 5: 
To evaluate the immunogenicity of the vaccine regimen 
Secondary endpoint 5: 
Immune responses at the study visits following the third and fourth vaccinations from 
assays based on the HVTN Laboratory Assay Algorithm such as vaccine-specific binding 
antibodies and T-cell responses. 
Secondary objective 6: 
To evaluate immunogenicity and immune response biomarkers among vaccine recipients 
after the third vaccination as correlates of risk of subsequent HIV acquisition and 
correlates of vaccine efficacy, if deemed applicable. 
Secondary endpoint 6: 
Immune responses from assays based on the HVTN Laboratory Assay Algorithm 
(available at https://atlas.scharp.org/) and/or more assays down-selected from a larger 
pool of pilot studies, in HIV-1–infected vaccine cases and HIV-1–uninfected vaccine 
controls 
Secondary objective 7: 
To evaluate VE adjusting for various demographic and other baseline characteristics 
Secondary endpoint 7: 
HIV-1 infection diagnosed after the third vaccination by demographic and other baseline 
characteristics  

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Secondary objective 8: 
If significant positive evidence of vaccine efficacy from month 7 through 24 months is 
seen, to assess if and how vaccine efficacy depends on genotypic characteristics of HIV 
such as signature mutations 
Secondary endpoint 8: 
HIV-1 infection diagnosed after month 7 through Month 24 and genotypic characteristics 
of viral sequences from HIV-1–infected participants at HIV-1 diagnosis, such as 
signature site mutations 
Secondary objective 9: 
To evaluate and compare genomic sequences of viral isolates from HIV-1–infected 
vaccine and placebo recipients, and use sieve analysis methods to assess whether VE 
differs by genotypic or phenotypic characteristics of exposing HIVs and whether there is 
evidence of vaccine-induced immune pressure on the viral sequences 
Secondary endpoint 9: 
Viral sequences from HIV-1–infected participants at the earliest available postinfection 
timepoint and possible subsequent visits 
5.3 
Exploratory objectives 
Exploratory objective 1: 
To evaluate vaccine effects (“vaccine activity”) on virologic and immunologic outcomes 
(eg, HIV-1 viral load (VL) and postdiagnosis CD4+ T-cell count) among HIV-1–infected 
participants for 6 months post diagnosis accounting for ARV use 
Exploratory objective 2: 
To explore the association between the vaginal microbiome as well as genital 
inflammation, and HIV infection risk 
Exploratory objective 3 
To evaluate early and innate immune responses (eg, whole blood transcriptomics, serum 
cytokines) one day after the third vaccination (ie, the first protein boost) as correlates of 
risk of subsequent HIV acquisition 
Exploratory objective 4: 
To evaluate local and systemic reactogenicity signs and symptoms that arise from day 4 
to day 7 at a subset of clinical research sites 

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Exploratory objective 5: 
To further evaluate the immunogenicity of the vaccine regimen, additional 
immunogenicity assays may be performed, and assays may be performed on samples 
from other timepoints, based on the HVTN Laboratory Assay Algorithm 
Exploratory objective 6: 
To assess use of biomedical interventions and biological and behavioral factors in the 
study cohort and how they modify vaccine efficacy 
Exploratory objective 7: 
To evaluate the role of host genetic factors in the immune response to the vaccine 
regimen and in vaccine effects on study endpoints 
Exploratory objective 8: 
To perform comparative analyses of correlates of risk identified in HVTN 705 and those 
identified in other HIV vaccine efficacy studies 
Exploratory objective 9:  
To conduct analyses related to furthering the understanding of HIV, immunology, 
vaccines, and clinical trial conduct 

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6 
Statistical considerations 
6.1 
Study populations 
The following study populations or analysis sets are used for addressing the study 
objectives. This terminology is used throughout this protocol and the statistical analysis 
plan (SAP). 
1. Full Analysis Set (FAS): all randomized participants who receive at least 1 vaccine 
administration  
2. Modified Intent-to-Treat (MITT) Population: participants in the FAS who are HIV-1 
uninfected on the date of first vaccination. 
3. Per-Protocol (PP) Population: participants in the FAS who are HIV-1 uninfected 4 
weeks after the 3rd vaccination visit, who received all planned vaccinations at the first 
3 vaccination visits within the respective visit windows and have no other major 
protocol deviations that were judged to possibly impact the efficacy of the vaccine. 
4. Full Immunization Set (FIS): participants in the FAS who are HIV-1 uninfected 4 
weeks after the 4th vaccination visit and who receive all planned vaccinations within 
the respective visit windows. 
5. At risk Immunogenicity Cohort (IC-at risk): participants in the FAS who are selected 
for measurement of immune response endpoints at the primary immunogenicity 
timepoints and who are HIV-1 uninfected 4 weeks after the 3rd vaccination visit, who 
have no other major protocol deviations that were judged to possibly impact the 
efficacy of the vaccine. 
6. Per Protocol Immunogenicity Cohort (IC-PP): Participants in the IC-at risk who 
received all planned vaccinations at the first 3 vaccination visits within the respective 
visit windows.  
The MITT population and the FAS are very similar but not identical to a full Intention-to-
Treat Cohort (ie, all randomized participants); the FAS differs by excluding randomized 
volunteers who do not enroll (ie, don’t receive any vaccinations); and the MITT 
population is the subset of the FAS that also excludes randomized participants discovered 
later to be HIV-1 positive by day 0. Because of blinding and the brief length of time 
between randomization and enrollment—typically no more than 4 working days—we 
expect almost all randomized volunteers to be in the FAS. Given that eligibility for the 
study requires recent evidence of being HIV-1 uninfected (within 45 days prior to 
enrollment), we expect almost all enrolled participants to also be in the MITT Cohort. 
The analyses of safety will be performed on the FAS. The primary analysis of vaccine 
efficacy will be based on the PP population. Secondary analyses of vaccine efficacy will 
be based on the MITT population and the FIS. Analyses of vaccine immunogenicity and 
immune correlates of risk will be based on IC-at risk, IC-PP and the FIS (for those with 
immunogenicity outcomes).  

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Since this is a proof-of-concept trial, all efficacy analyses will be done according to the as 
treated principle (ie, actually received treatments), except for analyses using the MITT 
population. 
In addition, 4 cohorts of participants who are diagnosed with HIV-1 infection during the 
trial are analyzed for addressing various study objectives. Terminology for these cohorts 
is defined in Table 6-1, which will be used throughout the protocol and SAP. 
Table 6-1 Cohorts of HIV-1–infected study participants 
Cohort Name 
Definition of cohort 
MITT infected by 24 Months cohort 
Participants in the MITT population who are 
diagnosed with HIV-1 infection during the follow-up 
period after enrollment through the Month 24 visit. 
MITT infected by end of study cohort 
Participants in the MITT population who are 
diagnosed with HIV-1 infection during the follow-up 
period after enrollment through the end of the study. 
Per-Protocol infected by 24 Months 
cohort 
Participants in the PP population who are diagnosed 
with HIV-1 infection during the follow-up period on 
or after the Month 7 visit through the Month 24 visit. 
Per-Protocol infected by end of study 
cohort 
Participants in the PP population who are diagnosed 
with HIV-1 infection during the follow-up period on 
or after the Month 7 visit through the end of the study. 
6.2 
Objectives 
The primary, secondary, and exploratory objectives are defined in Section 5. Primary and 
secondary endpoints are described in Sections 5.1 and 5.2. 
Since this is a proof-of-concept study, primary analyses of the HIV-1 infection endpoint 
and of vaccine activity endpoints will be based on the PP population (Section 6.1). 
Secondary analyses of the vaccine efficacy objectives will be based on the MITT 
population, the PP population and the FIS. 
Safety analyses will be based on the FAS. Analyses of vaccine immunogenicity and 
immune correlates of risk will be based on IC-at risk, IC-PP and the FIS (for those with 
immunogenicity outcomes). 
6.3 
Primary analysis of vaccine efficacy 
We define the vaccine efficacy parameter, VE(7-24), for the primary analysis as 1 minus 
the cumulative incidence ratio (vaccine/placebo) of the HIV-1 endpoint between Month 7 
and Month 24 after enrollment in the PP population. 
The cumulative incidence parameters used to define VE(7-24) will be estimated using the 
transformed Nelson-Aalen estimator for the cumulative hazard function at Month 24 in 
the PP population. 

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The target parameter for the primary analysis of VE is VE(7-24). A two-sided 95% log-
cumulative-hazard based Wald confidence interval will be reported for VE(7-24), without 
adjustment for interim monitoring.  
The primary analysis also reports a test of the null hypothesis  
H0: VE(7-24) = 0% against the alternative hypothesis H1: VE(7-24) ≠ 0% 
using a 2-sided α=0.05 level Wald test of the equality of log cumulative hazard functions 
at Month 24 in the PP population for the vaccine group and the placebo group. The p-
value of this test will also be reported, where this p-value will not be adjusted for interim 
monitoring. 
6.3.1 
Analysis to determine whether or not the trial will advance into Stage 2 
If the lower bound of the 2-sided 95% confidence interval for VE(7-24) is > 0% 
(equivalently, the 1-sided p-value for testing H0: VE(7-24) ≤0% vs. H1: VE(7-24)>0% is 
below 0.025), trial participants will continue blinded follow-up through the end of the 
study (timepoint of final analysis). On the other hand, if the lower bound of the 95% 
confidence interval for VE(7-24) is ≤ 0%, Stage 2 will not occur and the trial participants 
will be unblinded at the end of Stage 1 (timepoint of primary/final analysis). Pending 
availability and outcome of primary analysis results, participants will continue their 
normal scheduled visits beyond Month 24. 
6.4 
Accrual and sample size 
6.4.1 
Sample size calculation for proof of concept endpoints (vaccine efficacy of a prime-
boost regimen to prevent HIV-1 infection) 
A targeted total of 2,600 HIV-uninfected adult women will be recruited. Trial participants 
will be enrolled over a 14-month period approximately and randomized to a placebo or 
vaccine regimen (1:1 randomization). Participants will receive vaccinations at Months 0, 
3, 6, and 12 and be followed for HIV infection for a period of at least 2 years (stage 1) 
after enrollment until the primary analysis at the end of stage 1 is performed (when the last 
subject reaches the month 24 visit). If H0: VE(7-24) ≤ 0% is rejected at the end of Stage 1, 
then the trial participants will continue blinded follow-up for at least 36 months (stage 2). 
If stage 2 does not occur, then all trial participants will be unblinded at the end of stage 1. 
The trial is designed so that a 0.025-level Wald test has approximately 90% power in the 
PP population to reject the null hypothesis: 
H0: VE(7-24) ≤ 0% versus the alternative hypothesis H1: VE(7-24) > 0% if the level of 
VE(7-24) is 50%.  
The sample size calculations are based on the power of a 1-sided 0.025-level Wald test for 
comparing cumulative incidences of HIV-1 infection by the Month 24 visit between 
randomized groups, in the presence of the sequential monitoring described below. Power 
is computed by simulating a large number of efficacy trials under assumptions described 
below using the R package seqDesign [46,47] ,  
The following assumptions are made for the sample size calculations:  

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• 
10% annual dropout incidence in each of the study groups 
• 
halved VE in the first 7 months after enrollment  
• 
14-month uniform accrual with halved accrual during the first 3 months  
• 
visits approximately every 3months for HIV-1 diagnostic tests  
• 
4.2% annual HIV-1 incidence that is constant over time in the placebo group  
• 
Sequential monitoring of vaccine efficacy for the following outcomes:  
o Potential harm [Conclude that VE(0-24)< 0% based on the one-sided 
exact binomial test of the proportion of infections assigned to the vaccine 
group] 
o Non-efficacy [Conclude that VE(7-24) < 40% based on a 2-sided 95% 
nominal confidence interval for VE(7-24) lying completely below 40%, 
and VE(0-24) < 40% based on a 2-sided 95% nominal confidence interval 
for VE(0-24) lying completely below 40%]  
o High efficacy [Conclude that VE(0-36) >70% based on a 2-sided 95% 
nominal confidence interval for VE(0-36) lying completely above 70%] 
• 
5% of subjects with missed vaccinations, i.e. subjects who would be discarded 
from the PP population 
Based on the references in Section 4.4.5, the estimated annual incidence rate of HIV-1 in 
Sub-Saharan women is 5.0% (total HIV acquisition events divided by total person years 
at risk). For our power calculations a more conservative incidence of 4.2% was chosen to 
provide some margin for reduced incidence due to PrEP use during the study. Table 6-2 
provides the power estimates to reject the null hypothesis for the assumed incidence of 
4.2%, as well as for situations with lower (3.1%) or higher (5.5%) than expected 
incidence. With the current sample size this trial would still have approximately 80% 
power to detect VE(7-24) of 50% or more if the incidence in the control group were to 
drop as low as 3.1%. As can be seen from the table (VE=0%) the type I error is controlled 
in the presence of sequential monitoring. 

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Table 6-2 Estimated power to detect different levels of VE(7-24) in the presence of sequential 
monitoring for VE, based on a randomized sample size of N = 1300/group§: 
 
Power to reject H0: VE(7-24) ≤ 0%with a 1-sided 0.025-level test 
True  
VE(7-24) 
Annual placebo 
incidence 3.1% 
Annual placebo 
incidence 4.2% 
Annual placebo incidence 
5.5% 
0% 
2.11 
2.06 
1.70 
10% 
6.69 
5.72 
7.79 
20% 
15.66 
17.63 
22.39 
30% 
28.94 
41.86 
48.38 
40% 
57.19 
66.03 
75.61 
50% 
79.70 
87.56 
93.26 
60% 
93.56 
98.00 
98.19 
70% 
98.90 
99.60 
99.60 
80% 
99.70 
99.70 
99.90 
90% 
100.00 
100.00 
100.00 
§ Halved VE in first 7 months  
N=1300:1300 placebo:vaccine group 
14-month enrollment period with a uniform enrollment rate, halved in the first 3 months 
10% annual dropout 
Under the incidence assumptions, the study sample size also provides sufficient and 
slightly higher power for the secondary MITT analyses assuming VE is halved during the 
first 7 months after enrollment, as shown in Figure 6-1 below (dark blue bars). 
 
Figure 6-1 Estimated power to detect different levels of VE(0-24) and VE(7-24) based on a 
sample size of N = 1300/group and an HIV-1 incidence of 4.2% 
6.4.2 
Sample size calculations for primary safety endpoint 
A total of 2600 participants in the trial provides enough power for assessing safety of the 
vaccine regimen. The probability of observing at least 1 adverse event occurring at a rate 

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of 1/100 is >99.9% with 1300 participants. The probability of observing at least 1 adverse 
event occurring at a rate of 1/1,000 is 73% with 1300 participants.  
No (S)AE observed in the vaccine group (N = 1300) would provide us with 95% 
confidence that the true incidence is no more than 0.29%. 
If no events will be observed for a specific adverse event, for example an SAE, then the 
Bayesian posterior probability that the adverse event rate is below 1/1,000 equals 89.3% 
for 1300 participants when using Jeffrey’s prior, and the posterior probability that the 
adverse event rate is below 1/100 equals 99.99%. If no AE is observed in the vaccine 
group (N = 1300), the upper limit of the equal-tailed 95% credible interval will be 
0.19%.  
As shown in Figure 6-2, there is 80% power to detect a small event rate difference 
between the vaccine and placebo groups using a 2-sided 0.05-level Fisher’s exact test. For 
example, if the true safety event rate in the placebo group is 2%, there is 80% power to 
detect an event rate difference of 2% or higher in the vaccine group. 
 
Figure 6-2 Power to detect safety event rate differences between the vaccine (N = 1300) and 
placebo (N = 1300) arms for assumed true event rates of 2% (blue) and 4% (red) in the 
placebo arm 
6.5 
Trial monitoring 
The trial will be formally monitored. This may lead to a modification or termination of the 
trial.  
Table 6-3 lists the specification of parameters under which the power calculations were 
done. The details of the actual monitoring plan will be discussed in the Statistical 
Analysis Plan (SAP). Table 6-4 provides the different outcome probabilities when 
applying these sequential monitoring rules to the study, assuming an incidence of 4.2%. 
More details on the individual monitoring rules follow in the subsequent sections. 

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Table 6-3 Sequential monitoring specifications used for power calculations 
Monitoring 
Type 
Hypotheses 
Statistical Method 
Monitoring Plan 
Timing of Analyses 
 
Potential 
Harm 
H0: VE(0-24) ≥ 0% 
vs. 
H1: VE(0-24) < 0% 
 
Exact 1-sided binomial test of 
the fraction of infections 
assigned to receive the vaccine. 
Constant p-value cut- 
off controlling the 
FWER at =5% 
After every MITT infection 
starting by the 10th infection 
until the first non-efficacy 
analysis 
Non- Efficacy 
H0: VE(0-24) ≥ 40% 
H0: VE(7-24) ≥ 40% 
vs. 
H1: VE(0-24) <40% 
H1: VE(7-24)<40% 
For both VE(0-24) and VE(7-
24): LCLs of 95% CI<0% and 
UCLs of 95%CI<40% 
 
Unadjusted 95% 
confidence intervals 
around VE(0-24) and 
VE(7-24) 
6-monthly starting once all 
participants reach Month 13, 
and 60 MITT infections are 
observed, then through the end 
of Stage 1 
High Efficacy 
H0: VE(0-36) ≤ 70% 
vs. 
H1: VE(0-36) > 70% 
95%CI for VE(0-36) lies 
completely above 70% 
 
Unadjusted 95% 
confidence interval 
around VE(0-36) 
Harmonized with non-efficacy 
monitoring starting when 150 
participants reach 36 months of 
follow-up. If Stage 2 occurs, 
one additional analysis half-
way through Stage 2 
 
Table 6-4 Outcome probabilities under sequential monitoring of vaccine efficacy 
True VE(7-24) 
Potential 
Harm 
Non-efficacy 
(interim) 
High 
Efficacy 
UC Power 
(PP) (end 
Stage 1) 
UC Power 
(MITT) (end 
Stage 1) 
0 
4.57 % 
81.18 % 
0.0% 
2.18 % 
2.18 % 
10 
2.88 % 
65.97 % 
0.0% 
7.19 % 
7.41 % 
20 
1.70 % 
41.08 % 
0.0% 
20.17 % 
21.79 % 
30 
0.90 % 
19.32 % 
0.0% 
43.33 % 
45.80 % 
40 
0.64 % 
5.55 % 
0.0% 
69.90 % 
73.10 % 
50 
0.31 % 
1.26 % 
0.0% 
90.86 % 
91.58 % 
60 
0.21 % 
0.14 % 
0.02 % 
98.58 % 
98.70 % 
70 
0.14 % 
0.00 % 
0.13 % 
99.92 % 
99.83 % 
80 
0.04 % 
0.00 % 
1.20 % 
99.99 % 
99.95 % 
90 
0.03 % 
0.00 % 
8.26 % 
100.0% 
99.97 % 
In the simulations, the start of the non-efficacy and high-efficacy monitoring was set to assure that the trial was continued to be 
monitored for harm until the M13 time point under the trial pre-trial assumptions: 
 VE halved in first 7 months  
 N=1300:1300 placebo:vaccine group 
 4.2% annual incidence in placebo group 
 10% annual dropout 
 5% missed vaccinations 
6.5.1 
Monitoring for potential harm 
The unblinded statistician will continuously monitor the trial for early evidence of a higher 
infection rate of MITT HIV-1 infection in the vaccine group compared to the placebo group 
to ensure participant safety. The monitoring will start from the 10th infection onward 

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(pooled over vaccine and placebo) and after each additional infection it is decided whether 
the stopping boundary has been reached [VE(0-24)<0%]. It will continue until the first 
analysis for non-efficacy is performed. The potential harm monitoring uses the one-sided 
exact binomial test resulting in a boundary that is determined via controlling the overall type 
I error rate across tests at 5%. Figure 6-3 shows for example that when 60 infections are 
counted, with 40 infections in the active vaccine arm, the boundary has been reached. In 
general, the null hypothesis will be rejected when the probability that the observed infections 
are from the vaccine arm is significantly larger than 50% (blue line in Figure 6-3). If the 
prespecified stopping boundary is reached, then the unblinded statisticians will immediately 
inform the DSMB. In addition, the DSMB chair will be updated on the accruing unblinded 
HIV-1 infection data after each confirmed MITT infection. This monitoring guideline is 
chosen to allow stopping for prudence as early as possible, maximizing participant safety. 
 
 
Figure 6-3 Potential harm stopping boundary for the total number of HIV-1 infections in the 
active vaccine regimen versus placebo. Blue line is the potential harm stopping boundary, red 
line displays the case that all of the infections are in the vaccine arm. 
6.5.2 
Monitoring for non-efficacy 
Non-efficacy will be followed by means of a double monitoring rule. These analyses will 
start when all participants have reached the Month 13 timepoint, and 60 MITT infections 
have occurred, then approximately every 6 months until the end of Stage 1. The 
boundary is hit when the VE 95% CI upper limit is <40% for both VE(0-24) and VE(7-
24). Figure 6-4 shows the cumulative probability of hitting a non-efficacy bound in time. 
If the non-efficacy boundary is hit prior to reaching the end of Stage 1, the final analysis 
will be performed at the time the boundary is hit (prior to reaching the end of Stage 1) 
and the results will be reported. For participants that are already beyond 24 months of 
follow-up, no further follow-up will be required. For the other participants, a decision 
would be made, based on input from the OG, on whether to still follow them up until 
their month 24 visit. Stage 2 will not be started in this case. 

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Figure 6-4 Cumulative probability of hitting a potential harm or non-efficacy bound in time  
Additionally, the DSMB will monitor the trial for non-efficacy with the aim to detect early 
on scenarios where the null hypothesis would not be rejected if the study were to 
continue to its end. At each DSMB meeting, conditional power calculations will be 
provided. These calculations will help in interpreting the projected treatment-arm-pooled 
infection totals. The conditional power is defined as the power for rejecting H0: VE(0-24) 
≤ 0%, setting VE(0-24) = 50%. The conditional power will be calculated given the actual 
enrollment, dropout, and treatment-arm-pooled HIV-1 incidence data from trial start 
through the time of the interim analysis and compared to a benchmark of 50% power. 
 
6.5.3 
Monitoring for high efficacy 
The DSMB will also monitor for high vaccine efficacy (95% CI lower limit for VE [0-
36] >70%). Interim analyses for high efficacy will begin following the first participant’s 
36 month visit (end of Stage 2), and will be performed together with those for non-
efficacy monitoring. Stopping for high efficacy would entail study unblinding and 
offering placebo recipients vaccination. The criterion for continuing from Stage 1 to 
Stage 2 is given in Section 6.3. 
Figure 6-5 shows the trial design. Whereas the timing of interim analyses is event-driven, 
the total number of Stage 1 infections is not fixed. The end of Stage 1 is when the last 
enrolled participant reaches the Month 24 visit. Ensuring all participants are followed to 
Month 24 maximizes power and precision for assessing VE(7-24). 

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Figure 6-5 Study design and stages. Triangles represent vaccination timepoints. Stage 1 is the 
calendar time since trial start until the last enrolled participant reaches the Month 24 visit. Stage 2 
is the calendar time since the last enrolled participant reached the Month 24 visit until the last 
enrolled participant reaches the Month 36 visit.  Participants who completed their Month 36 visit will 
be followed further with scheduled clinical visits until the end of the study (ie, when the last Month 
36 visit is completed). 
Early stopping of the study while Stage 1 is still ongoing will be recommended if the 
potential harm or non-efficacy boundary is met at a pre-specified analysis time, in which 
case the final analysis will be performed and Stage 2 will not occur. If none of the 
stopping boundaries are reached by the end of Stage 1, the primary endpoint of vaccine 
efficacy from Month 7 through Month 24 [VE(7-24)] is evaluated at the end of Stage 1. If 
the lower bound of the 2-sided 95% confidence interval for VE(7-24) is > 0% at the end 
of Stage 1 (equivalently, the 1-sided p-value for testing H0: VE(7-24) ≤ 0% is below 
0.025), trial participants will continue blinded follow-up through Stage 2. On the other 
hand, if at the Stage 1 efficacy analysis the lower bound of the 95% confidence interval 
for VE(7-24) ≤ 0%, Stage 2 will not occur even if none of the stopping boundaries were 
reached by the end of Stage 1. 
6.5.4 
Monitoring for futility to assess VE 
The DSMB monitors the trial for futility to assess VE defined as overly slow progress 
toward the Target Number of Infections (defined below) or insufficient conditional power 
for the primary analysis given the observed data. This may occur if enrollment rates are 
too low and/or the incidence of HIV-1 infections is too low. The DSMB will monitor for 
futility to assess VE every 6 months starting no later than 12 months after the first 
participant is enrolled. All relevant data that are available regarding enrollment and 
dropout will be provided to the DSMB. Timings can be adapted at the discretion of the 
DSMB in case signs of futility to assess VE are seen. According to the design, enrollment 
is expected to take place within 14 months. 
We define the Target Number of Infections to be the number of primary HIV-1 endpoints 
after Month 7 and by the Month 24 visit such that the trial has approximately 70% power 
to reject H0: VE ≤ 0% if VE = 50% (using a 1-sided 0.025-level cumulative hazard-based 
Wald test). 
The DSMB will be provided with the distribution of infections together with the expected 
distribution of infections under the design assumptions (incidence, VE and dropout rates; 
table below). The conditional power for rejecting VE(7-24) ≤ 0% using the actual data, 
given a true vaccine efficacy of 50% in the future data, will also be provided to the 
DSMB at each interim analysis. More details on the data provided to the DSMB will be 
described in the DSMB charter. 

