VRC 603: A Phase I Dose-Escalation Study of the Safety of AAV8-VRC07 (VRC-HIVAAV070-00-GT) Recombinant AAV Vector Expressing VRC07 HIV-1 Neutralizing Antibody in Antiretroviral-Treated, HIV-1 Infected Adults With Controlled Viremia
Phase: PHASE1
Conditions: HIV-1 Infected Adults With Controlled Viremia
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Protocol Title: VRC 603: A Phase I Dose-Escalation Study of the Safety of AAV8-
VRC07 (VRC-HIVAAV070-00-GT) Recombinant AAV vector Expressing VRC07 
HIV-1 Neutralizing Antibody in Antiretroviral-Treated, HIV-1 Infected Adults with 
Controlled Viremia 
 
NCT: 03374202 
 
Documents: 
 IRB-approved Protocol (v8.0 09MAR2023) - Statistical Analysis Considerations located 
in Section 6 of the Protocol  
 IRB-approved Informed Consent (v7.0 11FEB2025) - IRB approval date: 18FEB2025 
 
 
 
 

Version 8.0
March 09, 2023
VACCINE RESEARCH CENTER
Protocol VRC 603
(NIH 18-I-0030)
A PHASE 1 DOSE-ESCALATION STUDY OF THE SAFETY OF AAV8-VRC07 
(VRC-HIVAAV070-00-GT) RECOMBINANT AAV VECTOR EXPRESSING VRC07 
HIV-1 NEUTRALIZING ANTIBODY IN ANTIRETROVIRAL-TREATED, HIV-1 
INFECTED ADULTS WITH CONTROLLED VIREMIA
Study Agent Provided by
Vaccine Research Center/NIAID/NIH, Bethesda, MD
Clinical Trial Sponsored by:
National Institute of Allergy and Infectious Diseases (NIAID)
Vaccine Research Center (VRC)
Bethesda, Maryland
IND 16979 - held by VRC, NIAID, NIH
Principal Investigator:
Joseph Casazza, M.D., Ph.D. 
VRC/NIAID/NIH
IRB Initial Review Date:  May 9, 2016
IRB Version 1.0 Approval Date: November 28, 2017

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 2 of 59
TABLE OF CONTENTS
Page
ABBREVIATIONS .........................................................................................................................5
PRÉCIS............................................................................................................................................8
STATEMENT OF COMPLIANCE.................................................................................................9
1.
INTRODUCTION..................................................................................................................10
1.1.
Study Rationale.............................................................................................................11
1.1.1.
Characteristics and Rationale for AAV vectors ..................................................11
1.1.2.
Dose Selection Rationale.....................................................................................12
1.2.
Specific Research Laboratory Assessments..................................................................13
1.3.
Previous Human Experience.........................................................................................14
1.3.1.
Human Experience with AAV8-VRC07.............................................................14
1.3.2.
VRC01 and VRC07-523LS Safety Data .............................................................15
1.3.3.
In Vivo Anti-Viral Effect of VRC01 and VRC07-523LS ...................................17
1.3.4.
Human Experience with Other rAAV Vectors....................................................18
1.4.
Pharmacokinetic Parameters.........................................................................................19
2.
STUDY AGENT ....................................................................................................................20
2.1.
AAV8-VRC07 (VRC-HIVAAV070-00-GT) ...............................................................20
2.2.
Preclinical Safety Studies..............................................................................................20
2.3.
Proof-of-Concept Studies with AAV8-VRC07 ............................................................21
3.
STUDY OBJECTIVES ..........................................................................................................22
3.1.
Primary Objectives........................................................................................................22
3.2.
Secondary Objectives....................................................................................................23
3.3.
Exploratory Objectives .................................................................................................23
4.
STUDY DESIGN ...................................................................................................................23
4.1.
Study Population...........................................................................................................24
4.1.1.
Inclusion Criteria.................................................................................................24
4.1.2.
Exclusion Criteria................................................................................................25
4.2.
Clinical Procedures and Laboratory Assays .................................................................26
4.2.1.
Screening .............................................................................................................26
4.2.2.
Enrollment, Study Days and Visit Numbers .......................................................26
4.2.3.
Administration of AAV8-VRC07 .......................................................................26
4.2.4.
Solicited Adverse Events and Clinical Follow-up...............................................27
4.2.5.
Pharmacokinetics Procedures..............................................................................27
4.2.6.
Mucosal Samples.................................................................................................28
4.2.7.
Schedule of Evaluations ......................................................................................28
4.2.8.
Concomitant Medications....................................................................................28
4.3.
Criteria for Dose Escalation..........................................................................................28
4.4.
Protocol Criteria for Pausing the Study and Resuming the Study ................................30
4.4.1.
Plan for Review of Pauses and Resuming Rules:................................................31
4.5.
Dose-Limiting Toxicity.................................................................................................31
5.
SAFETY AND ADVERSE EVENT REPORTING...............................................................31

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 3 of 59
5.1.
Adverse Events .............................................................................................................31
5.1.1.
Attribution Categories .........................................................................................32
5.2.
Serious Adverse Events (SAE) .....................................................................................32
5.3.
Adverse Event Reporting to the IND Sponsor..............................................................32
5.3.1.
IND Sponsor Reporting to the FDA....................................................................33
5.4.
Reporting to the Institutional Review Board ................................................................33
5.4.1.
Unanticipated Problem (UP) ...............................................................................34
5.4.2.
Non-Compliance Definition ................................................................................34
5.4.3.
Protocol Deviation...............................................................................................34
5.4.4.
Death....................................................................................................................35
5.4.5.
New Information .................................................................................................35
5.4.6.
Suspension or Termination of Research Activities .............................................35
5.4.7.
Expedited Reporting to the NIH IRB ..................................................................35
5.4.8.
Annual Reporting to the NIH IRB.......................................................................36
5.5.
Reporting to the Institutional Biosafety Committee .....................................................36
6.
STATISTICAL CONSIDERATIONS ...................................................................................36
6.1.
Overview.......................................................................................................................36
6.2.
Objectives......................................................................................................................36
6.3.
Size and Accrual ...........................................................................................................36
6.3.1.
Sample Size Considerations ................................................................................36
6.4.
Statistical Analysis........................................................................................................38
6.4.1.
Analysis Variables...............................................................................................38
6.4.2.
Baseline Demographics.......................................................................................38
6.4.3.
Safety Analysis....................................................................................................38
6.4.4.
Tolerability Evaluation........................................................................................38
6.4.5.
Pharmacokinetics Analysis..................................................................................39
6.4.6.
Interim Analyses..................................................................................................39
7.
PHARMACY PROCEDURES...............................................................................................39
7.1.
Study Product and Administration Regimen ................................................................40
7.2.
Study Product Storage...................................................................................................40
7.3.
Preparation of Study Product for Administration .........................................................40
7.3.1.
Preparation of the 5x1010 vg/kg dose ..................................................................41
7.3.2.
Preparation of the 5x1011 vg/kg dose ..................................................................41
7.3.3.
Preparation of the 2.5x1012 vg/kg dose ...............................................................41
7.4.
Labeling of Study Agents .............................................................................................41
7.5.
Study Agent Accountability..........................................................................................42
7.6.
Study Agent Disposition ...............................................................................................42
8.
HUMAN SUBJECT PROTECTIONS AND ETHICAL OBLIGATIONS............................42
8.1.
Institutional Review Board ...........................................................................................42
8.2.
Subject Identification and Enrollment of Study Participants........................................42
8.2.1.
Participation of Children .....................................................................................42
8.2.2.
Participation of NIH Employees .........................................................................42
8.2.3.
Participation of Decisionally Impaired Subjects .................................................43

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 4 of 59
8.3.
Informed Consent..........................................................................................................43
8.4.
Subject Confidentiality .................................................................................................43
8.5.
Risks and Benefits.........................................................................................................44
8.5.1.
Risks of AAV8-VRC07.......................................................................................44
8.5.2.
Other Risks..........................................................................................................45
8.5.3.
Study Benefits .....................................................................................................45
8.6.
Plan for Use and Storage of Biological Samples ..........................................................45
8.6.1.
Use of Samples, Specimens and Data .................................................................45
8.6.2.
Samples for Genetic Testing ...............................................................................46
8.6.3.
Storage and Tracking of Blood Samples and Other Specimens..........................46
8.6.4.
Disposition of Samples, Specimens and Data at Completion of the 
Protocol................................................................................................................46
8.6.5.
Loss or Destruction of Samples, Specimens or Data ..........................................46
8.7.
Compensation................................................................................................................47
8.8.
Safety Monitoring, Protocol Safety Review Team .......................................................47
9.
ADMINISTRATIVE AND LEGAL OBLIGATIONS ..........................................................47
9.1.
Protocol Amendments and Study Termination.............................................................47
9.2.
Study Documentation and Storage................................................................................47
9.3.
Study Monitoring, Data Collection and Data Sharing ..................................................48
9.3.1.
Study Monitoring.................................................................................................48
9.3.2.
Data Collection....................................................................................................48
9.3.3.
Data Sharing ........................................................................................................48
9.4.
Language.......................................................................................................................48
9.5.
Policy Regarding Research-Related Injuries ................................................................49
10. REFERENCES .......................................................................................................................50
LIST OF FIGURES 
Figure 1:
VRC 603 Decision Tree for Dose Escalation Based on Safety and VRC07 
Concentration in Serum..............................................................................................30
LIST OF TABLES
Table 1: In Vitro Preclinical Safety Studies with VRC07 .............................................................21
Table 2: Pre-clinical Proof-of-concept Studies of AAV8-VRC07 and Other Vectors..................22
Table 3: VRC 603 Study Schema..................................................................................................23
Table 4: Probability of observing event for different scenarios ....................................................37
Table 5: 95% confidence intervals of the true rate for all possible number of observed 
events within a group..................................................................................................37
APPENDICIES
 APPENDIX I   SCHEDULE OF EVALUATIONS .....................................................................54
APPENDIX II  TABLE FOR GRADING SEVERITY OF ADVERSE EVENTS.......................58

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 5 of 59
ABBREVIATIONS
Abbreviation
Term
AAV
adeno-associated virus 
ADA
anti-drug antibody
AE
adverse event
AIDS
Acquired Immunodeficiency Syndrome
ALT
alanine aminotransferase
AoU
Assessment of Understanding
ARV
antiretroviral
ART
antiretroviral therapy
AST
aspartate aminotransferase
AUC
area under the curve
β-HCG
human chorionic gonadotropin
CL
clearance
Cmax
maximum concentration
COVID-19
coronavirus disease 2019
cGMP
current Good Manufacturing Practice
DNA
deoxyribonucleic acid
dL
deciliter
EAE
expedited adverse event
EDTA
Ethylenediaminetetraacetate
ELISA
enzyme-linked immunosorbent assay
EOI
end of injection
F
bioavailability
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HRPP
Human Research Protections Program
IB
Investigator’s Brochure
IBC
Institutional Biosafety Committee
IC
informed consent 
ICH
International Council on Harmonization
IgG1
Immunoglobulin G1
IM 
intramuscular
IND
investigational new drug application
IRB
Institutional Review Board
ITR
inverted terminal repeats 
IV
intravenous
kg
kilogram
L
liter
LIMS
Laboratory Information Management System
LPLD
lipoprotein lipase deficiency

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 6 of 59
Abbreviation
Term
z
terminal slope of concentration vs time profile
MAb
monoclonal antibody
mcg
microgram
mcL
microliter
mg
milligram
mL
milliliter
mM
millimolar
MSD
Meso Scale Discovery
NIAID
National Institute of Allergy and Infectious Diseases
NIH
National Institutes of Health
NIH CC
National Institutes of Health Clinical Center
NHP
Non-human primate
OSP
Office of Science Policy
OHRP
Office for Human Research Protections
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
PI
Principal Investigator
PK
pharmacokinetic
PSRT
Protocol Safety Review Team
Q
Inter-compartmental clearance
QA
quality assurance
qPCR
quantitative PCR
rAAV
recombinant adeno-associated virus
RPE65
retinal pigment epithelial 65 kDa protein
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous
SHIV
simian-human immunodeficiency virus
SMN
survival motor neuron
SoE
schedule of evaluations
TCR
tissue cross reactivity
T½
half-life
Tmax
time of maximal concentration (Cmax)
UNAIDS
Joint United Nations Programme on HIV/AIDS
UP
unanticipated problem
ULN
upper limit of normal
USP
United States Pharmacopeia
vg
viral genome
VIP
Vaccine Immunology Program, formerly VITL/NVITAL 
VL
virus load
VRC
Vaccine Research Center
WBC
white blood cell

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 7 of 59
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE
VRC 603:    A Phase I Dose-Escalation Study of the Safety of AAV8-VRC07 (VRC-HIVAAV070-
00-GT) Recombinant AAV vector Expressing VRC07 HIV-1 Neutralizing Antibody in 
Antiretroviral-Treated, HIV-1 Infected Adults with Controlled Viremia.
I, the Principal Investigator for the study site indicated above, agree to conduct the study in full 
accordance with the provisions of this protocol and all applicable protocol-related documents. I 
agree to conduct the study in compliance with United States (US) Health and Human Services 
(HHS) regulations (45CFR 46); applicable US Food and Drug Administration (FDA) regulations; 
standards of the International Council on Harmonization Guidelines for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee (IRB/EC) determinations; all applicable in-country, 
state, and local laws and regulations; and other applicable requirements (e.g., US National Institutes 
of Health) and institutional policies. I will comply with all requirements regarding the obligations of 
investigators as outlined in the Statement of Investigator (Form FDA 1572), which I have also 
signed. The protocol signature page will be signed for subsequent protocol approvals.  
I agree to maintain all study documentation pertaining to the conduct of this study, including but not 
limited to, case report forms, source documents, laboratory test results, and medication inventory 
records, per FDA regulation (21 CFR 312.62) and all applicable requirements. No study records will 
be destroyed without prior authorization from VRC/NIAID. 
Publication of the results of this study will be governed by the VRC/NIAID policies. Any 
presentation, abstract, or manuscript will be made available by the investigators to VRC Leadership 
for review prior to submission.
I have read and understand the information in this protocol and will ensure that all associates, 
colleagues, and employees assisting in the conduct of the study are informed about the obligations 
incurred by their contribution to the study.
__________________________________
__________________________________
Name/Title of Principal Investigator 
Study Site Name
__________________________________ __________________________________
Signature of Principal Investigator               Date

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 8 of 59
PRÉCIS
VRC 603:
A Phase I Dose-Escalation Study of the Safety of AAV8-VRC07 (VRC-HIVAAV070-00-GT) 
Recombinant AAV vector Expressing VRC07 HIV-1 Neutralizing Antibody in Antiretroviral-
Treated, HIV-1 Infected Adults with Controlled Viremia.
Study 
Design:  
This is a Phase I study of the safety and tolerability of AAV8-VRC07 (VRC-HIVAAV070-00-
GT) expressing VRC07 human monoclonal antibody with broad HIV-1 neutralizing activity in 
HIV-1 infected adults.  It is a dose-escalation study to examine pharmacokinetics of VRC07 
expression following intramuscular (IM) administration of AAV8-VRC07 in subjects on anti-
retroviral therapy (ARV).  The hypotheses are: 1) AAV8-VRC07 will be safe for human 
administration and will not elicit hypersensitivity or anti-drug antibody (ADA) to VRC07; and 2) 
intramuscular delivery of AAV8-VRC07 will result in production of biologically active VRC07 
antibody at a concentration in serum that is measurable and safe.
Product
Description:  AAV8-VRC07 was developed by VRC, NIAID, NIH, and manufactured by the Clinical Vector 
Core, Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia 
(CHOP), Philadelphia, PA.  It is composed of an AAV8 recombinant vector expressing genes 
encoding the heavy and light chains of the VRC07 monoclonal antibody.  AAV8-VRC07 will 
be supplied at 2.84x1013 vg/mL.  
Subjects:
HIV-1 infected adult volunteers (18 to 65 years old) on a stable antiretroviral regimen for ≥ 3 
months, with controlled viremia, under the care of a physician, and without additional clinically 
significant medical conditions.
Study Plan: There are 3 dose escalation groups.  Sequentially enrolled subjects will be assigned to the 
dosage level being evaluated at the time of enrollment.  All injections will be administered 
intramuscularly (IM) by needle and syringe.  Cumulative safety data will be reviewed 
weekly by a Protocol Safety Review Team (PSRT) that includes an Independent Safety 
Monitor (ISM) while injections are being administered. Safety, including reactogenicity and 
unsolicited AEs, laboratory findings, pharmacokinetics, and VRC07 antibody levels in 
blood will be assessed after the injection and summarized for an interim analysis at 4 weeks 
post injection.  The second subject in each dose group will be injected after the 4 weeks 
safety assessment for the first subject.  Decisions regarding dose escalation and subject 
enrollments will be based on safety data and the VRC07 concentration in blood at 4 weeks 
after product administration (Section 4.3).  The pharmacokinetics of VRC07 at each dose 
level will be evaluated to determine the dose that would result in antibody production that 
achieves at least 50 mcg/mL VRC07 concentration in serum at 4 weeks post injection with a 
target set point of  ≥ 5 mcg/mL at 12 weeks post injection. 
VRC 603 Study Schema
Group
Dose
Subjects
Total product volume based on product concentration 
of 2.84x1013 vg/mL and a subject weight of 100 kg 
1
5x1010 vg/kg
2-5
0.18 mL
2
5x1011 vg/kg
2-5
1.76 mL
3
2.5x1012 vg/kg
2-5
8.80 mL
Total
2 to 5 subjects per group to enrollment of 15 subjects. Enrollment up to a total of 25 subjects is 
permitted in case there are subjects who do not complete the schedule, if additional PK 
evaluations are needed, or if an enrollment of additional subjects is recommended for safety 
evaluations.
Study Duration:  Each participant will be asked to complete 5 years of clinical follow up from the day of study 
injection.  The study dose escalation portion of the study is projected to take about a year.

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 9 of 59
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with the International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have completed 
Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment 
to the protocol will require review and approval by the IRB before the changes are implemented to 
the study.  In addition, all changes to the consent form will be IRB-approved; a determination will be 
made regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form.