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Table 6-5 Probability distribution of all Stage 1 infections  
VE* 
Percentiles of distribution of number of Infections (Post Month 7) 
  
1% 
2.5% 
5% 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
95% 
97.5% 
99% 
0% 
105 
110 
112 
116 
120 
123 
126 
128 
131 
134 
138 
143 
148 
151 
154 
50% 
76 
80 
83 
85 
89 
92 
94 
97 
99 
102 
105 
110 
113 
117 
120 
  
Percentiles of distribution of number of Infections (MITT) 
0% 
157 
164 
169 
173 
179 
183 
186 
190 
193 
196 
201 
206 
212 
216 
221 
50% 
124 
128 
131 
136 
141 
144 
147 
150 
153 
156 
160 
166 
171 
174 
179 
*Halved in first 7 months  
 N=1300:1300 placebo:vaccine group 
 4.2% annual incidence in placebo group 
 10% annual dropout 
6.5.5 
Monitoring for expanding enrollment 
At the time of each DSMB meeting for which there are enough HIV infections to conduct 
an analysis, the HVTN 705/HPX2008 Oversight Group (OG) will receive the results of 
the operational futility analysis (which are blinded—pooled across treatment arms). The 
OG will also be provided additional information at the time of a special DSMB meeting 
scheduled to take place approximately 2 months before the completion of enrollment—
based on ongoing projections of time until full enrollment by study statisticians. For this 
meeting, study statisticians will prepare a report that includes the calculations typically in 
an operational futility analysis, along with additional guidance as to whether the HIV 
incidence – pooled over treatment arms—is “too low” or “acceptable” to sufficiently 
power the study. (The details of this guidance will be described in the study SAP.) The 
report will be shared both with the DSMB and with the study OG. The OG will then have 
the opportunity to decide whether, if incidence is lower than anticipated but not so low 
that operational futility is declared, to expand enrollment beyond the originally planned 
2600, in order to maintain the ability of the study to meet the study’s primary objectives. 
The meeting will be timed before but near to the end of enrollment, to allow a potential 
decision to expand enrollment to occur before the enrollment apparatus is scaled down, 
while also allowing the decision to be made on the maximal amount of primary endpoint 
infections. The OG will also be presented information on the degrees of enrollment 
expansion that would be required in order to achieve conditional power and treatment-
arm-pooled infection totals at various levels. 
6.5.6 
Roles of study statisticians 
HVTN SDMC statisticians will be “blinded” or “unblinded”. Janssen statisticians will 
remain blinded until the primary analysis at Month 24. During protocol development and 
after primary follow-up is completed, there will be no distinction between the roles; both 
types of statisticians will be responsible for designing and analyzing the study. During the 
primary follow-up period, however, only the unblinded statisticians will see interim data 
broken down by treatment arm. Their role will be to conduct the interim monitoring and 
to produce and present reports on accruing data to the study DSMB. During the primary 
follow-up period, blinded statisticians will see only the interim data pooled across 
treatment arms. This way, blinded statisticians can assist protocol leadership in making 
decisions about modifications to the protocol without being influenced by interim 
efficacy results.  
 

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6.6 
Assessment of PrEP use 
The use of oral FTC/TDF as PrEP (either off-study or provided in the study) may impact 
study outcomes (e.g., by lowering HIV-1 incidence with a loss of study power). Dried 
blood spot (DBS) samples will be collected and stored for assessment of quantitative 
concentrations of intracellular tenofovir diphosphate (TFV-DP) (see Section 11.9). DBS 
samples will be collected and stored at pre-specified DBS sample collection days, which 
may vary by study site. The calendar-based selection of sample collection days will 
ensure representative sampling of participants across the entire visit schedule at all sites 
throughout the study. A detailed DBS sampling plan, specified in the statistical analysis 
plan, will be developed to prospectively monitor FTC/TDF use during the trial to inform 
the DSMB and to assess the potential impact of FTC/TDF use on endpoint accrual during 
the study. Prevalence of oral PrEP use will be reported both as the estimated percentage 
of person-years at-risk during highly adherent PrEP use (above the concentration of TFV-
DP designated as consistent with daily dosing) and the estimated percentage of person-
years at-risk during any detectable PrEP use (concentration of TFV-DP above the lower 
limit of detection for the DBS assay). PrEP use measures will be reported by arm to the 
DSMB in the closed session; in addition both the OG and the protocol team leadership 
will see pooled estimates of FTC/TDF use. 
6.7 
Randomization of treatment assignments 
The randomization sequence will be obtained by computer-generated random numbers 
through an Interactive Web Response System (IWRS) under provision by the sponsor and 
provided to each HVTN CRS. The randomization will be stratified by HVTN CRS and 
done in blocks to ensure balance across arms. At each institution, the pharmacist with 
primary responsibility for dispensing study products is charged with maintaining security 
of the treatment assignments. Participants and site staff will be blinded as to the treatment 
group assignment throughout both Stage 1 and Stage 2, if it occurs. 
6.8 
Blinding 
The study participants, study-site personnel (except for those with primary responsibility 
for study vaccine preparation and dispensing), and investigators will be blinded to study 
vaccine allocation throughout the study (both Stage 1 and Stage 2, if it occurs).  
Study product assignments are accessible to those HVTN CRS pharmacists and contract 
monitors, and SDMC staff who are required to know this information in order to ensure 
proper trial conduct. Any discussion of study product assignment between pharmacy staff 
and any other HVTN CRS staff is prohibited. The DSMB members also are unblinded to 
treatment assignment in order to conduct review of trial safety and efficacy.  
When a participant leaves the trial prior to study completion, the participant will be told 
she must wait until all participants have completed follow-up to learn her treatment 
assignment.  
Emergency individual unblinding decisions will be made by the site investigator when 
the timing is critical for medical management. Otherwise, the HVTN 705/HPX2008 
PSRT should be consulted before emergency unblinding occurs. 

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6.9 
Statistical analysis 
Statistical analysis will be done by close collaboration between HVTN SDMC and 
Janssen Vaccines. A general description of the statistical methods to be used to analyze 
the efficacy, safety and immunogenicity data is outlined below. Specific details will be 
provided in the SAP. 
This section describes the final study analysis with unblinded treatment groups. The 
primary efficacy analysis will be performed when all participants have reached the Month 
24 visit or discontinued earlier. The primary analyses of safety will be performed on the 
FAS. The primary analysis of vaccine efficacy will be based on the PP population. 
Secondary analyses of vaccine efficacy will be based on the MITT population and the 
FIS. Analyses of vaccine immunogenicity and immune correlates of risk will be based on 
the IC-at risk, IC-PP and the FIS. In general vaccination assignment will follow the as 
treated principle, except for analyses using the MITT population. 
Analyses for primary endpoints will be performed using SAS and R.  
No multiplicity corrections will be used unless stated otherwise.  
6.9.1 
Analysis variables 
The analysis variables consist of baseline participant characteristics, safety, efficacy, and 
immunogenicity. 
6.9.2 
Baseline comparability 
Treatment arms will be compared for baseline participant characteristics using descriptive 
statistics. 
6.9.3 
Safety/tolerability analysis 
All safety analyses will be tabulated by treatment group (active vaccine, placebo) and 
based on the FAS.  
6.9.3.1 
Reactogenicity 
The number and percentage of participants experiencing each type of reactogenicity sign 
or symptom will be tabulated by severity and treatment group and the percentages 
displayed graphically by arm. For a given sign or symptom, each participant’s 
reactogenicity will be counted once under the maximum severity for each injection visit. 
In addition, to the individual types of events, the maximum severity of local pain or 
tenderness, induration or erythema, and of systemic symptoms will be calculated. 
Kruskal-Wallis tests will be used to test for differences in severity between arms. 
6.9.3.2 
AEs and SAEs 
AEs will be summarized using MedDRA System Organ Class and preferred terms. 
Tables will show by treatment group the number and percentage of participants 
experiencing an AE within a System Organ Class or within preferred term category by 
severity and by relationship to study product. For the calculations in these tables, a 
participant with multiple AEs within a category will be counted once under the maximum 
severity and by causal relationship to study product. Formal statistical testing comparing 

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arms is not planned since interpretation of differences must rely heavily upon clinical 
judgment. Parallel analyses will include all AEs and AEs leading to participant 
withdrawal or early discontinuation of study product(s).  
A listing of SAEs reported to the Janssen Global Medical Safety Group will provide 
details of the events including severity, relationship to study product, time between onset 
and last vaccination, and number of vaccinations received. 
6.9.3.3 
Reasons for vaccination discontinuation and early study termination 
The number and percentage of participants who discontinue vaccination and who 
terminate the study early will be tabulated by treatment arm and including the reason for 
discontinuation. 
6.9.4 
Immunogenicity analysis 
Data from quantitative assays will be summarized (tabulated/graphically presented per 
timepoint available) by treatment group: N, geometric means and corresponding 95% 
CIs, percentage positive responses/responders (if available). 
Data from qualitative (ie, positive or negative) assays will be summarized by tabulating 
the frequency of positive responses for each assay by group at each timepoint that an 
assessment is performed. 
6.9.5 
Vaccine efficacy analyses 
6.9.5.1 
Primary vaccine efficacy analysis: HIV-1 infection 
The primary analysis will be done in the PP population where participants becoming HIV 
infected or dropping out before the visit after the third vaccination or not having received 
all of the first 3 vaccinations within the specified time window or having a major 
specified protocol deviation, will be excluded from the analysis. The date of HIV-1 
diagnosis will be the draw date of the first sample that leads to a positive test result by the 
diagnostic algorithm described in Section 10.3. Dropouts will be censored at the time of 
their last HIV-1 negative test. To evaluate the primary vaccine efficacy endpoint, the 
ratio of cumulative incidences of HIV-1 infection between Months 7 and 24 (vaccine vs. 
placebo), estimated using the transformed Nelson-Aalen cumulative hazard function 
estimator and tested via a Wald test. Cox proportional hazards model will also be used for 
estimating VE(7-24), measured by 1 minus the hazard ratio (vaccine vs. placebo) and for 
score testing whether the VE(7-24) differs from 0%.  
As a sensitivity analysis to the primary analysis of vaccine efficacy in the PP population, 
targeted minimum loss-based estimation (TMLE) is used to estimate of this vaccine 
efficacy parameter. In particular, TMLE is used to estimate the cumulative incidences of 
HIV-1 infection over time for each of the vaccine and placebo groups, through to the 
final timepoint Month 24. These estimates will then be contrasted to estimate the primary 
VE parameter VE(7-24), which adjusts for covariates. This analysis has the ability to 
correct for bias due to measured participant covariates that predict both per-protocol 
status and HIV-1 infection. Iterative mean-based TMLE is used for this analysis as 
described in Benkeser et al. (2016, PhD dissertation). As part of the implementation of 
the TMLE the Super Learner is used to generate initial estimates of the conditional 
censoring distribution and the iterated conditional means [48]. The Super Learner library 
includes both parametric and nonparametric learning algorithms that are specified in the 

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SAP; the SAP also specifies the input variables considered by the different learning 
algorithms. Each learning algorithm considers adjustment for baseline demographic 
covariates and the baseline behavioral risk score built via supervised learning. 
In addition, to assess potential time-effects of vaccine efficacy, the Kaplan-Meier method 
will be used to plot the estimated cumulative incidence rates over time for the vaccine 
and placebo groups. This method will be used to estimate cumulative vaccine efficacy 
over time, defined as [(1–ratio(vaccine/placebo) of cumulative incidence by time 
t)*100%], with the method of Parzen, Wei and Ying applied to estimate pointwise and 
simultaneous 95% Cis [49]. 
6.9.5.2 
Secondary vaccine efficacy analyses: HIV-1 acquisition 
Vaccine efficacy for MITT and FIS 
The analyses above will be repeated for the MITT population and the FIS. 
Durability of vaccine efficacy 
Vaccine efficacy over all available follow-up times will be assessed using the method of 
Parzen, Wei, and Ying described above, as well as with nonparametric hazard ratio 
estimation [50] and with Cox proportional hazards modeling with time-dependent 
covariates. If the analysis suggests time-invariant vaccine efficacy, then the Cox model 
will be used to estimate proportional-hazards VE and to test for VE different from zero 
accounting for all available follow-up time. The SAP will provide details of these 
analyses. 
Vaccine efficacy in the absence of PrEP 
The primary analysis will be repeated, where only MITT or PP infections in participants 
who were not using prophylactic ARVs at the time of HIV-1 diagnosis or first evidence 
of infection will be included in the analysis. Plasma drug levels will be used to determine 
eligibility for this analysis. A participant is eligible if the plasma drug levels are 
undetectable at the diagnosis visit and at the visit with earliest evidence of HIV-1 
infection (if different from the diagnosis visit). Since the ARVs are only detectable in 
plasma through roughly 14 days [51] and some participants may have become infected 
before the 14-day window, with this approach we are not assured that all those included 
in the analysis were not using prophylactic ARVs at the time of infection. Therefore, an 
additional analysis will address this issue by also excluding participants from the HIV-1 
acquisition analysis if they self-reported drug use in the last 30 days at either the 
diagnosis visit or the last visit prior to diagnosis. This additional analysis will evaluate 
uninfected participants without accounting for data on their plasma drug levels. 
Vaccine efficacy by subgroups 
The primary analysis may be repeated for different subgroups. Wald tests for interaction 
in the context of Cox proportional hazards models will be used to test for evidence of 
differential vaccine efficacy by subgroup. 
6.9.5.3 
Secondary vaccine efficacy and activity analyses of viral sequences 
Vaccine efficacy and genotypic characteristics  

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A variety of methods may be used to assess genotypic characteristics of HIV as potential 
effect modifiers of VE(0-24) [52]. The TMLE for estimating cumulative incidences in the 
presence of competing risks will also be applied as described in Benkeser et al. (2016, 
PhD dissertation). Like the TMLE efficacy analysis, this analysis incorporates Super 
Learner to increase precision. Details can be found in the SAP. 
Sieve analysis  
Acquisition sieve analysis methods including genome scanning tests described in Gilbert 
et al. and their extensions will be used to evaluate the relationship between VE(7-24) and 
VE(0-24), and the genotypic differences between the incoming exposing/founder 
sequences and the HIV insert sequence(s) represented in the vaccine construct [53]. 

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7 
Selection and withdrawal of participants 
Participants will be healthy, HIV-uninfected (seronegative) women who comprehend the 
purpose of the study and have provided informed consent. Volunteers will be recruited 
and screened; those determined to be eligible, based on the inclusion and exclusion 
criteria, will be enrolled in the study. Final eligibility determination will depend on 
results of medical history, hemoglobin, physical examinations, and answers to self-
administered and/or interview questions.  
Investigators should always use good clinical judgment in considering a volunteer’s 
overall fitness for trial participation. Some volunteers may not be appropriate for 
enrollment even if they meet all inclusion/exclusion criteria. Medical, psychiatric, 
occupational, limited ability to communicate, or other conditions may make evaluation of 
safety and/or immunogenicity difficult, and some volunteers may be poor candidates for 
retention. 
Determination of eligibility, taking into account all inclusion and exclusion criteria, must 
be made within 45 days prior to enrollment unless otherwise noted in Sections 7.1 and 
7.2. 
The HVTN 705/HPX2008 PSRT will be consulted for questions related to selection and 
withdrawal of participants that are not specifically addressed below or are ambiguous. All 
attempts to achieve consensus will be made. In the event that consensus cannot be 
reached, the participant will not be enrolled. 
7.1 
Inclusion criteria 
General and Demographic Criteria 
1. Persons born female (assigned female sex at birth) 
2. Age of 18 to 35 years 
3. Sexually active, defined as having had sexual intercourse with a male partner at least 
twice in the past 30 days prior to screening, and is considered by the site staff to be at 
risk for HIV infection. 
4. Access to a participating HVTN CRS and willingness to be followed for the planned 
duration of the study 
5. Ability and willingness to provide informed consent 
6. Assessment of understanding: volunteer demonstrates understanding of this study 
prior to first vaccination with verbal demonstration of understanding of all questions. 
7. Is not enrolled in, and agrees not to enroll in, another study of an investigational 
research agent until the participant is unblinded or their study participation ends, 
whichever occurs last 

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8. Good general health as shown by medical history, hemoglobin, and physical exam. 
STIs are not exclusionary, unless deemed to impact general health by the investigator. 
HIV-Related Criteria: 
9. Willingness to receive HIV test results 
10. Willingness to discuss HIV infection risks and willing to receive HIV risk reduction 
counseling and appropriate referrals to minimize HIV acquisition, as applicable. 
Laboratory Inclusion Values 
Virology 
11. Negative HIV-1 and -2 blood test: Sites may use locally available assays that have 
been approved by HVTN Laboratory Operations. 
Hemoglobin 
12. Hemoglobin ≥ 10.5 g/dL  
Reproductive Status 
13. Negative beta human chorionic gonadotropin (β-HCG) pregnancy test performed prior 
to vaccination on the day of initial vaccination. Persons who are NOT of reproductive 
potential due to having undergone total hysterectomy or bilateral oophorectomy 
(verified by medical records), are not required to undergo pregnancy testing. 
14. All volunteers must: 
• 
Agree to consistently use effective contraception (Appendix B) for sexual activity 
that could lead to pregnancy from at least 21 days prior to enrollment through 3 
months after the last vaccination. Effective contraception is defined as using 1 of the 
following methods of birth control. 
▪ 
Intrauterine device (IUD), 
▪ 
Hormonal contraception (in accordance with applicable national contraception 
guidelines), or 
▪ 
Any other contraceptive method approved by the HVTN 705/HPX2008 PSRT; 
• 
Or not be of reproductive potential, such as having been diagnosed with premature 
menopause (with no menses for 1 year) or having undergone hysterectomy, bilateral 
oophorectomy, or tubal ligation. 
15. Volunteers must also agree not to seek pregnancy through alternative methods, 
such as artificial insemination or in vitro fertilization until 3 months after the last 
vaccination 
7.2 
Exclusion criteria 
General 

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1. Blood products received within 90 days before first vaccination 
2. Investigational research agents received within 30 days before first vaccination 
3. Intent to participate in another study of an investigational research agent or any other 
study that requires non-HVTN HIV antibody testing or blood draws during the planned 
duration of the HVTN 705/VAC89220HPX2008 study 
4. Pregnant or breastfeeding (breastfeeding includes wet nursing) 
Vaccines and other Injections 
5. HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received 
control/placebo in an HIV vaccine trial, the HVTN 705/HPX2008 PSRT will determine 
eligibility on a case-by-case basis. 
6. Non-HIV experimental vaccine(s) received within the last year in a prior vaccine trial. 
Exceptions may be made for vaccines that have subsequently undergone licensure. For 
volunteers who have received control/placebo in an experimental vaccine trial, the HVTN 
705/HPX2008 PSRT will determine eligibility on a case-by-case basis. For volunteers 
who have received an experimental vaccine(s) greater than 1 year ago, eligibility for 
enrollment will be determined by the HVTN 705/HPX2008 PSRT on a case-by-case 
basis. 
7. Live attenuated vaccines received 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) 
8. Any vaccines that are not live attenuated vaccines and were received within 14 days 
prior to first vaccination (eg, tetanus, pneumococcal, Hepatitis A or B) 
Immune System 
9. Immunosuppressive medications received within 6 months before first vaccination. 
(Not exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical 
corticosteroids for mild, uncomplicated dermatitis; or [4] a single course of 
oral/parenteral prednisone or equivalent at doses < 60 mg /day and length of therapy < 11 
days with completion at least 30 days prior to enrollment.) 
10. Serious adverse reactions to vaccines including history of anaphylaxis and related 
symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain. (Not 
excluded from participation: a volunteer who had a non-anaphylactic adverse reaction to 
pertussis vaccine as a child.) 
11. Immunoglobulin received within 60 days before first vaccination 
12. Immunodeficiency 
Clinically significant medical conditions 
13. Clinically significant medical condition, physical examination findings, clinically 
significant abnormal laboratory results, or past medical history with clinically significant 

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implications for current health. A clinically significant condition or process includes but 
is not limited to: 
• 
A process that would affect the immune response, 
• 
A process that would require medication that affects the immune response, 
• 
Any contraindication to repeated injections or blood draws, 
• 
A condition that requires active medical intervention or monitoring to avert grave 
danger to the volunteer’s health or well-being during the study period, 
• 
A condition or process for which signs or symptoms could be confused with reactions 
to vaccine, or 
• 
Any condition specifically listed among the exclusion criteria below. 
14. Any medical, occupational, or other condition that, in the judgment of the investigator, 
would interfere with, or serve as a contraindication to, protocol adherence, assessment of 
safety or reactogenicity, or a volunteer’s ability to give informed consent 
15. Psychiatric condition or substance abuse issue that precludes compliance with the 
protocol, in the opinion of the investigator. 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. 
16. Active tuberculosis (TB) disease 
17. Uncontrolled BP elevation: systolic blood pressure (SBP) ≥ 160 mm Hg or diastolic 
blood pressure (DBP) ≥ 100 mm Hg 
18. Bleeding disorder (diagnosed by a doctor) contraindicating IM injection and/or blood 
draws, based on investigator’s judgment 
19. Malignancy (Not excluded from participation: Volunteer who has had malignancy 
excised surgically and who, in the investigator’s estimation, has a reasonable assurance of 
sustained cure or who is unlikely to experience recurrence of malignancy during the 
period of the study) 
20. History of hereditary angioedema, acquired angioedema, or idiopathic angioedema 
21. Employee of the investigator or study site, with direct involvement in the proposed study 
or other studies under the direction of that investigator or study site 
7.3 
Participant departure from vaccination schedule or withdrawal 
This section concerns an individual participant’s departure from the vaccination schedule. 
Pause rules for the trial as a whole are described in Section 12.3. 
7.3.1 
Delaying vaccinations for a participant 
Under certain circumstances, a participant’s scheduled vaccination will be delayed. The 
factors to be considered in such a decision include but are not limited to the following: 

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• 
Within 45 days prior to any study injection  
▪ 
Receipt of blood products or immunoglobulin 
• 
Within 30 days prior to any study injection 
▪ 
Receipt of live attenuated vaccines  
▪ 
Receipt of allergy treatment with antigen injections 
• 
Within 14 days prior to any study injection 
▪ 
Receipt of any vaccines that are not live attenuated vaccines (eg, Hepatitis)  
• 
Pre-vaccination abnormal vital signs or clinical symptoms that may mask assessment 
of vaccine reaction. 
• 
Pregnancy: For participants, who become pregnant, no study vaccinations will be 
given; except for participants who may have been pregnant during the study but are 
no longer pregnant as shown by 2 negative urine pregnancy tests taken from 2 
different urine samples; in this circumstance, the HVTN 705/HPX2008 PSRT should 
be consulted to determine if the participant may resume vaccinations. 
In order to avoid vaccination delays and missed vaccinations, participants who plan to 
receive licensed vaccines should be counseled to schedule receipt of these substances, 
when possible, outside the intervals indicated above. The effects of these substances on 
safety and immunogenicity assessments and their interactions with study vaccines are 
unknown. Therefore, if circumstances allow, these substances should also be avoided in 
the 4 weeks following study vaccination. 
7.3.2 
Participant departure from vaccination schedule 
Every effort should be made to follow the vaccination schedule per the protocol. 
Vaccinations should generally not be administered outside the visit window period 
specified in the HVTN 705/VAC89220HPX2008 Study Specific Procedures (SSP). If a 
participant cannot be vaccinated within the allowable window, the PSRT can determine 
on a case-by-case basis if the participant can still be vaccinated.  
If a participant misses a vaccination, the participant should be asked to continue study 
visits. The participant should resume the vaccination schedule with the next vaccination 
unless there are circumstances that require further delay or permanent discontinuation of 
vaccination (see Sections 7.3.1 and 7.3.3).  
7.3.3 
Discontinuing vaccination for a participant 
Under certain circumstances, an individual participant’s vaccinations will be temporarily 
or permanently discontinued. Specific events that will result in stopping a participant’s 
vaccination schedule include: 
• 
Co-enrollment in a study with an investigational research agent (rare exceptions 
allowing for the continuation of vaccinations may be granted with the unanimous 
consent of the HVTN 705/HPX2008 PSRT). 
• 
Clinically significant condition (ie, a condition that affects the immune system or for 
which continued vaccinations and/or blood draws may pose additional risk), 
including but not limited to the following: 

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▪ 
Pregnancy: Vaccinations will be stopped while a participant is pregnant. If the 
participant is no longer pregnant, vaccinations may resume (Sections 7.3.1 and 
7.3.2); 
▪ 
Any related SAE; 
▪ 
Any grade 4 local or systemic reactogenicity symptom, lab abnormality, or AE 
that is subsequently considered to be related to vaccination; 
▪ 
Any grade 3 lab abnormality or other clinical AE (exception: fever or vomiting 
and subjective local and systemic symptoms) that is subsequently considered to 
be related to vaccination after confirmation by the PSRT. For grade 3 injection 
site erythema and/or induration, upon review, the PSRT may allow continuation 
of vaccinations; or 
▪ 
Clinically significant type 1 hypersensitivity reaction associated with study 
vaccination. Consultation with the HVTN 705/HPX2008 PSRT is required prior 
to subsequent vaccinations following any type 1 hypersensitivity reaction 
associated with study vaccination; or 
• 
Investigator determination in consultation with PSRT and sponsor (eg, for repeated 
nonadherence to study staff instructions; recognition of non-disclosed preexisting 
condition of clinical significance). 
Such participants should be counseled on the importance of continuing with the study and 
strongly encouraged to participate in follow-up visits and protocol-related procedures per 
the protocol for the remainder of the trial, unless medically contraindicated. 
In addition, vaccinations will be stopped for participants diagnosed with HIV infection. 
7.3.4 
Participant termination from the study 
Under certain circumstances, an individual participant may be terminated from 
participation in this study. Specific events that will result in early termination include: 
• 
Participant refuses further participation, 
• 
Participant relocates and remote follow-up or transfer to another HVTN CRS is not 
possible, 
• 
HVTN CRS determines that the participant is lost to follow-up,  
• 
Investigator decides, in consultation with the PSRT, to terminate participation (eg, if 
participant exhibits inappropriate behavior toward clinic staff). 
• 
Any condition where termination from the study is required by applicable 
regulations. 