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
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      PROTOCOL DATE MARCH 09, 2023 
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1.
INTRODUCTION
The global incidence of new human immunodeficiency virus (HIV) infection peaked in the mid-
1990s.  As reported by Joint United Nations Programme on HIV/AIDS (UNAIDS), about 2.1 million 
people became newly infected with HIV in 2015, down from 2.9 million in 2005, with an estimated 
global total of 36.7 million people living with HIV.  The decrease in incidence is an encouraging 
trend, but the scope and cost of the epidemic remain of great global concern.  The reduction of HIV 
incidence is attributed to multiple factors that include prevention and treatment programs.  The wider 
availability of antiretroviral (ARV) therapy, mother to child transmission prevention programs, and a 
diverse array of other prevention programs have all contributed to turning the tide of the epidemic 
[1].  Each effective form of prevention and treatment is a welcome public health measure. 
The National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health 
(NIH) is committed to the development of safe and effective methods to prevent and treat HIV 
infection and AIDS worldwide.  In this regard, the Vaccine Research Center (VRC), NIAID, NIH, 
plans to evaluate the potential clinical uses of the investigational AAV8-VRC07 gene transfer 
product that expresses an HIV-specific broadly neutralizing human monoclonal antibody (MAb), 
VRC07.
The VRC, NIAID, NIH recently discovered highly potent and broadly neutralizing HIV-1 human 
monoclonal antibodies (MAb) that target the HIV-1 CD4 binding site on the HIV envelope protein 
[2-5].  VRC01 neutralizes 88% of viral envelope (Env) pseudoviruses at concentration <50mcg/mL 
and 74% at <1mcg/mL [2].  The VRC01 MAb, currently in clinical trials under IND 113611 for 
prevention indication and INDs 126001 and 12664 for therapeutic indication, was originally 
discovered in a subject infected with HIV-1 for more than 15 years and whose immune system 
controlled the virus without ARV[5].  
VRC07 is a clonal relative of VRC01 isolated from the same chronically HIV-1 infected person who 
had sera with broad cross neutralizing activity.  VRC07 IgG heavy chain shares 90% nucleotide 
sequence identity with VRC01, but differs at 15 amino acid positions and contains a 4 amino acid 
insertion in the third complementarity determining region (CDRH3) that provides more extensive 
contacts with the envelope protein [3, 4].  The natural light chain of VRC07 is unknown, as heavy 
and light chains were sequenced en masse from peripheral blood mononuclear cells (PBMCs). Thus, 
the VRC07 heavy chain was paired with the VRC01 light chain to generate a more potent and 
broadly reactive anti-HIV antibody than VRC01 [3, 4].    
HIV-infected individuals who develop this class of highly neutralizing antibodies against HIV-1 
naturally have shown good immune control of the virus [2, 3].  However, potent antibodies that exert 
strong control of HIV-1 do not naturally develop in most HIV-infected individuals and, thus far, 
investigational vaccines have not induced such antibodies. Although ARV medications have 
improved the control of virus in HIV-infected individuals, additional methods of viremia control that 
have a long durability of action would be potentially beneficial to individuals and to the overall 
slowing the epidemic.  Gene transfer for a potent neutralizing antibody, such as VRC07, may lead to 
sustained production of these antibodies in vivo and contribute to sustained control of viremia.
The adeno-associated virus (AAV) vector-based investigational product, AAV8-VRC07, was 
therefore designed with the goal to achieve production of a highly neutralizing MAb against the 
HIV-1 virus in vivo.  The clinical development plan for AAV8-VRC07 is based on two potential 
indications of the product: 

Therapeutic application in HIV-1-infected individuals (vectored immunotherapy), and, 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 11 of 59

Prophylactic application in healthy subjects at high risk for HIV infection (vectored 
immunoprophylaxis). 
1.1.
Study Rationale     
Phase 1 clinical trials of VRC01 in both HIV-infected and healthy adults have been completed [6, 7].  
Doses up to 40 mg/kg IV have been well tolerated (Section 1.3.1).  VRC01 is currently being further 
evaluated for potential therapeutic and preventive uses in healthy and HIV infected adults and in 
infants at risk of mother-to-child HIV transmission.
Data accumulated in HIV-1 infected subjects demonstrate the VRC01 mediated anti-viral effect and 
support the hypothesis that a schedule with sustained antibody expression may have a beneficial 
clinical effect.  In VRC 601 study, 6 of 8 viremic HIV-infected subjects infused with a single 40 
mg/kg dose of VRC01 experienced a 1.1 to 1.8 log10 reduction in plasma viremia [7].  VRC07 is 
about 2-fold more potent than VRC01 and neutralizes 93% of viral envelope (Env) pseudoviruses at 
concentrations of <50 mcg/mL, and 83% at <1 mcg/mL.  Therefore it could be expected that VRC07 
may have the same or even more prominent anti-viral effect [3]. 
The AAV-mediated antibody expression has been studied in several animal models [8-12].  The 
proof-of-concept animal studies (Section 2.3) confirmed that AAV8-VRC07 induces the sustained 
VRC07 expression that is protective against HIV/SHIV infection [8-10]. 
AAV8-VRC07 is an investigational product which has not been administered to humans.  It is 
intended to provide a long-term expression of VRC07 upon intramuscular (IM) administration.  In 
this first in human phase 1 study, safety and tolerability of AAV8-VRC07 will be evaluated in HIV-
1 infected subjects.
1.1.1.
Characteristics and Rationale for AAV vectors
AAV is a nonpathogenic parvovirus with a single-stranded DNA genome encapsulated within a non-
enveloped capsid.  AAV has an ability to infect both dividing and non-dividing cells; there are 12 
described serotypes of AAV with different tissue specificity.  Wild type AAV has not been 
associated with any human disease [13-15]. Efficient replication of AAV requires helper function 
from an adenovirus or herpesvirus.  Following infection in the absence of helper virus, wild type 
AAV enters a latent phase and DNA is retained in extrachromosomal episomal form or integrated 
selectively into the genomic DNA at a specific site on the human chromosome 19 [15-17].
Simple AAV genome organization that facilitates engineering of recombinant vector DNA, easy 
manipulation of the AAV cap gene which encodes the viral shell proteins essential for genome 
packaging, and absence of known pathogenicity have made recombinant versions of AAV (rAAV) 
good candidates for therapeutic gene delivery [14, 15].  In the last 50 years, multiple rAAV vectors 
have been developed with the goal of using these for gene transfer [18].  In rAAV vectors, genes 
encoding for viral proteins are deleted and a gene of interest is inserted between the inverted 
terminal repeats (ITR) that are sufficient for viral packaging.  The non-replicating rAAV vector 
genomes persist as extra-chromosomal circular forms in non-dividing tissues such as normal skeletal 
muscle and are capable of mediating long-term gene expression following administration to muscle 
[17, 19]. 
Preexisting immunity to AAV is a limitation of rAAV vectors as gene delivery vehicles, with host 
immune responses being a concern in clinical studies [20-22].  Published reports estimate that up to 
60-80% of the human population have some level of preexisting immunity to AAV [14, 23].  

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 12 of 59
Measured by antibody level, AAV2 and AAV1 have the highest prevalence of preexisting immune 
responses ranging 50-60% of the population, and the lowest prevalence was observed for AAV8 
(19%) and AAV5 (3%).  In addition, about 70-100% of individuals seropositive for AAV5, AAV8, 
and AAV9 have low antibody titers [23].
In a non-human primate (NHP) model developed by VRC to inform clinical AAV-based approaches 
to passive immunization, AAV8-mediated SIV antibody expression was confirmed in serum and 
mucosal surfaces [24].  Antibody expression increased proportionally with the number of 
administered injections, and development of anti-vector and anti-transgene immune responses was 
evaluated. It was demonstrated that animals with low/intermediate pre-existing anti-vector immunity 
(AAV8 antibody titers 1:100 and 1:1000) can be successfully transducted with the level of transgene 
expression being similar to animals who have not had pre-existing immunity to the vector [24]. 
Several studies have noted that the rAAV-mediated gene transfer results in dose-dependent 
activation of capsid-specific T cells [21, 25].  Immune-mediated elimination of transduced cells has 
been thought to limit efficacy of gene transfer and account for a loss of transgene expression with 
time [21, 25, 26].  To overcome immune responses and prolong the transgene expression, 
immunosuppressive agents have been used in clinical studies in subjects with lipoprotein lipase 
deficiency (LPL) and in gene therapy studies for hemophilia [27, 28].  In addition, using 
immunosuppressants such as cyclosporine or mycophenolate mofetil starting 3 days before and for 
12 weeks after IM administration is recommended as a part of the administration regimen for 
Glybera® (alipogene tiparvovec), the first rAAV1-based gene therapy product authorized for 
distribution in Europe [29]. 
The FDA guidance “Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse 
Events” classifies rAAV vectors as “non-integrating” [30].  There is no evidence that these vectors 
reactivate following latency and, therefore, subjects may be  at low risk of gene-therapy-related 
delayed adverse events [30].   
1.1.2.
Dose Selection Rationale
The proposed dosages of AAV8-VRC07 are based on publicly available data from human clinical 
trials, experience with other rAAV vectors developed for use in gene transfer studies for human 
diseases, and preclinical animal studies with AAV8-VRC07 and related simian constructs.  
Two primate studies of passive immunotherapy with other highly potent neutralizing antibodies in 
SHIV-infected macaques (3BNC117 and 10-1074, [31]) and rhesus monkeys (PGT121, [32]) also 
indicate that the immunotherapy approach may have a therapeutic effect in HIV-infected individuals.  
The intravenous antibody dosage in these NHP studies was in the 5-20 mg/kg range; and the 
therapeutic plasma concentration of antibodies that induced a rapid decline in viral load was found to 
be in the range of 5-10 mcg/mL.  In NHP studies with VRC01, sustained passive transfer of a simian 
version of VRC01 antibody to macaques maintained therapeutic levels of antibody and provided 
complete protection against SHIV infection.  These findings support the feasibility and potential of 
long-term passive antibody for protection against HIV in humans [33]. 
Studies in mice demonstrated that after a single intramuscular injection with 1x1010-1x1011 viral 
genomes (vg) of the AAV8-VRC01 construct, a level up to 100 mcg/mL of VRC01 in serum was 
observed.  On average, a level of 10 mcg/mL was achieved after IM injection of about a 1.3x1010 vg 
dose of rAAV8-VRC01 [8].  In the mouse challenge model, the protective VRC07 concentration was 
defined in the range of 3 to 6 mcg/mL.  This antibody concentration was achieved with a vector 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 13 of 59
similar to AAV8-VRC07 dose between 0.63x1010 vg and 1.25x1010 vg per mouse.  Assuming that a 
mouse weighs 0.02 kg, the protective dose of rAVV8-VRC07 was about 3x1011 to 6x1011 vg/kg in 
the mouse model.
A serum level of 50 mcg/mL at 4 weeks post injection has been selected for the study design dose 
escalation threshold based on the PK data for AAV8-VRC07 and similar constructs in mice and 
NHP that showed a peak level of at least 50 mcg/mL achieved at 3-5 weeks post injection, and then 
transgene concentration stabilized at a trough in the range of 5-10 mcg/mL. 
Refer to the Investigator’s Brochure (IB) for more information on these proof-of-concept preclinical 
studies. 
Based on pre-clinical animal data and projected product concentration, dose escalation in the 
proposed Phase 1 study was designed in the 5x1010 to 2.5x1012 vg/kg range.  This dose range is 
similar to that used in the clinical trials for the AAV8-mediated human factor IX (FIX) gene transfer 
by IV (2x1011 to 2x1012 vg/kg) [34] and in earlier studies for the AAV2-mediated FIX transfer by IM 
injection (2x1011-1.8x1012 vg/kg) [35, 36].  Similarly, the AAV1 vector expressing lipoprotein lipase 
(Glybera®, alipogene tiparvovec) is authorized for marketing in Europe at 1x1012 vg /kg 
administered IM. 
1.2.
Specific Research Laboratory Assessments
Research assays designed to characterize the investigational product rather than assess the health of 
the subjects are described below.
Laboratory assessments in the Phase 1 study of AAV8-VRC07 include VRC07 pharmacokinetic 
(PK) analysis, testing for the AAV8-VRC07 presence in plasma, evaluation of pre-existing antibody 
responses to the AAV8, assessment for the development of anti-VRC07 antibodies post dosing, 
assessment for the development of anti-vector (anti-AAV8) immune responses, and functional 
capacity of the MAb in the collected research specimens for HIV neutralization.
For the PK analysis, VRC07 concentration may be measured by ELISA using the VRC01 anti-
idiotype, Fab-specific 5C9 monoclonal antibody, as previously described [6] or by other similar and  
more sensitive assay.  
Testing to detect the AAV8-VRC07 in blood will be done by a quantitative PCR (qPCR) similar to 
previously described [37, 38]. Plasma samples will be collected monthly and tested in batches. 
Testing will continue for each subject until 2 consecutive VRC07-AAV8 negative samples are 
identified. 
Assessment of pre- and post-exposure anti-AAV8 antibodies will be done by ELISA using a vector-
matched AAV8 capsid as the capture agent.  Serial dilutions of sera will be analyzed to determine an 
end point antibody titer at specified time-points as described in the Schedule of Evaluations (SoE).
Assessment of anti-VRC07 antibodies in subject sera will be performed using the Meso Scale 
Discovery (MSD) platform based on electrochemiluminescence.  The developed anti-drug antibody 
(ADA) assay uses the biotin-labeled VRC07 immobilized on a streptavidin-coated MSD plate as the 
capture molecule, and the SULFO-TAG labeled VRC07 as the reporter molecule.  This assay is 
independent of the anti-VRC07 antibody isotype, and permits the detection of both high and low 
affinity antibodies.