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8 
Study product preparation and administration 
CRS pharmacists should consult the Site Investigational Product Procedures Manual, 
provided by the Sponsor for further instructions on study product preparations. The 
protocol schema is shown in Table 3-1. See the Investigator’s Brochures for further 
information about study products. 
All study products must be stored at 2°C - 8°C. Refer to the Site Investigational Product 
Procedures Manual for additional guidance on study drug preparation, handling, and 
storage. 
8.1 
Vaccine regimen 
The schedule of vaccination is shown in Table 3-1.The vaccine is given on Months 0, 3, 
6, and 12 and additional information is given below. 
Group 1 
Treatment 1 (T1): 
Ad26.Mos4.HIV 5 x 1010 vp to be administered as 0.5 mL IM into the LEFT deltoid 
(unless medically contraindicated) on Months 0, 3, 6, and 12. 
AND  
Clade C gp140 (250 mcg) mixed with Aluminum phosphate adjuvant to be 
administered as 0.5 mL IM into the RIGHT deltoid (unless medically 
contraindicated) on Months 6 and 12. 
Group 2 
Placebo 2 (P2): 
Placebo for Ad26.Mos4.HIV to be administered as 0.5 mL IM into the LEFT deltoid 
(unless medically contraindicated) on Months 0, 3, 6, and 12. 
AND 
Placebo for Clade C gp140 / Aluminum phosphate adjuvant to be administered as 0.5 
mL IM into the RIGHT deltoid (unless medically contraindicated) on Months 6 and 
12. 
8.2 
Study product formulation  
8.2.1 
Ad26.Mos4.HIV [Labeled as Ad26.Mos4.HIV] 
The Ad26.Mos4.HIV vaccine is formulated as a tetravalent vaccine 1x1011 vp/mL , and is 
supplied as a colorless to slightly yellowish/brownish solution for IM injection. The 

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vaccine will be provided in single-use vial containing a volume to deliver 0.5 mL of 
5x1010 Ad26 Mos4.HIV.  
The study product is described in further detail in the Investigator’s Brochure (IB). 
8.2.2 
Placebo for Ad26.Mos4.HIV 
Sodium chloride for injection USP, 0.9% will be used as the placebo for 
Ad26.Mos4.HIV. 
8.2.3 
Clade C gp140 (250 mcg) + Aluminum Phosphate adjuvant  
Clade C gp140 and aluminum phosphate adjuvant will either be co-formulated or 
supplied in separate vials: 
The Clade C gp140 (250mcg) and aluminum phosphate adjuvant are co-formulated as a 
white to off-white suspension in single-use vials with a deliverable volume of 0.5 mL of 
0.5 mg/mL Clade C gp140 and 0.85 mg/mL aluminum phosphate adjuvant. The study 
product is described in detail in the Investigator’s Brochure (IB).  
OR 
Clade C gp140 is formulated as a colorless to slightly yellowish/brownish solution and 
will be practically free from particles. Clade C gp140 will be supplied at a nominal 
strength of 1 mg/mL. The aluminum phosphate adjuvant is formulated as a white to off-
white suspension with a nominal aluminum content of 1.7 mg/mL. It will be mixed with 
Clade C gp140 at the site pharmacy prior to administration. The study products are 
described in detail in the IB. 
8.2.4 
Placebo for Clade C gp140 /Aluminum Phosphate adjuvant 
Sodium chloride for injection, 0.9% will be used as the placebo for Clade C 
gp140/Aluminum Phosphate adjuvant.  
8.3 
Preparation of study products 
CRS pharmacists should consult the Site Investigational Product Procedures Manual, 
provided by the Sponsor for further instructions on study product preparations. 
8.3.1 
Procedures to preserve blinding 
The pharmacist will prepare all doses for administration and dispense to the clinic. In 
order to preserve blinding, the pharmacist will place an overlay on ALL the syringes. 
8.4 
Administration 
All injections are to be given IM by blinded study staff in the deltoid indicated.  
CRS pharmacists should consult the Site Investigational Product Procedures Manual, 
provided by the Sponsor for further instructions on study product administration. 

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8.5 
Acquisition of study products 
Ad26.Mos4.HIV, the co-formulated Clade C gp140 with aluminum phosphate adjuvant, 
the individual Clade C gp140 product, the individual aluminum phosphate adjuvant, and 
Placebo will be provided by Janssen Vaccines & Prevention B.V. (Leiden, The 
Netherlands). 
Once an HVTN CRS has completed all procedures for study start, study products can be 
obtained by the pharmacist from the sponsor. 
8.6 
Pharmacy records 
The HVTN CRS pharmacist is required to maintain complete records of all study 
products. The pharmacist of record is responsible for maintaining randomization codes 
and randomization confirmation notices for each participant in a secure manner. 
8.7 
Product quality complaint handling 
A product quality complaint (PQC) is defined as any suspicion of a product defect related 
to manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, 
quality, durability, or reliability of a product, including its labeling or package integrity. 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, 
and complete reporting and analysis of PQC information from studies are crucial for the 
protection of participants, for the investigators, and for the sponsor, and are mandated by 
regulatory agencies worldwide. Janssen has established procedures in conformity with 
regulatory requirements worldwide to ensure appropriate reporting of PQC information; 
all studies conducted by the sponsor or its affiliates will have to be conducted in 
accordance with those procedures. 
8.7.1 
Procedures 
All initial PQCs must be reported to Janssen by the HVTN CRS staff within 3 business 
days after being made aware of the event. If the defect is combined with an SAE, the 
CRS staff must report the PQC to Janssen according to the SAE reporting timelines. A 
sample of the suspected product should be maintained for further investigation if 
requested by the sponsor. 
8.7.2 
Contacting Sponsor Regarding Product Quality 
The names (and corresponding contact information) of the individuals who should be 
contacted regarding product quality issues can be found on the protocol home page on the 
HVTN Members’ site (https://members.hvtn.org/protocols/hvtn705). 
8.8 
Final disposition of study products 
All unused study products must be returned to the sponsor or destroyed after the study is 
completed or terminated according to the instructions provided in the Site Investigational 
Product Procedures Manual.  

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9 
Clinical procedures 
The schedule of clinical procedures is shown in Appendix G and Appendix H. 
All study data will be recorded on paper source documents prior to being entered into the 
study database (see the HVTN 705/VAC89220HPX2008 SSP). 
During the COVID-19 pandemic, procedures are in place so that study visits may be 
conducted remotely, such as via phone, text message, email, or other electronic means, in 
lieu of, or in combination with, in-person visits (see HVTN 705/VAC89220HPX2008 
SSP for additional details). 
9.1 
Informed consent 
Informed consent is the process of working with participants so that they fully understand 
what will and may happen to them while participating in a research study. The HVTN 
informed consent form documents that a participant (1) has been informed about the 
potential risks, benefits, and alternatives to participation, and (2) is willing to participate 
in an HVTN study. Informed consent encompasses all written or verbal study information 
HVTN CRS staff provide to the participant, before and during the trial. HVTN CRS staff 
will obtain informed consent of participants according to HVTN policies and procedures. 
The informed consent process continues throughout the study. Key study concepts should 
be reviewed periodically with the participant and the review should be documented. At 
each study visit, HVTN CRS staff should consider reviewing the procedures and 
requirements for that visit and for the remaining visits. Additionally, if any new 
information is learned that might affect the participants’ decisions to stay in the trial, this 
information will be shared with trial participants. If necessary, participants will be asked 
to provide revised informed consent. 
An HVTN CRS may employ recruitment efforts prior to the participant consenting. For 
example, some HVTN CRSs use a telephone script to prescreen people before they come 
to the clinic for a full screening visit. Participants must sign a screening or protocol-
specific consent before any procedures are performed to determine eligibility. HVTN 
CRSs must submit recruitment and prescreening materials to their IRB/EC and any 
applicable regulatory entity (RE) for human subjects protection review and approval. 
Note: An RE is “Any group other than the local IRB/EC responsible for reviewing and/or 
approving a clinical research protocol and site-specific ICFs [informed consent forms] 
prior to implementation at a site.” CRSs are responsible for knowing the requirements of 
their applicable REs. 
9.1.1 
Screening consent form 
Some HVTN CRSs have approval from their IRB/EC and any applicable RE to use a 
general screening consent form that allows screening for an unspecified HIV vaccine 
trial. In this way, HVTN CRS staff can continually screen potential participants and, 
when needed, proceed quickly to obtain protocol-specific enrollment consent. Sites 
conducting general screening or prescreening approved by their IRB/EC and any 
applicable RE may use the results from this screening to determine eligibility for this 

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protocol, provided the tests are conducted within the time periods specified in the 
eligibility criteria.  
9.1.2 
Protocol-specific consent forms 
The protocol-specific consent forms describe the study products to be used and all 
aspects of protocol participation, including screening and enrollment procedures. A 
sample protocol-specific consent form for the main study is located in Appendix A. A 
separate sample consent form for other uses of specimens is located in Appendix C. 
Each HVTN CRS is responsible for developing a protocol-specific consent form(s) for 
local use, based on the sample protocol-specific consent forms in Appendix A and 
Appendix C. The consent form(s) must be developed in accordance with requirements of 
the following: 
• 
CRS’s IRB/EC and any applicable REs, 
• 
CRS’s institution, and 
• 
Elements of informed consent as described in Title 45, CFR Part 46 and Title 21 
CFR, Part 50, and in the International Conference on Harmonisation (ICH) E6, 
Good Clinical Practice: Consolidated Guidance 4.8.  
Study sites are strongly encouraged to have their local CABs review their site-specific 
consent forms. This review should include, but should not be limited to, issues of cultural 
competence, local language considerations, and the level of understandability. 
The sample informed consent form includes instructions throughout the document for 
developing specific content. 
Sites should follow the instructions in the Protocol-specific Official Memo distributed 
along with this protocol regarding when they may begin using their site-specific protocol 
consent forms. 
9.1.3 
Assessment of Understanding 
Study staff are responsible for ensuring that participants fully understand the study before 
enrolling them. This process involves reviewing the informed consent form with the 
participant, allowing time for the participant to reflect on the procedures and issues 
presented, and answering all questions completely.  
An Assessment of Understanding is used to document the participant’s understanding of 
key concepts in this HIV vaccine trial and that in a previous trial there was an association 
of increased HIV acquisition with receipt of that study vaccine. The participant must 
complete the Assessment of Understanding before enrollment. Staff may provide 
assistance in reading and understanding the questions and responses, if necessary. 
Participants must verbalize understanding of all questions answered incorrectly. This 
process and the participant’s understanding of the key concepts should be recorded in 
source documentation at the site. 
IRB/EC and any applicable RE may require that a participant has signed either a 
screening or protocol-specific consent document prior to administering the Assessment of 

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Understanding. The consent process (including the use of the Assessment of 
Understanding) should be explained thoroughly to the IRB/EC and any applicable RE, 
whose recommendations should be followed. 
9.2 
Pre-enrollment procedures 
Screening may occur over the course of several contacts/visits, up to and including before 
vaccination on day 0. All inclusion and exclusion criteria must be assessed within 45 
days before enrollment, unless otherwise specified in the eligibility criteria (or below in 
this section). 
After the appropriate informed consent has been obtained and before enrollment, the 
following procedures are performed: 
• 
Medical history, documented in the case history record; 
• 
Assessment of Understanding (see Section 9.1.3); 
• 
Assessment of risk for HIV infection 
• 
Complete physical examination, including height, weight, vital signs, and clinical 
assessments of head, ears, eyes, nose, and throat; neck; lymph nodes; heart; chest; 
abdomen; extremities; neurological function; and skin; 
• 
Assessment of concomitant medications the volunteer is taking, including 
prescription and nonprescription drugs, vitamins, topical products, 
alternative/complementary medicines (eg, herbal and health food supplements), 
recreational drugs, vaccinations, and allergy shots; 
• 
Laboratory tests as defined in the inclusion and exclusion criteria, including: 
▪ 
Screening HIV testing at local lab, 
▪ 
Pregnancy test, 
▪ 
Hemoglobin; 
• 
Obtaining of volunteer demographics in compliance with the NIH Policy on 
Reporting Race and Ethnicity Data: Subjects in Clinical Research, Aug. 8, 2001 
(available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-053.html); 
• 
Counseling on HIV testing and risk reduction, as described in Section 9.7; and 
• 
Discussion of pregnancy prevention. A pregnant or breastfeeding person may not be 
enrolled in this trial. Specific criteria and assessment of contraception and pregnancy 
status are described in study inclusion criteria.  
9.2.1 
Use of screening results from another HVTN study 
If a participant screens for an HVTN study at the same HVTN CRS but then does not join 
that study, screening results from that effort may be applied to the screening for this 
protocol, as long as the screening was done under participant consent, the participant has 
signed a consent form to begin screening for this study, and the tests were conducted 
within the time periods specified in the eligibility criteria (see Sections 7.1 and 7.2). 

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9.3 
Enrollment and vaccination visits 
Enrollment is simultaneous with first vaccination. The time interval between 
randomization and enrollment should not exceed 4 working days. The HVTN CRS 
registers the participant by scheduling the day 0 visit (enrollment) via the Web-based 
randomization system, and requests the randomization assignment. Circumstances may 
require a participant’s enrollment visit to be changed. This may exceed the 4-day 
randomization time limit. 
At all vaccination visits, the following procedures are performed before vaccination: 
• 
Abbreviated physical examination, including weight, vital signs, and a symptom-
directed evaluation by history and/or appropriate physical exam based on participant 
self-reported symptoms or complaints; 
• 
Assessment of baseline reactogenicity parameters; 
• 
Assessment of concomitant medications (as described in Section 9.2); 
• 
Assessment of any new or unresolved AEs/ intercurrent illnesses; 
• 
Confirm that participants received HIV test results from previous visit. If not provide 
test results and post-test counseling as appropriate; 
• 
Pregnancy test. Persons who are NOT of reproductive potential due to having 
undergone total hysterectomy or bilateral oophorectomy (verified by medical 
records), are not required to undergo pregnancy testing; and 
• 
Specimen collection as applicable. 
Following completion of all procedures in the preceding list, and if results indicate that 
vaccination may proceed, vaccination is prepared and administered (see Sections 8.3 and 
8.4). 
Administration of all injections during a vaccination visit must be accomplished within 1 
calendar day. 
Immediately following vaccination, the participant remains in the clinic for observation. 
An initial reactogenicity assessment is made at a target of 30 minutes after injection, with 
an acceptable range of 25-60 minutes. Before leaving the clinic, the participant is given a 
postvaccination memory tool and is instructed on how to complete it. The site will make 
arrangements to obtain a report of reactogenicity events from the participant after the 
reactogenicity period (as described in Section 9.9). 
The following procedures will be performed at all vaccination visits. These procedures 
may be performed prior to or following vaccination:  
• 
Risk reduction counseling (as described in Section 9.7);  
• 
Pregnancy prevention assessment (as described in Section 9.2 and 9.8);  
• 
Assessment of new or unresolved social impacts (site staff will ask participant about 
the status of any unresolved social impacts and if she has experienced any new social 
impacts as a result of the trial participation). 
Additional procedures will be performed at scheduled visits as specified in Appendix G:  

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• 
Gonorrhea and Chlamydia trachomatis (GC/CT) testing (before vaccination); 
• 
Trichomonas vaginalis testing (before vaccination); 
• 
Syphilis testing (before vaccination); 
• 
Microbiome/mucosal collections: vaginal swab and cervical cup (before vaccination); 
• 
Behavioral risk assessment questionnaire; 
• 
Outside testing and belief questionnaire; and 
• 
HIV infection assessment. 
9.4 
Follow-up visits 
The following procedures are performed at all scheduled follow-up visits: 
• 
Risk reduction counseling (as described in Section 9.7); 
• 
Assessment of new or unresolved social impacts (site staff will ask participant about 
the status of any unresolved social impacts and if s/he has experienced any new 
social impacts as a result of the trial participation); 
• 
Specimen collection as applicable; 
• 
Assessment of new or continuing concomitant medications (as described in Section 
9.2); and 
• 
Assessment of new or unresolved AEs/intercurrent illnesses. 
Additional procedures will be performed at scheduled follow-up visits as specified in 
Appendix E and Appendix G:  
• 
Pregnancy prevention assessment (as described in Section 9.2 and 9.8); 
• 
Microbiome/mucosal collections: vaginal swab and cervical cup (before vaccination); 
• 
GC/CT testing; 
• 
Trichomonas vaginalis testing; 
• 
Syphilis testing;  
• 
Abbreviated physical examination, including weight, vital signs, and a symptom-
directed evaluation by history and/or appropriate physical exam based on participant 
self-reported symptoms or complaints; 
• 
Complete physical examination, including height, weight, vital signs, and clinical 
assessments of head, ears, eyes, nose, and throat; neck; lymph nodes; heart; chest; 
abdomen; extremities; neurological function; and skin; 
• 
HIV infection assessment including pre-test counseling. A subsequent follow-up 
contact is conducted to provide post-test counseling and to report results to 
participant; 
• 
Confirm that participants received HIV test results from previous visit. If not, provide 
test results and post-test counseling as appropriate; 
• 
Behavioral risk assessment questionnaire; 

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• 
Outside Testing and Belief Questionnaire; and 
• 
Urine pregnancy test. Persons who are NOT of reproductive potential due to having 
undergone total hysterectomy or bilateral oophorectomy (verified by medical 
records), are not required to undergo pregnancy testing. 
9.5 
Procedures for HIV-infected participants 
The following procedures are performed at follow-up visits for HIV-infected participants, 
as specified in Appendix F and Appendix H: 
• 
Counseling on HIV-1 testing/diagnosis; 
• 
Referral to medical professionals for care; 
• 
Abbreviated physical examination including weight, vital signs, and a symptom-
directed evaluation by history and/or appropriate physical exam based on participant 
self-reported symptoms or complaints; 
• 
Complete physical examination, including clinical assessments of head, ears, eyes, 
nose, and throat; neck; lymph nodes; heart; chest; abdomen; extremities; neurological 
function; and skin; 
• 
Assessment of HIV/AIDS-related conditions and non-HIV disease progression-
related events; 
• 
Assessment of new or continuing concomitant medications (as described in 9.2); 
• 
Assessment of new or continuing antiretroviral therapies and reason for initiation or 
change in therapy; 
• 
Assessment of new or unresolved AEs/intercurrent illnesses; 
• 
Counseling to reduce the risk of HIV transmission; 
• 
Administration of behavioral risk assessment questionnaire; 
• 
Assessment of new or unresolved social impacts (site staff will ask participant about 
the status of any unresolved social impacts and about any new social impacts 
experienced as a result of the trial participation); 
• 
Specimen collection (Appendix F). 
9.6 
Mucosal sampling 
Vaginal swabs and cups will be collected from study participants at the visits indicated in 
Appendix E and Appendix G. These samples will be used for vaginal microbiome 
analysis and assessment of markers of inflammation including but not limited to 
cytokines, chemokines and other soluble mediators. 

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9.7 
HIV counseling and testing 
HIV counseling will be performed in compliance with the CDC’s guidelines or other 
local guidelines for HIV counseling and referral. HIV testing will be performed in 
accordance with the current HVTN HIV testing algorithm following enrollment. 
Participants will be counseled routinely during the trial on the avoidance of HIV infection 
and on the potential negative social impacts of testing antibody positive due to the 
vaccine. They will also be counseled on the risks of HIV antibody testing outside of the 
HVTN CRSs and will be discouraged from doing so during study participation and/or 
during any period of vaccine-induced positive serology. 
Study staff will take particular care to inform study participants of the likelihood of 
routine HIV testing being offered or performed outside the study CRS at emergency 
rooms, clinics, and medical offices. CRS staff should inform participants of their right to 
opt out of HIV testing outside the study site. CRS staff should inform study participants if 
regulations permit medical providers to perform HIV testing without first informing 
patients. If this is the case, then CRS staff should advise study participants that they may 
decline testing preemptively. CRS staff should also inform participants if positive results 
must be reported to local public health authorities. CRS staff should also inform 
participants of the need to maintain study blinding by getting HIV testing only at the 
study CRS. CRS staff should provide participants with CRS contact information and 
should encourage participants to ask medical providers to contact the CRS. The CRS can 
verify that the participant is in an HIV vaccine clinical trial and should only be tested at 
the study CRS. 
Potential participants identified as being HIV infected during screening are not enrolled. 
All participants who are identified as being HIV infected during the study will be 
followed for approximately 6 months as detailed in Appendix F and Appendix H. 
9.7.1 
Distinguishing intercurrent HIV infection from vaccine-induced positive serology 
The study product may elicit an antibody response to HIV proteins. Therefore, vaccine-
induced positive serology may occur in this study. Several precautionary measures will 
be taken to distinguish intercurrent HIV infection from vaccine-induced positive 
serology. These precautionary measures include: 
• 
Participants will have physical examinations at visits specified in Appendix G. Signs 
or symptoms of an acute HIV infection syndrome, an intercurrent illness consistent 
with HIV-1 infection, or probable HIV exposure (ie, unprotected sex with a known 
HIV positive partner), would prompt a diagnostic workup per the HVTN algorithm 
for Recent Exposure/Acute Infection Testing to determine HIV infection. 
• 
HIV testing will be performed at multiple timepoints throughout the study (see 
Appendix E and Appendix G). The Laboratory Program (or approved diagnostic 
laboratory) will follow 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.  
• 
All participants can receive HIV-1 diagnostic testing from the site following their last 
scheduled visit until they are told that they did not receive an HIV vaccine  
• 
All participants who received vaccine product and who have vaccine-induced 
positive or indeterminate HIV-1 serology (as measured by the standard anti-HIV 

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antibody screening tests) at or after the study is unblinded will be offered poststudy 
HIV-1 diagnostic testing (per the HVTN poststudy HIV-1 testing algorithm) 
periodically and free of charge as medically/socially indicated (approximately every 
6 months) unless or until HIV antibody testing is no longer the standard test in 
clinical settings.  
9.7.2 
VISP registry  
Experimental HIV vaccines may induce antibody production to HIV antigens, producing 
reactive results on commercially available HIV test kits. This is called “vaccine-induced 
seropositivity” (VISP). In order to provide poststudy HIV testing to distinguish between 
VISP and HIV infection, and to mitigate potential social harms resulting from VISP in 
HIV vaccine recipients who are not infected with HIV, the HVTN has created a VISP 
registry. Following study unblinding, the registry will allow trained staff to verify that an 
individual has received an HIV vaccine, and therefore has the potential for VISP. 
Information in the VISP registry will not be used for research. Rather, the registry exists 
to support provision of poststudy testing and counseling services to HIV vaccine 
recipients. The registry contains the names of all study participants, unless they request 
that their names be removed. 
9.8 
Pregnancy prevention assessment 
Contraception status is assessed and documented at scheduled clinic visits as specified in 
Appendix G for a participant who is sexually active in a way that could cause that 
participant to become pregnant. Prior to enrollment and throughout the study, staff will 
ask participants to verbally confirm their use of adequate contraceptive methods. A 
participant who is sexually active in a way that could cause that participant to become 
pregnant should be reminded at scheduled clinic visits, specified in Appendix G, of the 
importance of using contraception and should be referred to specific counseling, 
information, and advice as needed. (Specific contraception requirements are listed in 
Section 7.1). This reminder should be documented in the participant’s study record. 
Self-reported infertility—including having reached menopause (no menses for 1 year) or 
having undergone hysterectomy, bilateral oophorectomy, or tubal ligation—must be 
documented in the participant’s study record. 
9.9 
Assessments of reactogenicity 
For all participants, baseline assessments are performed before and reactogenicity 
assessments are performed after each vaccination. All reactogenicity symptoms are 
followed until resolution and graded according to the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 
2017, except as noted in Section 12.2.2. 
The reactogenicity assessment period is 3 full days following each vaccination. At some 
sites the reactogenicity assessment period may be 7 full days following each vaccination. 
The maximum severity reached for each symptom during the assessment period is 
reported on CRFs. Participants will be given a postvaccination memory tool to assist with 
recall of symptoms. The site staff and the participant will make multiple efforts in good 
faith to be in contact after the last day of the reactogenicity period, or sooner if indicated, 

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to review reactogenicity data. Clinic staff will follow new or unresolved reactogenicity 
symptoms present at the last day of the reactogenicity assessment period to resolution. 
Participants are instructed to contact the clinic for events that arise during the period 
between vaccination and the next scheduled visit. In general, a participant who self-
reports any postvaccination reaction greater than mild is seen by a clinician within 48 
hours after onset, unless the reaction is improving and/or has resolved completely. 
Reactogenicity assessments include assessments of systemic and local symptoms and 
vaccine-related lesions. Events not listed on a CRF, or with an onset after the 
reactogenicity assessment period, or those meeting SAE/AEs criteria requiring expedited 
reporting, are recorded on an AE log form. 
9.9.1 
Assessment of systemic and local symptoms 
Systemic symptoms include increased body temperature, malaise and/or fatigue, myalgia, 
headache, chills, arthralgia, nausea, and vomiting. Local symptoms include pain and/or 
tenderness proximal to the injection site.  
Body temperature is measured by oral or infrared thermometry and reported in degrees 
Celsius. A measurement is taken once daily during the assessment period and should be 
repeated if participant is feeling feverish. 
9.9.2 
Assessment of injection site 
Typical injection site reactions are erythema/redness and induration/swelling. The 
maximum horizontal and maximum vertical measurements for all injection site reactions 
are recorded. 
All injection site reactions are monitored until resolution. Areas greater than 25 cm2 are 
followed daily; otherwise, the frequency of follow-up is based on clinician judgment. 
9.10 
Visit windows and missed visits 
Visit windows are defined in HVTN 705/VAC89220HPX2008 Study Specific 
Procedures. For a visit not performed, a Missed Visit form is completed. If the missed 
visit is one that required safety assessments or local safety labs, HVTN CRS staff should 
attempt to bring the participant in for an interim visit as soon as possible. 
Procedures performed at an interim visit are usually toxicity/safety assessments 
(including local safety labs) and HIV testing. With the exception of HIV testing, these 
procedures are performed only if they were required at the missed visit or if clinically 
indicated. HIV testing may be performed as deemed appropriate by the study staff. Blood 
samples for immunogenicity assays are not typically collected at interim visits. 
If a missed visit required vaccination, please refer to Section 7.3.2 and Section 7.3.3 for 
resolution. 

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9.11 
Early termination visit 
In the event of early participant termination, site staff should consider if the following 
assessments are appropriate: a final physical examination, AE and concomitant 
medication reporting, pregnancy testing, social impact assessment, risk reduction 
counseling, and HIV test. 
9.12 
Pregnancy 
All initial reports of pregnancy must be reported to Janssen Vaccines by the study-site 
personnel within 3 business days of their knowledge of the event using the appropriate 
form(s). If a participant becomes pregnant during the course of the study, no more 
injections of study product will be given during the pregnancy, but remaining visits and 
study procedures should be completed unless medically contraindicated or applicable 
regulations require termination from the study. For participants who are no longer 
pregnant, see Section 7.3.1. If the participant terminates from the study prior to the 
pregnancy outcome, the site should make every effort to keep in touch with the 
participant in order to ascertain the pregnancy outcome. All pregnancies and pregnancy 
outcomes should be recorded and reported (see the HVTN 705/VAC89220HPX2008 
Study Specific Procedures). 

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10 
HIV-1 infection assessment and clinical management 
10.1 
HIV-1 symptom assessment 
At scheduled visits indicated in Appendix G 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. 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 probable recent HIV 
exposure (eg, unprotected sex with a known HIV-positive partner) would prompt a 
diagnostic work-up per the protocol-specific algorithm to determine HIV infection, 
except that in this instance the algorithm is modified to conduct serology and nucleic acid 
testing simultaneously. 
10.2 
HIV-1 screening test  
As part of screening, participants will be screened for HIV-1/2 infection by blood tests 
approved by the US FDA or locally available assays that have been approved by HVTN 
Laboratory Operations. Potential participants identified as being HIV infected during 
screening will be referred for medical treatment and management of the HIV infection. 
These individuals may also be referred to appropriate ongoing clinical trials or 
observational studies. 
10.3 
HIV-1 testing postvaccination 
Surveillance for HIV-1 takes place at vaccination visits and follow-up visits specified in 
Appendix E and Appendix G. 
In-study HIV testing will be performed according to the HVTN HIV diagnostic testing 
algorithms. Routinely, specimens are initially assayed with an HVTN Lab Program–
approved HIV 1/2 enzyme immunoassay (EIA) or chemiluminescent microparticle 
immunoassay (CMIA). If the EIA/CMIA is reactive, nucleic acid polymerase chain 
reaction (PCR) test to detect HIV-1 RNA will be performed as indicated in the algorithm. 
The algorithm is repeated on a second specimen to confirm a diagnosis of HIV-1 
infection. The second specimen for confirmatory testing may be collected at an interim 
visit (designated as visit #.X, where # is the visit at which the first reactive test was 
obtained and X designates the interim visit; specified in Appendix F and Appendix H). 
Samples to be stored for future immunogenicity or virology studies will also be collected 
at this time (Appendix F). 
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 PCR viral load test. Confirmation of HIV-1 infection will be 
determined as dictated by the HVTN HIV testing algorithm (available on the HVTN 705 
protocol-specific website). Before issuing an HIV-1 infection report for a participant 
diagnosed with HIV-1 infection prior to study unblinding, all testing results will be 
reviewed by a blinded, independent Endpoint Adjudicator(s) and/or designee(s) (Section 
10.4). 

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If a participant is confirmed to have become HIV-1 infected prior to study unblinding, 
plasma HIV-1 viral RNA will be measured on archived samples collected according to 
Appendix E. In addition to plasma HIV-1 viral RNA testing, participants may also have 
measurements of immunogenicity assessments and a clinical assessment performed at all 
postinfection visits (see Appendix F). 
The HVTN Laboratory Program is responsible for all in-study diagnostic HIV testing. 
10.4 
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 an HIV 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 HIV-1, standard diagnostic tests may be more difficult to assess. 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, prior to 
study unblinding, tests positive per the HVTN 705 HIV-1 diagnostic testing algorithm. 
The assessment of the Endpoint Adjudicator(s) or designee(s) will be reported to the 
SDMC and to the HIV diagnostics laboratory. 
The Endpoint Adjudicator(s) and/or designee(s) 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(s) and/or designee(s) will be an expert in the fields of 
infectious diseases or laboratory medicine independent of the clinical investigators 
participating in this trial.  
10.5 
HIV-1 infection during the study 
It is critical to the success of the study that HIV-1–infected participants are properly 
identified and all data postdiagnosis are carefully recorded. Information obtained from 
these cases of HIV-1 infection will form the basis of the primary endpoint assessment. 
Participants who develop HIV-1 infection following receipt of study product may remain 
in the study for follow-up but will receive no further injections. All participants who 
become HIV-1 infected following enrollment will be monitored as indicated in Appendix 
F and Appendix H. Archived samples from earlier visits may also be tested to determine 
the earliest date of HIV-1 infection. 
Once the last HIV-1 uninfected participant completes the Month 36 visit, the study is 
considered completed. Further monitoring as indicated in Appendix F and Appendix H 
will not be required for participants who received confirmation of HIV-1 infection status 
after the study is considered complete. Redraw Visits (Visit #.X) to confirm HIV 
infection status may still be performed after the study is complete. 

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10.6 
Medical care for participants who become HIV-1 infected 
It is anticipated that some study participants, whether they are randomized to receive 
vaccine or placebo, will become HIV-1 infected during the course of the trial. It is critical 
that these HIV-1–infected participants receive appropriate medical care. 
The investigators associated with this trial will refer participants who develop HIV 
infection while participating in this trial to medical professionals for care. 

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11 
Laboratory 
11.1 
HVTN CRS laboratory procedures 
The HVTN 705/HPX2008 Site Lab Instructions and SSP provide further guidelines for 
operational issues concerning the clinical and processing laboratories. These documents 
include guidelines for general specimen collection, special considerations for 
phlebotomy, specimen labeling, whole blood processing, HIV screening/diagnostic 
testing, and general screening and safety testing. 
Tube types for blood collection are specified in Appendix E and Appendix F. For tests 
performed locally, the local lab may assign appropriate tube types. 
In specific situations, the blood collection tubes may be redirected to another laboratory 
or may require study-specific processing techniques. In these cases, laboratory special 
instructions will be posted on the protocol-specific section of the HVTN website. 
11.2 
Total blood volume 
Required blood volumes per visit are shown in Appendix E and Appendix F. Not shown 
is any additional blood volume needed if additional testing were required, or if a serum 
pregnancy test needs to be performed. The additional blood volume would likely be 
minimal. The total blood volume drawn for each participant will not exceed 500 mL in 
any 56-day (8-week) period. 
11.3 
Immunogenicity assays 
Endpoint assays for humoral and cellular responses will be run primarily in the context of 
case control studies. Pilot studies with a selected subset of samples may be conducted to 
inform the choice of assays for the case control studies. The primary immunogenicity 
timepoints in this study are 4 weeks after the third vaccination visit and 4 weeks after the 
fourth vaccination visit. Assays for humoral and cellular responses may be performed on 
participants at other timepoints; the schedules are shown in Appendix E and Appendix F. 
11.4 
Endpoint assays: humoral 
11.4.1 
HIV-1 multiplex antibody assay 
Total binding IgG and IgA antibodies to HIV-1 Env proteins contained in the vaccine 
regimen will be assessed on serum samples from study participants taken at the primary 
immunogenicity timepoints and baseline. In addition, binding to cross-clade Env proteins 
and IgG isotypes will be assessed. Specimens from other timepoints as well as other HIV 
antigens may also be assayed based on the results of the initial assay. 

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11.4.2 
Env-specific binding antibody assay 
Total IgG Env-specific binding antibodies against HIV Env clade A (92UG037), B 
(1990A), C (ConC) and vaccine proteins gp140 Clade C and Mosaic (C97ZA and Mos1) 
will be assessed by ELISA in serum samples from study participants. 
11.4.3 
Neutralizing antibody (nAb) assay 
HIV-1–specific nAb assays will be performed on serum samples from study participants 
taken at the primary immunogenicity timepoints. Specimens from the baseline and other 
timepoints may also be analyzed at the discretion of the HVTN Laboratory Program, 
which may be contingent on the results of the primary immunogenicity timepoints. 
11.4.4 
Antibody-dependent cellular phagocytosis (ADCP) assay 
Antibody-dependent cellular phagocytosis assesses the ability of antibodies to induce the 
phagocytosis of antigen-coated beads by monocytes. Antigen-coated beads are incubated 
with increasing concentrations of purified antibodies and the monocytic cell line THP-1. 
The extent of phagocytosis is measured via flow cytometry, and the data is reported as a 
phagocytic score, which takes into account the proportion of effector cells that 
phagocytosed a bead and the degree of phagocytosis. 
11.4.5 
Antivector antibody studies 
Baseline Ad26 neutralizing antibodies (nAb) will be assessed from cryopreserved 
specimens in a subset of participants. 
11.5 
Endpoint assays: cellular 
11.5.1 
Flow cytometry 
Flow cytometry will be used to examine vaccine-specific CD4+ and CD8+ T-cell 
responses following stimulation of PBMCs with synthetic HIV peptides that span the 
proteins encoded by the vaccine. ICS parameters will include cytokines such as IFN-γ, 
interleukin (IL)-2, and tumor necrosis factor (TNF)-α, and may include other cytokines 
(such as cytokines relevant to Th2 and Th17 responses) to identify T cells of specific 
functionality. Markers of cytotoxic potential (eg, Granzyme B) and of Tfh functionality 
(eg, CXCR5 and PD-1) may also be included. Data will be reported as percentages of 
CD4+ or CD8+ T cells responding to a specific peptide pool. Additional cell surface 
markers, cytokines, or functional markers may also be analyzed. 
11.5.2 
IFN- ELISpot 
Ex vivo HIV-specific T-cells will be assessed by IFN-γ ELISpot. To this end, PBMCs 
will be stimulated with synthetic peptide pools that span the proteins encoded by the 
vaccine constructs. Data will be reported as the number of spot-forming cells (SFC) per 
106 cells recognizing specific peptide pools. 

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11.6 
Innate immunity assays 
Innate immune and anamnestic responses may be assessed at baseline, on the day of third 
vaccination and one day later. 
11.6.1 
Soluble factors in serum 
Multiplex cytokine assays and/or enzyme-linked immunosorbent assays (ELISA) may be 
used to measure soluble cytokines, chemokines, and other immunomodulatory factors in 
the serum. Analytes may include IFN-γ, IL-2, IL-4, IL-10, IL-12, IL-13 TNF- α, IL-1 , 
MIP-1, MIP-1 and IP-10. Other analytes may also be included. 
11.6.2 
RNA gene expression 
Whole blood will be cryopreserved in an RNA protection reagent. RNA from whole 
blood or from sorted PBMC may be isolated and used for RNAseq and/or real-time PCR. 
Signatures of gene expression changes for different cell types will be compared pre- and 
post-vaccination. Data will be reported as fold change over baseline pre-vaccine 
expression.  
11.7 
Mucosal studies 
11.7.1 
Vaginal microbiome analysis 
Vaginal swab specimens are processed to enable nucleic acid sequencing. 16S rRNA 
sequences will then be determined by high throughput sequencing methods.  
11.7.2 
Inflammatory marker analysis 
Assays may be performed using cervical secretion specimens to examine cytokines, 
chemokines, and other immunomodulatory factors using a multiplex bead array 
(Luminex) or Meso-Scale Discovery (MSD) platform. 
11.8 
Viral sequencing 
Viral sequencing may be conducted on the earliest available plasma specimens with 
positive HIV-1 RNA PCR tests from study participants who are diagnosed with HIV-1 
infection. Viral sequencing may be conducted on subsequently collected samples to 
assess viral evolution. 
11.9 
ARV detection 
ARV testing will be performed using a test that measures the amount of tenofovir-
diphosphate (a metabolite of tenofovir) in red blood cells. This test utilizes a dried blood 
spot as the sample source and analyzes for tenofovir diphosphate by liquid 
chromatography and tandem mass-spectroscopy, as previously described [54,55]. Stored 
serum and plasma (see Appendix F) will allow additional assessment of PrEP use if 
warranted.  

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11.10 
Genotyping 
Molecular human leukocyte antigen (HLA) typing may be performed on enrolled 
participants using cryopreserved PBMC collected at baseline, initially on specimens from 
participants who demonstrate vaccine-induced T-cell responses at postvaccination 
timepoints. Other participants (including control recipients) may be HLA-typed to 
support future studies of immunological interest at the discretion of the HVTN 
Laboratory Program. Other markers, such as genes associated with immune responses or 
HIV-1 disease progression may also be assessed. 
11.11 
Lab assay algorithm 
The Lab Assay Algorithm lists assays to characterize cellular, humoral, and innate 
immune responses as well as host genetics that may be conducted to determine endpoints 
in HVTN vaccine trials. The type of assay(s) employed will be dependent on the response 
obtained by the primary immunogenicity assays at relevant timepoints. Please note that 
the Lab Assay Algorithm will be updated periodically to include new assays. 
11.12 
Exploratory studies 
Samples may be used for other testing and research related to furthering the 
understanding of HIV immunology or vaccines. In addition, cryopreserved samples may 
be used to perform additional assays to support standardization and validation of existing 
or newly developed methods. 
11.13 
Other use of stored specimens 
The HVTN stores specimens from all study participants indefinitely, unless a participant 
requests that specimens be destroyed or if required by IRB/EC or RE. 
Other use of specimens is defined as studies not described in the protocol. 
This research may relate to HIV, vaccines, the immune system, and other diseases. This 
could include limited genetic testing and, potentially, genome-wide association studies. 
This research is done only to the extent authorized in each study site’s informed consent 
form, or as otherwise authorized under applicable law. Other testing on specimens will 
occur only after review and approval by the HVTN and Janssen Vaccines, the IRB/EC of 
the researcher requesting the specimens, and the CRS’s IRBs/ECs if required. 
The protocol sample informed consent form is written so that the participant either 
explicitly allows or does not allow their samples to be used in other research when they 
sign the form. Participants who initially agree to other use of their samples may rescind 
their approval once they enter the study; such participants will remain in this study and 
their samples will only be used for the studies described in this protocol. If a participant 
decides against allowing other research using his or her samples, or at any time rescinds 
prior approval for such other use, the study site investigator or designee must notify 
HVTN Regulatory Affairs in writing. In either case, HVTN Regulatory Affairs directs the 
HVTN Lab Program not to use samples from these participants for such other uses. 

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CRSs must notify HVTN Regulatory Affairs if institutional or local governmental 
requirements pose a conflict with or impose restrictions on other use of specimens. 
11.14 
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 
applicable agencies. 
All dangerous goods materials, including Biological Substances, Category A or Category 
B, must be transported according to instructions detailed in the International Air 
Transport Association Dangerous Goods Regulations. 

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12 
Safety monitoring and safety review 
12.1 
Safety monitoring and oversight 
12.1.1 
HVTN 705/HPX2008 PSRT 
The HVTN 705/HPX2008 PSRT is composed of the following members: 
• 
Sponsor study responsible physician, 
• 
Sponsor Global Medical Safety physician, 
• 
DAIDS medical officer representative, 
• 
Protocol chair and cochairs, 
• 
Protocol Team leader/Core medical monitor,  
• 
Clinical safety specialist (CSS), and 
• 
Regional medical liaison (RML). 
The clinician members of HVTN 705/HPX2008 PSRT are responsible for decisions 
related to participant safety, as outlined in the PSRT charter. 
The Protocol Team clinic coordinator, clinical data manager, vaccine developer 
representative, clinical trial manager, and others may also be included in HVTN 
705/HPX2008 PSRT meetings. 
12.1.2 
NIAID DSMB 
The NIAID DSMB assesses the effects of the study vaccine during the trial, provides 
other monitoring as described in Section 12.4.3, and may give advice to the HVTN 
705/VAC89220HPX2008 Protocol Team leadership, the OG, and PSRT. More details on 
the role of and the data provided to the DSMB will be described in a DSMB charter and 
SAP. 
12.1.3 
SDMC roles and responsibilities in safety monitoring  
The roles and responsibilities of the SDMC in relation to safety monitoring include: 
• 
Maintaining a central database management system in coordination with Janssen; 
• 
Providing reports of clinical data to appropriate groups such as the HVTN 
705/HPX2008 PSRT, Janssen Global Medical Safety, and NIAID DSMB (see 
Section 12.4.3). 
12.1.4 
HVTN Core roles and responsibilities in safety monitoring 
• 
Daily monitoring of clinical data for events that meet the safety pause and HVTN 
705/HPX2008 PSRT AE review criteria (see Section 12.3); 
• 
Notifying HVTN CRSs and other groups when safety pauses are instituted and lifted 
(see Section 12.3); 

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• 
Querying HVTN CRSs for additional information regarding reported clinical data; 
and 
• 
Providing support to the HVTN 705/HPX2008 PSRT. 
12.1.5 
Sponsor roles and responsibilities in safety monitoring 
• 
Report SAEs/SUSARs to FDA or other Regulatory Authorities according to local 
requirements 
• 
Notifying the FDA, the SAHPRA, and other health authorities as applicable when 
safety pauses are instituted and lifted (see Section 12.3); 
• 
Providing support to the HVTN 705/HPX2008 PSRT. 
12.2 
Safety reporting 
12.2.1 
Submission of safety forms to SDMC 
Sites must enter all safety data (eg, reactogenicity, AE, concomitant medications) before 
the end of the next business day after receiving the information, excluding federal or 
bank holidays. The forms should not be held in anticipation of additional information at a 
later date. If additional information is received at a later date, the forms should be 
updated and resubmitted before the end of the next business day after receiving the new 
information. For the case of a longer site holiday closure, site staff must submit the data 
by the end of the 5th day (local time) after receiving the information even if this day is a 
holiday. 
For example: If the site becomes aware of an AE on Thursday (Day 0), the site must 
submit the data by the end of the next business day, on Friday. If there is a longer site 
holiday closure, then this AE must be reported no later than the end of the fifth day, 
Monday (Day 4). If Monday is a holiday as well, all safety forms still need to be 
submitted by the end of Monday (Day 4). 
12.2.2 
AE reporting 
Sites are expected to notify the CSS/RML of any serious safety concern requiring their 
attention (see Table 12-1). Telephone numbers and email addresses are found on the 
protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/hvtn705). Concerns requiring immediate attention 
should be communicated by calling the clinical safety phone. 
In the case of email notification, the CSS/RML will reply during working hours (US 
Pacific Time or South Africa Time) to confirm that the email has been received and 
reviewed. If email service is not available, the HVTN CRS should notify the CSS/RML 
of the event by telephone, then submit CRFs. 
In addition, site investigators are required to submit AE information in accordance with 
IRB/EC and any applicable RE requirements. 

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12.2.2.1 
Reactogenicity event 
Reactogenicity events are predefined local (at the injection site) and systemic events 
occurring in a predefined postvaccination period for which the subject is specifically 
questioned (see Section 9.9). 
12.2.2.2 
Adverse event 
An AE is any untoward medical occurrence in a clinical investigation participant 
administered a study product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of an investigational study product/procedure(s), whether or not related to 
the investigational study product/procedure(s).  
All AEs are graded according to the Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, available on the 
RSC website at http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-
grading-tables, except: 
• 
Unintentional weight loss is required to be reported as an AE only if it is considered 
to be potentially deleterious to the participant’s health (see HVTN 705 Study Specific 
Procedures); 
• 
Injection Site Erythema or Redness and Injection Site Induration or Swelling will not 
consider interference with usual social and functional activities such that: 
▪ 
Grade 1 is: 2.5 to < 5 cm in diameter OR 6.25 to < 25 cm2 surface area; 
▪ 
Grade 2 is: ≥ 5 to < 10 cm in diameter OR ≥ 25 to < 100 cm2 surface area; 
▪ 
Grade 3 is: ≥ 10 cm in diameter OR ≥ 100 cm2 surface area OR Ulceration OR 
Secondary infection OR Phlebitis OR Sterile abscess OR Drainage; 
▪ 
Grade 4 is: Potentially life-threatening consequences (eg, abscess, exfoliative 
dermatitis, necrosis involving dermis or deeper tissue). 
Adverse Events (AE) will be collected over a period of 30 days after each vaccination 
visit. AEs with the onset date outside the timeframe defined above (>30 days after 
previous study vaccination), which are ongoing on the day of the subsequent vaccination, 
should be recorded on the AE log CRF. All collected AEs are reported to the SDMC on 
the appropriate CRF. Clinic staff should evaluate every AE to determine if (1) the AE 
meets SAE reporting criteria (Section 12.2.3), (2) if the AE meets the criteria for a safety 
pause/prompt AE review (Section 12.3), and (3) if the AE is a potential immune-
mediated disease that may be listed as an AE of special interest (AESI). A sample list of 
AESI is provided in Appendix I. 
Certain AEs will be collected and reported throughout the entire study:  
• 
SAEs,  
• 
AESIs, 
• 
STIs, 

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• 
AEs leading to early participant withdrawal or early discontinuation of study 
product(s) administration. 
12.2.2.3 
Serious adverse event 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use (as well as other pertinent national guidelines) is any 
untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (The subject was at risk of death at the time of the event. It does 
not refer to an event that hypothetically might have caused death if it were more 
severe.) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Suspected transmission of any infectious agent via a medicinal product  
• 
Is Medically Important* 
*Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in other situations, such as important medical events that 
may not be immediately life threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above. These should usually be considered serious.  
For the duration of the study, all events that meet the definition of a serious adverse event 
will be reported from the site to Janssen Vaccines as serious adverse events, regardless of 
whether they are protocol-specific assessments. Janssen Vaccines will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame 
specified in the protocol.  
All related SAEs that are ongoing at study completion should be followed by the 
investigator until resolution or until clinically stable. 
12.2.3 
SAE reporting to Janssen Vaccines 
All SAEs, as defined in Section 12.2.2 must be reported to Janssen Vaccines by the 
study-site personnel within 3 business days of their knowledge of the event. Sites will 
submit SAE reports by documenting the information on the SAE Form and e-mailing or 
faxing it to the Janssen Local Safety Officer (LSO). The email address and fax number 
can be found on the protocol home page on the HVTN Members’ site 
(https://members.hvtn.org/protocols/hvtn705). 
The SAE reporting period for this study comprises the entire study period for each 
individual participant (from study enrollment until study completion or discontinuation 
from the study). 
The study products for which expedited reporting are required are: 
• 
Ad26.Mos4.HIV 

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• 
Placebo for Ad26.Mos4.HIV 
• 
Clade C gp140 with alum 
• 
Placebo for Clade C gp140 with alum 
If the PSRT believes unblinding of the site PI to treatment assignment will assist with the 
clinical management of the SAE, the PSRT may consult the independent NIAID DSMB 
for a recommendation. In the event the PSRT and/or the NIAID DSMB determines that 
unblinding is indicated, the unblinded statistician, DSMB Chair, or designee will inform 
the site physician of the participant’s treatment assignment in such a manner as to 
maintain the study blind of the PSRT and study team. For emergency medical 
management of a participant, unblinding decisions will be made by the site investigator, 
when the timing is critical for medical management. Otherwise, the HVTN 
705/HPX2008 PSRT should be consulted before emergency unblinding occurs. 
12.2.4 
Expedited reporting of AEs to pertinent national regulatory authorities  
The study sponsor or designee(s) prepares and files expedited reports to appropriate 
regulatory authorities within the timelines required.  
Site IoRs/designees will submit AE information and any other relevant safety information 
to their ECs/IRBs and any other relevant authority in accordance with applicable local 
requirements. 
12.3 
Safety pause and prompt PSRT AE review 
When a trial is placed on safety pause, all enrollments and vaccinations with the product 
related to the event that triggered the pause will be held until further notice. The AEs that 
will lead to a safety pause or prompt HVTN 705/HPX2008 PSRT AE review are 
summarized in Table 12-1. Vaccinations may be suspended for safety concerns other than 
those described in the table, or before pause rules are met, if, in the judgment of the 
HVTN 705/HPX2008 PSRT, participant safety may be threatened. Criteria for an 
individual participant’s departure from the schedule of vaccinations are listed in Section 
7.3. 