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 14 of 59
Depending upon the VRC07 concentrations measured in collected specimens, samples may be 
assessed for their functional capacity to neutralize HIV by an in vitro cell-based virus neutralization 
assay using the pseudotyped viruses [39-41].
In addition to plasma viral load evaluation by a CLIA-certified laboratory assay, ultrasensitive 
single-copy research assay may be used to assess for a potential effect of VRC07 expression on a 
viral load as described previously [42]. 
Also subjects may be evaluated for their IgG1 allotypes to determine the potential for theoretical 
allotype-specific impacts on the VRC07 pharmacokinetics [43-45].  Coded stored samples will be 
used for evaluation of the genetic sequence of the immunoglobulin heavy chain constant region 
allotype.
In a potential event of tumor development reported by a subject during the long-term follow-up, 
tumor tissue, if available, may be analyzed for AAV vector integration by methods similar to those 
previously described [46].
Sample testing will be conducted by the Vaccine Immunology Program (VIP, formerly VITL / 
NVITAL), Gaithersburg, MD, by VRC Laboratories in Building 40 and by approved scientific 
collaborators.
1.3.
Previous Human Experience
There is a limited human experience with AAV8-VRC07 administration accumulated in this study.  
Data accumulated in studies with VRC01, a clonal relative of VRC07, and an engineered variant of 
VRC07 of the same binding specificity designated VRC07-523LS, as well as with other rAAV 
vectors, can be used to inform the safety and potential efficacy of AAV8-mediated VRC07 
expression in adults.
1.3.1.
Human Experience with AAV8-VRC07 
As of May 9, 2022, 10 subjects have been enrolled in VRC 603 study and received injections of 
AAV8-VRC07 at the 5x1010 vg/kg (3 subjects, Group 1), the 5x1011 vg/kg (3 subjects, Group 2), and 
the 2.5x1012 vg/kg (4 subjects, Group 3) dose.
The first subject enrollment and study product administration occurred on January 11, 2018. The last 
subject enrollment and study product administration occurred on August 4, 2021. Nine (9) out of 10 
subjects are being followed for safety; one subject in Group 2 (5x1011 vg/kg dose) is off study due to 
an unrelated SAE of methamphetamine overdose and subsequent death. Subjects are to be followed 
for 5 years after product administration.
No study pause rules have been met. Two dose escalation reviews have been completed as per 
protocol. The VRC07 concentration in serum was evaluated as less than 1μg/ml (the lower limit of 
detection for the assay used for testing) for subjects in Groups 1 and 2 at 4 weeks post product 
administration, supporting the dose escalation decisions.  
The AAV8-VRC07 administrations were well tolerated at all doses, and no safety signals or dose-
limiting toxicity have been detected.  
No solicited local reactogenicity symptoms were reported during 7 days after product administration 
at doses 5x1010 vg/kg and 5x1011 vg/kg.  Four out of 4 (100.0%) Group 3 subjects (2.5x1012 vg/kg 
dose) reported mild pain/tenderness that began during the 7-day period after product administration 
and resolved after the solicited period. One subject reported mild pain/tenderness on Day 1 and Day 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 15 of 59
6 post product administration that resolved on Day 14, 7 days after the solicited period.  One subject 
reported mild pain/tenderness on Day 5 that resolved on Day 9, 2 days after the solicited reporting 
period. One subject reported mild pain/tenderness on Day 1 and Day 5 post product administration 
that resolved on Day 10, 3 days after the solicited reporting period. One subject reported mild 
pain/tenderness on Day 6 post product administration that resolved on Day 11, 4 days after the 
solicited reporting period. No other solicited local reactions were reported.
As to systemic reactogenicity symptoms, three (3) out of 10 (30.0%) subjects reported one or more 
solicited systemic reactogenicity symptoms. One Group 2 subject (5x1011 vg/kg dose) reported mild 
myalgia, one Group 3 subject (2.5x1012 vg/kg dose) reported mild myalgia and mild headache, and 
one Group 3 subject (2.5x1012 vg/kg dose) reported mild headache. These symptoms were reported 
on Day 1 and resolved the same day for all subjects. No fever or other solicited systemic 
reactogenicity symptoms were reported. 
As of May 9, 2022, 6 out of 10 (60.0%) subjects had one or more unsolicited AEs. Mild serum 
creatinine elevation was the most frequently reported event, reported for 3 out of 10 (30.0%) 
subjects.
One SAE of a fatal illicit drug overdose was reported and assessed as unrelated to study product: a 
Group 2 subject (5x1011 vg/kg dose) died because of a methamphetamine overdose 716 days post 
product administration. 
One severe AE of diarrhea in a Group 1 subject (5x1010 vg/kg dose) occurred at 44 days post product 
administration, evaluated as not related to study product, and resolved in 4 days with no residual 
effects. 
Two AEs of mild aspartate aminotransferase (AST) elevation were reported for two Group 1 
subjects (5x1010 vg/kg dose). For one subject, grade 1 AST elevation was detected at 7 days post 
product administration, evaluated as not related to study product and resolved with no residual 
effects. The grade 1 AST elevation (52U/L) in another subject was detected at 49 days post product 
administration and was initially attributed to alcohol consumption. This attribution was later changed 
to the product related because of the identification of the concurrent AAV8 capsid-specific cytotoxic 
CD8 T cells by a research laboratory.
Mild upper respiratory tract infection (URTI) was reported for one Group 2 subject (5x1011 vg/kg 
dose) at 54 days post product administration, evaluated as not related to study product, and resolved 
with no residual effects.
Four episodes of mild serum creatinine elevation were reported for three subjects, with one event 
reported for a Group 3 subject (2.5x1012 vg/kg dose) at 7 days post product administration evaluated 
as related to study product. 
Study results from the time of first enrollment in VRC 603 through a period of 104-198 weeks after 
product administration for 8 of the 10 subjects are included in a publication by Casazza, J.P. et al. 
[47].
1.3.2.
VRC01 and VRC07-523LS Safety Data 
Evaluations of the highly neutralizing antibody VRC01 started in September 2013.  VRC01 has been 
tested in HIV-infected adults in VRC 601 study [6], in healthy adults in VRC 602 [7] and HVTN 
104 studies, and in infants born from HIV-1 infected mothers in P1112 study (IND 113611).  Further 
evaluation of safety, tolerability, PK and effect of VRC01 in HIV-1 infected adults, healthy adults 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 16 of 59
and infants is currently ongoing in several clinical studies in the United States (U.S.) and 
internationally.  
As of March 2019, VRC01 administered in the dose ranges from 1 to 40 mg/kg by the IV route and 
5 to 40 mg/kg by the SC route has been assessed as well-tolerated in adults and infants and safe for 
further evaluation.  Cumulatively, VRC01 has been administered either IV or SC to over 3370 HIV-
uninfected and HIV-infected adults, and 45 HIV-uninfected and HIV-Infected infants.  There have 
been no serious adverse events (SAE) related to VRC01, as assessed by the Sponsor, and no study 
pauses for any adverse events.  
The majority of human experience is being accumulated in two ongoing phase 2 trials, HVTN 
704/HPTN 085 and HVTN 703/HPTN 081, collectively known as AMP trials (Antibody Mediated 
Prevention). 4,625 HIV-uninfected healthy participants were enrolled and received either VRC01 
(two-thirds of participants) or placebo (one-third of participants) by IV route. The most common 
adverse events in the two AMP trials assessed as related to study product administration have been 
infusion related reactions. In both phase 2 trials combined, a total of 136 (2.9 %) participants 
experienced infusion reactions. Of the 136 participants with infusion reactions, 64 experienced 
urticarial reactions, most of which occurred during the first infusion.  Both trials are still blinded 
with product administration ongoing as per protocols.  The infusion reaction symptoms are typical of 
infusion reactions observed with other monoclonal antibodies administered IV, and these are not 
expected to occur upon vector-mediated production of VRC07 in muscle cells. 
VRC01 IV administration to adults has been well tolerated. Observed local reactogenicity events 
included pain/tenderness, bruising, swelling, and localized erythema at the site of infusion that 
resolved within a few minutes to a few hours after the administration. Most participants reported no 
systemic reactogenicity symptoms with VRC01 IV administration; when observed, systemic solicited 
symptoms were of mild or moderate severity, started 1-3 days after administration of study product 
and lasted 1-2 days, with malaise/fatigue, myalgias, headaches and mild nausea being most common. 
There have been no severe solicited reactogenicity symptoms related to VRC01 IV injections.  
VRC01 SC administration has been well tolerated in adults and infants.  Most study participants had 
either no local reactogenicity or only mild local symptoms limited to injection site pain and/or 
tenderness, redness, and mild localized pruritus (itchiness), which resolved within a few minutes to a 
few hours after the administration was completed. There have been no severe solicited reactogenicity 
symptoms related to VRC01 SC injections.  
Overall, VRC01 administration in the dose range from 1 to 40 mg/kg IV and at 5 mg/kg SC has been 
assessed as well-tolerated and safe for further evaluation. 
The VRC 605 study designed to assess the safety and PK of VRC07-523LS in healthy adults has 
been recently completed [48]. Overall, 25 subjects have received at least one product administration 
by IV (17 subjects) or SC (8 subjects) route, for a total of 25 IV and 16 SC product administrations 
during the study.  There were no serious adverse events (SAEs), and no study pauses for adverse 
events (AEs).  A total of 6 AEs were assessed as related to study product mild dizziness, mild 
abdominal pain, and 4 infusion reactions (1 mild and 3 moderate, reported for 2 subjects).  One 40 
mg/kg IV recipient developed moderate infusion reaction within one hour of infusion, and one 20 
mg/kg IV recipient experienced mild to moderate infusion reactions with 3 infusions, with symptoms 
complete resolution within 12 hours. Symptoms were typical of infusion reactions observed with 
other monoclonal antibodies in terms of characteristics and temporal onset [49].  No participant 
required epinephrine or steroid administration. All AEs assessed as related to the study product 
resolved without residual effects. Other reported unsolicited AEs have been mild or moderate in 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 17 of 59
severity.
Within this limited dataset for solicited local reactogenicity, 2 of 17 (11.8%) subjects in IV groups 
reported mild pain and bruising at the injection site, and 4 of 8 (50.0%) subjects in SC groups 
reported mild symptoms of pain (n=4) and moderate redness (n=1) at the injection site.
For solicited systemic adverse events reported 3 days after product administration, 4 of 17 subjects 
(23.5%) receiving VRC07-523LS IV reported mild or moderate systemic reactogenicity symptoms of 
malaise (n=3); myalgia (n=3); joint pain (n=2); headache (n=2), chills (n=2), nausea (n=1), and fever 
(n=1).  Five (5) of 8 subjects (62.5%) receiving VRC07-523LS SC reported mild systemic 
reactogenicity symptoms: malaise (n=3), headache (n=3), myalgia (n=2), joint pain (n=2), chills (n=1), 
and nausea (n=1).
Overall, VRC07-523LS administrations have been generally well tolerated with no unexpected 
reactions or SAEs reported; no safety signals or dose limited toxicity were detected.
1.3.3.
In Vivo Anti-Viral Effect of VRC01 and VRC07-523LS
Analysis of the VRC 601 viral load data obtained from 8 viremic adults shows that VRC01 has a 
statistically significant in vivo virological effect on HIV viral load when administered as a single 40 
mg/kg IV dose.  None of these adults were taking ARV therapy when enrolled into the study and had 
not started on ARV during the time period when the viral load data were collected.  Six of the eight 
adult subjects had ≥1 log10 copies/mL decrease in viral load and two subjects had a viral load drop of 
0.26 and 0.18 log10 copies/mL respectively [7].
These data indicate the following for a single dose of VRC01 at 40 mg/kg IV:

A statistically significant change from baseline viral load post-infusion days 5 to 16; 

The median time to reach ≥0.5 log10 decrease in viral load is 5 days; and,

The median time to greatest decrease in viral load is 7 days.
A 0.5 log10 copies/mL or greater decrease in viral load is considered to be a positive response to 
ART [50].  To have clinical benefit, such a change would need to be sustained.  In VRC 601, 
subjects were administered only one dose of VRC01 at 40 mg/kg and, thus, a sustained effect on 
viral load was not expected.  However, the data demonstrate a VRC01 mediated anti-viral effect and 
that the established benchmarks can be obtained, and support the hypothesis that a schedule with 
repetitive dosing or with sustained antibody expression may have a beneficial clinical effect. 
In protocol A5340, of the 13 evaluable participants who received VRC01 and underwent an analytic 
treatment interruption, 38% remained suppressed (HIV-1 RNA <200 copies/mL) at the week 4 visit, 
compared to 13% in historic controls (p=0.04). By week 8 only one of 13 (8%) participants 
maintained viral suppression, compared to 3% in historic controls (p=0.44) [51]. 
In protocol NIH 15-I-0140, all 10 participants with chronic HIV infection undergoing analytical 
treatment interruption experienced plasma viral rebound (>40 copies/ml) with a median time to 
rebound of 39 days (interquartile range, 29 to 39) or 5.6 weeks (interquartile range, 4.1 to 5.6) 
following cessation of ART [51].
In individuals with chronic HIV-1 infection on ART (protocol A5342), VRC01 infusions were safe 
and well tolerated but did not affect plasma viremia, cellular HIV-1 RNA/DNA levels, or stimulated 
virus production from CD4+ T cells [52]. 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 18 of 59
In protocol RV397, after ART interruption, only one participant who received VRC01 achieved viral 
suppression for 24 weeks. The other 17 participants who underwent treatment interruption restarted 
ART because of confirmed recording of 1000 or more HIV-1 RNA copies per mL before 24 weeks 
[53].
In a limited experience with VRC07-523LS in HIV-infected, viremic adults enrolled in protocol 
VRC 607/A5378, preliminary interim viral load data showed that at 7 days post infusion, 8 of 9 
participants had a ≥1.2 log10 decrease in viral copies/mL and 2 of 9 participants had a ≥ 2 log10 
decrease. By day 14 post infusion, 6 of 9 participants had a > 1.5 log10 decrease in viral load [54]. 
1.3.4.
Human Experience with Other rAAV Vectors
Evaluation of rAAV vectors in human clinical trials thus far demonstrated that these vectors are safe 
and well tolerated in humans [20, 22].  
One serious adverse event resulting in a patient death was reported in 2007 and was evaluated as 
unlikely to be related to study product. In this study for rheumatoid arthritis, a TNF-α inhibitor was 
expressed using the rAAV2 vector.  The event was reviewed by the Recombinant DNA Advisory 
Committee (RAC) and a panel of experts.  A combination of factors including concurrent anti-TNF-
α therapy, other immunosuppressive therapy, and residence in an area endemic for histoplasmosis 
was thought to be the likely explanation for the participant’s fatal disseminated histoplasmosis [55]. 
Overall, investigational rAAV vectors have been used in clinical trials since the mid-1990s, with a 
strong safety record established upon local or systemic administration in over 300 subjects treated by 
2011 [20].  An indication for potential clinical efficacy has been observed in the treatment against a 
number of diseases including congenital blindness [56], Parkinson disease [57, 58], and hemophilia 
[34, 35, 59].   Notably, a clinical trial of the rAAV8 vector expressing human factor IX (FIX) used 
for treatment of severe hemophilia B has been reported [34].  This study used a single intravenous 
infusion of AAV8-FIX; the treatment was well tolerated up to the highest dose of 2x1012 vg/kg body 
weight and the transgene was expressed in the range of 3-11% of normal levels.  The study reported 
long-term follow up data for 10 patients along with a conclusion that the infusion of a single dose of 
rAAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical 
improvement.  No late toxic effects from the therapy were reported within a follow-up period up to 3 
years [60].
An IM delivery of the rAAV1 vector expressing lipoprotein lipase (Glybera®, alipogene tiparvovec) 
at doses up to 1x1012 vg /kg has been demonstrated to be safe and well-tolerated in subjects with 
lipoprotein lipase deficiency (LPLD) [27].  On November 2, 2012, the European Commission 
approved the marketing authorization for Glybera®, as a treatment for LPLD, under exceptional 
circumstances, in all EU member states.  
Two gene therapy products based on AAV vectors have been recently approved by the FDA for 
treatment of genetic diseases. Luxturna® was approved for treatment of the Leber’s congenital 
amaurosis type 2, a retinal dystrophy in persons with reduced or absent levels of biologically active 
human retinal pigment epithelial 65 kDa protein, RPE65 (1.5 x 1011 vg of the AAV2 vector carrying 
a functional copy of the RPE65 gene to cells of the retina, administered by subretinal injection [61, 
62]). Zolgensma® was approved for treatment of a spinal muscular atrophy in children less than 2 
years of age with bi-allelic mutations in the survival motor neuron (SMN) gene (2.0 x 1014 vg/kg of 
the AAV9 vector carrying a functional copy of the SMN gene, administered IV [63, 64]). 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 19 of 59
rAAV vectors have been tested for HIV-1 antibody expression in animal studies [8-10].  In one 
study completed in 21 healthy volunteers (NCT01937455) with a gp 120 V1/V2-specific PG9 
antibody, delivered IM using the rAAV1 vector to mediate antibody expression, no safety concerns 
were identified [65]. Reactogenicity was generally mild or moderate and resolved without 
intervention. No serious adverse events or adverse events evaluated as related to product were 
recorded. The PG9 antibodies were detected by HIV neutralization in the serum of four subjects and 
not detected by ELISA. PG9 anti-drug antibody was present in ten volunteers in the higher dose 
groups. Both anti-AAV1 antibodies and AAV1-specific T-cell responses were detected [65].
Recent reports indicated that three deaths occurred in a clinical study of the AAV8-based gene 
therapy product for a rare genetic neuromuscular disorder, x-linked myotubular myopathy 
(XLMTM) [66-68]. Per a brief report from the July 3, 2020 issue of Science [66], Audentes 
announced on June 23, 2020 that 2 patients in its phase III AT132 XLMTM trial had died from 
sepsis related to liver dysfunction. These patients received 3 x 1014 vg/kg of the AT123 product by 
IV infusion. At least one of these two patients had pre-existing liver disease. Earlier dosing of the 
product resulted in improved muscle function in other participants in this trial. A new press release 
from Audentes confirmed death of the third subject in the same study [69].  By preliminary report, 
the third subject died of gastrointestinal bleeding; 3 of 17 subjects treated with the high IV dose of 
the AT123 product have now died [70].  
The only similarity of the vector used in the Audentes study to that used in VRC 603 is the AAV8 
coat protein; the promoter sequence and the gene expressed are different. The gene therapy product 
dose administered by IV infusion to subjects in the Audentes XLMTM trial is more than 100 times 
greater than our highest VRC 603 injection dose administered IM. No hepatotoxicity has been 
observed on the VRC 603 study so far, and this new information may not be applicable to the VRC 
603 study since the product in Audentes study has different indication, different route of 
administration, and was administered at much higher dose. The 8 subjects that are currently enrolled 
in VRC 603 already received the study product without safety concerns identified and are currently 
being followed for safety. 
1.4.
Pharmacokinetic Parameters
PK parameters of the passively administered MAbs VRC01 and VRC07-523LS have been evaluated 
in a limited number of healthy and HIV-infected adults [6, 7, 71].  Studies are ongoing to further 
describe the PK of VRC01 and VRC07-523LS after a single dose and a repeat dosing by IV and SC 
routes. 
In animal studies in humanized mice, rAAV8 vector encoding HIV-specific MAb 4E10 was 
administered IM and induced a detectable level of antibody in circulation after a week. Expression 
continued to rise to maximum levels at 10-16 weeks, and then decreased 2 or 3 folds before 
stabilizing for the 64-week study [8].  Similar PK parameters were observed with AAV8-VRC01 
and AAV8-VRC07 constructs in humanized mice, and protection from HIV infection was 
demonstrated [8, 9]. 
In NHPs, rAAV8 vector encoding a simianized form of VRC07 provided for detectable antibody in 
blood within a week after IM administration at 1x1013 vg, with a peak VRC07 concentration in 
plasma in the range 2.5-7.7 mcg/mL between weeks 2 and 4.  Strong immune response to the 
product was noted, and VRC07 became undetectable in the blood of all macaques by week 9.  With 
immune suppression by cyclosporine, VRC07 circulated in macaques for 16 weeks at levels up to 66 
mcg/mL [10].  

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 20 of 59
PK parameters of VRC07 delivered by episomal gene expression using the AAV8 vector in humans 
will be evaluated in this study.
2.
STUDY AGENT
The study agent, AAV8-VRC07 (VRC-HIVAAV070-00-GT) was produced under current Good 
Manufacturing Practice (cGMP) regulations by the Clinical Vector Core, Center for Cellular and 
Molecular Therapeutics, The Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA, under 
contract to VRC.  Refer to the IB for manufacturing information.  Quality Assurance (QA) lot 
release testing and ongoing stability studies verify conformance to product specifications.
2.1.
AAV8-VRC07 (VRC-HIVAAV070-00-GT)
AAV8-VRC07, developed by VRC/NIAID/NIH, is a gene transfer product intended for long-term 
expression of VRC07, a broadly neutralizing human MAb targeted against the HIV-1 CD4 binding 
site.  The product is composed of a serotype 8 adeno-associated viral capsid containing a DNA 
expression cassette for genes encoding the heavy and light chains of the VRC07 monoclonal 
antibody.  AAV8-VRC07 is provided at a concentration of 2.84x1013 vg/mL in a volume of 1 
mL/vial.
The construct is non-replicating, and both heavy and light chain genes are expressed in the same 
reading frame and then processed post-translationally to produce the heavy and light chain proteins.  
Flanking each end of the construct are ITRs from the AAV serotype 2 that allow for vector genome 
packaging into AAV particles. The ITRs are the only AAV sequences remaining in the vector 
genome. The open reading frames for the AAV Rep and Cap gene products have been removed from 
the vector and therefore, there are no AAV proteins encoded by the construct. The AAV8 capsid 
protein was provided in trans during manufacturing.
The expressed VRC07 is a natural antibody and a clonal relative of VRC01. The variable region of 
the VRC07 heavy chain has 15 amino acid differences from VRC01 and a 4 amino acid insertion in 
the complementarity-determining region (CDR) H3. The VRC07 heavy chain (IgG1) was paired 
with the VRC01 light chain. Using a panel of 179 Env pseudoviruses, VRC07 was able to neutralize 
93% of primary HIV-1 viruses with a half-maximal inhibitory concentration (IC50) less than 50 
mcg/mL and 83% of viruses with an IC50 less than 1 mcg/mL [3, 4].  
Refer to the IB for more details on AAV8-VRC07 composition and manufacturing. 
2.2.
Preclinical Safety Studies 
The in vitro preclinical safety studies performed to assess potential off target binding of VRC07 are 
summarized in Table 1. 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 21 of 59
Table 1: In Vitro Preclinical Safety Studies with VRC07
Study Purpose
Study Outcome
1
Assessment of anti-phospholipid reactivity 
by binding to cardiolipin.
VRC07 does not react to phospholipids [3]
2
Assessment of anti-nuclear antigen reactivity
VRC07 does not react with nuclear antigens
3
Assessment of anti-phospholipid reactivity 
by impact on activated partial thromboplastin 
time (aPTT)
VRC07 does not react to phospholipids
4
Assessment of binding to a human epithelial 
cell line (HEp-2) by Immunohistochemistry
VRC07 does not bind to HEp-2 cells [3]
5
Assessment of potential “off target” binding 
in a human Tissue Cross-Reactivity study 
with VRC07
VRC07 staining of the cytoplasmic 
compartment was judged of no toxicologic 
relevance as staining was observed in the 
cytoplasmic compartment [72, 73]. No 
binding to membranous targets was 
observed.  Extracellular granules/globules 
often observed in connective tissue or in 
vascular walls and/or perivascular connective 
tissue were stained in several human tissues.
A single dose safety and biodistribution GLP study of AAV8-VRC07 (VRC-HIVAAV070-00-GT) 
administered by intramuscular injection was conducted in male and female BALB/c mice. No 
toxicologically meaningful findings or changes were seen in clinical observations, body weight, food 
consumption, body temperature, dose site irritation, ophthalmology, or clinical chemistry that could 
be attributed to AAV8-VRC07 administration, and no target organs of toxicity were identified upon 
histopathologic examination.
Biodistribution analysis revealed that all high-dose (2.4x1013 vg/kg) treated mice were positive for 
AAV8-VRC07 in each of the 15 examined tissues on Days 7, 30, and 90. Levels of AAV8-VRC07 
in blood were below the lower limit of quantitation (LLQ, <40 copies/mcg gDNA) in half of the 
animals on Day 90. In general, the levels of AAV8-VRC07 did not differ meaningfully between 
males and females.
Refer to the IB for more information on these and other preclinical studies with AAV8-VRC07. 
2.3.
Proof-of-Concept Studies with AAV8-VRC07
VRC conducted several proof-of-concept studies with the proposed clinical construct and with 
laboratory modifications of AAV8-VRC07 vectors (1835-rAAV8-VRC07 and 1830-rAAV8-
VRC07) (Table 2).  More information on these research grade vectors and on proof-of-concept 
studies can be found in the IB.  Murine and non-human primate studies conducted with research-
grade AAV8-VRC07 vectors provide a foundation for understanding the activity of VRC07 vectored 
immunoprophylaxis and vectored immunotherapy.