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Table 12-1 AE notification and safety pause/AE review rules 
Event and 
relationship to 
study products 
Severity 
HVTN CRS actiona 
Sponsor action 
SAE, related 
Grade 5 or 
Grade 4 or 
Grade 3 
Phone immediately, 
email/fax and submit 
applicable forms 
immediately 
Immediate pause and 
HVTN 705/HPX2008 
PSRT notification 
SAE, related 
Grade 2 or 
Grade 1 
Email/fax and submit 
applicable forms 
immediately 
Prompt HVTN 
705/HPX2008 PSRT AE 
review to consider pause 
SAE, not related 
Grade 5 
Phone immediately, 
email/fax and submit 
applicable forms 
immediately 
Immediate HVTN 
705/HPX2008 PSRT 
notification 
AEb, related 
Grade 4 or 
3 
Email/fax and submit 
applicable forms 
immediately 
Prompt HVTN 
705/HPX2008 PSRT AE 
review to consider pause 
a Phone numbers, fax numbers and email addresses are found on the Protocol home page on the HVTN Members’ site 
(https://members hvtn org/protocols/hvtn705)  
b Does not include subjective reactogenicity symptoms (injection site pain, tenderness, fatigue/malaise, myalgia, arthralgia, chills, headache, 
nausea)  Objective reactogenicity symptoms, grade 3, need to be ongoing for 3 days  
For all safety pauses, HVTN Core notifies the HVTN 705/HPX2008 PSRT, Janssen 
Global Regulatory Affairs, HVTN Regulatory Affairs, and participating HVTN CRSs. 
When an immediate safety pause is triggered, HVTN Core notifies the DSMB. 
Once a trial is paused, the HVTN 705/HPX2008 PSRT reviews safety data and decides 
whether the pause can be lifted or permanent discontinuation of vaccination is 
appropriate, consulting the DSMB if necessary. HVTN Core notifies the participating 
HVTN CRSs, Janssen Global Regulatory Affairs, and HVTN Regulatory Affairs of the 
decision regarding resumption or discontinuation of study vaccinations. Based on the 
HVTN 705/HPX2008 PSRT assessment, Janssen Vaccines notifies the FDA, the 
SAHPRA, and other pertinent national and regional authorities as appropriate. 
If an immediate HVTN 705/HPX2008 PSRT notification or prompt HVTN 
705/HPX2008 PSRT AE review is triggered, HVTN Core notifies the HVTN 
705/HPX2008 PSRT as soon as possible during working hours (US Pacific Time)—or, if 
the information was received during off hours, by the morning of the next work day. If a 
prompt HVTN 705/HPX2008 PSRT AE review cannot be completed within 72 hours of 
notification (excluding weekends), an automatic safety pause occurs. 
The HVTN requires that each CRS submit to its IRB/EC and any applicable RE protocol-
related safety information (such as IND safety reports, notification of vaccine holds due 
to the pause rules, and notification of other unplanned safety pauses). CRSs must also 
follow all applicable RE reporting requirements. 
In addition, all other AEs are reviewed routinely by the HVTN 705/HPX2008 PSRT (see 
Section 12.4.2). 
12.4 
Review of cumulative safety data 
Routine safety review occurs at the start of enrollment and then throughout the study. 

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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.  
12.4.1 
Daily review 
Blinded daily safety reviews are routinely conducted by HVTN Core for events that meet 
immediate HVTN 705 PSRT notification criteria, as described in Section 12.3. 
12.4.2 
Twice-monthly review 
During the injection phase of the trial, the HVTN 705/HPX2008 PSRT reviews clinical 
safety reports on a twice-monthly basis and conducts calls to review the data as 
appropriate. After the 4-week-post-final-vaccination visits are completed, less frequent 
reporting and safety reviews may be conducted at the discretion of the HVTN 
705/HPX2008 PSRT. HVTN Core reviews reports of all reported AEs. Events identified 
during the review that are considered questionable, inconsistent, or unexplained are 
referred to the HVTN CRS clinic coordinator for verification. 
12.4.3 
DSMB review of cumulative safety data 
The DSMB will periodically review accumulating unblinded safety data by group. Prior 
to each meeting, the SDMC will provide the DSMB with data as described in Section 6.5. 
Reports will be cumulative, generated from an up-to-date data file. 
Based upon the reports, the DSMB will determine whether to recommend that the study 
should be continued, modified, or stopped, including for safety reasons. 
12.5 
Study termination 
This study may be terminated early upon recommendation by the DSMB and/or the OG. 

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13 
Protocol conduct 
This protocol and all actions and activities connected with it will be conducted in 
compliance with the principles of GCP (ICHe6), and according to DAIDS, Janssen 
Vaccines, and HVTN policies and procedures as specified in the HVTN Manual of 
Operations, Janssen Vaccines Standard Operation Procedures, and DAIDS Clinical 
Research Policies and Standard Procedures Documents including procedures for the 
following: 
• 
Protocol activation and implementation; 
• 
Site initiation; 
• 
Informed consent, screening, and enrollment; 
• 
Study participant reimbursement; 
• 
Clinical and safety assessments; 
• 
Safety monitoring and reporting; 
• 
Data collection, documentation, transfer, and storage; 
• 
Participant confidentiality; 
• 
Study follow-up and close-out; 
• 
Unblinding of staff and participants; 
• 
Quality control; 
• 
Protocol monitoring and compliance; 
• 
Advocacy and assistance to participants regarding negative social impacts associated 
with the vaccine trial; 
• 
Risk reduction counseling;  
• 
Specimen collection, processing, and analysis;  
• 
Exploratory and ancillary studies and sub-studies, and 
• 
Destruction of specimens. 
Any policies or procedures that vary from DAIDS, Janssen Vaccines, and HVTN 
standards or require additional instructions (eg, instructions for randomization specific to 
this study) will be described in the HVTN 705/VAC89220HPX2008 Study Specific 
Procedures.  
13.1 
Protocol governance 
13.1.1 
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. The Protocol Team will remain blinded to the treatment 
group assignment of individual participants during the course of the study. 

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13.1.2 
PSRT 
The PSRT will review all clinical and laboratory safety data during the course of the 
study as described in Section 12.4. 
13.1.3 
Oversight group (OG) 
The OG provides the overall scientific direction for the trial, and will receive and decide 
on any recommendations made by the DSMB, including stopping the study.  
13.1.4 
NIAID DSMB 
The NIAID DSMB assesses the effects of the study vaccine during the trial and may give 
advice to Janssen Vaccines and to the Oversight Group. The DSMB membership for this 
trial will include representatives from Africa. With the exception of an unblinded 
statistician, the members of the committee are independent of Janssen Vaccines, DAIDS, 
the HVTN, and clinical investigators participating in this trial. They will not have any 
other involvement in the study, and will not have any relation to study participants. More 
details will be provided in the DSMB charter. The DSMB will monitor the trial for 
evidence of beneficial or adverse effects of the study vaccine using the guidelines 
proposed by the protocol. The DSMB may recommend any steps to ensure the safety of 
study participants and the integrity of the trial. Furthermore, it may recommend that the 
trial be terminated or that specific groups be withdrawn from the study, if any subgroup 
manifests serious or widespread side effects. To guarantee the unrestricted performance 
of its task, the DSMB may receive the individual study morbidity and mortality data from 
the unblinded statistician. 
The DSMB will be informed immediately by an independent statistician if the pre-
specified stopping boundary is met, indicating that the vaccine causes harm by increasing 
the rate of HIV acquisition (Section 6.5.1). In addition, the DSMB will monitor the study 
for futility to detect vaccine activity (Section 6.5.2), for high vaccine efficacy (Section 
6.5.3), and for operational futility, defined as an unacceptably low rate of HIV-1 
infections and by other measures of under-performance (Section 6.5.4). Semiannual 
DSMB meetings will be held for monitoring operational futility. 
Should ongoing clinical trials of HIV prevention modalities produce results having 
implications for recruitment or endpoint enrollment in HVTN 705/VAC89220HPX2008, 
those results will be reported to the DSMB, whose recommendations will inform 
consultations with applicable experts and stakeholders regarding possible changes in trial 
design and conduct. 
13.2 
Social impacts 
Participants in this study risk experiencing discrimination or other personal problems, 
resulting from the study participation itself or from the development of VISP. The HVTN 
CRS is obliged to provide advocacy for and assistance to participants regarding these 
negative social impacts associated with the vaccine trial. If HVTN CRS staff have 
questions regarding ways to assist a participant dealing with a social impact, a designated 
NIAID or HVTN Core representative can be contacted.  

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Social harms are tabulated by the SDMC and are subjected to descriptive analysis. The 
goal is to reduce their incidence and enhance the ability of study staff to mitigate them 
when possible. 
Summary tables of social impact events will be generated weekly, and made available for 
review by the protocol chairs, protocol team leader, and Janssen Vaccines and NIAID 
representatives. 
13.3 
Compliance with NIH guidelines for research involving products 
containing recombinant DNA 
Because this study is evaluating products containing recombinant or synthetic DNA, it 
must comply with regulations set forth in the NIH Guidelines for Research Involving 
Recombinant or Synthetic Nucleic Acid Molecules(April 2016). Information about 
the study must be submitted to site Institutional Biosafety Committees (IBCs). 
Investigators at each site are responsible for obtaining IBC approval per NIH Guidelines 
section IV-B7-a-(1). IBC review and approval must be documented by the investigator 
before participants can be enrolled at the site. If this protocol is amended, investigators 
should follow the requirements of their IBC. 
13.4 
Emergency communication with study participants 
As in all clinical research, this study may generate a need to reach participants quickly to 
avoid imminent harm, or to report study findings that may otherwise concern their health 
or welfare.  
When such communication is needed, the CRS will request that its IRB/EC and any 
applicable RE expedite review of the message. If this review cannot be completed in a 
timeframe consistent with the urgency of the required communication, the site should 
contact the participant first, and then notify the IRB/EC and any applicable RE of the 
matter as soon as possible. 

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14 
Version history 
The Protocol Team may modify the original version of the protocol. Modifications are 
made to HVTN protocols via clarification memos, letters of amendment, or full protocol 
amendments.  
The version history of, and modifications to, Protocol HVTN 705/VAC89220HPX2008 
are described below. 
Protocol history and modifications 
Date: June 12, 2020 
Protocol version: Version 4.0 
Protocol modification: Full Protocol Amendment 3 
Item 1 Revised in Section 3, Overview, Section 5.2, Secondary objectives and 
endpoints, Table 6-1, Cohorts of HIV-1-infected study participants, Figure 6.5, 
Study design and stages, Section 10.5, HIV infection during the study, and 
Appendices A, D, E, G: redefining end of study, adding additional visits every 
3 months until last Month 36 visit is complete 
Item 2 Revised in Section 6.5, Trial monitoring, Section 6.5.1, Monitoring for 
potential harm, Section 6.5.2, Monitoring for non-efficacy: timing of 
assessment of non-efficacy to the point when all participants have reached 
Month 13. 
Item 3 Added to Section 2.4, Appropriate informed consent, Section 7, Selection and 
withdrawal of participants, Section 9, Clinical procedures, and Appendix A, 
Sample informed consent form: information regarding remote study visits and 
consenting during the COVID-19 pandemic 
Item 4 Added to Section 3, Overview, Section 6.3.1, Analysis to determine whether or 
not the trial will advance into Stage 2, and Figure 6.5, Study design and stages: 
text clarifying definition of Stage 1 and 2 
Item 5 Updated in Section 3, Overview: protocol team members 
Item 6 Added to Section 4.1, Rationale for trial concept, and Section 17, Literature 
cited: recent information regarding the HIV vaccine efficacy study HVTN 702 
Item 7 Updated in Appendix A, Sample informed consent form and Appendix C, 
Sample consent form for use of samples and information in other studies: 
SAHPRA contact information 
Item 8 Updated with changes described in Letter of Amendment 1 dated May 6, 2019 
Item 9 Updated with changes described in Clarification memo 1 dated March 08, 2019 
Item 10 Version history updated in Section 14 

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Date: May 06, 2019 
Protocol version: Version 3.0 
Protocol modification: Letter of Amendment 1 
Item 1 
Revised in Section 7.3.1, Delaying vaccinations for a participant, Section 7.3.2, 
Participant departure from vaccination schedule, and Section 7.3.3, Discontinuing 
vaccination for a participant :guidance regarding vaccination out of window 
Date: March 08, 2019 
Protocol version: Version 3.0 
Protocol modification: Clarification memo 1 
Item1 
Revised in Section 9.10, Visit windows and missed visits: Missed Visit form 
completion 
Date: July 26, 2018 
Protocol version: Version 3.0 
Protocol modification: Full Protocol Amendment 2 
 
Item 1 
Added in Section 4.3, Clade C gp140: Clade C gp140 (L-Histidine buffer) study 
product to be mixed with aluminum phosphate adjuvant by the pharmacist 
Item 2 
Corrected in Section 9.4, Follow-up visits, Section 9.8, Pregnancy prevention 
assessment, and Appendix G, Schedule 1:Procedures at HVTN CRS for HIV-
uninfected participants: pregnancy prevention assessment timepoints 
Item 3 
Added in Appendix G, Schedule 1:Procedures at HVTN CRS for HIV-uninfected 
participants: behavioral risk assessment timepoints at month 7 and month 36 
Item 4 
Corrected in Appendix F, Laboratory procedures for HIV-infected participants, 
footnote 5: visits in Schedule 1 that may affect redraw guidance. 
Item 5 
Corrected in Appendix E, Schedule 1:Laboratory procedures for HIV-uninfected 
participants, footnote 14 and Appendix G, Procedures at HVTN CRS for HIV-
uninfected participants, footnote 8: hemoglobin assessment and potential blood 
draw adjustment visits 
Item 6 
Added in Section 3, Overview, and Appendices E and F, Laboratory Procedures: 
UW-VSL as a backup laboratory for HIV diagnostics 
Item 7 
Updated in Section 11.1, HVTN CRS laboratory procedures: source for guidelines 
concerning the clinical and processing laboratories 
Item 8 
Updated in Section 12.1.5, Sponsor roles and responsibilities in safety monitoring, 
Section 12.3, Safety pause and prompt PSRT AE review, Appendix A, Sample 
Informed Consent, Appendix C, Sample consent form for use of samples and 
information in other studies: MCC and contact information updated to SAHPRA 
Item 9 
Clarified in Appendix A, Sample Informed Consent, item 26: insurance company 
and funds refer to the clinic’s insurance company and funds 
Item 10 Added in Appendix A, Sample Informed Consent and Appendix C, Sample consent 
form for use of samples and information in other studies: broad regulatory access to 
participant study records 
Item 11 Clarified in Section 9.9, Assessments of reactogenicity: contact between staff and 
participant 

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Item 12 Added in Appendix G, Procedures at HVTN CRS for HIV-uninfected participants: 
HIV infection assessment at screening 
Item 13 Corrected in Section 4.5, Combination prevention of HIV acquisition: misplaced 
reference 
Item 14 Clarified in Section 7.3.3, Discontinuing vaccination for a participant: vaccinations 
may continue upon review by the PSRT for grade 3 erythema and/or induration 
Item 15 Corrected in Section 9.1.1, Screening consent form: when screening can take place 
Item 16 Clarified in Section 12.2.1, Submission of safety forms to SDMC: timing of 
submission of safety forms and federal or bank holidays 
Item 17 Revised in Section 7.2, Exclusion criteria items 7 and 8, and Section 7.3.1, Delaying 
vaccination for a participant: timing of influenza vaccination made consistent with 
other live attenuated viruses 
Item 18 Updated in Section 3.1, Protocol Team: affiliations and new members 
Date: April 13, 2018 
Protocol version: Version 2.0 
Protocol modification: Full Protocol Amendment 1 
Item 1 
Added: Clade C gp140 and separate aluminum phosphate adjuvant study product 
formulation 
Item 2 
Updated in Section 3.1, Protocol team: email address and phone number for 
 
 
Item 3 
Updated: items from Clarification memo 1 dated September 25, 2017 
Date: September 25, 2017 
Protocol version: Version 1.0 
Protocol modification: Clarification memo 1 
Item 1  Updated in Section 9.9, Assessments of reactogenicity, Section 12.2.2 AE reporting, 
and Section 15, Document references: AE Grading table version 
Item 2 
Clarified in Appendix D, Table of procedures (for sample informed consent) HIV-
infected participants, Appendix F, Schedule 2 Laboratory procedures for HIV-
infected participants, and Appendix H, Schedule 2 Procedures at HVTN CRS for 
HIV-infected participants: pregnancy testing for HIV-infected participants at months 
3 and 6 
Item 3 
Updated in Section 3.1, Protocol team: email address for 
 
Item 4 
Updated in Section 3.1, Protocol team: new team member 
 
Date: February 17, 2017 
Protocol version: 1.0 
Protocol modification: 
Original protocol 
 
PPD
PPD
PPD
PPD

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15 
Document references (other than literature 
citations) 
Other documents referred to in this protocol, and containing information relevant to the 
conduct of this study, include: 
• 
Assessment of Understanding. Accessible through the HVTN protocol-specific 
website. 
• 
Current CDC Guidelines. Revised Recommendations for HIV Testing of Adults, 
Adolescents, and Pregnant Women in Health-Care Settings. Available at 
http://www.cdc.gov/mmwr/PDF/rr/rr5514.pdf   
• 
Division of AIDS (DAIDS) Clinical Research Policies and Standard Procedures 
Documents. Available at https://www.niaid.nih.gov/research/daids-clinical-research-
policies-standard-procedures  
• 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events. Corrected Version 2.1, July 2017. Available at http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids-grading-tables  
• 
HVTN Certificate of Confidentiality. Accessible through the HVTN website. 
• 
HVTN 705/VAC89220HPX2008 Special Instructions. Accessible through the HVTN 
protocol-specific website. 
• 
HVTN 705/VAC89220HPX2008 Study Specific Procedures. Accessible through the 
HVTN protocol-specific website. 
• 
HVTN 705/VAC89220HPX2008 Site Lab Instructions. 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. 
• 
Dangerous Goods Regulations (updated annually), International Air Transport 
Association. Available for purchase at 
http://www.iata.org/publications/dgr/Pages/index.aspx  
• 
Lab assay algorithm 
• 
HVTN algorithm for diagnosis of HIV infections. Part of the HVTN Laboratory 
Manual of Operations (see above). 
• 
International Conference on Harmonisation (ICH) E6 (R1), Guideline for Good 
Clinical Practice: Section 4.8, Informed consent of trial subjects. Available at 
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html 
• 
Participants’ Bill of Rights and Responsibilities. Accessible through the HVTN 
website. 
• 
NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid 
Molecules, April 2016. Available at 
http://osp.od.nih.gov/sites/default/files/resources/NIH_Guidelines.pdf 
• 
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. 
• 
Janssen Site Investigational Product Procedures Manual. 

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• 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials. Available at https://www.niaid.nih.gov/sites/default/files/daids-
sourcedocpolicy.pdf  
• 
Title 21, Code of Federal Regulations, Part 50. Available at 
http://www.ecfr.gov/cgi-bin/text-idx?SID=7e6fd19033c54083955c83c75675f72e&m
c=true&node=pt21.1.50&rgn=div5 
• 
Title 45, Code of Federal Regulations, Part 46. Available at 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html 
See Section 17 for literature cited in the background and statistics sections of this 
protocol. 

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16 
Acronyms and abbreviations 
Ad 
adenovirus 
AE 
adverse event 
ART 
antiretroviral therapy 
CAB 
Community Advisory Board 
CBC 
complete blood count 
CDC 
US Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
case report form 
CRPMC 
NIAID Clinical Research Products Management Center 
CRS* 
clinical research site 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS (US NIH) 
DHHS 
US Department of Health and Human Services 
DSMB 
NIAID Data and Safety Monitoring Board 
EC 
Ethics Committee 
EIA 
enzyme immunoassay 
ELISA 
enzyme-linked immunosorbent assay 
ELISpot 
enzyme-linked immunospot 
FDA 
US Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HLA 
human leukocyte antigen 
HVTN 
HIV Vaccine Trials Network 
IB 
Investigator’s Brochure 
IBC 
Institutional Biosafety Committee 
ICH 
International Conference on Harmonisation 
ICS 
intracellular cytokine staining 
IFN-γ 
interferon gamma 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
MMR 
measles, mumps, and rubella 
nAb 
neutralizing antibody 
NHP 
nonhuman primate 
NIAID 
National Institute of Allergy and Infectious Diseases (US NIH) 
NICD 
National Institute for Communicable Diseases (Johannesburg, South Africa) 
NIH 
US National Institutes of Health 
OG 
Oversight Group 
OPV 
oral polio vaccine 

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PAB 
DAIDS Pharmaceutical Affairs Branch 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PI 
Principal Investigator 
PSRT 
Protocol Safety Review Team 
RAB 
DAIDS Regulatory Affairs Branch 
RE 
regulatory entity 
RSC 
DAIDS Regulatory Support Center 
SAE 
serious adverse event 
SCHARP Statistical Center for HIV/AIDS Research and Prevention 
SDMC 
statistical and data management center 
SFC 
spot-forming cell 
SHIV 
simian-human immunodeficiency virus 
SIV 
simian immunodeficiency virus 
TB 
tuberculosis 
VISP 
Vaccine induced seropositivity 
* CRSs were formerly referred to as HIV Vaccine Trial Units (HVTUs). Conversion to 
use of the term CRS is in process, and some HVTN documents may still refer to HVTUs. 

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17 
Literature cited 
 
  1.   UNAIDS. Ethical considerations in biomedical HIV prevention trials. 2007. 
 
  2.   The National Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Subjects of Research. 1979. 
 
  3.   Council for International Organizations of Medical Sciences (CIOMS). International ethical 
guidelines for biomedical research involving human subjects. Bull Med Ethics 2002;17-
23. 
 
  4.   UNAIDS/JC1853E (Second edition J2. Good participatory practice: Guidelines for 
biomedical HIV prevention trials.  2011.   
 
  5.   Vella S. Addressing barriers to the end of AIDS by 2030. Lancet HIV 2015;2:e360-e361. 
 
  6.   Fischer W, Perkins S, Theiler J, Bhattacharya T, Yusim K, Funkhouser R, Kuiken C, Haynes 
B, Letvin NL, Walker BD, Hahn BH, Korber BT. Polyvalent vaccines for optimal 
coverage of potential T-cell epitopes in global HIV-1 variants. Nat Med 2007;13:100-6. 
 
  7.   Barouch DH, O'Brien KL, Simmons NL, King SL, Abbink P, Maxfield LF, Sun YH, La Porte 
A, Riggs AM, Lynch DM, Clark SL, Backus K, Perry JR, Seaman MS, Carville A, 
Mansfield KG, Szinger JJ, Fischer W, Muldoon M, Korber B. Mosaic HIV-1 vaccines 
expand the breadth and depth of cellular immune responses in rhesus monkeys. Nat Med 
2010;16:319-23. 
 
  8.   Santra S, Liao HX, Zhang R, Muldoon M, Watson S, Fischer W, Theiler J, Szinger J, 
Balachandran H, Buzby A, Quinn D, Parks RJ, Tsao CY, Carville A, Mansfield KG, 
Pavlakis GN, Felber BK, Haynes BF, Korber BT, Letvin NL. Mosaic vaccines elicit 
CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV 
strains in monkeys. Nat Med 2010;16:324-8. 
 
  9.   Stephenson KE, SanMiguel A, Simmons NL, Smith K, Lewis MG, Szinger JJ, Korber B, 
Barouch DH. Full-length HIV-1 immunogens induce greater magnitude and comparable 
breadth of T lymphocyte responses to conserved HIV-1 regions compared with 
conserved-region-only HIV-1 immunogens in rhesus monkeys. J Virol 2012;86:11434-
40. 
   10.   Buchbinder SP, Mehrotra DV, Duerr A, Fitzgerald DW, Mogg R, Li D, Gilbert PB, Lama JR, 
Marmor M, Del RC, McElrath MJ, Casimiro DR, Gottesdiener KM, Chodakewitz JA, 
Corey L, Robertson MN. Efficacy assessment of a cell-mediated immunity HIV-1 
vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept 
trial. Lancet 2008;372:1881-93. 
   11.   Flynn NM, Forthal DN, Harro CD, Judson FN, Mayer KH, Para MF. Placebo-controlled 
phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J 
Infect Dis 2005;191:654-65. 
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Appendix A 
Sample informed consent form 
Title: A multicenter, randomized, double-blind, placebo-controlled phase 2b efficacy 
study of a heterologous prime/boost vaccine regimen of Ad26.Mos4.HIV and aluminum 
phosphate-adjuvanted Clade C gp140 in preventing HIV-1 infection in women in sub-
Saharan Africa 
Protocol number: HVTN 705/VAC89220HPX2008 
Site: [Insert site name] 
Thank you for your interest in our research study. Please read this consent form or ask 
someone to read it to you. If you decide to join the study, we will ask you to sign or make 
your mark on this form. We will offer you a copy to keep. We will ask you questions to 
see if we have explained everything clearly. You can also ask us questions about the 
study.  
Research is not the same as treatment or medical care. The purpose of a research study is 
to answer scientific questions. 
About the study 
The HIV Vaccine Trials Network (HVTN), Janssen Vaccines and Prevention B.V., and 
[Insert site name] are doing a study to test HIV vaccines. HIV is the virus that causes 
AIDS. 
About 2600 women will take part in this study at multiple sites in several sub-Saharan 
African countries. The researcher in charge of this study at this clinic is 
[Insert name of site PI]. The US National Institutes of Health (NIH), the Bill & Melinda 
Gates Foundation, and Janssen Vaccines & Prevention, B.V. are paying for the study.  
1. We are doing this study to answer several questions. 
• 
Do the study vaccines lower people’s chances of getting infected with HIV? 
• 
Are the study vaccines safe to give to people? 
• 
Are people able to take the study vaccines without becoming too uncomfortable? 
• 
How do people’s immune systems respond to the study vaccines? (Your immune 
system protects you from disease.) 
• 
Do the study vaccines lower how much HIV is in people’s blood if they get HIV?  
2. The study vaccines cannot give you HIV. 
It is impossible for the study vaccines to give you HIV. Also, they cannot cause you to 
give HIV to someone else. The study vaccines are not made from actual HIV. Below, we 
will tell you about how the vaccines in this study are made.  
3. We do not know if the study vaccines will decrease, increase, or not change your 
risk of becoming infected with HIV if you are exposed to the virus. 
Sites: Any change to the language in this section requires approval from HVTN 
Regulatory Affairs. 