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
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      PROTOCOL DATE MARCH 09, 2023 
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Table 2: Pre-clinical Proof-of-concept Studies of AAV8-VRC07 and Other Vectors
Study Purpose
Study Outcome
1
Kinetics of expression of VRC07 by 
AAV8-VRC07, 1830- and 1835–
rAAV8-VRC07 vectors in NSG 
immunodeficient mice
When administered IM at 1 x 1011 vg to NSG immunodeficient 
mice, the 1830-rAAV8-VRC07 vector expressed approximately 
200 mcg/mL of VRC07 within 8 weeks of administration. 1835-
rAAV8-VRC07 and AAV8-VRC07 exhibited somewhat lower 
levels of expression at >100 mcg/mL within 8 weeks.  
2
Dose-dependent VRC07 expression in 
immunocompetent BALB/c mice 
mediated by AAV8-VRC07
When AAV8-VRC07 was administered IM to BALB/c mice at 
doses of 5 x 109 vg, 5 x 1010 vg, 5 x 1011 vg and 1 x 1011 vg, the 
VRC07 expression was dose dependent and resulted in high-
level expression for at least 12 weeks in immunocompetent 
mice despite the presumed ability of the mice to generate an 
anti-human immunoglobulin and anti-AAV8 response.
3
Dose response efficacy of the 1830 -
rAAV8-VRC07 vector in a NSG 
mouse HIV challenge model
When 1830-rAAV8-VRC07, a vector similar to AAV8-VRC07, 
was administered IM at two-fold decreasing doses of the vector, 
starting at 1 x 1011 vg, the minimal protective serum 
concentration of VRC07 was determined to be 3 to 6 mcg/mL in 
NSG mice.
4
Ability of VRC07 expressed by 1835-
rAAV8-VRC07 vector to control HIV-
1 infection in BLT humanized mice 
BLT humanized mice with an established HIV-1 infection were 
able to control viral replication after a single IM administration 
of 1835-rAAV8-VRC07 at 5x1011 vg, as viral load approached 
the assay lower limit of detection (LOD) in animals even after 
discontinuation of Highly Active Antiretroviral Therapy 
(HAART).
5
Efficacy of AAV8-simVRC07 in 
rhesus macaques immunosuppressed 
by transient cyclosporine 
administration
One dose of AAV8-simVRC07 at 1 x 1013 vg administered IM 
5.5 weeks prior to a single intrarectal challenge with SHIV, 
prevented infection in 4/6 rhesus macaques. Of the 2 infected 
macaques, one had no detectable simVRC07 in circulation, and 
the other showed anti-simVRC07 plasma activity and had the 
lowest sim-VRC07 concentration on the day of challenge [10].
3.
STUDY OBJECTIVES
3.1.
Primary Objectives

To evaluate the safety and tolerability of AAV8-VRC07 administered IM at 5x1010 vg/kg, 
5x1011 vg/kg, or 2.5x1012 vg/kg to HIV-1 infected adults on effective ARV therapy. 

To evaluate the pharmacokinetics of VRC07 at each dose level through 24 weeks after 
injection and to determine the AAV8-VRC07 dose that achieves at least 50 mcg/mL 
VRC07 concentration in serum at 4 weeks post injection with a target set point of ≥5 
mcg/mL at 12 weeks post injection. 

To describe immune responses to the AAV8-VRC07 product.

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
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      PROTOCOL DATE MARCH 09, 2023 
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3.2.
Secondary Objectives

To assess for potential clinical effects of the pAAV8-VRC07 administration on CD4 cell 
count and viral load in study participants.

To determine the serum concentration of VRC07 at specified time intervals for 1 year 
after injection, and if persistent, then every 6 months as long as there is detectable 
antibody in serum.
3.3.
Exploratory Objectives

To determine if measurable levels of VRC07 can be found in oral mucosal secretions 
after AAV8-VRC07 administration. 

To evaluate for evidence of functional activity of VRC07 in samples collected at 
representative timepoints throughout the study.

To test subjects for the IgG1 allotypes in order to evaluate allotype-specific effects on 
VRC07 pharmacokinetics.

To investigate immune responses to the AAV8-VRC07 product.
4.
STUDY DESIGN
This is a Phase I dose-escalation study of the safety and tolerability of AAV8-VRC07 expressing a 
HIV-1 CD4 binding site-specific neutralizing antibody, VRC07, in HIV-1 infected adults on ARV 
therapy.  The study will also examine the pharmacokinetics of VRC07 expression following IM 
administration of AAV8-VRC07.  The hypotheses are: 1) AAV8-VRC07 will be safe for human 
administration and will not elicit hypersensitivity or anti-drug antibody (ADA) to VRC07; and 2) 
intramuscular (IM) delivery of AAV8-VRC07 will result in VRC07 antibody production at a 
concentration in serum that is measurable and safe. 
The study schema is shown in Table 3.
Table 3: VRC 603 Study Schema
Group
Dose
Subjects
Total product volume based on product 
concentration of 2.84x1013 vg/mL and a subject 
weight of 100 kg
1
5x1010 vg/kg
2-5
0.18 mL
2
5x1011 vg/kg
2-5
1.76 mL
3
2.5x1012 vg/kg
2-5
8.80 mL
Total
2 to 5 subjects per group to enrollment of 15 subjects. Enrollment up to a total of 25 subjects is 
permitted in case there are subjects who do not complete the schedule, if additional PK evaluations 
are needed, or if an enrollment of additional subjects is recommended for safety evaluations.
Subjects will be enrolled sequentially and assigned to the dosage level being evaluated at the time of 
enrollment.  Cumulative safety data will be reviewed weekly by a Protocol Safety Review Team 
(PSRT) while injections are being administered. 
Each subject will receive a single dose of study product, as one or more IM injections.  Safety, 
including reactogenicity and unsolicited AEs, laboratory findings, and VRC07 levels in blood will 
be assessed after the injection and summarized for an interim analysis at 4 weeks post injection.  The 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
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second subject in each dose group will be injected after the 4 weeks safety assessment for the 
first enrolled subject. 
Decisions on dose escalation and subject enrollments will be based on safety data and the VRC07 
concentration in blood achieved at 4 weeks after product administration (Section 4.3).  The 
pharmacokinetics of VRC07 at each dose level will be evaluated to determine the dose that achieves 
at least 50 mcg/mL VRC07 concentration in serum at 4 weeks post injection with a target set point 
of ≥ 5 mcg/mL at 12 weeks post injection.
Safety lab samples will be collected per Schedule of Evaluations (Error! Reference source not 
found.).  Subjects will keep a daily diary of solicited systemic symptoms for 7 days after product 
administration.  PK samples will be collected at specified intervals through 52 weeks after product 
administration, and if persistent, every 6 months through 5 years after injection.
In subjects who agree to the optional mucosal sample collection, oral fluid samples will be obtained 
at specified time-points (Section 4.2.6).
The study will be conducted by the VRC Clinic at the NIH Clinical Center (NIH CC).
4.1.
Study Population
All inclusion and exclusion criteria must be met for eligibility.
4.1.1.
Inclusion Criteria
A volunteer must meet all of the following criteria:
1. Able and willing to complete the informed consent process.
2. 18 to 65 years of age.
3. HIV-1 infected. 
4. On a stable antiretroviral regimen for ≥ 3 months.
5. Available for clinical follow-up through the last study visit.
6. Based on history and examination, must be in general good health with no evidence of 
clinically significant lab abnormalities and without additional clinically significant medical 
conditions as per exclusion criteria.
7. Willing to maintain or establish a relationship with a primary health care provider for 
medical management of HIV infection while participating in the study. 
8. Willing to have blood samples collected, stored indefinitely, and used for research purposes. 
9. Able to provide proof of identity to the satisfaction of the study clinician completing the 
enrollment process.
10. Laboratory tests assessing subject health will be conducted within 84 days prior to 
enrollment and values must meet the following criteria:
a.
White blood cell count (WBC) 2,500-12,000/mm3;
b. WBC differential either within institutional normal range or accompanied by approval of 
the Principal Investigator (PI) or designee;
c.
Platelets = 125,000 – 400,000/mm3;
d. Hemoglobin ≥ 10.0 gm/dL;

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 25 of 59
e.
Creatinine ≤ 1.25 x upper limit of normal (ULN);
f.
ALT ≤ 1.1 x ULN;
g. AST≤ 1.1 x ULN; and,
h. VL ≤ 50 copies/mL and a CD4 count ≥ 300/mcL. 
Male-Specific Criteria:
1. Males must agree to use condoms for all sexual activity of any reproductive potential for 52 
weeks after receiving the study product.
Female-Specific Criteria:
1. If a woman is sexually active with a male partner and has no history of hysterectomy, tubal 
ligation or menopause, she must agree to use either a prescription birth control method or a 
barrier birth control method from the time of study enrollment through study Week 52, or to 
be monogamous with a partner who has had a vasectomy.
2. Negative β-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day of 
enrollment for women presumed to be of reproductive potential.
4.1.2.
Exclusion Criteria
A volunteer will be excluded if one or more of the following conditions apply:
1. Previous receipt of monoclonal antibody whether licensed or investigational.
2. Previous receipt of gene therapy product.
3. Ongoing AIDS-related opportunistic infection (including oral thrush). 
4. Active injection drug use or active drug or alcohol use or dependence that, in the opinion of 
the site investigator, would interfere with adherence to study requirements. 
5. A titer of pre-existing antibodies to AAV8 capsid is > 1:90.
6. Weight > 115 kg for Group 3 subjects only. 
7. History of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis 
within the 2 years prior to enrollment that has a reasonable risk of recurrence.
8. Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or platelet 
disorder requiring special precautions) or significant bruising or bleeding difficulties with IM 
injections or blood draws. 
9. Active liver disease such as chronic hepatitis.
10. Hypertension that is not well controlled by medication.
11. Woman who is breast-feeding or planning to become pregnant during the study participation. 
12. Receipt of any investigational study agent within 28 days prior to enrollment.
13. Current infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
14. Any other chronic or clinically significant medical condition that in the opinion of 
investigator would jeopardize the safety or rights of the volunteer, including, but not limited 
to:  diabetes mellitus type I; OR clinically significant forms of asthma, autoimmune disease, 
psychiatric disorders, heart disease, or cancer.

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
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4.2.
Clinical Procedures and Laboratory Assays
Evaluation of safety for this study will include clinical laboratory assessments, medical history, and 
physical examination by clinicians.  In response to the coronavirus disease 2019 (COVID-19) 
pandemic and changing information related to testing, all NIH CC epidemiologic and testing 
guidelines will be followed in the study conduct.
The study schedule is provided in Error! Reference source not found..  Total blood volume drawn 
from each subject will comply with the NIH Clinical Center Guidelines, which is available on the 
NIH intranet at the following link: http://cc-internal.cc.nih.gov/policies/PDF/M95-9.pdf. 
4.2.1.
Screening
Screening for this study will be completed through the Vaccine Research Center’s screening 
protocol, VRC 500 (NIH 11-I-0164).  Volunteers will be recruited through Institutional Review 
Board (IRB)-approved advertising.  The evaluations and sample collection that will be included in 
screening are a medical history, physical exam, laboratory tests and procedures listed in APPENDIX 
I, any laboratory tests needed to confirm eligibility, and pregnancy test (for females of reproductive 
potential).  Additional clinical and laboratory assessments of health may be conducted at screening 
based on clinical judgment.  Screening evaluations must be completed within 84 days prior to 
enrollment and may be repeated as needed to confirm eligibility within this time interval.  
A nasopharyngeal swab to evaluate for current SARS-CoV-2 infection must be collected no more 
than 5 days prior to enrollment and study product administration on Day 0. The testing result must 
be negative for a subject to participate in the study.
Research samples of PBMCs, plasma and serum will also be collected during the screening period.  
VRC 603 informed consent documents will be reviewed.  Counseling related to potential risks of 
study agent and pregnancy prevention will be performed.  An Assessment of Understanding (AoU) 
will be completed in association with enrollment into VRC 603.  
4.2.2.
Enrollment, Study Days and Visit Numbers 
In this study, Day 0 is defined as the day of protocol enrollment and the day of AAV8-VRC07 
product administration.  Informed consent is obtained on Day 0 prior to enrollment.  The study 
identification number and study group schedule will be assigned in the clinical database on Day 0.  
For all subjects, a clinician will discuss the timing of the study product administration and PK 
sample collection before completing an enrollment to help ensure that the subject can comply with 
the projected schedule. 
Medical history and Day 0 evaluations prior to the study product administration are the baseline for 
subsequent safety assessments.  For calculating elapsed days, each subsequent calendar date is 
labeled by the next sequential “Study Day” as shown in Error! Reference source not found..  The 
visit schedule is the same for all groups, and it is based on intervals of time after study injection 
(Error! Reference source not found.).
The schedule of study visits, permitted windows for completing the visits, and evaluations 
performed at each visit are shown in (Error! Reference source not found.).  
4.2.3.
Administration of AAV8-VRC07
All study agent administrations will be completed according to the assigned group.  For women of 
childbearing potential, study agent administration may not proceed unless a negative pregnancy test 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 27 of 59
has been obtained within the previous 24 hours.  Prior to administration, temperature, blood 
pressure, heart rate (pulse) and weight will be collected and a targeted physical examination (based 
on signs, reported symptoms or interim medical history) will be conducted.  A subject who arrives at 
the clinic with fever or evidence of an acute illness that would preclude administration of the product 
may be rescheduled for a later date.
Injections will be administered into the deltoid muscle and/or in a thigh.  The administration site(s) 
to be used will be discussed with the subject and must be assessed as acceptable by the clinician and 
the subject. All injections will be administered intramuscularly (IM) by needle and syringe in 1 to 11 
sites depending on the volume.  Not more than 1 mL will be administered at a single injection site.
Refer to Section 7 for AAV8-VRC07 preparation for administration procedures. For administration 
of the prepared product in the clinical setting, the clinical staff should practice universal precautions 
and dispose of the used needles and syringes in keeping with the required practices for handling 
sharps in the medical facility. 
In all study groups, the subject will be observed for at least 30 minutes following each product 
administration. 
4.2.4.
Solicited Adverse Events and Clinical Follow-up  
Subjects will be given a “Diary Card” to use as a memory aid for solicited adverse events, on which 
to record temperature and systemic symptoms daily for 7 days after study product administration.  
Subjects will be trained and encouraged to use the secure database but may complete the paper diary 
if necessary.  When the 7-day diary card parameters are recorded directly by the subject through a 
password-protected secure database, the subject’s electronic record will be the source for these data.  
The written (paper) diary card may be used as a source document.  When neither a written nor 
electronic diary card is available from the subject, the study clinician will note the source of 
reactogenicity information recorded in the study database. 
For this study, solicited adverse events occurring during the 7 days after receipt of study agent will 
include: unusually tired/feeling unwell, muscles ache, headache, chills, nausea, and joint pain.  
Subjects will also record the highest measured temperature daily.  Local reactogenicity parameters 
will include pain/tenderness, swelling, and redness at the injection site(s). 
The diary cards will be reviewed for accuracy and completeness at follow-up visits.  Clinicians will 
follow and collect resolution information for any reactogenicity symptoms that are not resolved 
within 7 days.
Events that may require a clinic visit include rash, urticaria, fever of 38.6˚C (Grade 2) or higher 
lasting greater than 24 hours or significant impairment in the activities of daily living.  Clinical 
concerns may prompt an unscheduled study visit based on the judgment of a study clinician. Clinical 
laboratory assays and clinical evaluations will assess safety and tolerability at specified intervals 
after product administration.
4.2.5.
Pharmacokinetics Procedures 
Pharmacokinetic samples will be collected as close as reasonably possible to the target timepoint.  
Actual time of collection will be recorded for all samples.  PK timepoints are shown in Error! 
Reference source not found..