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Several studies have tested whether HIV vaccines can reduce the risk of getting HIV 
from another person. In some studies, people who got the vaccine seemed to have the 
same risk of getting HIV as people who did not get the vaccine. In one study, people who 
got the vaccine seemed to have a lower risk of getting HIV than people who did not get 
the vaccine. In studies with a different vaccine, some people who got the vaccine had a 
higher risk of getting HIV than people who did not get the vaccine.  
The studies that found a higher risk of HIV infection were testing a vaccine made from a 
weakened common cold virus called adenovirus type 5 (Ad5).  
In one study, the group of men at higher risk had some things in common. In addition to 
getting the vaccine, they either:  
• 
had antibodies to Ad5 (your body makes antibodies to fight infection),  
• 
or they were uncircumcised (still had the foreskin on their penises),  
• 
or both. 
Men who were circumcised and did not have these antibodies did not have higher risk 
when they got the vaccine. In the group with higher risk after vaccination, the risk 
seemed to lessen after about a year and a half.  
Only a few women in that study got HIV, so we can’t tell if the vaccine affected their 
risk. 
In another study, men who got the vaccine had higher risk whether or not they were 
circumcised or had antibodies to Ad5. Many women became HIV infected during the 
study but we can’t tell if the vaccine affected their risk. 
This study differs from those studies in several ways. It is testing a vaccine made from 
adenovirus type 26 (Ad26), not Ad5. We can tell you about other differences. 
We do not know whether the vaccines in this study will affect your risk of getting HIV 
from another person. The risk could be higher, lower, or unchanged. It’s very important 
to avoid exposure to HIV during and after the study. We will tell you how to avoid HIV. 
4. These study vaccines are experimental. 
The study vaccines are called Ad26.Mos4.HIV and Clade C gp140. From here on, we 
will call them Ad26 and Protein, or the study vaccines.  
The study vaccines are experimental HIV vaccines. That means we do not know whether 
the vaccines will be safe to use in people, or whether they will work to prevent HIV 
infection. These vaccines are used only in research studies. 
The vaccines were developed by Janssen Vaccines & Prevention B.V. The Ad26 vaccine 
is made from a virus called Adenovirus type 26. Adenovirus type 26 is a virus that can 
cause the common cold. However, the adenovirus used in this study vaccine has been 
weakened so it cannot cause colds. This study vaccine has been designed to tell the body 
to make proteins similar to proteins found in HIV.  

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The Protein vaccine includes a man-made protein called gp140 that is similar to the 
protein found on the outside of HIV. The gp140 protein vaccine is mixed with an 
adjuvant called aluminum phosphate, or alum for short. An adjuvant is something added 
to a vaccine to help the immune system respond better. Alum is an approved adjuvant 
that is used in many common vaccines such as those for Hepatitis A and B, diphtheria, 
and tetanus.  
General risks of vaccines: 
All vaccines can cause fever, chills, rash, aches and pains, nausea, headache, dizziness, 
and feeling tired. Vaccines can also cause pain, redness, swelling, or itching where you 
got the injection. Most people can still do their planned activities after getting a vaccine. 
Rarely, people experience side effects that limit their normal activities or make them go 
to the doctor. 
Rarely, a vaccine can cause an allergic reaction, including a rash, hives, or difficulty 
breathing. Allergic reactions can be life-threatening. You should tell us if you have ever 
had a bad reaction to any injection or vaccine. 
Very rarely, a vaccine causes an autoimmune disease in a person, or makes an 
autoimmune disease worse. An autoimmune disease happens when your immune 
system attacks your own body, instead of attacking an infection. 
Risks of the study vaccines: 
This section lists the side effects we know about. There may be others that we don’t yet 
know about, even serious ones. We will tell you if we learn about any new side effects. 
The Ad26 vaccine: 
The Ad26 vaccine is being tested in 2 other studies (HVTN 117/HPX2004 and HVTN 
118/HPX2003) that started before this study. About 235 people in the United States, 
Rwanda, and Kenya are participating in those studies. 
Two similar vaccines have been tested in other studies. One of the similar vaccines has 
been given to over 200 people. That vaccine did not make people too uncomfortable or 
cause them serious health problems. The other similar vaccine has been given to about 
380 people. In those studies, that vaccine did not make people too uncomfortable. One 
person did have a serious allergic reaction and chest pain. The symptoms went away in 
about 1 day. Studies with a small number of people do not tell us everything about the 
safety of a study vaccine. 
The gp140 Protein vaccine: 
The Protein vaccine is being tested in 5 other studies (HVTN 117/HPX2004, HVTN 
118/HPX2003, HPX1002, HIV-V-A003, and HIV-V-A004) that started before this study. 
As of January 2017, about 300 people received the gp140 Protein vaccine. So far, it has 
not made them too uncomfortable or caused them serious health problems. However, 
studies with a small number of people do not tell us everything about the safety of a study 
vaccine. 

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A similar Protein vaccine (gp120 Protein) has been given to thousands of people in other 
studies over 10 years. In these studies, the gp120 Protein vaccine did not cause serious 
health problems. 
Aluminum phosphate adjuvant:  
As we told you, gp140 Protein vaccine is mixed with an adjuvant called aluminum 
phosphate. Too much aluminum in the body can cause problems with nerves and bones, 
mostly for people who already have problems with their kidneys. The aluminum in 
vaccines is much less than what people eat or take in medicines such as antacids. 
5. It is completely up to you whether or not to join the study.  
Take your time in deciding. If it helps, talk to people you trust, such as your doctor, 
friends or family. If you decide not to join this study, or if you leave it after you have 
joined, your other care at this clinic and the benefits or rights you would normally have 
will not be affected. 
If you join this study, you may not be allowed to join other HIV vaccine or HIV 
prevention studies now or in the future. You cannot be in this study while you are in 
another study where you get a study product. Also during the study, you should not 
donate blood or tissue. We will tell you more about this below.  
If you choose not to join this study, you may be able to join another study. 
Site: Remove item 6 if you use a separate screening consent that covers these procedures. 
6. If you want to join the study, we will screen you to see if you are eligible. 
Screening involves a physical exam, HIV test and health history. A physical exam may 
include, but is not limited to: 
• 
Checking your weight, temperature and blood pressure 
• 
Looking in your mouth and throat 
• 
Listening to your heart and lungs 
• 
Feeling your abdomen (stomach and liver) 
We will also test your blood for hemoglobin. This test tells us about the health of your 
blood. We will also do a pregnancy test. We will ask you about medications you are 
taking. We will ask you about behaviors that might put you at risk for getting HIV.  
We will review the screening results with you. The screening results may show you are 
not eligible to join the study, even if you want to.  
Sites: adapt the following section so it is applicable to the care available at your site. 
7. If we find that you have a health problem during screening or during the study, we 
will tell you about the care that we can give here for free.  
For the care that we cannot give, we will explain how we will help you get care 
elsewhere. For health problems that are unrelated to the study, we will not pay for care.  

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8. If you could become pregnant, you must agree to use birth control to join this study. 
Site: If you want to include Appendix B, Approved birth control methods (for sample 
informed consent form), in this consent form, paste it below and delete paragraph below. 
You should not become pregnant during the study because we do not know how the study 
vaccines could affect the developing baby. You must agree to use effective birth control 
from 21 days before your first injection until 3 months after your last study injection. We 
will talk to you about effective birth control methods. They are listed on a handout that we 
will give to you.  
Being in the study 
If you meet the study requirements and want to join, here is what will happen: 
9. You will come to the clinic for scheduled visits about [#] times over 
[Insert period of time]. 
Site: Insert number of visits and range of visit lengths. (There is site-specific variation in 
screening protocols and in the number of possible follow-up visits between protocol-
mandated visits.) 
Visits can last from [#] to [#] hours. 
You may have to come for more visits if you have a lab or health issue. 
We may contact you after the study ends (for example, to tell you about the study 
results). 
In response to the COVID-19 pandemic, we want to make it easier for you to stay in the 
study. If lockdowns or stay-at-home orders make travel to the clinic difficult, we may 
offer to arrange transport for you to the clinic and back home. Or we can do some parts of 
these visits over the phone or through electronic communication such as text messages 
and email. We will discuss with you what works best. 
10. We will give you [Site: Insert compensation] for each study visit you complete. 
This amount is to cover the costs of [Site: Insert text] 
Site: Insert any costs to participants (eg, birth control costs for female participants who 
could become pregnant). 
You do not have to pay anything to be in this study. 
11. We will give you either the study vaccines or a placebo.  
Not everyone in this study will get the study vaccines. Some people will get a placebo, a 
substance that does not contain vaccine. We will compare the results from people who 
got the placebo with results from people who got the study vaccines. In this study, the 
placebo is sterile salt water. 

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You have a 1-in-2 chance of getting the study vaccines. Site: Modify the randomization 
metaphor in the next sentence as appropriate to your local culture. Whether you get the 
study vaccines or the placebo is completely random, like flipping a coin.  
We have no say in whether you get the study vaccines or the placebo. We will not know 
which one you are getting, and neither will you. Only the pharmacist at this clinic will 
have this information while the study is going on.  
Unless the study is stopped early, you will have to wait until everyone completes their 
final study visits to find out whether you got the study vaccines or the placebo. This 
could be several years. But, if you have a serious medical problem and need to know 
what you got before the end of the study, we can find out and tell you. 
If the study shows that the vaccines are working, the researchers will talk to you about 
how this may affect your participation. 
12. We will give you the study products on a schedule. 
You will be in 1 of 2 groups, vaccine or placebo. You will get a total of 6 injections into 
the upper arms during the study. You will get 1 injection of either the Ad26 vaccine or 
placebo at your first injection visit. Three (3) months later, you will get the same 
injection. Six (6) and 12 months after your first injection, you will get 2 injections at each 
visit. You will get either the Ad26 vaccine or placebo in your left arm, and the Protein 
vaccine or placebo in your right arm.  
Site: You may insert the picture version of the injection schedule (Appendix J) in place of 
(or in addition to) the text version or give it as a separate document to volunteers if you 
believe it will be helpful to them. You are not required to do either. 
 
Injection Schedule 
Group 
First 
injection 
3 months 
after first 
injection 
6 months 
after first 
injection 
12 months 
after first 
injection 
1 
Ad26 
Ad26 
Ad26 + 
Protein/Alum 
Ad26 + 
Protein/Alum 
2 
Placebo 
Placebo 
Placebo 
Placebo 
Site: If your site has been selected for the 7-day reactogenicity assessment then replace 3 
more days in the next paragraph with 7 more days. 
You will have to wait in the clinic for about a half hour after each injection to see if there 
are any problems. Then for that night and for 3 more days, you will need to keep track of 
how you are feeling and if you have any symptoms. To help you do this we will give you 
a memory tool and show you how to use it. We will call you about a week after your 
injection visit to see how you are doing. Contact the clinic staff if you have any issues or 
concerns after getting an injection. If you have a problem, we will continue to check on 
you until it goes away. 

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13. In addition to giving you the study products, we will:  
• 
Do regular HIV testing, as well as counseling on your results and on how to avoid 
getting HIV; 
• 
Do physical exams; 
• 
Do pregnancy tests;  
• 
Ask questions about your health, including medications you may be taking; 
• 
Ask questions about any personal problems or benefits you may have from being in 
the study; and 
• 
Take blood and urine samples. 
When we take blood, the amount will depend on the lab tests we need to do. It will be 
some amount between 10 mL and 350 mL (2 teaspoons to 1½ cup). Your body will make 
new blood to replace the blood we take out.  
Site: You may want to add a sentence to the end of the previous paragraph 
contextualizing the blood volumes described (eg, “To compare, people who donate blood 
in the US can give a total of about 500 mL in an 8-week period.”). Modify the example 
for cultural relevance and alter blood volumes as necessary. 
Site: Insert Appendix D, “Table of procedures (for informed consent form), HIV-
uninfected participants” in this section or distribute it as a separate sheet if it is helpful 
to your study participants. You are not required to do either. 
We will be looking for side effects. We will review the results of these procedures and 
tests with you at your next visit, or sooner if necessary. If any of the results are important 
to your health, we will tell you.  
14. You are being asked to have additional visits in this study.  
The purpose of the additional visits is to collect more information about the safety of this 
vaccine and how your immune system responds to the vaccine. The number of additional 
visits will depend on when you started the study. For example, if you started in 
November 2017 then you may have 6 or 7 extra visits; if you started in May 2019 you 
may have no or 1 extra visits. We will complete the study for all people at the same time 
about July 2022. 
We will not give you any more study products at these extra visits. We will:  
• 
Do regular HIV testing, as well as counseling on your results and on how to avoid 
getting HIV; 
• 
Ask questions about your health, including medications you may be taking; 
• 
Do physical exams if required;  
• 
Ask questions about any personal problems or benefits you may have from being in 
the study; and 
• 
Take blood and urine samples. 

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Site: Insert Appendix D, “HIV-uninfected participants: Additional visits” in this section 
or distribute it as a separate sheet if it is helpful to your study participants. You are not 
required to do either. 
15. We will also collect vaginal fluid and swabs. 
We want to see if the bacteria that live in your vagina affect your risk of getting HIV.  
At 5 visits, we will ask you to collect vaginal fluid using a disposable menstrual cup. We 
will explain how you can insert and remove the cup, or we can do it for you. We will 
explain how long you will wear the cup. At these same visits, we will also ask you to 
collect a vaginal swab. We will ask you to place the swab into your vagina. We will teach 
you how to do this. If you do not want to swab yourself, we can do it for you. 
At these same 5 visits, plus up to 5 more additional visits, we will also test you for 
gonorrhea, chlamydia, syphilis, and Trichomonas vaginalis. These are all common 
sexually transmitted infections.  In order to do some of these tests, we will ask you to 
collect another vaginal swab at those visits. We will give you your test results. If we find 
that you have an infection and you need care, we will tell you about the care we can give 
you here. We will also tell you about care we can help you get elsewhere. 
Sites: Do not make changes to the following section without obtaining approval from 
HVTN Regulatory Affairs at vtn.core.reg@hvtn.org. 
16. We will counsel you on avoiding HIV infection. 
We will ask you personal questions about your HIV risk factors such as sexual behavior, 
alcohol, and drug use. Site: Modify this next sentence based on what you provide: We 
will provide you with condoms and lubricant. We will talk with you about ways of 
lowering your risk of getting HIV. We will help you develop a risk reduction plan. Our 
counseling may include: 
• 
What you think causes risky behavior for you. 
• 
Ways to avoid getting HIV. 
• 
If you become infected with HIV, we will talk with you about ways to avoid giving 
the virus to someone else. 
These may include not having sex, using condoms, or other behavior changes, such as 
cutting down on alcohol. We will talk about new methods of HIV prevention as these 
become available, and will give you information on how to access them. 
These methods may include the use of anti-HIV drugs taken every day to prevent HIV. 
This is called pre-exposure prophylaxis or PrEP. A combination of two anti-HIV drugs 
(TDF/FTC) has been licensed in South Africa for use to prevent HIV infection in people 
at high risk, and we think that PrEP will become more available in other southern African 
countries. Studies have shown this drug combination may reduce the risk of getting HIV 
when it is taken every day. The drug combination is not always effective and HIV 
infections may happen, especially if the medicine is not taken every day. Where PrEP is 
licensed, this drug combination will be available in the private health sector by 
prescription from a doctor. In southern Africa, the national departments of health are 
working with international donors to establish “demonstration projects” that may provide 

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this drug combination to people free of charge. Where available, we can refer you to the 
nearest of these programs if you are interested. In this study, we will look at how many 
participants use PrEP. We will also try to find out if using PrEP has any effect on how the 
study products work. 
17. We will test your samples for this study. 
We will send your samples (without your name) to labs approved by the HVTN for this 
study, which are located in the United States, South Africa, and Europe. Researchers at 
these labs will test your samples to see how your immune system responds to the study 
products. In rare cases, some of your samples may be sent to labs approved by the HVTN 
in other countries for research related to this study. 
Researchers may also do genetic testing related to this study on your samples. Your genes 
are passed to you from your birth parents. They affect how you look and how your body 
works. The differences in people’s genes can help explain why some people get a disease 
while others do not. These types of genetic tests involve some of your genes, not all of 
your genes (your genome). The researchers will study the genes related to the immune 
system and HIV and those that affect how people get HIV.  
The researchers may look at all of the genes of the bacteria found in your vaginal 
samples. If you become HIV infected, the researchers may look at all of the genes of the 
virus found in your samples. In both cases, the researchers will use this information to 
learn more about HIV and the study products. The researchers may put this information 
about the virus and/or bacteria into a protected database so that other researchers can 
access it. They would not be able to link the information to you. 
In some cases, researchers may take cells from your samples and grow more of them over 
time, so that they can continue to contribute to this study. 
In some participants, we may test for antibodies against Ad26. This can tell us if you 
have been previously exposed to this virus. We want to see if this has an effect on how 
the vaccine works. 
Tests done on your samples are for research purposes, not to check your health. The labs 
will not give the results to you or this clinic because their tests are not approved for use in 
making health care decisions. These labs are only approved to do research tests.  
When your samples are no longer needed for this study, the HVTN will continue to store 
them. 
Site: Delete next section if using separate consent for use of samples and information in 
other studies 
18. When samples are no longer needed for this study, the HVTN wants to keep them 
for use in other studies by HVTN or other researchers. We will call these “extra 
samples.” 
This section gives you information so you can decide if you want your extra samples and 
study-related information used in other studies. You will mark your decision at the end of 
the form. If you have any questions, please ask.  

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Do I have to agree? No. You are free to say yes or no, or to change your mind after you 
sign this form. At your request, we will destroy all extra samples that we have. Your 
decision will not affect your being in this study or have any negative consequences here.  
Where are the samples stored? Extra samples are stored in a secure central place called a 
repository. [Site: insert specific information if your regulatory authority requires it.] 
Your samples will be stored in the HVTN repository in South Africa.  
How long will the samples be stored? There is no limit on how long your extra samples 
will be stored. [Site: insert limits if your regulatory authority imposes them.] 
Will I be paid for the use of my samples? No. Also, a researcher may make a new 
scientific discovery or product based on the use of your samples. If this happens, there is 
no plan to share any money with you. The researcher is not likely to ever know who you 
are. 
Will I benefit from allowing my samples to be used in other studies? Probably not. 
Results from these other studies are not given to you, this clinic, or your doctor. They are 
not part of your medical record. The studies are only being done for research purposes. 
Will the HVTN sell my samples and information? No, but the HVTN may share your 
samples with other researchers. Once we share your samples and information, we will not 
be able to get them back. 
How do other researchers get my samples and information? When a researcher wants to 
use your samples and/or information, their research plan must be approved by the HVTN. 
Also, the researcher’s institutional review board (IRB) or ethics committee (EC) will 
review their plan. [Site: If review by your institution’s IRB/EC/RE is also required, insert 
a sentence stating this.] IRBs/ECs protect the rights and well-being of people in research. 
If the research plan is approved, the HVTN will send your samples to the researcher’s 
location. 
What information is shared with other researchers? The samples and limited information 
will be labeled with a code number. Your name will not be part of the information. 
However, some information that we share may be personal, such as your race, ethnicity, 
sex, health information from the study, and HIV status. We may share information about 
the study product you received and how your body responded to the study product.  
What kind of studies might be done with my extra samples and information? The studies 
will be related to HIV, vaccines, the immune system and other diseases.  
Researchers may also do genetic testing on your samples.  
Researchers may look at all of the genes of the bacteria found in your vaginal samples. If 
you become HIV infected, the researchers may look at all of the genes of the virus found 
in your samples. In both cases, the researchers will use this information to learn more 
about HIV and the study products.  
In some cases, researchers may take cells from your samples and grow more of them over 
time, so that they can continue to contribute to this study.  

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If you agree, your samples could also be used for genome wide studies. In these studies, 
researchers will look at all of your genes (your genome). The researchers compare the 
genomes of many people, looking for common patterns of genes that could help them 
understand diseases. The researchers may put the information from the genome-wide 
studies into a protected database so that other researchers can access it. Usually, no one 
would be able to look at your genome and link it to you as a person. However, if another 
database exists that also has information on your genome and your name, someone might 
be able to compare the databases and identify you. If others found out, it could lead to 
discrimination or other problems. The risk of this is very small. 
Who will have access to my information in studies using my extra samples?  
People who may see your information are: 
• 
Researchers who use your stored samples and limited information for other research 
• 
Government agencies that fund or monitor the research using your samples or 
information 
• 
The researcher’s Institutional Review Board or Ethics Committee 
• 
Any regulatory agency that reviews clinical trials 
• 
The people who work with the researcher  
All of these people will do their best to protect your information. The results of any new 
studies that use your extra samples or information may be published. No publication will 
use your name or identify you personally. 
19. We will do our best to protect your private information. 
Your study records and samples will be kept in a secure location. We will label all of 
your samples and most of your records with a code number, not your name or other 
personal information. However, it is possible to identify you, if necessary. We will not 
share your name with the lab that does the tests on your samples, or with anyone else who 
does not need to know your name. 
Sites: Any change to the following boxed text requires approval from HVTN Regulatory 
Affairs.  
We do need to share your name with the HVTN in case you need proof in the future that 
you participated in an HIV vaccine study. The HVTN will keep your name in a secure 
file with these items:  
• The name of your study  
• Your age or date of birth  
• Your study ID number  
• What study product(s) you received  
There are no HIV test results kept in this file. The HVTN will not share any information 
that could identify you without your agreement. The HVTN will remove your name from 
the file if you do not want it there. 

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Clinic staff will have access to your study records. Your records may also be reviewed by 
groups who watch over this study to see that we are protecting your rights, keeping you 
safe, and following the study plan. These groups include: 
• 
The US National Institutes of Health and its study monitors, 
• 
The US Food and Drug Administration, 
• 
Any regulatory agency that reviews clinical trials, 
• 
[Insert name of local IBC], 
• 
[Insert name of local IRB/EC] , 
• 
[Insert name of local and/or national regulatory authority as appropriate], 
• 
Janssen Vaccines & Prevention B.V., people who work for them, and their chosen 
South African representatives, 
• 
The HVTN and people who work for them,  
• 
The NIAID Data Safety and Monitoring Board, and 
• 
The US Office for Human Research Protections. 
All reviewers will take steps to keep your records private. 
We cannot guarantee absolute privacy. At this clinic, we have to report the following 
information:  
Site: Include any public health or legal reporting requirements. Bulleted examples should 
include all appropriate cases (reportable communicable disease, risk of harm to self or 
others, etc.). 
• 
[Item 1] 
• 
[Item 2] 
• 
[Item 3] 
The results of this study may be published. No publication will use your name or identify 
you personally. 
We may share information from the study with other researchers and those groups paying 
for this study. We will not share your name or information that can identify you. 
Sites: The text below may not be deleted or changed, per FDA requirement. It’s OK to 
remove the box around it. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This website will not include information that can identify you. At 
most, the website will include a summary of the results. You can search this website at 
any time. 

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20. We may stop your injections or take you out of the study at any time. We may do 
this even if you want to stay in the study and even if you were scheduled for more 
injections.  
This may happen if: 
• 
you do not follow instructions, 
• 
we think that staying in the study might harm you, 
• 
you enroll in a different research study where you get another study product,  
• 
people who got the study vaccines are getting infected with HIV more than people 
who got the placebo, or 
• 
the study is stopped for any reason. 
If we stop your injections, we may ask you to stay in the study to complete other study 
procedures. 
21. We will stop your injections if you become pregnant before your last injection.  
We will encourage you to stay in the study if you choose. We will discuss your study 
options with you. 
If you leave the study while you are still pregnant, we will contact you after your due date 
to ask some questions about your pregnancy and delivery. 
22. If you get infected with HIV during the study, we will help you get care and support. 
We will counsel you about your HIV infection and about telling your partner(s). We will 
tell you where you can get support and medical care. Site: Modify the following sentence 
as appropriate. We will not provide or pay for any of your HIV care directly.  
We will also ask you to come to the clinic for about 3 visits over the following 6 months, 
but we will not give you any more injections. Even though your study injections will 
have stopped, learning about your health is an essential part of this study. At these visits, 
we will: 
• 
Ask questions about your health; 
• 
Do physical exams based on how you tell us you are feeling; 
• 
Ask questions about your risk of infecting others with HIV, including sexual 
behavior and drug use; 
• 
Counsel you on how to avoid infecting others with HIV; 
• 
Do pregnancy tests;  
• 
Collect blood samples (about 230 mL; about a cup at each visit); and 
• 
Ask questions about any personal problems or benefits you may have from 
participating in the study. 