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4.2.6.
Mucosal Samples
In order to begin to understand the tissue distribution and duration of VRC07 expression, this 
protocol includes exploratory collection of oral mucosal samples.  Subject will be offered the option 
of participating in the mucosal sampling schedule, but it will not be required.  If subjects agree to the 
procedures, an oral fluid sample will be obtained before the product administration. All subjects will 
have an option to participate in collection of oral mucosal samples at specified intervals through the 
study (APPENDIX I).  Samples will be collected using small ophthalmic sponges designed for 
clinical use. 
Oral fluid samples may be collected at enrollment and on Days 42, 84, 168, 252, and 336 after 
product administration.
4.2.7.
Schedule of Evaluations 
Refer to Error! Reference source not found. for details on the schedule of evaluations and the 
windows permitted for completion of each visit.  After Day 0, deviations from the visit windows in 
completing study visits are discouraged and will be recorded as protocol deviations but are permitted 
at the discretion of the PI (or designee) in the interest of completing the follow-up schedule and 
obtaining subject safety and VRC07 PK evaluations.
Additional visits and blood drawing may be scheduled during the study if needed to assess subject 
safety or for sample collection for immunological testing.
Any evaluation for an adverse event or possible exacerbation of a pre-existing condition may be 
evaluated at study team discretion as a “protocol related” evaluation.
4.2.8.
Concomitant Medications
Only routine prescription medications will be entered in the database at the time of enrollment.  
After administration of AAV8-VRC07, only concomitant medications associated with a change in 
the ARV regimen, an adverse event that requires expedited reporting, or the development of a new 
chronic condition requiring ongoing medical management will be recorded in the database.  
Otherwise, concomitant medications taken throughout the study will be recorded in the subject’s 
chart as needed for general medical records but will not be recorded in the study database.  
4.3.
Criteria for Dose Escalation
The Protocol Safety Review Team (PSRT, Section 8.8) will conduct an interim safety data review 
before dose escalation may occur.  The PSRT must assess the data as showing no significant safety 
concerns before proceeding with enrollment of the next dose level. 
Safety, including reactogenicity and unsolicited AEs, laboratory findings, pharmacokinetics and 
VRC07 levels in blood will be assessed after the injection and summarized for an interim analysis at 
4 weeks post injection for each subject.
The following algorithm will be used for enrollments and dose escalation: 

If serum levels of 50 mcg/mL VRC07 are not achieved at 4 weeks post-injection in the first 2 
subjects in the dose group, and if there are no safety concerns, the dose escalation will occur 
and the same procedure will be followed for the next higher dose group as shown in the 
decision tree schema (Figure 1). 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
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      PROTOCOL DATE MARCH 09, 2023 
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
If both of the first two subjects in a dose group achieve a serum VRC07 level of at least 50 
mcg/mL at 4 weeks post injection with an acceptable safety profile, then 3 more subjects will 
receive this dose at no more than 1 subject per day.  

If all 5 subjects within a dose group reach the 50 mcg/mL concentration of VRC07 in serum 
at 4 weeks post-injection, escalation to the next dose level will not be conducted and the 
study will be closed for accrual.  

If less than 5 subjects achieve serum levels of 50 mcg/mL of VRC07 AND
-
There are no safety concerns, then accrual will begin at the next dosage level. 
-
There are safety concerns, the PSRT may recommend evaluation of additional subjects at 
the current dose level and reassess for safety and VRC07 concentration before proceeding 
to a higher dose level (Figure 1: VRC 603 Decision Tree for Dose Escalation Based on 
Safety and VRC07 Concentration in Figure 1).

If a dose-limiting toxicity is detected as per Section 4.5, the safety and dose escalation 
review will include a decision on accrual continuation at a lower product dose that was 
evaluated to be safe. 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
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Figure 1:
VRC 603 Decision Tree for Dose Escalation Based on Safety and VRC07 
Concentration in Serum
* As defined in Section 4.5. 
** Before proceeding to a higher dose level, the PSRT may recommend evaluation of additional subjects 
at the current dose level.
If there are discontinuations from the study before there are sufficient data to conduct the dose 
escalation review for a group, then extra subjects may be enrolled into that group in order to have the 
requisite data.  
The IRB, the IND sponsor, and the FDA will be provided with documentation of the safety review 
process and notification of the dose escalation.   
4.4.
Protocol Criteria for Pausing the Study and Resuming the Study
Administration of the study agent and new enrollments will be paused by the study PI according to 
the criteria noted below.  
Pause criteria are as follows: 
VRC 603
2 subjects enrolled into 
a dosage group
Safety 
Concerns?
3 more subjects 
enrolled at this dose 
level
50 mcg/mL achieved in 
2 subjects at 4 weeks
Study closed
to accrual
Dose Escalation
Safety 
Concerns?
*Dose-Limiting Toxicity
Decision Point
Yes
No
Yes
No
Yes
50 mcg/mL achieved in 
5 subjects at 4 weeks
Yes
No**
No**

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
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      PROTOCOL DATE MARCH 09, 2023 
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
One (or more) subject experiences a Serious Adverse Event (SAE) that is assessed as 
related to study agent, or

Two (or more) subjects experience the same Grade 3 or higher adverse events (AE) 
assessed as related to study agent. 
4.4.1.
Plan for Review of Pauses and Resuming Rules:  
Administration of the study agent and enrollments would resume only if review of the adverse 
events that caused the pause resulted in a recommendation to permit further study product 
administrations and study enrollments.  The reviews to make this decision will occur as follows:
Pauses for related SAEs: The IND Sponsor, with participation by the PI, will consult with the FDA 
to conduct the review and make the decision to resume, amend, or close the study.  The IRB will be 
notified accordingly.
Pauses for Grade 3 or higher related AEs: The IND Sponsor and the study PI will conduct the 
review and make the decision to resume, amend or close the study for the Grade 3 or higher events 
that meet the criteria for pausing the study. As part of the pause review, the reviewers will also 
advise on whether the study needs to be paused again for any subsequent events of the same type.  
The FDA and the IRB will be notified of pause reviews triggered by Grade 3 or higher AEs and the 
IND sponsor decisions.
4.5.
Dose-Limiting Toxicity
Dose-limiting toxicity is defined in this protocol as an AE that prevents a dose escalation of the 
study product or prevents continuation of study injections at a given dosage level. If the study is 
paused as per criteria in Section 4.4 and a decision is made to not resume the study injections at the 
current dose, then the safety review will include a decision as to whether or not to continue accrual 
at a lower product dose that was evaluated to be safe in order to achieve the target study accrual of 
15 subjects. 
5.
SAFETY AND ADVERSE EVENT REPORTING
5.1.
Adverse Events
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (e.g., abnormal physical exam or laboratory finding), symptom, or 
disease temporally associated with the subject’s participation in research, whether or not considered 
related to the study treatment.  In the context of FDA-required reporting, an AE means any untoward 
medical occurrence associated with the use of a drug in humans, whether or not considered drug 
related.
Severity of AEs will be assessed using the DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events. Additional information can be found in Error! Reference source not 
found.I. 
Injection site bruising is an expected adverse event and will not be generally recorded as an AE.  
Clinically significant hematomas will be recorded as an AE.

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 32 of 59
Reporting of all AEs will occur during the period from the study agent administration through a visit 
completed at 56 days after product administration (Visit 10, week 8).  After this through completion 
of study participation only serious adverse events (SAE) and new chronic medical conditions that 
require ongoing medical management will be recorded as AEs in the study database.
5.1.1.
Attribution Categories
Attribution categories used (i.e., terms used for assessment of relationship of AE to study agent) for 
this study will be as follows:

Related – There is a reasonable possibility that the AE may be related to the study 
agent(s).

Not Related – There is not a reasonable possibility that the AE is related to the study 
agent(s).
If circumstances arise where other attribution categories are used in describing an adverse event, the 
attribution terms “Definitely,” “Probably,” and “Possibly” related will be mapped to the “Related” 
category while the terms “Unlikely,” “Probably Not Related,” and “Not Related” will be mapped to 
the “Not Related” category.
5.2.
Serious Adverse Events (SAE)
The term “Serious Adverse Event” (SAE) is defined in 21 CFR 312.32 as follows:  “An adverse 
event or suspected adverse reaction is considered serious if, in the view of either the investigator or 
the sponsor, it results in any of the following outcomes:  Death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect.  Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.”
“Life-threatening” refers to an adverse event that at occurrence represents an immediate risk of death 
to the subject. An event that may cause death if it occurs in a more severe form is not considered 
life-threatening. Similarly, a hospital admission for an elective procedure is not considered a Serious 
Adverse Event.  In Section 5.3 the term “Expedited Adverse Event” (EAE) encompasses the events 
that would be considered an SAE by the 21 CFR 312.32 definition.
5.3.
Adverse Event Reporting to the IND Sponsor
Adverse events that meet SAE reporting requirements per the FDA definition (Section 5.2)  must be 
reported and submitted by the clinical site on an expedited basis to the IND Sponsor, 
VRC/NIAID/NIH, according to sponsor guidelines as follows: 

results in death

is life threatening

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 33 of 59

results in persistent or significant disability/incapacity

requires unplanned inpatient hospitalization or prolongation of existing hospitalization

is a congenital anomaly/birth defect in the offspring of a study subject

is an important medical event that may jeopardize the subject or may require intervention 
to prevent one of the other outcomes listed above. 
In addition, any event, regardless of severity, which in the judgment of an investigator represents a 
serious adverse event, may be reported on an expedited basis.
An investigator will communicate the initial SAE report within 24 hours of site awareness of 
occurrence to the IND sponsor. 
A written report by investigator should be submitted to the IND Sponsor within 3 working days.  In 
order for the IND Sponsor to comply with regulations mandating sponsor notification of specified 
SAEs to the FDA within 7 or 15 calendar days, the investigator must submit additional information 
as soon as it is available.
5.3.1.
IND Sponsor Reporting to the FDA
The IND Sponsor is responsible for making the determination of which SAEs are suspected 
unexpected serious adverse reactions (SUSARs) that meet criteria for expedited reporting as defined 
in 21 CFR 312.32.

Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.

Unexpected Adverse Event means an AE that is not listed in the Investigator’s Brochure 
or is not listed at the specificity or severity that has been observed.  
All SUSARs (as determined by the IND Sponsor) will be reported to the FDA as IND Safety 
Reports as soon as possible but not exceeding 7 calendar days for unexpected fatal or life-
threatening events, and not exceeding 15 calendar days for other qualifying events. 
The IND Sponsor will also submit an IND Annual Report of the progress of the investigation to the 
FDA as defined in 21 CFR 312.33.
The IND Sponsor is responsible for providing copies of IND Safety Reports to the Clinical Site for 
submission to the IRB.
5.4.
Reporting to the Institutional Review Board
The following information is consistent with NIH IRB Policy 801: Reporting Research Events, 
Version 1, effective July 1, 2019. 
Reportable Event - An event that occurs during the course of human subjects research that requires 
notification to the IRB.
For the purposes of this policy, reportable events include the following:

Unanticipated problems involving risks to subjects or others (UPs)

Non-compliance (including major protocol deviations and noncompliance that is not related 
to a protocol deviation)

Deaths related or possibly related to research activities

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 34 of 59

New information that might affect the willingness of subjects to enroll or continue 
participation in the study
5.4.1. Unanticipated Problem (UP) 
An “Unanticipated Problem (UP)” is defined as any incident, experience, or outcome that meets all 
three of the following criteria:

Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB approved research 
protocol and informed consent document: and (b), the characteristics of the subject 
population being studied; and,

Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and,

Suggests that the research places subjects, or others (which may include research staff, 
family members or other individuals not directly participating in the research) at a 
greater risk of harm (including physical, psychological, economic, or social harm) 
related to the research than was previously known or expected.
An UP must be reported to the NIH IRB within 7 calendar days of an investigator becoming aware 
of the actual or suspected UP.
5.4.2. Non-Compliance Definition
Non-compliance is the failure of investigator(s) to follow the applicable laws, regulations, or 
institutional policies governing the protection of human subjects in research, or the requirements or 
determinations of the IRB, whether intentional or not. 
Non-compliance may be unintentional (e.g. due to lack of understanding, knowledge, or 
commitment), or intentional (e.g. due to deliberate choice to ignore or compromise the requirements 
of any applicable regulation, organizational policy, or determination of the IRB). 
Non-compliance is further characterized as serious or continuing as follows:

“Serious non-compliance” - Non-compliance, whether intentional or not, that results in 
harm or otherwise materially compromises the rights, welfare and/or safety of the subject. 
Non-compliance that materially effects the scientific integrity or validity of the research 
may be considered serious non-compliance, even if it does not result in direct harm to 
research subjects.

“Continuing non-compliance” - A pattern of recurring non-compliance that either has 
resulted, or, if continued, may result in harm to subjects or otherwise materially 
compromise the rights, welfare and/or safety of subjects, affect the scientific integrity of 
the study or validity of the results.  The pattern may comprise repetition of the same non-
compliant action(s), or different noncompliant events.  .
Any actual or suspected non-compliance by any investigator or entity associated with the protocol 
must be reported to the IRB by the PI/designee within 7 calendar days of any investigator or 
individual associated with the protocol first becoming aware 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 35 of 59
5.4.3. Protocol Deviation
A Protocol Deviation is a non-compliance defined as any change, divergence, or departure from the 
IRB-approved research protocol and is further characterized as major and minor as follows:

Major Deviations – Deviations from the IRB approved protocol that have, or may have the 
potential to, negatively impact, the rights, welfare or safety of the subject, or to substantially 
negatively impact the scientific integrity or validity of the study. 

Minor Deviations – Deviations that do not have the potential to negatively impact the rights, 
safety, or welfare of subjects or others, or the scientific integrity or validity of the study.  
For the reporting purposes, failure of subjects to comply with the research protocol does not 
represent non-compliance unless that failure is due to an action or omission of a member of the 
research team, for example, the failure to give adequate instruction to the subject.
A major deviation must be reported to the NIH IRB within 7 calendar days of an investigator 
becoming aware of an actual or suspected deviation.  Although protocol deviations are also non-
compliance, these should only be reported once as deviations.  Major deviations resulting in death 
must be reported within 24 hours of the occurrence of the event or of any member of the study team 
becoming aware of the death.  
A series of minor deviations pointing toward a more global issue that could affect the rights, safety 
or welfare of the participant or affect the validity of the study should be reported as a major 
deviation.  In all other instances, a summary of minor deviations should be provided to the IRB at 
the time of continuing review.  
5.4.4. Death
Any death of a research subject that is possibly, probably or definitely related to the research must be 
reported within 24 hours of an investigator becoming aware of the death.
5.4.5. New Information 
New information that might affect the willingness of a subject to enroll or remain in the study should 
be reported within 7 calendar days of an investigator first becoming aware.
5.4.6. Suspension or Termination of Research Activities
Any suspension or termination of research activities, including holds on new enrollment, placed 
upon the research by the study sponsor, NIH leadership, or any regulatory agency must be reported 
to the NIH IRB within 7 calendar days of an investigator becoming aware.
5.4.7.
 Expedited Reporting to the NIH IRB
Death related to research must be reported within 24 hours.
The following will be reported within 7 calendar days of investigator awareness:

Actual or suspected UPs;

Actual or suspected non-compliance; 

Actual or suspected major protocol deviations;

SAEs that are actual or suspected UPs;

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 36 of 59

New information that might affect the willingness of a subject to enroll or remain in the 
study;

Suspension or termination of research activities, including holds on new enrollment, 
placed upon the research by the study sponsor, NIH leadership, or any regulatory agency.
5.4.8. Annual Reporting to the NIH IRB
The following will be reported to the NIH IRB in summary at the time of Continuing Review:

Summary of UPs and non-compliance;

Adverse Events (AEs), including Serious Adverse Events (SAEs), that are not UPs, as a 
narrative summary statement indicating whether these events were within the expected 
range;

Minor Protocol Deviations (aggregate summary); and, 

Any trends or events which in the opinion of the investigator should be reported.
5.5.
Reporting to the Institutional Biosafety Committee
The NIH Institutional Biosafety Committee (IBC) (Bethesda, MD) reviews research using 
recombinant DNA for compliance with NIH Guidelines.  In keeping with IBC requirements, any 
SAE report sent to the IRB will be subsequently provided to the IBC. 
6.
STATISTICAL CONSIDERATIONS
6.1.
Overview
This is a Phase I study of the safety, tolerability and pharmacokinetics of AAV8-VR07 (VRC-
HIVAAV070-00-GT) expressing VRC07 human monoclonal antibody with broad HIV-1 
neutralizing activity in HIV-1 infected adults.  It is a dose-escalation study to examine safety, 
tolerability, dose and pharmacokinetics of VRC07 expression following IM administration of 
AAV8-VRC07 in subjects on ARV therapy.
6.2.
Objectives
The primary objectives of the study are to evaluate the safety and tolerability of AAV8-VRC07, to 
evaluate the pharmacokinetics of VRC07 expression, and to estimate the dose of AAV8-VRC07 that 
results in antibody production that achieves VRC07 concentration of at least 50 mcg/mL in serum at 
4 weeks after product administration.  Immune responses to the product will also be evaluated.
6.3.
Size and Accrual
6.3.1.
Sample Size Considerations
This study is primarily descriptive.  For safety analysis, the goal is to identify safety concerns 
associated with different AAV8-VRC07 dosages.  There may be as few as 2 to 5 subjects in a group 
at the time of a dose escalation; therefore, this section considers group sizes of both n=2 and n=5.

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 37 of 59
The ability to identify serious adverse experiences is best expressed by the maximum true rate of 
SAE that would unlikely be observed and the minimum true SAE rate that would very likely be 
observed.  Within a group of size n=2, there is an 80% chance of observing at least 1 event if the true 
rate is no less than 0.55 and a 90% chance of observing no event if the true rate is no bigger than 
0.05.  Within a group of size n=5, there is an 80% chance of observing at least 1 event if the true rate 
is no less than 0.28 and a 90% chance of observing no event if the true rate is no bigger than 0.02.
Probabilities of observing 0 or more than 1 event are presented in Table 4 for a range of possible true 
event rates.  These calculations provide a complete picture of the sensitivity of this study design to 
identify potential safety problems with the study agent.  For example, within the group of size n=2, if 
the true event rate is 0.01, then there is a probability of 0.81 to observe no event and a probability of 
0.01 to observe more than 1 event; while, within the group of size n=5, if the true event rate is 0.1, 
then there is a probability of 0.590 to observe no event and a probability of 0.081 to observe more 
than 1 event. 
Table 4: Probability of observing event for different scenarios
Within a group
(n=2)
Within a group
(n=5)
True event rate
Pr(0 event 
observed)
Pr(more than 1 
event observed)
Pr(0 event 
observed)
Pr(more than 1 
event observed)
0.05
0.903
0.003
0.774
0.023
0.1
0.810
0.010
0.590
0.081
0.2
0.640
0.040
0.328
0.263
0.3
0.490
0.090
0.168
0.472
0.4
0.360
0.160
0.078
0.663
Table 5 gives the upper and lower bounds for 95% exact binomial confidence intervals for all 
possible number of observed events within a group.  Within the group of size n=2, if no subjects 
experience the event, the 95% exact 2-sided confidence interval for the true rate has upper bound as 
0.84; if all subjects experience the event, the 95% exact 2-sided confidence interval for the true rate 
has lower bound as 0.16.  Within the group of size n=5, if no subjects experience the event, the 95% 
exact 2-sided confidence interval for the true rate has upper bound as 0.522; if all subjects 
experience the event, the 95% exact 2-sided confidence interval for the true rate has lower bound as 
0.478.
Table 5: 95% confidence intervals of the true rate for all possible number of observed events 
within a group
Within a group (n=2)
95% confidence interval
Within a group (n=5)
95% confidence interval
Observed rate
Lower bound
Upper bound
Observed rate
Lower bound
Upper Bound
0/2
0
0.842
0/5
0
0.522
1/2
0.013
0.987
1/5
0.005
0.716
2/2
0.158
1
2/5
0.053
0.853
3/5
0.147
0.947
4/5
0.284
0.995
5/5
0.478
1
Tables 4 and 5 also apply to the secondary and exploratory endpoints. 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 38 of 59
6.4.
Statistical Analysis 
6.4.1.
Analysis Variables
Analysis variables consist of baseline variables, pharmacokinetics and safety variables for primary 
and secondary objective analyses.
6.4.2.
Baseline Demographics
Baseline characteristics including demographics and laboratory measurements will be summarized 
using descriptive statistics.
6.4.3.
Safety Analysis
Summaries of the number and percentage of subjects experiencing any AE or reactogenicity will be 
tallied by subgroup, and presented along with exact 95% confidence intervals for the proportion.
Solicited Adverse Events:
Solicited adverse event data is collected after the product is administered in this study.  The number 
and percentage of subjects experiencing each type of solicited sign or symptom will be tabulated by 
severity.  For a given sign or symptom, each subject’s solicited AEs will be counted once under the 
maximum severity for all assessments.  
Adverse Experiences:
Unsolicited AEs are coded into Medical Dictionary for Regulatory Activities (MedDRA) preferred 
terms.  The number and percentages of participants experiencing each specific AE will be tabulated 
by severity and relationship to treatment. For the calculations in these tables, each participant’s 
adverse experience will be counted once under the maximum severity or strongest recorded causal 
relationship to treatment.
A complete listing of adverse experiences for each participant will provide details including severity, 
relationship to treatment type, onset, duration and outcome.
Local laboratory values:
Boxplots of local laboratory values will be generated for baseline values and for values measured 
during the course of the study.  Each boxplot will show the 1st quartile, the median, and the 3rd 
quartile.  Outliers, or values outside the boxplot, will also be plotted.  If appropriate, horizontal lines 
representing boundaries for normal values will be plotted.
6.4.4.
Tolerability Evaluation 
The tolerability of the medical product represents the degree to which overt adverse effects can be 
tolerated by the subject [74].  VRC 603 is the first trial of AAV8-VRC07 in HIV-1 infected adults.  
The tolerability evaluation will be mostly descriptive by nature and consist of solicited adverse 
events that occur during the 7 days following each AAV8-VRC07 administration and reasons for 
any withdrawal or discontinuation based upon subject discomfort.  This early assessment of 
tolerability of AAV8-VRC07 will inform which parameters should be solicited or routinely assessed 
to further characterize the tolerability profile in larger number of subjects. 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 39 of 59
6.4.5.
Pharmacokinetics Analysis
Blood samples for PK evaluations will be collected at timepoints defined in the Schedule of 
Evaluations (Error! Reference source not found.). 
Individual Subject Pharmacokinetic Analysis:  A non-compartmental pharmacokinetic analysis 
will be performed using Phoenix (Centara) or a similar program on the VRC07 concentration data 
generated from each subject.  Calculated pharmacokinetic parameters for all groups will include: 
area-under-the-curve (AUC), maximum concentration (Cmax), time to Cmax (Tmax), terminal rate 
constant (z) and the terminal half-life (T1/2). Cmax and Tmax will be taken directly from the 
observed concentration-time data.  The terminal slope, z, will be determined from the log-linear 
portion of the curve and the T1/2 calculated as 0.693/z. AUC0-Clast will be determined using the 
linear trapezoidal method, where Clast is the concentration at 24 weeks after the dose.  If the final 
sample (Clast) has measurable VRC07 concentrations, the remaining AUC after the final 
concentration (AUCClast-inf) will be estimated as Clast/z.  Data will be summarized by dose group.
Population Pharmacokinetic Analyses:  Population pharmacokinetic analyses will be attempted on 
the VRC07 pharmacokinetic data to determine compartmental PK parameters using the program 
NONMEM.  Based on prior PK studies of VRC01 and the preclinical PK studies of AAV8 -VRC07, 
VRC07 concentrations will initially be assessed using a one compartment PK model as initial 
generation of VRC07 from AAV8-VRC07 is expected to be much slower than the PK distribution of 
VRC07.  Generation of VRC07 from AAV8-VRC07 will be modeled using zero and first order 
processes including a generation plateau and potential decline in production over time.  The impact 
of AAV8-VRC07 dose will be assessed as a potential fixed effect on the input and decline of VRC07 
generation.  The population analysis will generate estimates for initial and final volumes of 
distribution (Vd1 and Vdss), inter-compartmental clearance (Q), clearance (CL) and bioavailability 
(F).  Given the small subject numbers, the population PK analysis will not include an exploratory 
covariate analysis to assess clinical factors as fixed effects associated with VRC07 PK parameters 
with the exception of dose level (5x1010 vg/kg vs. 5x1011 vg/kg vs. 2.5x1012 vg/kg). The terminal 
half-life, t1/2 will be determined from CL/F, Vdss/F and the estimated VRC07 generation.  Final 
model selection will be based on changes in the objective function and graphically by goodness of fit 
plots.  The final population model will be assessed using bootstrap analysis.  The AAV8-VRC07 
dosing strategies and their ability to achieve and maintain of target VRC07 concentrations will be 
performed using the final population PK model and Monte Carlo simulations with at least 5000 
replicates.
6.4.6.
Interim Analyses
Preliminary PK analyses may be done once per dose level as the data for each dose level is obtained.  
This will be used to inform decisions about the dose levels to be administered in studies that may 
begin while the study is still in progress. 
7.
PHARMACY PROCEDURES
The study groups and study agent dosing schedule are shown in Table 3.  Refer to the IB for further 
information about the investigational study agent.  The Investigational Drug Control Unit (CC-
PHAR IDCU) at the Clinical Center Pharmacy (Building 10/1N257, 301-496-1031) will prepare the 
product for administration as described below.

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 40 of 59
7.1.
Study Product and Administration Regimen
The study includes investigational products described as follows:

AAV8-VRC07 (VRC-HIVAAV070-00-GT)

Excipient (AAV8-VRC07 Diluent)
AAV8-VRC07 is a sterile, aqueous buffered solution filled into single dose 1.5 mL cryovials.  Each 
cryovial contains 1 mL (with 10% overage) of AAV8-VRC07 at a concentration of 2.84x1013 vg/mL 
in formulation buffer composed of 180mM sodium chloride, 10mM sodium phosphate plus 0.001% 
Pluronic F68 at pH 7.3.  Vials are intended for single use only and thus do not contain a preservative. 
In calculating the dose to administer and number of vials to thaw, it should be assumed that the 
concentration is 2.84x1013 vg/mL and that a volume of at least 1 mL can be withdrawn from a vial.  
Preparation of AAV8-VRC07 may require a dilution to deliver a required dose relative to the 
subject’s weight. 
Excipient (formulation buffer, AAV8-VRC07 diluent) is composed of 180mM sodium chloride, 
10mM sodium phosphate plus 0.001% Pluronic F68 at pH 7.3, and will be provided in vials that 
contain 1 mL of diluent with 10% average.
7.2.
Study Product Storage
The AAV8-VRC07 product label designates the long-term storage temperature as <-60°C.  
The diluent product label designates storage temperature as <-10°C.
Clinical site storage in a qualified, continuously monitored, temperature-controlled freezer is 
acceptable.
The site pharmacist must promptly report any storage temperature excursions to the Study PI and the 
IND sponsor’s authorized representative.  The effected product must be quarantined in a separate 
area.  The IND Sponsor’s authorized representative will notify the site pharmacist if continued 
clinical use of the product is acceptable.
7.3.
Preparation of Study Product for Administration 
This section describes how the site pharmacist will prepare the study product for administration and 
how the clinician will administer the product.  Clinician instructions on how to select an 
administration site are in Section 4.2.3.  
Preparation is to be done in a clean preparation unit with limited access.  Preparation should be done 
using aseptic technique, in a laminar flow biosafety cabinet.   Standard universal precaution practices 
should be followed for handling of AAV8-VRC07 in the pharmacy.  Personal protection including 
laboratory coat, gloves, and safety glasses are recommended.  Assure that only the required vials are 
present in the preparation unit during dilution, and medication labels are strictly segregated to avoid 
errors. 
Thaw the vial(s) containing AAV8-VRC07 and vials containing diluent (if needed) at ambient 
temperature, 15 to 27°C, immediately prior to use. Gently mix the vials by swirling.
It is expected that each product vial will be used for no more than 1 mL withdrawal volume 
(2.84x1013 vg/mL), however, more may be withdrawn if it is possible to do so.

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 41 of 59
No more than 1 mL will be administered per single injection site.  Total volume for a dose will be 
calculated based on subject weight using formulas provided below.
Following initial thaw, the product may be stored at room temperature and should be used within 4  
hours.  The prepared product may be stored at room temperature and should be administered within 
4 hours after the initial thaw.
It is expected that up to 11 injections may need to be administered at the highest dose.  Product for 
each injection will be filled in a separate syringe at no more than 1 mL per injection.  For example, if 
a volume of 1.1 mL is needed as calculated using the formula below, two injections, 0.5 mL and 0.6 
mL, can be administered.
7.3.1.
Preparation of the 5x1010 vg/kg dose
Diluent will be provided for product dilution at 1 mL/vial. For each 5x1010 vg/kg dose preparation, 
thaw one vial of the product and 3 vials of diluent. 
Step 1: Dilute the product with diluent at a 1:10 ratio by aspirating 0.25 mL of the product from a 
vial and mixing it with 2.25 mL of a diluent.
Step 2: Calculate volume of the diluted product needed for injection, based on subject’s weight:
𝑉(𝑚𝐿) = [𝒘𝒆𝒊𝒈𝒉𝒕](𝑘𝑔) ∗[𝒅𝒐𝒔𝒆](𝑣𝑔/𝑘𝑔)
2.84 ∗1013 (𝑣𝑔/𝑚𝐿)
∗10
As an example for a 115 kg subject, V= ((115 kg * 5x1010 vg/kg) / 2.84x1013 vg/mL) *10 = 2.03 mL, 
and therefore 2.03 mL of the 1:10 diluted product is needed for injection.
7.3.2.
Preparation of the 5x1011 vg/kg dose
The following formula will be used for calculations of the product volume needed for injection, 
based on subject’s weight:
𝑉(𝑚𝐿) = [𝒘𝒆𝒊𝒈𝒉𝒕](𝑘𝑔) ∗[𝒅𝒐𝒔𝒆](𝑣𝑔/𝑘𝑔)
2.84 ∗1013 (𝑣𝑔/𝑚𝐿)
An example of product volume calculations for the 5x1011 vg/kg dose administered to a 115 kg 
subject:
V= (115 kg * 5x1011 vg/kg) / 2.84x1013 vg/mL = 2.03 mL of undiluted product.
7.3.3.
Preparation of the 2.5x1012 vg/kg dose
The formula provided in Section 7.3.2 will be used for calculations of the product volume needed for 
injection, based on subject’s weight.
An example of product volume calculations for the 2.5x1012 vg/kg dose administered to a 115 kg 
subject:
V= (115 kg * 2.5x1012 vg/kg) / 2.84x1013 vg/mL = 10.12 mL of undiluted product.
7.4.
Labeling of Study Agents
Vials of study agents will be individually labeled with the name of the material, volume, lot number, 
concentration, storage instructions, Investigational Use Statement (“Limited by Federal Law to 
Investigational Use”), and manufacturer information.

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
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      PROTOCOL DATE MARCH 09, 2023 
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7.5.
Study Agent Accountability
The study pharmacist is responsible for maintaining an accurate record of the codes, inventory, and 
an accountability record of study agent supplies.  Electronic documentation as well as paper copies 
may be used.
7.6.
Study Agent Disposition
The empty vials and the unused portion of a vial will be discarded in a biohazard containment bag 
and incinerated or autoclaved.  Any unopened vials that remain at the end of the study will be 
returned to the production facility or discarded at the discretion of the sponsor in accordance with 
policies that apply to investigational agents.  Partially used vials will not be administered to other 
subjects or used for in vitro experimental studies.  These vials be disposed of in accordance with 
institutional or pharmacy policy.
8.
HUMAN SUBJECT PROTECTIONS AND ETHICAL OBLIGATIONS
This research study will be conducted in compliance with the protocol, Good Clinical Practices 
(GCP), and all applicable regulatory requirements.
8.1.
Institutional Review Board
A copy of the protocol, informed consent form, other written subject information, and any 
advertising material will be submitted to the IRB for written approval.
The investigator must submit and, where necessary, obtain approval from the IRB for all subsequent 
protocol amendments and changes to the informed consent document.  The investigator will notify 
the IRB of unanticipated problems, non-compliance, deviations from the protocol, and serious SAEs 
as described in Section 5.4.
The investigator will be responsible for obtaining IRB approval of the annual Continuing Review 
throughout the duration of the study.
8.2.
Subject Identification and Enrollment of Study Participants
All study activities will be carried out at the NIH CC.  Study subjects will be recruited through on-
site and off-site advertising done for the screening protocol, VRC 500 (NCT 01375530).  Effort will 
be made to include women and minorities in proportions similar to that of the community from 
which they are recruited and will be limited to persons at least 18 years of age and no older than 65 
years of age at enrollment.
8.2.1.
Participation of Children
Children are not eligible to participate in this clinical trial because the study agent has not been 
previously evaluated in adults.  If the product is assessed as safe for further study other protocols 
specifically designed for children may be conducted.
8.2.2.
Participation of NIH Employees
NIH employees and members of their immediate families may participate in this protocol.  The 
Guidelines for the Inclusion of Employees in NIH Research Studies will be followed. Each NIH 

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
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      PROTOCOL DATE MARCH 09, 2023 
Page 43 of 59
employee considering participation in this trial will receive a copy of the “NIH Information Sheet on 
Employee Research Participation” and a copy of the “Leave Policy for NIH Employees Participating 
in NIH Medical Research Studies.”  Neither participation nor refusal to participate will have an 
effect, either beneficial or adverse, on the participant’s employment or work situation. The employee 
subject’s privacy and confidentiality will be preserved in accordance with NIH CC and NIAID 
policies.  For NIH employee subjects, consent will be obtained by an individual who is independent 
of the employee’s team.  If the individual obtaining consent is a co-worker to the subject, 
independent monitoring of the consent process will be included through the Bioethics Consultation 
Service.  Protocol study staff will be trained on obtaining potentially sensitive and private 
information from co-workers or subordinates. 
8.2.3.
Participation of Decisionally Impaired Subjects
Per protocol inclusion criterion #1 (Section 4.1.1), volunteers must be able and willing to complete 
the informed consent process to participate in the study. Decisionally impaired adults are not eligible 
to enroll in the study, and a probability of already enrolled subjects to become decisionally impaired 
is not anticipated to be higher than in general population. 
Subjects will get a dose of AAV8-VRC07 on a day of study enrollment and will be encouraged to 
keep follow-up visits to monitor their health.  Collection of samples that are for research purposes 
only may be terminated based on clinical judgement and subject willingness/ability to participate.
8.3.
Informed Consent
The study informed consent is provided as a stand-alone document.  It describes the investigational 
product and all aspects involved in protocol participation.
Before a subject’s participation in the study, it is the investigator’s responsibility to obtain written 
informed consent from the subject, after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific procedures are 
conducted or study agent is administered.  The Assessment of Understanding quiz will be completed 
before the study consent is signed.
The acquisition of informed consent will be documented in the subject’s medical records, as required 
by 21 CFR 312.62.  The informed consent form will be signed and personally dated by the subject 
and the person who conducted the informed consent discussion.  The original signed informed 
consent form will be retained in the medical chart and a copy will be provided to the subject.  
8.4.
Subject Confidentiality
The investigator must ensure that no information identifying the subject will be released to any 
unauthorized party.  Individual identifying information will not be included in any reports.  Subjects 
will be identified only by coded numbers.  All records will be kept confidential to the extent 
provided by federal, state and local law.  Medical records are made available for review when 
required by the FDA or other authorized users, such as the study agent manufacturer, only under the 
guidelines set by the Federal Privacy Act.  Direct access includes examining, analyzing, verifying, 
and reproducing any records and reports that are important to the evaluation of the study.  The 
investigator is obligated to inform the subjects that the above-named representatives will review 
their study-related records without violating the confidentiality of the subjects. 

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8.5.
Risks and Benefits 
8.5.1.
Risks of AAV8-VRC07
AAV8-VRC07:  There is limited human experience with administration of AAV8-VRC07 as 
described in Section 1.3.1.   The AAV8-VRC07 injections were well tolerated in 8 subjects, and no 
safety signals or dose-limiting toxicity have been detected.  The most frequently experienced 
reactogenicity was mild pain/tenderness at the injection site that resolved in about 8-14 days. Since 
the product is targeted for a long-term expression of VRC07 HIV-1 neutralizing antibody delivered 
by episomal gene expression using rAAV8 vector, potential risks of monoclonal antibodies and risks 
of vector administration are described below.  
Risks of Monoclonal Antibodies:  There is no prior human experience with administration of the 
VRC07 antibody. First human clinical trials of the clonal relative of VRC07, VRC01 MAb, 
administered by passive transfer determined that VRC01 is safe for further evaluation in HIV-
infected and healthy adults.  Solicited local and systemic signs and symptoms following 
administration of VRC01 were generally none to mild.  The SC administrations were infrequently 
associated with mild local transient reactions (Section 1.3.2). 
In the VRC 605 study, 25 healthy adult subjects have received at least one VRC07-523LS 
administration. Product administrations were well tolerated. Two subjects, one in the 20 mg/kg and 
one in the 40 mg/mL IV groups, experienced an infusion reaction that began within an hour after 
infusion and was manifested by chills, fever, myalgia, malaise, and headache, and had all symptoms 
resolved within 1 day (Section 1.3.2). 
Administration of some MAbs may cause immune reactions such as acute anaphylaxis, serum 
sickness and the generation of anti-drug antibodies.  However, these reactions are rare and more 
often associated with MAbs targeted to human proteins or with the use of murine monoclonal 
antibodies which would have a risk of human anti-mouse antibodies [75].  In this regard, VRC07 is 
targeted to a viral antigen and is a human monoclonal antibody and, therefore, expected to have a 
low risk of such side effects. 
Typically, the side effects of other MAbs are mild but may include fever, chills, rigors, nausea, 
vomiting, pain, headache, dizziness, shortness of breath, bronchospasm, hypotension, hypertension, 
pruritus, rash, urticaria, angioedema, diarrhea, tachycardia or chest pain.  Clinical use of MAbs that 
are targeted to cytokines or antigens associated with human cells may be associated with an 
increased risk of these side effects and in some cases, infections [75]; however, this is not expected 
to be a risk for a MAb like VRC07 that is targeted to a viral antigen.
Delayed allergic reactions to other MAbs may include a serum sickness type of reaction, which may 
include rash, fever, lymph node enlargement, and joint pains.  These symptoms may not appear until 
several days after the exposure to the MAb and are noted to be more common with chimeric types of 
MAb rather than with human MAb such as VRC07 [75].  
Participation in this study may limit a subject’s eligibility for other future MAb clinical trials.
Risks of the AAV8 Vector:  rAAV vectors have been evaluated in human clinical studies for testing 
of recombinant investigational products as having good safety profiles.  One of these products, 
Glybera®, was granted marketing authorization in Europe (Section 1.3.4). Another 2 products, 
Luxturna® and Zolgensma® have received approval from the FDA for marketing in the U.S. (Section 
1.3.4). 