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Site: Insert Appendix D, “Table of procedures (for informed consent form), HIV-infected 
participants” in this section or distribute it as a separate sheet if it is helpful to your 
study participants. You are not required to do either. 
Other Risks 
23. There are other risks to being in this study. 
This section describes the other risks and restrictions we know about. There may also be 
unknown risks, even serious ones. If you have a problem because you are in this study, 
we will help you. We will tell you if we learn anything new that may affect your 
willingness to stay in the study.  
Risks of routine medical procedures:  
In this study, we will do some routine medical procedures. These are taking blood and 
giving injections. These procedures can cause bruising, pain, fainting, soreness, redness, 
swelling, itching, a sore, bleeding, and (rarely) muscle damage or infection where you got 
the injection. Taking blood can cause a low blood cell count (anemia), making you feel 
tired. 
Risks of menstrual cup: 
You may feel some discomfort when inserting or removing the menstrual cup.  
Risks of vaginal swabs: 
You may have some discomfort when you swab your vagina.  
Personal problems/discrimination/testing HIV antibody positive: 
About 1 or 2 in 10 people who join HVTN studies report personal problems or 
discrimination because of joining an HIV vaccine study. Family or friends may worry, 
get upset or angry, or assume that you are infected with HIV or at high risk and treat you 
unfairly as a result. Rarely, a person has lost a job because the study took too much time 
away from work, or because their employer thought they had HIV.  
The body makes antibodies to fight or prevent infection. Most vaccines cause the body to 
make antibodies as a way of preventing infection. Your body may make antibodies to 
HIV because you received HIV study vaccines. The study vaccines are likely to cause 
you to test positive on some types of HIV antibody tests, even if you are not infected with 
HIV. This is called vaccine-induced seropositivity (VISP). VISP means that after you get 
the study vaccines, a routine HIV test done outside this clinic is likely to say you have 
HIV, even if you don’t. For this reason, you should plan to get HIV tests only at this 
clinic during the study. Our tests can tell the difference between true HIV infection and a 
positive result that is caused by the study vaccines. 
If you have a positive test result caused by the study vaccines at any time, it does not 
mean that there is a problem with your health. But, we can arrange free HIV testing for as 
long as you need it. If this happens, we do not know how long you will test HIV positive 
due to the study vaccines. If you receive a positive HIV test result and we determine it is 
because you have HIV, we will refer you for follow-up care. 

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It is unlikely, but you could test negative at the end of the study and positive some time 
later, even though you don’t have HIV. This could happen if different HIV tests come 
into use. We will give you a phone number to call for more information.  
Site: Modify the following paragraph if applicable. If someone believes you are infected 
with HIV even if you are not, you could face discrimination and other problems. For 
example, in some countries, you could be denied medical or dental care, employment, 
insurance, a visa, or entry into the military. If you do have a positive HIV antibody test 
caused by the study vaccines, you will not be able to donate blood or organs. Your family 
and friends may treat you differently. We will give you a brochure that tells you more 
about testing HIV positive because of an HIV vaccine, and how you can avoid some of 
these problems. 
If you become pregnant during or after the study and have VISP, we don't know if the 
antibodies could be passed to your baby. We know that this happens with other vaccines, 
like tetanus vaccine. These antibodies from the mother are not a danger to the baby, and 
they go away over time. For most babies antibodies from the mother last for about six 
months. 
You should always tell the delivery staff if you have VISP. However, you may still be 
tested for HIV using the antibody test when you deliver your baby. If your test is positive 
and the delivery staff believes you have an HIV infection, your baby may be started on 
antiretroviral treatment when it is not needed. If this happens, we can arrange for you and 
the baby to have a test that can tell the difference between true HIV infection and a VISP 
result. If you or the baby continue to have VISP, we can arrange this testing for free for 
as long as it is needed. 
Embarrassment/anxiety:  
You may feel embarrassed when we ask about your HIV risks, such as having sex and 
using drugs. Also, waiting for your HIV test results or other health test results could 
make you feel anxious. You could feel worried if your test results show that you are 
infected with HIV. If you feel embarrassed or anxious, please tell us and we will try to 
help you. 
Risks of disclosure of your personal information: 
We will take several steps to protect your personal information. Although the risk is very 
low, it is possible that your personal information could be given to someone who should 
not have it. If that happened, you could face discrimination, stress, and embarrassment. 
We can tell you more about how we will protect your personal information if you would 
like it.  
Risks of genetic testing: 
The genetic testing could show you may be at risk for certain diseases. If others found 
out, it could lead to discrimination or other problems. However, it is almost impossible 
for you or others to know your test results from the genetic testing. The results are not 
part of your study records and are not given to you.  
Unknown risks:  

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We do not know if the study vaccines will increase, decrease, or not change your risk of 
becoming infected with HIV if exposed. If you get infected with HIV, we do not know 
how the study vaccines might affect your HIV infection or how long it takes to develop 
AIDS. 
We do not know if getting these study vaccines will affect how you respond to any future 
approved HIV vaccine. It could be that a future HIV vaccine may not work as well for 
you because you got the study vaccines. Currently, no HIV vaccine has been approved 
for use.  
We do not know how the study vaccines will affect a pregnant participant or a developing 
baby.  
Benefits 
24. The study may not benefit you. 
We do not know whether getting the study vaccines might benefit you in any way. 
However, being in the study might still help you in some ways. The counseling that you 
get as part of the study may help you avoid getting HIV. The lab tests and physical exams 
that you get while in this study might detect health problems you don’t yet know about.  
This study may help in the search for a vaccine to prevent HIV. However, if the study 
vaccines later become approved and sold, there are no plans to share any money with 
you.  
Your rights and responsibilities 
25. If you join the study, you have rights and responsibilities. 
You have many rights that we will respect. You also have responsibilities. We list these 
in the Participant’s Bill of Rights and Responsibilities. We will give you a copy of it. 
Leaving the study 
26. Tell us if you decide to leave the study.  
You are free to leave the study at any time and for any reason. Your care at this clinic and 
your legal rights will not be affected, but it is important for you to let us know.  
We will ask you to come back to the clinic one last time for a physical exam, and we may 
ask to take some blood and urine samples. We will also ask about any personal problems 
or benefits you have experienced from being in the study. We believe these steps are 
important to protecting your health, but it is up to you whether to complete them. 
Injuries 
Sites: Do not make changes to the following section without obtaining approval from 
HVTN Regulatory Affairs at vtn.core.reg@hvtn.org. 

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27. If you get sick or injured during the study, contact us immediately. 
Your health is important to us. (Sites: adjust the following 2 sentences if applicable to the 
care available at your site) We will tell you about the care that we can give here. For the 
care that we cannot provide, we will explain how we will help you get care elsewhere. 
If you become sick or injured in this study, there is a process to decide if it is related to 
the study products and/or procedures. If it is, we call it a study-related injury. There are 
funds to pay for treatment of study-related injuries if certain conditions are met. The 
funds may come from different groups, as described below.  
(Sites: adjust the language in this paragraph (or remove altogether) so it is applicable to 
your site. Note: insurance is purchased for all southern African countries; however, the 
ABPI guidelines apply to South Africa and Mozambique only.) In this study, our clinic 
has insurance to cover your medical treatment in the case of a study-related injury, 
following the Association of the British Pharmaceutical Industry guidelines for payment 
of study-related injury. We can give you a copy of these guidelines. In rare cases, the 
clinic’s insurance funds may not be enough. In case the clinic’s insurance company does 
not fully cover those medical costs, the sponsor of the study (Janssen Vaccines) can pay 
the remaining medical costs that are not covered by the clinic’s insurance company, 
provided the injury is objectively determined to be caused directly by the vaccination in 
the trial with its candidate vaccine. 
For study-related injuries that cannot be funded as described above, the HVTN has 
limited funds to pay medical costs that it determines are reasonable. (Sites: insert locale- 
appropriate medical insurance language in the following sentence) If the injury is not 
study related, then you and your health insurance will be responsible for treatment costs.  
Some injuries are not physical. For example, you might be harmed emotionally by being 
in an HIV vaccine study. Or you might lose wages because you cannot go to work. 
However, there are no funds to pay for these kinds of injuries, even if they are study 
related. 
You may disagree with the decision about whether your injury is study related. If you 
wish, the HVTN will ask independent experts to review the decision. You always have 
the right to use the court system if you are not satisfied. 
Questions  
28. If you have questions or problems at any time during your participation in this 
study, use the following important contacts. 
If you have questions about this study, contact 
[name and telephone number of the investigator or other study staff]. 
If you have any symptoms that you think may be related to this study, contact 
[name and telephone number of the investigator or other study staff]. 
If you have questions about your rights as a research participant, or problems or concerns 
about how you are being treated in this study, contact 
[name/title/phone of person on IRB or other appropriate organization]. 

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 129 of 146 
If you want to leave this study, contact 
[name and telephone number of the investigator or other study staff]. 
Remainder of section for South African sites only.  
If you have questions about this trial you should first discuss them with your doctor or the 
ethics committee (contact details as provided on this form). After you have consulted 
your doctor or the ethics committee and if they have not provided you with answers to 
your satisfaction, you should write to the South African Healthcare Products Regulatory 
Authority (SAHPRA) at: 
 
 
 
South African Health Products Regulatory Authority 
Department of Health 
Private Bag X828 
PRETORIA 
0001 
 
Tel: 
 
 
e-mail: 
 
Your permissions and signature  
Site: Delete this section if using a separate consent for use of samples and information in 
other studies 
29. In Section 17 of this form, we told you about possible other uses of your extra 
samples and limited information, outside this study. Please choose only one of the 
options below and write your initials or make your mark in the box next to it. 
Whatever you choose, the HVTN keeps track of your decision about how your 
samples and information can be used. 
 
PPD
PPD
PPD

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 130 of 146 
 
I allow my extra samples combined with limited information to be used for other 
studies related to HIV, vaccines, the immune system, and other diseases. This may 
include genetic testing and keeping my cells growing over time.  
OR 
 
 
I agree to the option above and also to allow my extra samples combined with limited 
information to be used in genome wide studies. 
OR 
 
 
I do not allow my extra samples to be used in any other studies. This includes not 
allowing genetic testing, growing more of my cells, or genome wide studies.  
 
30. If you agree to join this study, you will need to sign or make your mark below. 
Before you sign or make your mark on this consent form, make sure of the 
following: 
• 
You have read this consent form, or someone has read it to you. 
• 
You feel that you understand what the study is about and what will happen to you if 
you join. You understand what the possible risks and benefits are. 
• 
You have had your questions answered and know that you can ask more. 
• 
You agree to join this study. 
You will not be giving up any of your rights by signing this consent form. 
 
 
 
 
 
 
 
Participant’s name (print) 
 
Participant’s signature or mark 
 
Date 
 
Time 
 
 
 
 
 
 
 
Clinic staff conducting consent 
discussion (print) 
 
Clinic staff signature 
 
Date 
 
Time 
For participants who are unable to read or write, a witness should complete the signature 
block below: 
 
 
 
 
 
 
 
Witness’s name (print) 
 
Witness’s signature  
 
Date 
 
Time 
*Witness is impartial and was present for the consent process. 
 
 

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 131 of 146 
Appendix B 
Approved birth control methods (for sample 
informed consent form) 
You should not become pregnant during the study because we do not know how the study 
vaccines could affect the developing baby. 
You must agree to use effective birth control from 21 days before your first injection until 
3 months after your last study injection.  
Effective birth control means using any of the following methods every time you have 
sex: 
• 
Birth control drugs that prevent pregnancy – given by pills, shots, patches, 
vaginal rings, or inserts under the skin; or 
• 
Intrauterine device (IUD); or 
• 
Any other contraceptive method approved by the researchers. 
You do not have to use birth control if: 
• 
You have been diagnosed with early menopause, with no menstrual periods for 
one year; or 
• 
You have had a hysterectomy (your uterus removed); or 
• 
You have had your ovaries removed; or 
• 
You have a tubal ligation (your “tubes tied”) or confirmed successful placement 
of a product that blocks the fallopian tubes. 
Remember: You need to use male or female condoms to protect yourself from HIV infection.  
If you join the study, we will test you for pregnancy at some visits, including before each 
study injection. 

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 132 of 146 
Appendix C 
Sample consent form for use of samples and 
information in other studies 
Title: A multicenter, randomized, double-blind, placebo-controlled phase 2b efficacy 
study of a heterologous prime/boost vaccine regimen of Ad26.Mos4.HIV and aluminum 
phosphate-adjuvanted Clade C gp140 in preventing HIV-1 infection in women in sub-
Saharan Africa 
Protocol number: HVTN 705/VAC89220HPX2008 
Site: [Insert site name] 
When samples are no longer needed for this study, the HVTN wants to keep them for use 
in other studies. We will call these “extra samples.” 
This form gives you information so you can decide if you want your extra samples and 
study-related information used in other studies. You will mark your decision at the end of 
the form. If you have any questions, please ask.  
1. Do I have to agree?  
No. You are free to say yes or no, or to change your mind after you sign this form. At 
your request, we will destroy all extra samples that we have. Your decision will not affect 
your being in this study or have any negative consequences here.  
2. Where are the samples stored?  
Extra samples are stored in a secure central place called a repository. [Site: insert specific 
information if your regulatory authority requires it.] Your samples will be stored in the 
HVTN repository in South Africa. 
3. How long will the samples be stored?  
There is no limit on how long your extra samples will be stored. [Site: insert limits if your 
regulatory authority imposes them.] 
4. Will I be paid for the use of my samples?  
No. Also, a researcher may make a new scientific discovery or product based on the use 
of your samples. If this happens, there is no plan to share any money with you. The 
researcher is not likely to ever know who you are. 
5. Will I benefit from allowing my samples to be used in other studies?  
Probably not. Results from these other studies are not given to you, this clinic, or your 
doctor. They are not part of your medical record. The studies are only being done for 
research purposes. 
6. Will the HVTN sell my samples and information?  
No, but the HVTN may share your samples with other researchers. Once we share your 
samples and information, we will not be able to get them back. 

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 133 of 146 
7. How do other researchers get my samples and information?  
When a researcher wants to use your samples and/or information, their research plan 
must be approved by the HVTN. Also, the researcher’s institutional review board (IRB) 
or ethics committee (EC) will review their plan. [Site: If review by your institution’s 
IRB/EC/RE is also required, insert a sentence stating this.] IRBs/ECs protect the rights 
and well-being of people in research. If the research plan is approved, the HVTN will 
send your samples to the researcher’s location. 
8. What information is shared with other researchers?  
The samples and limited information will be labeled with a code number. Your name will 
not be part of the information. However, some information that we share may be 
personal, such as your race, ethnicity, gender, health information from the study, and HIV 
status. We may share information about the study product you received and how your 
body responded to the study product.  
9. What kind of studies might be done with my extra samples and information?  
The studies will be related to HIV, vaccines, the immune system and other diseases. 
Researchers may also do genetic testing related to this study on your samples.  
Researchers may look at all of the genes of the bacteria found in your vaginal samples. If 
you become HIV infected, the researchers may look at all of the genes of the virus found 
in your samples. In both cases, the researchers will use this information to learn more 
about HIV and the study products. 
In some cases, researchers may take cells from your samples and grow more of them over 
time, so that they can continue to contribute to this study. 
If you agree, your samples could also be used for genome wide studies. In these studies, 
researchers will look at all of your genes (your genome). The researchers compare the 
genomes of many people, looking for common patterns of genes that could help them 
understand diseases. The researchers may put the information from the genome-wide 
studies into a protected database so that other researchers can access it. Usually, no one 
would be able to look at your genome and link it to you as a person. However, if another 
database exists that also has information on your genome and your name, someone might 
be able to compare the databases and identify you. If others found out, it could lead to 
discrimination or other problems. The risk of this is very small. 
10. What are the risks of genetic testing?  
The genetic testing could show you may be at risk for certain diseases. If others found 
out, it could lead to discrimination or other problems. However, it is almost impossible 
for you or others to know your test results from the genetic testing. The results are not 
part of your study records and are not given to you.  
11. Who will have access to my information in studies using my extra samples? 
People who may see your information are: 
• 
Researchers who use your stored samples and limited information for other research  

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 134 of 146 
• 
Government agencies that fund or monitor the research using your samples or 
information 
• 
The researcher’s Institutional Review Board or Ethics Committee 
• 
Any regulatory agency that reviews clinical trials 
• 
The people who work with the researcher  
All of these people will do their best to protect your information. The results of any new 
studies that use your extra samples or information may be published. No publication will 
use your name or identify you personally. 
Questions  
12. If you have questions or problems about allowing your samples and information to 
be used in other studies, use the following important contacts. 
If you have questions about the use of your samples or information or if you want to 
change your mind about their use, contact 
[name and telephone number of the investigator or other study staff]. 
If you think you may have been harmed because of studies using your samples or 
information, contact [name and telephone number of the investigator or other study staff]. 
If you have questions about your rights as a research participant, contact 
[name/title/phone of person on IRB or other appropriate organization]. 
Remainder of section for South African sites only.  
If you have questions about this trial you should first discuss them with your doctor or the 
ethics committee (contact details as provided on this form). After you have consulted 
your doctor or the ethics committee and if they have not provided you with answers to 
your satisfaction, you should write to the South African Healthcare Products Regulatory 
Authority (SAHPRA) at: 
 
 
  
South African Health Products Regulatory Authority 
Department of Health 
Private Bag X
 
PRETORIA 
0001 
 
Tel: 
 
 
e-mail: 
 
PPD
PPD
PPD
PP

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 135 of 146 
Please choose only one of the options below and write your initials or make your mark in 
the box next to it. Whatever you choose, the HVTN keeps track of your choice about how 
your samples and information can be used. 
 
I allow my extra samples combined with limited information to be used for other 
studies related to HIV, vaccines, the immune system, and other diseases. This may 
include genetic testing and keeping my cells growing over time.  
OR 
 
 
I agree to the option above and also to allow my extra samples combined with limited 
information to be used in genome wide studies. 
 
OR 
 
 
I do not allow my extra samples to be used in any other studies. This includes not 
allowing genetic testing, growing more of my cells, or genome wide studies.  
 
 
 
 
 
 
 
 
 
 
Participant’s name (print) 
 
Participant’s signature or mark 
 
Date 
 
Time 
 
 
 
 
 
 
 
Clinic staff conducting consent 
discussion (print) 
 
Clinic staff signature 
 
Date 
 
Time 
For participants who are unable to read or write, a witness should complete the signature 
block below: 
 
 
 
 
 
 
 
Witness’s name (print) 
 
Witness’s signature  
 
Date 
 
Time 
*Witness is impartial and was present for the consent process. 

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 136 of 146 
Appendix D 
Table of procedures (for sample informed 
consent form) 
 
HIV-uninfected participants 
Procedure 
Screenin
g visit(s) 
First 
injection 
visit 
 
Time after 1st injection visits (in months) 
3 
6 
6# 
7 
9 
12 
13 
15 
18 
21 
24 
27 
30 
33 
36 
Injection 
 
√ 
√ 
√ 
 
 
 
√ 
 
 
 
 
 
 
 
 
 
Medical history 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
physical 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
Brief physical 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Blood drawn 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Pregnancy test* 
√ 
√ 
√ 
√ 
 
 
 
√ 
 
 
 
 
 
 
 
√ 
 
Vaginal swab(s) 
 
√ 
 
√ 
 
 
 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
Cervical fluid 
 
√ 
 
√ 
 
 
 
√ 
 
 
√ 
 
√ 
 
 
 
 
STI testing 
 
√ 
 
√ 
 
 
 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
HIV testing & 
pretest 
counseling 
√ 
√ 
√ 
√ 
 
√ 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Risk reduction 
counseling 
√ 
√ 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Interview/ 
questionnaire 
√ 
√ 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Not shown in this table is a time after all study participants have completed their last scheduled visit when you can find out what products 
you received. 
# One day after vaccination visit. 
*Persons who had a complete hysterectomy (removal of the uterus verified by medical records) or removal of both ovaries (verified by 
medical records), are not required to have a pregnancy test. 
 
 
HIV-uninfected participants: Additional visits 
 
The number of extended follow-up visits for any individual will depend in part on the time of enrollment.  
For example, if you enrolled around November 2017 then you may have 6 -7 extra visits; if you enrolled around  
May 2019 you may have 0 or 1 extra visits. We will end the study for all participants at the same time around July 
2022. 
Procedure 
Time after 1st injection visits (in months) 
39 
42 
45 
48 
51 
54 
57 
Brief physical 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Blood drawn 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
STI testing 
 
√ 
 
√ 
 
√ 
 
HIV testing & pretest counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Risk reduction counseling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Interview/questionnaire 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Not shown in this table is a time after all study participants have completed their last scheduled visit when you can find out 
what products you received. 
 

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 137 of 146 
 
Appendix D (continued) Table of procedures (for sample 
informed consent form)  
 
HIV-infected participants 
 
Time after 1st positive HIV test 
(in months) 
Procedure 
About 2 
weeks 
3 
6 
Medical history (as needed) 
√ 
√ 
√ 
Brief physical (as needed) 
√ 
√ 
 
Complete physical 
 
 
√ 
HIV testing & pretest 
counseling 
√ 
 
 
Risk reduction counseling 
√ 
√ 
√ 
Questions/questionnaire 
√ 
√ 
√ 
Blood drawn 
√ 
√ 
√ 
Vaginal swab 
√ 
 
 
Pregnancy test* 
 
√ 
√ 
Not shown in this table is a time when you can find out what products you received. 
*Persons who had a complete hysterectomy (removal of the uterus verified by medical records) or removal of both ovaries (verified by 
medical records), are not required to have a pregnancy test. 
**Once the last HIV uninfected participant completes their Month 36 visit, the study is completed. Redraw visits to confirm HIV infection 
status may still be performed after the study is complete.

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 138 of 146 
Appendix E 
 Schedule1: Laboratory procedures for HIV-uninfected participants 
 
 
1BARC = Bio Analytical Research Corporation South Africa (Pty) Ltd (Johannesburg, South Africa); HSML-NICD = HIV Sero-Molecular Laboratory-National Institute for Communicable Diseases (Johannesburg, South Africa); UW-VSL = University of 
Washington Virology Specialty Laboratory (Seattle, Washington, USA)  
2HVTN Laboratories include: Cape Town HVTN Immunology Laboratory (CHIL, Cape Town, South Africa); South African Immunology, Laboratory–National Institute for Communicable Diseases (SAIL-NICD, Johannesburg, South Africa); Fred Hutchinson 
Cancer Research Center (FHCRC, Seattle, Washington, USA); Duke University Medical Center (Duke, Durham, North Carolina, USA); University of Cape Town (Cape Town, South Africa), University of Colorado Denver (Aurora, Colorado, USA)  Non-HVTN 
laboratory: Janssen = Janssen Prevention and Vaccines (Leiden, The Netherlands)  TBD = Laboratories to be determined by the HVTN laboratory Program  
3Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination  
4Local labs may assign appropriate alternative tube types for locally performed tests  
5Immunogenicity assays will be performed at M0 (for binding antibody assay), M7 and M13  Based on the number of responders observed at these timepoints, lab assays may be performed on participants for humoral and cellular responses at other timepoints  
6Genotyping may be performed on enrolled participants using cryopreserved PBMC collected at baseline, initially in participants who demonstrate vaccine-induced T-cell responses at postvaccination timepoints  
7Pregnancy test must be performed on the day of vaccination with negative results received prior to vaccination  Persons who have undergone total hysterectomy or bilateral oophorectomy (verified by medical records) are not required to undergo pregnancy testing  
Visit
1
2
3
41
51
61
7
81
91
10
11
12
13
14
15
16
17
Day
D0
D84
D168
D169
D182-196
D273
D364
D378-394
D455
D546
D637
D728
D819
D910
D1001
D1092
Week
W0
W12
W24
W26-28
W39
W52
W54-56
W65
W78
W91
W104
W117
W130
W143
W156
Month
M0
M3
M6
M6.5-7
M9
M12
M12.5-13
M15
M18
M21
M24
M27
M30
M33
M36
Ad26.Mos4.HIV
or
Placebo
Ad26.Mos4.HIV
or
Placebo
Ad26.Mos4.HIV +
gp140/Alum
or
Placebo
Ad26.Mos4.HIV +
gp140/Alum
or
Placebo
Procedure
Ship to1,2
Assay
location2
Tube 
Type
Tube size
(vol. capacity)
Total
BLOOD COLLECTION
Screening/Diagnostic
        Screening HIV test
Local lab
Local lab
SST
5mL
5
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
5
        HIV diagnostics 8
HSML-NICD /
UW-VSL
HSML-NICD /
UW-VSL
EDTA
10mL
—
10
10
10
—
10
10
10
—
10
10
10
10
10
10
10
208
150
Safety labs
        Hemoglobin
Local lab
Local lab
EDTA
5mL
5
—
—
5
—
—
—
5
—
—
—
—
—
—
—
—
—
15
STI Serology
        Syphilis15
Local lab
Local lab
SST
5mL
—
515
—
515
—
—
—
515
—
—
515
—
515
—
515
—
515
35
ARV detection by serum or plasma9, 10
BARC
TBD
SST
8.5mL
—
y
—
y
—
—
—
y
—
—
y
—
y
—
y
—
y
0
ARV detection by dried blood spots 11
BARC
HVTN Labs
EDTA
2mL
—
0
Immunogenicity & virologic assays 5
        Host genetics 6
BARC
HVTN Labs
Na Hep
10mL
—
20
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
20
        Cellular assays
        ICS
BARC
HVTN Labs
Na Hep
10mL
—
50
—
—
—
50
—
50
50
—
50
—
50
—
50
—
50
400
        IFN-g ELISpot
BARC
HVTN Labs
Na Hep
10mL
—
30
—
—
—
30
—
30
30
—
30
—
30
—
30
—
30
240
        Humoral assays
        Binding Ab
BARC
HVTN Labs
SST
8.5mL
—
8.5
—
—
—
8.5
—
8.5
8.5
—
8.5
—
8.5
—
8.5
—
8.5
68
        Neutralizing Ab
BARC
HVTN Labs
SST
8.5mL
—
8.5
—
—
—
8.5
—
8.5
8.5
—
8.5
—
8.5
—
8.5
—
8.5
68
        Env-specific ELISA
BARC
Janssen
SST
8.5mL
—
8.5
—
—
—
8.5
—
8.5
8.5
—
8.5
—
8.5
—
8.5
—
8.5
68
        Ad26 neutralizing Ab
BARC
Janssen
SST
8.5mL
—
y
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
0
        Antibody-dependent cellular phagocytos
BARC
HVTN Labs
SST
8.5mL
—
y
—
—
—
y
—
y
y
—
y
—
y
—
y
—
y
0
Innate Immunity 
        RNA gene expression
BARC
HVTN Labs
Tempus
3mL
—
3
—
3
3
—
—
—
—
—
—
—
—
—
—
—
—
9
        Serum cytokines
BARC
HVTN Labs
SST
8.5mL
—
8.5
—
8.5
8.5
—
—
—
—
—
—
—
—
—
—
—
—
26
        Transcriptional profiling
BARC
HVTN Labs
Na Hep
10mL
—
40
—
40
40
—
—
—
—
—
—
—
—
—
—
—
—
120
Viral isolation/sequencing9
BARC
TBD
EDTA
10mL
—
10
10
10
—
10
10
10
2013
10
10
10
10
10
10
10
10
160
STORAGE
        PBMC
BARC
Na Hep
10mL
—
100
—
—
—
100
—
50
100
—
50
—
50
—
50
—
50
550
        Serum
BARC
SST
8.5mL
—
42.5
—
—
—
42.5
—
17
42.5
—
17
—
17
—
17
—
17
213
Visit total
10
347
22
84
54
270
22
205
270
22
200
22
200
22
200
22
210
2178
56 Day total12
10
357
22
84
137
407
22
205
475
22
200
22
200
22
200
22
210
URINE COLLECTION
        Pregnancy test7
Local lab
Local lab
X
X
X
X
—
—
—
X
—
—
—
—
—
—
—
X
—
EITHER URINE OR CERVICAL/VAGINAL SWAB COLLECTION
        Urine - Chlamydia/Gonorrhea16
Local lab
Local lab
—
X17
—
X17
—
—
—
X17
—
—
X17
—
X17
—
X17
—
X17
        Cervical/vaginal swab -
        Chlamydia/Gonorrhea16
Local lab
Local lab
—
X17
—
X17
—
—
—
X17
—
—
X17
—
X17
—
X17
—
X17
CERVICAL/VAGINAL SWAB COLLECTION
        Trichomonas vaginalis 18
Local lab
Local lab
—
X18
—
X18
—
—
—
X18
—
—
X18
—
X18
—
X18
—
X18
MUCOSAL COLLECTIONS 
        Vaginal swab
BARC
TBD
—
X
—
X
—
—
—
X
—
—
X
—
X
—
—
—
—
        Cervical secretions
BARC
HVTN Labs
—
X
—
X
—
—
—
X
—
—
X
—
X
—
—
—
—
See footnote 11
Screening 
visit3