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PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
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The FDA guidance “Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse 
Events”, classifies rAAV vectors as “non-integrating” and at low risk of gene-therapy-related 
delayed adverse events [30]. 
Theoretical risks of a viral vector may include potential integration into the human genome and an 
integration-mediated tumorogenicity.  Wild type AAV can integrate in the genome at a preferred site 
on human chromosome 19 without causing any known human disease.  In one recent report, wild 
type AAV2 integration in known cancer driver genes was implicated in hepatocellular carcinoma 
development in humans [76].  There is no evidence that this rAAV vector would integrate in the 
human genome, and it was not designed to integrate.  The risk of insertional mutagenesis is 
considered to be low with these vectors [46, 77, 78].  There has been no carcinogenesis reported in 
human studies with rAAV vectors [20].
An even more remote theoretical risk of rAAV vectors is germline transmission.  In GLP 
biodistribution studies in mice, AAV8-VRC07 was detected in all 15 tested tissues including testes 
and ovaries. However, it has been noted that motile germ cells may be resistant to AAV infection, 
suggesting that insertion of new genetic material in germ line is extremely unlikely [78]. In human 
studies with AAV2 vector, there were no evidence of vector DNA in semen at any time after IM 
product administration [36].
Another risk of the AAV8-VRC07 product is development of immune responses to AAV8 and/or to 
VRC07.  These immune responses may decrease efficacy of future treatments with AAV vectors or 
effect eligibility for treatment with other monoclonal antibodies in the future. There may be other 
unknown risks of AAV8-VRC07.
8.5.2.
Other Risks
Risks of Intramuscular Injection: IM injections may cause stinging, discomfort, redness of the skin, 
or mild bruising at injection sites. 
Risks of Blood Drawing:  Blood drawing may cause pain and bruising and may, infrequently, cause 
a feeling of lightheadedness or fainting.  Rarely, it may cause infection at the site where the blood is 
taken. 
Risks of Mucosal Sample Collection:  Collection of samples by swabs and wicks by rubbing them 
over the mucosal surfaces can cause momentary discomfort and, in some cases, minor bleeding.  
8.5.3.
Study Benefits
There are no direct benefits to study subjects from study participation.  Others may benefit from 
knowledge gained in this study that may aid in the development of HIV prevention or therapeutic 
methods. 
8.6.
Plan for Use and Storage of Biological Samples
The plan for use and storage of biological samples from this protocol is as outlined in the following 
sections.
8.6.1.
Use of Samples, Specimens and Data
Samples, specimens and data collected under this protocol may be used to conduct protocol-related 
safety and immune response evaluations, exploratory laboratory evaluations related to the type of 

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      PROTOCOL DATE MARCH 09, 2023 
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infection the study agent was designed to prevent, exploratory laboratory evaluations related to 
vaccine or infectious disease research in general and for research assay validation.  
8.6.2.
Samples for Genetic Testing
Some of the blood research samples collected in this study may be used for genetic testing related to 
immune system investigation and PK analyses.  Blood samples used in these genetic tests will be 
coded and the results will not be in subjects’ medical records.  Genetic testing will be performed in 
accordance with the genetic testing information that was included in the study informed consent.                          
When HLA typing is done through the NIH Clinical Center medical laboratory, the HLA type results 
will be in subjects’ medical records.  Any genetic testing, including HLA testing, will be done for 
research purposes only and the results will not be communicated to subjects. All genetic test results 
are confidential, will be kept securely and will not be released without subject’s permission.
8.6.3.
Storage and Tracking of Blood Samples and Other Specimens
All of the stored study research samples are labeled by a code (such as a number) that only the VRC 
Clinic can link to the subject.  Samples are stored at the Vaccine Immunology Program (VIP, 
formerly VITL / NVITAL), Gaithersburg, MD, or VRC Laboratories in Building 40, which are both 
secure facilities with limited access.  Data will be kept in password-protected computers.  Only 
investigators or their designees will have access to the samples and data.  Samples will be tracked in 
the Laboratory Information Management System (LIMS) database or using another software 
designed for this purpose (e.g., Freezerworks).
8.6.4.
Disposition of Samples, Specimens and Data at Completion of the Protocol 
In the future, other investigators (both at NIH and outside) may wish to study these samples and/or 
data.  IRB approval must be sought prior to any sharing of samples.  Any clinical information shared 
about those samples would similarly require prior IRB approval.  The research use of stored, 
unlinked or unidentified samples may be exempt from the need for prospective IRB review and 
approval.  Exemption requests will be submitted in writing to the NIH Office of Human Subjects 
Research, which is authorized to determine whether a research activity is exempt.
At the time of protocol termination, samples will remain in the VIP facility or VRC laboratories or, 
after IRB approval, transferred to another repository.  Regulatory oversight of the stored samples and 
data may be transferred to a stored samples protocol as part of the IRB-approved termination plan.  
Data will be archived by the VRC in compliance with requirements for retention of research records, 
or after IRB and study sponsor approval, it may be either destroyed or transferred to another 
repository.
8.6.5.
Loss or Destruction of Samples, Specimens or Data
The NIH Intramural Protocol Deviation definition related to loss of or destruction of samples or data 
will be followed.  Any loss or unanticipated destruction of samples (for example, due to freezer 
malfunction) or data (for example, misplacing a printout of data with identifiers) that compromises 
the scientific integrity of the study will be reported to the IRB in accordance with institutional 
policies.  The PI will also notify the IRB if the decision is made to destroy the remaining samples.

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      PROTOCOL DATE MARCH 09, 2023 
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8.7.
Compensation
Subjects will be compensated for time and inconvenience in accordance with the standards for 
compensation of the Clinical Research Volunteer Program.  Compensation will be $200 for 
outpatient scheduled visits that include oral swabs and/or blood drawing.  Compensation for the 
study agent administration visit will depend on the number of injection sites used for administration:  
$315 for 1-2 sites, $450 for 3-5 sites, $600 for 6-8 sites, and $750 for 9-12 sites.  Compensation is 
$100 for clinic visits that do not include a blood draw or procedure, and $25 for timely completion 
of electronic diary card. 
8.8.
Safety Monitoring, Protocol Safety Review Team 
Close cooperation between the designated members of the Protocol Team will occur to evaluate and 
respond to individual AEs in a timely manner.  The VRC designated Safety Officer for the day 
conducts a daily safety review of clinical data per VRC Standard Operating Procedures.  The 
Protocol Safety Review Team (PSRT), comprised of the PI, Associate Investigators, Study 
Coordinator, Protocol Specialists, other Study Clinicians, and an Independent Safety Monitor (ISM), 
will review the summary study safety data reports on a weekly basis while injections are being 
administered and through 8 weeks after the last subject receives the last product administration in 
order to be certain that the study agent has an acceptable safety profile, and will continue to monitor 
the study safety data reports on a monthly basis through completion of the last study visit.  
9.
ADMINISTRATIVE AND LEGAL OBLIGATIONS
9.1.
Protocol Amendments and Study Termination
Protocol Amendments must be made only with the prior approval of the IND sponsor, VRC, NIAID.  
Agreement from the investigator must be obtained for all protocol amendments and amendments to 
the informed consent document.  All study amendments will be submitted to the IRB for approval.
The VRC, the Principal Investigator, the NIAID IRB, the Office of Human Research Protections, 
and FDA reserve the right to terminate the study.  The PI will notify the IRB in writing of the 
study’s completion or early termination.
9.2.
Study Documentation and Storage
The PI will maintain a list of appropriately qualified persons to whom trial duties have been 
delegated.
Source documents are original documents, data, and records from which the subject’s data are 
obtained.  These include but are not limited to hospital records, clinical and office charts, laboratory 
and pharmacy records, microfiches, radiographs, and correspondence. 
The PI and staff are responsible for maintaining a comprehensive and centralized filing system of all 
study-related (essential) documentation, suitable for inspection at any time by representatives from 
the VRC, IRB, FDA, and/or applicable regulatory authorities.  Elements include:

Subject files containing completed informed consent forms, and supporting copies of 
source documentation (if kept)

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      PROTOCOL DATE MARCH 09, 2023 
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
Study files containing the protocol with all amendments, Investigator Brochures, copies 
of all correspondence with the IRB and the Vaccine Research Center
In addition, all original source documentation must be maintained and be readily available.
All essential documentation should be retained by the institution for the same period of time required 
for medical records retention.  The FDA requires study records to be retained for up to two years 
after marketing approval or refusal (21 CFR 312.62).  No study document should be destroyed 
without prior written agreement between the Vaccine Research Center and the Investigator.  Should 
the investigator wish to assign the study records to another party or move them to another location, 
they must notify the NIAID and VRC in writing of the new responsible person and/or the new 
location.
9.3.
Study Monitoring, Data Collection and Data Sharing
9.3.1.
Study Monitoring
The VRC regulatory authority inspectors or their authorized representatives are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the trial, provided that subject confidentiality is respected.
Site visits by study monitors will be made in accordance with the IND Sponsor policy to monitor the 
following: study operations, the quality of data collected in the research records, the accuracy and 
timeliness of data entered in the database, and to determine that all process and regulatory 
requirements are met.
Site investigators will allow the study monitors, the IRB, and FDA to inspect study documents (e.g., 
consent forms, drug distribution forms, and case report forms) and pertinent hospital or clinic 
records for confirmation of the study data.
9.3.2.
Data Collection
Clinical research data will be collected in a secure electronic data management system through a 
contract research organization, the Emmes Company, LLC, Rockville, MD.  Extracted data without 
patient identifiers will be sent to the PSRT for safety review and to the protocol statistician for 
statistical analysis.
9.3.3.
Data Sharing
Data generated in this study will be shared as de-identified data in the government-funded public 
repository, www.ClinicalTrials.gov.  Data may be shared prior to publication at approved public 
presentations or for collaborative development and will be shared at the time of publication or within 
1 year of the primary study completion date (data collection completed for primary outcome).
9.4.
Language
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood. 

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9.5.
Policy Regarding Research-Related Injuries
The NIH CC will provide short-term medical care for any injury resulting from participation in this 
research.  In general, the NIH, the Clinical Center, or the U.S. Government will provide no long-
term medical care or financial compensation for research-related injuries.

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PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 52 of 59
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PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
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PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 54 of 59
APPENDIX I
 SCHEDULE OF EVALUATIONS

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 55 of 59
VRC 603 Schedule of Evaluations
Visit 
02
02A
03
04
05
06
07
08
09
10
11
12
13
14
15
16
17
18
Study Week
Wk0 Wk1 Wk1 Wk2 Wk3 Wk4 Wk5 Wk6 Wk7 Wk8 Wk9 Wk10 Wk11 Wk12 Wk14 Wk16 Wk18 Wk20
1Day of Study 0 to -84
D0
D1
D7
D14
D21
D28
D35
D42
D49
D56
D63
D70
D77
D84
D98 D112 D126 D140
Clinical
Tube*
Screen
VRC 500 Screening Consent
X
VRC 603 AoU; Consent
X
2Physical exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
3Medical history
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Product Administration
X
Phone contact; clinic visit if needed
X
CBC / differential
EDTA
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
ALT, AST, creatinine
GLT
4
4
4
4
4
4
4
4
4
4
4
4
4
4
Alpha-fetoprotein (AFP)
SST
4
4
Drug screen
Urine
X
4Pregnancy test: urine or serum
X
X
X
X
4Pregnancy prevention counseling
X
X
X
X
HIV positive prevention counseling
X
X
X
X
5HIV 1/2 Ab/Ag Combo
EDTA
3
Hepatitis BsAg
SST
4
Hep C viral load
SST
4
HIV-1 RNA (viral load)
EDTA
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
CD4/CD8
EDTA
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
6SARS-CoV-2 PCR, nasopharyngeal 
swab
X
7ARV medication record
X
X
8HLA type
EDTA
20
Research Samples / Research Test Schedule
9PK samples
SST
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
10Oral sample
[X]
[X]
[X]
11Plasma for qPCR (2x spin)
EDTA
6
6
6
6
6
6
Plasma for ultrasensitive VL (2x spin)
EDTA
12
12
12
12
PBMC and plasma (2x spin)
EDTA
20
20
40
40
40
20
20
20
20
Serum
SST
24
16
16
16
16
16
16
16
16
AAV8 antibody test /ADA test
X
X
X
X
X
X
X
X
X
Daily Volume (mL)
87
77
0
20
76
20
82
20
88
20
62
16
20
36
62
4
74
4
62
Cumulative Volume (mL)
87
165
165
185
261
281
363
383
471
491
553
569
589
625
687
691
765
769
831
Visit windows: Visit 02A (+ 1 day), Visits 03-06 ( 1 day), Visits 07-14 ( 2 days), and Visits 15-18 ( 3 days). 
*Tube types for clinical labs are according to institutional requirements and are shown to estimate blood volumes.  Different tubes for clinical evaluations may be used to meet site 
requirements. Research sample tube types and blood volumes must be used as shown or as otherwise instructed by the IND sponsor.

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 56 of 59
VRC 603 Schedule of Evaluations Continued
Long Term Follow-up
Visit 
19
20
21
22
23
24
25
26
27
Visit
28
29
30
31
32
33
34
35
Study Week
Wk22 Wk24 Wk28 Wk32 Wk36 Wk40 Wk44 Wk48 Wk52 Study 
year
2
2
3
3
4
4
5
5
1Day of Study
D154
D168
D196
D224
D252
D280
D308
D336
D364 Study 
Week
78
104
130
156
182
208
234
260
Clinical
Tube*
2 Physical exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
3Medical history
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CBC / differential
EDTA
3
3
3
3
3
3
3
3
3
3
3
3
3
ALT, AST, creatinine
GLT
4
4
4
4
4
4
4
4
4
4
4
4
4
Alpha-fetoprotein (AFP)
SST
4
4
4Pregnancy test: urine or serum
X
X
X
X
4Pregnancy prevention counseling
X
X
X
HIV positive prevention counseling
X
X
X
X
X
X
X
X
X
X
X
X
HIV PCR (viral load)
EDTA
6
6
6
6
6
6
6
6
6
6
6
6
6
CD4/CD8
EDTA
3
3
3
3
3
3
3
3
3
3
3
3
3
Research Samples / Research Test Schedule
9PK samples
SST
4
4
4
4
4
4
4
4
4
[4]
[4]
[4]
[4]
[4]
[4]
[4]
[4]
10Oral sample 
[X]
[X]
[X]
11Plasma for qPCR(2x spin)
EDTA
6
Plasma for ultrasensitive viral load (2x spin)
EDTA
12
12
PBMC and plasma (2x spin)
 EDTA
20
20 
 
20 
20 
 
20 
20
20
20
20
20
20
20
20
Serum
SST
16
16 
 
16 
16 
 
16 
16
16
16
16
16
16
16
16
AAV8 antibody test /ADA test
X
X
X
X
X
X
X
X
X
X
X
X
X
Daily Volume (mL)
4
78
56
4
56
4
56
8
68
56
56
56
56
56
56
56
56
Cumulative Volume (mL)
835
913
969
973
1029
1033
1089
1097
1165
1221 1277 1333 1389 1445 1501 1557 1613
Visit windows: Visits 19-27 (3 days), Visits 28-35 (14 days).
*Tube types for clinical labs are according to institutional requirements and are shown to estimate blood volumes.  Different tubes for clinical evaluations may be used to meet site 
requirements. Research sample tube types and blood volumes must be used as shown or as otherwise instructed by the IND sponsor.

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 57 of 59
1 Day of Study: Day 0=day of product administration.  Medical history and Day 0 evaluations prior to AAV8-VRC07 administration are the baseline for assessing subsequent AEs.  
2 Physical Exam: A complete physical exam is performed at screening, including height (ht) and weight (wt).  At other visits, if medically indicated, a targeted exam is performed. 
Otherwise physical exam includes only vital signs (blood pressure (BP), pulse, and temperature), except at Visit 02 when the current weight is also obtained to use for ordering the 
study agent dosed on a “vg/kg” basis. For the long term follow-up visits, vital signs will be collected and kept in subject’s chart, but will not be recorded in the study database.
3 Medical History: A complete medical history is collected at screening. After that only an interim medical history is required.
4 Pregnancy test and pregnancy prevention counseling are required at visits as indicated for women of reproductive potential.  Negative urine or serum pregnancy test result must be 
confirmed for women of reproductive potential prior to study agent administration. 
5 The HIV confirmatory testing by HIV 1/2 Ab/Ag Combo and/or detectable HIV-1 RNA does not need to be repeated if previously performed at the NIH Clinical Center and 
results are available in the NIH medical record (outside lab test results are not acceptable). HIV-1 RNA testing must be performed for all subjects at screening. 
6A nasopharyngeal swab for the SARS-CoV-2 PCR should be collected no more than 5 days prior to product administration.
7ARV medications will be documented in the medical history at screening and recorded in the database at Visit 02. Only subsequent changes to the ARV regimen will be recorded 
in the database.
8 HLA type blood sample is collected once at any timepoint in the study and is shown as a Visit 13 evaluation for convenience; however, if HLA type is already available in the 
medical record it does not need to be repeated.  HLA type may also be obtained from a stored frozen sample: blood sample for HLA testing may not be collected when a frozen 
stored sample is used for testing. 
9 PK samples are collected relatively to the exact time of the end of injection (EOI). The exact time of EOI and the time of PK blood draw are recorded to ensure accurate PK 
analysis. PK samples are collected at the long term follow up Visits 28-34 only if VRC07 persisted at a prior visit.
10 Oral mucosal sample collection is encouraged for all subjects, but it is not mandatory.
11 Plasma for qPCR: Samples will be collected every 4 weeks and tested in batches until two consecutive serum samples show no detectable AAV8-VRC07.