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 139 of 146 
8At an early termination visit for a withdrawn or terminated participant (see Section 9 11), blood should be drawn for HIV diagnostic testing, as shown for visit 17 above  
9EDTA blood collected for plasma may also be used for ARV detection, if necessary  
10Testing plan for ARV detection to be determined  
11EDTA blood for dried blood spots will be collected on regularly scheduled calendar days throughout the study  Refer to the Specimen Collection SSP for more information  
12The total 56-day blood collection includes 2mL EDTA blood collection for dried blood spots  It is highly improbably that the 2mL EDTA blood collection will occur at every possible timepoint, but it is reflected in the blood draw totals for every visit to account for 
this extreme possibility  
13EDTA blood collected for viral isolation/sequencing may also be used for HIV diagnostics, if necessary  
14Based on hemoglobin levels at visits 4 and 8, blood draws at visits 5, 6 and 9 may be reduced  Refer to the Specimen Collection SSP for more information  
15Syphilis testing will be done by serology and will be performed at visits 2, 4, 8, 11, 13, 15 and 17; in addition, testing may occur at any other visit if clinically indicated   
16 Chlamydia/gonorrhea testing will be done with either urine or cervical/vaginal swabs  Either urine or swab is acceptable, and clinics will determine which specimen will be collected and tested   
17Chlamydia/gonorrhea testing will be performed at visits 2, 4, 8, 11, 13, 15 and 17; in addition, testing may occur at any other visit if clinically indicated   
18Cervical/vaginal swab will be collected for Trichomonas testing at visits 2, 4, 8, 11, 13, 15 and 17; in addition, testing may occur at any other visit if clinically indicated  
y = SST blood collected for humoral assays and serum storage will also cover specimen needs for ARV detection, Ad26 neutralizing antibody,  and antibody-dependent cellular phagocytosis; no separate blood draw is needed  
 
 

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 140 of 146 
Appendix E (continued) Schedule1: Laboratory procedures for HIV-uninfected participants, 
extension phase  
 
Visit
18
19
20
21
22
23
24
Month
M39
M42
M45
M48
M51
M54
M57
Procedure
Ship to1,2
Assay
location2
Tube 
Type3
Tube size
(vol. capacity)3
Total
BLOOD COLLECTION
Diagnostic
        HIV diagnostics 8
HSML-NICD /
UW-VSL
HSML-NICD /
UW-VSL
EDTA
10mL
10
10
10
10
10
10
10
90
Safety labs
        Hemoglobin
Local lab
Local lab
EDTA
5mL
—
—
—
—
—
—
—
0
STI Serology
        Syphilis8
Local lab
Local lab
SST
5mL
—
5
—
5
—
5
—
35
ARV detection by serum or plasma
BARC
TBD
SST
8.5mL
y
y
—
y
—
0
ARV detection by dried blood spots 5
BARC
HVTN Labs
EDTA
2mL
0
Immunogenicity & virologic assays
        Cellular assays
        ICS
BARC
HVTN Labs
Na Hep
10mL
—
50
—
50
—
50
—
150
        IFN-g ELISpot
BARC
HVTN Labs
Na Hep
10mL
—
30
—
30
—
30
—
90
        Humoral assays
        Binding Ab
BARC
HVTN Labs
SST
8.5mL
—
8.5
—
8.5
—
8.5
—
26
        Neutralizing Ab
BARC
HVTN Labs
SST
8.5mL
—
8.5
—
8.5
—
8.5
—
26
        Env-specific ELISA
BARC
Janssen
SST
8.5mL
—
8.5
—
8.5
—
8.5
—
26
        Antibody-dependent cellular phagocytos
BARC
HVTN Labs
SST
8.5mL
—
y
—
y
—
y
—
0
Viral isolation/sequencing7
BARC
TBD
EDTA
10mL
10
10
10
10
10
10
10
90
STORAGE
        PBMC
BARC
Na Hep
10mL
—
50
—
50
—
50
—
150
        Serum
BARC
SST
8.5mL
—
17
—
17
—
17
—
51
Visit total
22
200
22
200
22
200
22
687
56-Day total6
22
200
22
200
22
200
22
EITHER URINE OR CERVICAL/VAGINAL SWAB COLLECTION
        Urine - Chlamydia/Gonorrhea9
Local lab
Local lab
—
X
—
X
—
X
—
        Cervical/vaginal swab -
        Chlamydia/Gonorrhea9
Local lab
Local lab
—
X
—
X
—
X
—
CERVICAL/VAGINAL SWAB COLLECTION
        Trichomonas vaginalis 10
Local lab
Local lab
—
X
—
X
—
X
—
See footnote 5
 
1BARC = Bio Analytical Research Corporation South Africa (Pty) Ltd (Johannesburg, South Africa); HSML-NICD = HIV Sero-Molecular Laboratory-National Institute for Communicable Diseases 
 (Johannesburg, South Africa); UW-VSL = University of    Washington Virology Specialty Laboratory (Seattle, Washington, USA)  
2 HVTN Laboratories include: Cape Town HVTN Immunology Laboratory (CHIL, Cape Town, South Africa); South African Immunology Laboratory–National Institute for Communicable Diseases 
 (SAIL-NICD, Johannesburg, South Africa); Fred Hutchinson Cancer Research Center (Seattle, Washington, USA); Duke University Medical Center (Durham, North Carolina, USA); University of 
 Cape Town (Cape Town, South Africa); University of Colorado Denver (Aurora, Colorado, USA)  Non-HVTN laboratory: Janssen = Janssen Prevention and Vaccines (Leiden, The Netherlands)  
 TBD = Laboratories to be determined by HVTN Laboratory Program  
3 Local labs may assign appropriate alternative tube types for locally performed tests  
4 EDTA blood collected for plasma may also be used for ARV detection, if necessary  
5EDTA blood for dried blood spots will be collected on regularly scheduled calendar days throughout the study  Refer to the Specimen Collection SSP for more information  
6The total 56-day blood collection includes 2mL EDTA blood collection for dried blood spots  It is highly improbable that the 2mL EDTA blood collection will occur at every possible timepoint,  
but it is reflected in the blood draw totals for every visit to account for this extreme possibility  
7EDTA blood collected for viral isolation/sequencing may also be used for HIV diagnostics, if necessary  
8Syphilis testing will be done by serology at visits 19, 21, and 23; in addition, testing may occur at any visit if clinically indicated 
9Chlamydia/gonorrhea testing will be performed at visits 19, 21 and 23; in addition, testing may occur at any visit if clinically indicated  Chlamydia/gonorrhea testing will be done with either urine 
 or cervical/vaginal swab  Either urine or swab is acceptable, and clinics will determine which specimen will be collected and tested  
10Cervical/vaginal swab will be collected for Trichomonas testing at visits 19, 21, and 23; in addition, testing may occur at any visit if clinically indicated  
y = SST blood collected for humoral assays and serum storage will also cover specimen needs for ARV detection, and antibody-dependent cellular phagocytosis assays; no separate blood draw is needed  
 

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 141 of 146 
Appendix F 
Schedule 2: Laboratory procedures for HIV-infected participants 
 
1BARC = Bio Analytical Research Corporation, South Africa (Pth) Ltd (Johannesburg, South Africa); HSML-NICD = HIV Sero-Molecular Laboratory-National Institute for Communicable Diseases (Johannesburg, South Africa); UW-VSL = University of 
Washington Virology Specialty Laboratory (Seattle, Washington, USA)  
2HVTN Laboratories include: Cape Town HVTN Immunology Laboratory (CHIL, Cape Town, South Africa); South African Immunology, Laboratory–National Institute for Communicable Diseases (SAIL-NICD, Johannesburg, South Africa); Fred Hutchinson 
Cancer Research Center (FHCRC, Seattle, Washington, USA); Duke University Medical Center (Duke, Durham, North Carolina, USA)  Non-HVTN laboratory: Janssen = Janssen Prevention and Vaccines (Leiden, The Netherlands)  TBD = Laboratories to be 
determined by the HVTN laboratory Program  
3Local labs may assign appropriate alternative tube types for locally performed tests  
4Visit # X indicates a Redraw visit where # is a Schedule 1 visit number  Confirmatory draw for HIV diagnostics will be collected at the Redraw visit  The Redraw visit should occur as soon as possible after the clinic receives a Redraw Request from the HIV 
diagnostics laboratory  Multiple subsequent Redraw visits may be necessary; only the EDTA blood specimen for HIV diagnostics, viral isolation/sequencing, and plasma storage will be collected at the subsequent Redraw visits  
5If the first Redraw visit is preceded by visit 2, 6, 8, or 9, in Schedule 1, the clinic should contact HVTN Lab Ops immediately prior to scheduling the participant for the Redraw visit  HVTN Lab Ops will provide guidance on what blood specimens to collect in 
order to not exceed the 56-day blood volume limit   
6One tube will remain as a whole blood specimen and be shipped ambient to the HIV diagnostics laboratory; it should not be processed for plasma by the site-associated laboratory  The other tube will be processed for plasma as usual  
7Vaginal swab will only be collected at the first Redraw visit 
8Date of diagnosis = date of initial specimen draw that led to first Redraw Request  
9Persons who have undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing  
y = SST blood collected for humoral assays and serum storage will also cover specimen needs for Env-specific binding Ab and antibody-dependent cellular phagocytosis; no separate blood draw is needed  
Visit:
#.X4, 5
Visit:
31
32
Weeks after 
diagnosis 8:
W12
W24
Month:
M3
M6
Procedure
Ship to1 2
Assay location2
Tube 
Type3
Tube size
(vol. capacity)3
Total
BLOOD COLLECTION
Screening/Diagnostic
        HIV diagnostics
HSML-NICD /
UW-VSL
HSML-NICD /
UW-VSL
EDTA
10mL
206
—
—
20
        HIV PCR viral load
HSML-NICD /
UW-VSL
HSML-NICD /
UW-VSL
EDTA
10mL
—
10
10
20
        CD4+T cell count
Local lab
Local lab
EDTA
5mL
5
5
5
15
Immunogenicity & virologic assays
        Cellular assays
        ICS
BARC
HVTN Labs
Na Hep
10mL
50
50
50
150
        IFN-g ELISpot
BARC
HVTN Labs
Na Hep
10mL
20
20
20
60
        Humoral assays
        Binding Ab
BARC
HVTN Labs
SST
8 5mL
8 5
8 5
8 5
25.5
        Neutralizing Ab
BARC
HVTN Labs
SST
8 5mL
8 5
8 5
8 5
25.5
        Env-specific ELISA
BARC
Janssen
SST
8 5mL
y
y
y
0
        Antibody-dependent cellular phagocytosis
BARC
HVTN Labs
SST
8 5mL
y
y
y
0
Viral isolation/sequencing
BARC
TBD
EDTA
10mL
10
10
10
30
STORAGE
        PBMC
BARC
Na Hep
10mL
50
50
50
150
        Plasma
BARC
EDTA
10mL
10
10
10
30
        Serum
BARC
SST
8 5mL
17
17
17
51
Visit total
199
189
189
577
56-Day total
199
189
189
URINE COLLECTION
Pregnancy Test9
Local lab
Local lab
—
X
X
MUCOSAL COLLECTION
        Vaginal swab
BARC
TBD
X7
—
—

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 142 of 146 
Appendix G 
Schedule 1: Procedures at HVTN CRS for HIV-uninfected participants 
Visit: 
011  
022 
03 
04 
0511 
06 
07 
08 
09 
10 
11 
12 
13 
14 
15 
16 
17 
Post 
Day: 
 
D0 
D84 
D168 
D169 
D196 
D273 
D364 
D394 
D455 
D546 
D637 
D728 
D819 
D910 
D1001 
D1092 
 
Month: 
 
M0 
M3 
M6 
M6 
M7 
M09 
M12 
M13 
M15 
M18 
M21 
M24 
M27 
M30 
M33 
M36 
 
Procedure 
Scr. 
VAC1 
VAC2 
VAC3 
 
 
 
VAC4 
 
 
 
 
 
 
 
 
 
 
Study procedures3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed screening consent (if used) 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Assessment of understanding 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Signed protocol consent  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Medical history  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
HIV risk assessment 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Complete physical exam 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
Abbreviated physical exam 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
— 
Risk reduction counseling 
X 
X 
X 
X 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Pregnancy prevention assessment4 
X 
X 
X 
X 
— 
X 
X 
X 
X 
X 
— 
— 
— 
— 
— 
— 
— 
— 
Behavioral risk assessment questionnaire 
— 
X 
— 
— 
— 
X 
— 
X 
— 
— 
— 
— 
X 
— 
— 
— 
X 
— 
Confirm eligibility, obtain demographics, randomize  
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Social impact assessment 
— 
X 
X 
X 
— 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Outside testing and belief questionnaire 
— 
— 
— 
X 
— 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
— 
— 
— 
Concomitant medications 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
Intercurrent illness/adverse experience 
— 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
— 
HIV infection assessment5 
X 
X 
X 
X 
— 
X 
X 
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 
X 
X 
X 
X 
X 
X 
Local lab assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening HIV test 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Pregnancy6 
X 
X 
X 
X 
— 
— 
— 
X 
— 
— 
— 
— 
— 
— 
— 
X 
— 
— 
GC/CT7 
— 
X 
— 
X 
— 
— 
— 
X 
— 
— 
X 
— 
X 
— 
X 
— 
X 
— 
Syphilis7 
— 
X 
— 
X 
— 
— 
— 
X 
— 
— 
X 
— 
X 
— 
X 
— 
X 
— 
Trichomonas vaginalis7 
— 
X 
— 
X 
— 
— 
— 
X 
— 
— 
X 
— 
X 
— 
X 
— 
X 
— 
Cervicovaginal secretion collection7 
— 
X 
— 
X 
— 
— 
— 
X 
— 
— 
X 
— 
X 
— 
— 
— 
— 
— 
Vaginal swabs7 
— 
X 
— 
X 
— 
— 
— 
X 
— 
— 
X 
— 
X 
— 
— 
— 
— 
— 
Hemoglobin (Hb)8 
X 
— 
— 
X 
— 
— 
— 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Vaccination procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination9 
— 
X 
X 
X 
— 
— 
— 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Reactogenicity assessments10 
— 
X 
X 
X 
 
— 
— 
X 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
Poststudy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblind participant  
— 
— 
— 
— 
 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
X 
 
1 Screening may occur over the course of several contacts/visits up to and including day 0 prior to vaccination  
2 Specimens collected at the enrollment visit may be obtained within the 14 days prior to vaccination, except for a pregnancy test which must be performed on the day of vaccination with negative results received prior to vaccination  
3 For specimen collection requirements, see Appendix E  
4 Pregnancy prevention assessment is required only for participants who are capable of becoming pregnant  
5 Includes pre-test counseling  A subsequent follow-up contact is conducted to provide post-test counseling and to report results to participant   

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 143 of 146 
 
6 Pregnancy test must be performed on the day of vaccination with negative results received prior to vaccination  Pregnancy test to determine initial eligibility may be performed at screening, but must also be done on day 0 prior to first vaccination  Persons who 
have undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing  
7 Must be performed prior to vaccination  
8 Based on hemoglobin levels at visits 4 and 8, blood draws at visits 5, 6, and 9 may be reduced, respectively  Refer to the Specimen Collection SSP for more information  
9 Specimen collection required at vaccination visits must be performed prior to vaccination; however, it is not necessary to have results prior to vaccination, except for results of a pregnancy test, if indicated   
10 Reactogenicity assessments are performed as described in Section 9 9  
11May be performed offsite   
 
 
Schedule 1: Procedures at HVTN CRS for HIV-uninfected participants during 
extension phase 
Extension phase visit: 
18 
19 
20 
21 
22 
23 
24 
Post 
Month: 
M39 
M42 
M45 
M48 
M51 
M54 
M57 
 
Study procedures1 
 
 
 
 
 
 
 
 
Abbreviated physical exam 
X 
X 
X 
X 
X 
X 
X 
— 
Risk reduction counseling 
X 
X 
X 
X 
X 
X 
X 
— 
Behavioral risk assessment 
questionnaire 
— 
— 
— 
X 
— 
— 
— 
— 
Social impact assessment 
X 
X 
X 
X 
X 
X 
X 
— 
Concomitant medications 
X 
X 
X 
X 
X  
X 
X 
— 
Intercurrent illness/adverse 
experience 
X 
X 
X 
X 
X 
X 
X 
— 
HIV infection assessment2 
X 
X 
X 
X 
X 
X 
X 
— 
Confirm HIV test results provided 
to participant 
X 
X 
X 
X 
X 
X 
X 
X 
Local lab assessment 
 
 
 
 
 
 
 
 
GC/CT 
— 
X 
— 
X 
— 
X 
— 
— 
Syphilis 
— 
X 
— 
X 
— 
X 
— 
— 
Trichomonas vaginalis 
— 
X 
— 
X 
— 
X 
— 
— 
Poststudy 
 
 
 
 
 
 
 
 
Unblind participant  
— 
— 
— 
— 
— 
— 
— 
X 
1 For specimen collection requirements, see Appendix E, Table for Extension phase. 
2 Includes pre-test counseling. A subsequent follow-up contact is conducted to provide post-test counseling and to report results to participant. 

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 144 of 146 
Appendix H 
Schedule 2: Procedures at HVTN CRS for HIV-infected participants 
Visit:
#.X1 
 
Visit:
31 
32 
 
 
 
 
Weeks after diagnosis: 
W12 
W24 
 
Month: 
M3 
M6 
Study procedures2 
 
 
 
 
Counseling on HIV-1 testing/diagnosis 
X 
 
 
— 
— 
Abbreviated physical exam 
X 
 
 
X 
— 
Complete physical exam3 
— 
 
 
— 
X 
ART assessment 
X 
 
 
X 
X 
Concomitant medications 
— 
 
 
X 
X 
Intercurrent illness/adverse experience 
— 
 
 
X 
X 
Transmission risk reduction counseling 
X 
 
 
X 
X 
Behavioral risk assessment questionnaire 
— 
 
 
— 
X 
Social impact assessment 
X 
 
 
X 
X 
Vaginal swab4 
X 
 
 
— 
— 
Pregnancy test5 
— 
 
 
X 
X 
 
1 Visit #.X = interim visit for the purpose of drawing samples for confirmatory HIV testing 
2 For specimen collection requirements, see Appendix F. 
3 Includes assessment of HIV/AIDS-related conditions. 
4 Vaginal swab collected at first Redraw visit only. 
5 Persons who have undergone total hysterectomy or bilateral oophorectomy (verified by medical records), are not required to undergo pregnancy testing. 

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 145 of 146 
Appendix I 
Adverse events of special interest 
AEs of special interest (AESI) for this protocol include but are not limited to potential immune-mediated diseases; 
representative examples of AESI are listed below. Updates to AESI will be provided as an appendix to the HVTN 
705/HPX2008 Study Specific Procedures. 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve disorders, including 
paralyses/paresis (eg Bell’s palsy)  
• 
Optic neuritis 
• 
Multiple sclerosis 
• 
Transverse myelitis 
• 
Guillain-Barré syndrome, including 
Miller Fisher syndrome and other 
variants 
• 
Acute disseminated 
encephalomyelitis, including site 
specific variants: eg non-infectious 
encephalitis, encephalomyelitis, 
myelitis, myeloradiculoneuritis 
• 
Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome  
• 
Immune-mediated peripheral 
neuropathies and plexopathies, 
(including chronic inflammatory 
demyelinating polyneuropathy, 
multifocal motor neuropathy and 
polyneuropathies associated with 
monoclonal gammopathy). 
• 
Narcolepsy 
• 
Systemic lupus erythematosus and 
associated conditions 
• 
Systemic scleroderma (Systemic 
sclerosis), including diffuse 
systemic form and CREST 
syndrome 
• 
Idiopathic inflammatory 
myopathies, including 
dermatomyositis  
• 
Polymyositis  
• 
Antisynthetase syndrome 
• 
Rheumatoid arthritis, and 
associated conditions including 
juvenile chronic arthritis and Still’s 
disease 
• 
Polymyalgia rheumatica 
• 
Spondyloarthritis, including 
ankylosing spondylitis, reactive 
arthritis (Reiter's Syndrome) and 
undifferentiated spondyloarthritis  
• 
Psoriatic arthropathy 
• 
Relapsing polychondritis 
• 
Mixed connective tissue disorder 
• 
Psoriasis 
• 
Vitiligo 
• 
Erythema nodosum 
• 
Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid and 
dermatitis herpetiformis) 
• 
Alopecia areata 
• 
Lichen planus 
• 
Sweet’s syndrome 
• 
Localized Scleroderma 
(Morphea)  
• 
Cutaneous lupus 
erythematosus 
 
Metabolic disorders 
• 
Addison’s disease 
• 
Autoimmune thyroiditis 
(including Hashimoto 
thyroiditis) 
• 
Diabetes mellitus type I 
• 
Grave's or Basedow’s disease 
Vasculitides 
Blood disorders 
Others 
• 
Large vessels vasculitis including: 
giant cell arteritis such as 
Takayasu’s arteritis and temporal 
arteritis.  
• 
Medium sized and/or small vessels 
vasculitis including: polyarteritis 
nodosa, Kawasaki's disease, 
microscopic polyangiitis, Wegener’s 
granulomatosis, Churg-Strauss 
syndrome (allergic granulomatous 
angiitis), Buerger’s disease 
(thromboangiitis obliterans), 
necrotizing vasculitis and anti-
neutrophil cytoplasmic antibody 
(ANCA) positive vasculitis (type 
unspecified), Henoch-Schonlein 
purpura, Behcet’s syndrome, 
leukocytoclastic vasculitis. 
• 
Autoimmune hemolytic anemia 
• 
Autoimmune thrombocytopenia 
• 
Antiphospholipid syndrome 
• 
Pernicious anemia 
• 
Autoimmune aplastic anemia 
• 
Autoimmune neutropenia  
• 
Autoimmune pancytopenia 
 
Gastrointestinal disorders 
• 
Celiac disease 
• 
Crohn’s disease 
• 
Ulcerative colitis 
• 
Ulcerative proctitis 
 
Liver disorders 
• 
Autoimmune cholangitis 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing cholangitis 
• 
Autoimmune 
glomerulonephritis (including 
IgA nephropathy, 
glomerulonephritis rapidly 
progressive, membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and 
mesangioproliferative 
glomerulonephritis) 
• 
Ocular autoimmune diseases 
(including autoimmune uveitis 
and autoimmune retinopathy) 
• 
Autoimmune 
myocarditis/cardiomyopathy 
• 
Sarcoidosis 
• 
Stevens-Johnson syndrome 
• 
Sjögren’s syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Goodpasture syndrome 
• 
Raynaud’s phenomenon 
 

HVTN 705/VAC89220HPX2008, Version 4.0 / FINAL 
HVTN705_HPX2008_v4.0_Final / Page 146 of 146 
Appendix J Injection Schedule for sample informed consent