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 58 of 59
APPENDIX II  
TABLE FOR GRADING SEVERITY OF ADVERSE EVENTS

PRODUCT: AAV8-VRC07 (VRC-HIVAAV070-00-GT)                        
PROTOCOL: VRC 603, VERSION 8.0
      PROTOCOL DATE MARCH 09, 2023 
Page 59 of 59
The U.S. Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. 
[July 2017] will be used in this study.  The table is available at the following link:
https://rsc.tech-res.com/docs/default-source/safety/daidsgradingcorrecetedv21.pdf
The grading table and supplementary tutorial can be found on the Division of AIDS Regulatory 
Support Center (RSC) website: 
http://rsc.tech-res.com/safetyandpharmacovigilance/
The Table will be used as posted at the link above with the following exemption:

Weight loss will be recorded as an adverse event only if it is considered deleterious to 
the participant’s health.

Injection site bruising is an expected adverse event and will not be generally recorded 
as an AE. Clinically significant hematomas will be recorded as an AE.

PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
18I0030 VRC 603 V7
Page 1 of 12
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Joseph Casazza, M.D., Ph.D. 
STUDY TITLE: VRC 603 (18-I-0030): A Phase I, Dose-Escalation Study of the Safety of 
                             AAV8-VRC07 (VRC-HIVAAV070-00-GT) Recombinant AAV Vector 
                             Expressing VRC07 HIV-1 Neutralizing Antibody in Antiretroviral –Treated, 
                             HIV-1 Infected Adults with Controlled Viremia
STUDY SITE:    NIH / NIAID / VRC / Vaccine Evaluation Clinic (VEC)
Cohort:                VRC 603 HIV-1 infected subjects
Consent Version: Version 7; February 11, 2025
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator: Joseph Casazza, M.D., Ph.D.,
 at
  
Study Coordinator: Laura Novik, RN, 
at
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time 
needed to ask any questions and discuss this study with NIH staff, and with your family, friends, 
and personal health care providers. Taking part in research at the NIH is your choice.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may 
change your mind and stop participating in the study at any time and for any reason. In either 
case, you will not lose any benefits to which you are otherwise entitled. However, to be seen at 
the NIH, you must be taking part in a study or are being considered for a study. If you do choose 
to leave the study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
This is the study of an experimental gene transfer treatment called “AAV8-VRC07.”  Scientists 
have created a gene in the laboratory that could be transferred to the cells in the body.  This gene 
carries information to tell the cells how to make an antibody called VRC07.  VRC07 is an 
antibody against HIV.  There is no HIV virus in this experimental treatment, and this treatment is 
not a vaccine.  The VRC07 gene is ‘packaged’ into a man-made version of a virus called AAV8.  
The AAV8 cannot make more AAV8 viruses in your body.  It is only being used because its 
IRB NUMBER: 18I0030
IRB EFFECTIVE DATE: 2/18/2025

PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
18I0030 VRC 603 V7
Page 2 of 12
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
outer shell helps to carry the VRC07 gene into the muscle of the body where the VRC07 
antibody can be made. The AAV8 is very similar to other man-made viruses (viral vectors) that 
have been used in other gene transfer studies.  
The main purpose of this study is to see if the administration of AAV8-VRC07 is safe.  We will 
also study if AAV8-VRC07 causes cells to produce VRC07 antibody.  We will study the amount 
of VRC07 made in the body and how long it lasts.
About 15 to 25 people will take part in this study at the NIH Clinical Center in Bethesda, 
Maryland.  The study will include a total of 34 clinic visits per person over 5 years.  
STUDY PRODUCT
The Vaccine Research Center (VRC) at the NIH developed AAV8-VRC07 and made it in a drug 
manufacturing facility. The U.S. Food and Drug Administration (FDA) allows this experimental 
product to be used for research only. Sometimes we refer to AAV8-VRC07 simply as the “study 
product.” 
There are many research gene transfer products in development for different diseases including 
hemophilia, inherited blindness, and Parkinson’s disease.  As of 2011, over 300 people received 
experimental gene transfer with AAV vectors.  There are two AAV-based products currently 
approved by the FDA. Luxturna®, for treatment of a form of inherited blindness and 
Zolgensma®, for treatment of an inherited spinal muscular atrophy in children.
Antibodies are part of the immune system and help fight infection.  Everyone who becomes 
infected with HIV makes antibodies against the virus, but most of these antibodies are not able to 
stop infection.  VRC07 is a newly found HIV antibody that binds to a part of the HIV virus 
needed for infection and blocks it from doing further harm.  It was discovered in a person with 
HIV.  
Over 3370 adults with and without HIV infection received antibodies similar to VRC07 in other 
research studies. These antibodies were found to be safe and well tolerated.  This study was the 
first study to give AAV8-VRC07 to people.
You cannot get re-infected with HIV from the study product.  It will not protect against or cure 
HIV infection.  There is currently no cure for HIV.  We do not expect the study product to 
control HIV.  You should not change or stop your HIV medications before discussing it with 
your primary health care provider.  
We do not know how long the study product will stay in the muscle.  We also do not know if and 
how long it will make VRC07.  In laboratory and animal studies, the study product made VRC07 
antibodies that attach to and inactivate many types of HIV viruses.  In mice and in monkeys, this 
study product prevented infection with HIV.  We do not know if the study product will act the 
same way in people.  It will take many studies to learn if the study product will be useful for 
preventing or treating HIV.  This study alone will not answer this question. 
STUDY PROCEDURES
The study will have 3 groups of 2-5 people each.  Participants will get a different amount (dose) 
of study product in each group by one or more injection(s) in the upper arm(s) or a thigh(s) using 
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a needle.  The study product administration visit will last about 4-6 hours.  Other clinic visits will 
take 1-2 hours.  
If you agree to take part in this study, you will get the study product only on the first day of the 
study (Day 0).  The dose depends on the group.  You will know what dose you will get.  Each 
person gets an amount of study product based on how much they weigh.  We will measure your 
weight on Day 0 to calculate the dose.  You may get up to 11 injections on Day 0, depending on 
the group and your weight.  After the injection(s) we will watch you in the clinic for at least 30 
minutes.  
The Study Groups are shown in the following table:
VRC 603
Group
Dose of AAV8-VRC07
Participants
Estimated Number of 
Injections
1
5x1010 vg/kg
2-5
1-2
2
5x1011 vg/kg
2-5
1-3
3
2.5x1012 vg/kg
2-5
5-11
Total
A total of 6 to 15 subjects may take part in the study. This number can increase to 25 
subjects if needed to achieve the study goals.
The study started by enrolling people in Group 1 at the lowest dose.  People are only being 
enrolled in a higher dose group if there are no safety concerns in the dose group before it. 
Women who can become pregnant will have a pregnancy test on Day 0.  The test result must be 
negative to get an injection. 
For 7 days after you get the study product, we will ask you to check your temperature with a 
thermometer that we give. We will ask you to make note of any symptoms you may have.  We 
will give you access to a secure electronic “diary” to enter the information. You may choose to 
use a paper form instead.  If you have any side effects, you should tell a study nurse or a doctor 
as soon as possible.  You can reach the clinic staff by phone 24 hours a day.  If you have 
symptoms, we may ask you to come into the clinic for an exam before your next study visit.  It is 
very important that you follow the instructions you get from the clinic staff.
After you get the study injection(s), you will need to come to the clinic once a week for the first 
12 weeks.  Then you will have clinic visits every other week for another 12 weeks.  After 24 
weeks, you will have follow-up visits about once a month.  After one year of study participation, 
you will return to the clinic every 6 months for the next 4 years.  Total study participation is 5 
years.
At each visit, we will check you for any health changes or problems.  We will ask you how you 
are feeling and if you have taken any medications.  We will draw your blood at each study visit, 
and we may also ask for saliva samples (explained below).  We will draw about 1 to 13 tubes of 
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blood from you, depending on the visit.  The volume of blood will not exceed the NIH Clinical 
Center limits.
We will tell you right away if any of your test results show a health problem.  We will use some 
blood samples to study if your body develops immune response (antibody) to the study product.  
Results of these tests are not for checking your health.  We will not give you these results.  We 
may ask you to come into clinic for additional follow-up and blood collection if you have any 
health changes. 
Clinical studies follow a set schedule.  This helps us answer the research questions.  The visit 
schedule is a little flexible, but it is important that you work with the staff to follow the schedule 
as closely as possible.  You should try to not miss any visits.
Collection of Saliva for Research
If we find VRC07 in your blood and if you are willing, we will collect saliva samples for 
research at some clinic visits.  Collection of these samples is encouraged but not required.  You 
may choose not to donate these samples but still take part in the study. 
We collect these samples to see if VRC07 reaches different parts of your body.  These sample 
collections will not be for checking your health and do not replace routine health care. 
If you agree, we may collect saliva samples at 6 visits using small disposable sterile swabs or 
sponges.  The swabs are shaped like a “Q-tip” and placed in your mouth to soak up your saliva. 
HIV TESTING AND MANAGEMENT
All participants in this study are HIV infected.  As part of your participation in this study, we 
will frequently test your HIV viral load and CD4+ T cell count for research purposes.  We will 
share these and other test results with you during the study.  If you have any questions about 
your HIV infection, you should discuss them with your primary care doctor.  With your 
permission, we can give copies of your test results to you and your doctor.   
This study does not include regular medical care or the management of your HIV infection.  
You will not be given HIV medications as part of this research study.  You should already have 
a primary health care provider for regular medical care and HIV care.  Please tell a study 
clinician if there is a change in your primary care doctor, or if you are having trouble getting 
HIV medications.  All decisions about starting, stopping, or changing ARV medications will be 
between you and your primary health care provider.  
We expect you to inform us about changes in your HIV medications, but these changes will not 
affect your continued participation in the study. 
MONITORING OF THE STUDY
A group of physicians and scientists at NIH will monitor this study. This group will review the 
study data and will pay close attention to harmful reactions.
GENETIC TESTING
Some of the research blood drawn as part of this study will be used for genetic tests.  Some 
genetic tests are done in research studies to see if genetic differences in people cause different 
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types of immune responses.  Your blood sample used in these genetic tests will not have your 
name on it and the results will not be in your medical record.  These tests are not used to check 
your health and we will not tell you the results. 
A special genetic test, called HLA typing, may be done through the NIH Clinical Center medical 
laboratory.  If this test is done at the NIH Clinical Center, your HLA type results will be in your 
medical record.  These results are not used to check your health.  Any genetic testing, including 
HLA testing, is for research purposes only.  Any genetic information collected or learned about 
you will be kept confidential.  Medical records, including HLA test results are kept securely.  We 
will not give any genetic information that is in your medical record to anyone without your 
permission.
STORED SAMPLES
We will collect samples (including blood, and possibly saliva) from you during the study.  We 
will keep these samples indefinitely for future research to learn more about monoclonal 
antibodies, vaccines, the immune system, and/or other medical conditions.  Results from research 
done with your stored samples will not be in your medical record or reported to you. 
Labeling of Stored Samples: We will label your stored samples by a numeric code.  Only the 
study team can link this code to you.  Any identifying information about you will be kept 
confidential as much as the law allows.  Despite protections, there is a small chance that 
information identifying you will be given to someone who should not get it.
Risks from Stored Samples: There is a risk of unplanned release of information from your 
medical records. The chance that this information will be given to an unauthorized person 
without your permission is very small. Possible problems with the unplanned release of 
information include discrimination when applying for insurance and employment. Similar 
problems may occur if you give information yourself or agree to have your medical records 
released.
Future Studies: In the future, other investigators at NIH or outside of NIH may wish to study 
your stored samples. When your stored samples are shared, they will be marked with a code. 
Your samples will not have any identifying information on them.  Some information about you, 
such as your sex, age, health history, or ethnicity may also be shared with other researchers.
Any future research studies using your samples will be conducted in a way that protects the 
rights and privacy of study participants.
Your stored samples will be used only for research and will not be sold.  The research done with 
your materials may be used to develop new products in the future but you will not receive 
payment for such products.
Making your Choice: You cannot take part in this study if you do not want us to collect or store 
your blood samples.  If you agree to take part in this study, you must also agree to let us keep 
any of your samples for future research.  
If you decide not to take part in this study, you may still take part in other studies at NIH. 
   
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POSSIBLE STUDY RISKS
Possible risks from IM injections:  General risks of needle injections include temporary stinging, 
discomfort, pain, soreness, itchiness, redness, bruising, and or swelling at the needle insertion 
site. There is a very small chance of infection.
Possible risks from AAV8-VRC07: This is the first time this study product has been given to 
people.  The FDA and other agencies that regulate research reviewed results of AAV8-VRC07 
testing in animals.  The study product is expected to make VRC07 antibody targeted against 
HIV-1 using the AAV8 vector.  As of May 4, 2020, 8 subjects have received AAV8-VRC07 and 
no safety concerns were identified. The most frequent symptoms were mild pain/tenderness at 
the injection site that resolved in about 8-14 days after injection of product. Risks of the 
antibodies and risks of the vector are described separately below.
Possible risks of VRC07: We will not give VRC07 to people in this study.  VRC07 is expected 
to be made by your own cells after the study product injection.  This study is the first time that 
VRC07 is expected to be made in people.  
VRC07 has never been given to people. It is very similar to VRC01 and VRC07-523LS 
antibodies.  More than 3370 adults have received one or more doses of VRC01 given IV (in the 
vein) or SC (in the fatty tissue).  These studies showed that VRC01 is safe for further evaluation 
in HIV-infected and healthy adults.  Twenty five (25) adults have received at least one dose of 
VRC07-523LS by IV or SC routes.  
A small number of subjects in VRC01 and VRC07-523LS studies developed infusion reactions 
shortly after IV product administration.  The symptoms of the infusion reaction were chills, 
fever, headache, and muscle pain.  These are typical of infusion reactions observed with other 
monoclonal antibodies.  All symptoms went away within one day.  We believe that infusion 
reactions should not occur with production of VRC07 antibody by muscle cells. However, 
VRC07 may have other unknown risks and side effects.
There are several antibody products that FDA approved for use in people.  Other research 
antibody products have been given safely by both the IV and the SC routes.  Most side effects 
tend to occur within the first 24 hours after antibody administration.  Side effects of some 
monoclonal antibodies may include fever, chills, shaking, nausea, vomiting, pain, headache, 
dizziness, trouble breathing, high or low blood pressure, itchiness, rash, hives, lip or face 
swelling, diarrhea, racing heart or chest pain.  However, we rarely saw these reactions when a 
monoclonal antibody like VRC07 was given.  When reactions were reported, they were usually 
mild.  Antibodies given by the SC route have sometimes caused mild itchiness, redness and/or 
swelling at the injection site.  These symptoms usually cleared within a few minutes to hours 
after the product was given.  
Some antibody products have a risk of serious allergic reactions that can be life-threatening.  
•
Anaphylaxis is one type of allergic reaction that may happen soon after an antibody 
product administration.  This reaction can include difficulty breathing, low blood 
pressure, hives or rash, swelling in the mouth and face.    
•
Serum sickness is a delayed type of allergic reaction that may happen several days to 
three weeks after an antibody product administration.  This reaction can include hives or 
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rash, fever, swollen lymph nodes, muscle pains, joint pains, chest discomfort and 
shortness of breath.  
The described possible allergic reactions are rare and more often occur with antibodies against 
human proteins, or with mouse antibodies rather than with human monoclonal antibodies like 
VRC07. Some antibodies of the type that attack human proteins can increase the risk of serious 
infections.  VRC07 is not expected to increase the risk of serious infections because it attacks a 
virus and not a human protein.
In addition to the possible risks that are listed above, VRC07 may have other side effects that we 
do not know about yet.
Taking part in this study may affect your eligibility for future research studies with other HIV-
related monoclonal antibodies.
Possible risks of AAV8 vector: AAV vectors have been studied in human clinical trials for 
testing of experimental products and found to be generally safe. 
A theoretical risk of viral vectors in general is the possibility for insertion into the human DNA 
that could cause cancer. Insertion means that viral DNA becomes a part of human DNA.  There 
was one report that found wild type AAV in human liver tumors.  The AAV8 vector in this study 
product was designed NOT to insert into DNA and has no genes from wild type AAV proteins.  
There is no evidence that the AAV8 vector would become a part of human DNA.  There have 
been no cancers reported in human studies with AAV vectors.  As a precaution, we will test your 
blood for alpha-fetoprotein, which can indicate a liver tumor.
Another theoretical risk that is even more unlikely, is the insertion of AAV vectors in 
reproductive cells potentially causing birth defects and cancer in babies.  Studies in mice found 
AAV8-VRC07 in all 15 tested tissues including testes and ovaries.  However, the likelihood of 
AAV8-VRC07 getting into DNA of these cells is very unlikely.  There is evidence that these 
cells may be resistant to AAV.  AAV8-VRC07 was designed NOT to insert into DNA.  
A potential risk of the study product is the development of immune responses (antibody) to 
AAV8 vector or to VRC07.  This antibody should not affect your health but could decrease 
effectiveness of future treatments with AAV vectors or effect eligibility for treatment with other 
experimental antibodies in the future. 
There may be other risks of the study product that we don’t know about yet.
We will give you any new information about risks or other information that becomes available 
that may affect your participation in the study.
Possible risks of blood drawing:  Blood drawing may cause pain and bruising, and possibly a 
feeling of lightheadedness or fainting.  Rarely, it may cause infection at the blood draw site.  
Possible risks of saliva sample collection: Collection of samples by swabs may cause brief 
discomfort and, rarely, a little bleeding. 
Possible risks during pregnancy: We do not know what effects the study product may have on 
a fetus or nursing infant.  Women who can have children must agree to not get pregnant during 
the first year of study participation.  Effective birth control includes not having sex; use of 
male or female condoms; use of diaphragm or cervical cap with spermicide; use of intrauterine 
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device; use of birth control pills, patch or injections and other prescription methods; or a male 
partner who has had a vasectomy.  We will discuss effective birth control methods with you.  
Women must have a negative pregnancy test before getting the study product.  You must notify 
the clinic staff right away if you have become pregnant during this study or think that you 
might be pregnant.  If you become pregnant, we will not collect any more blood for research.  
However, you will be asked to continue with study follow-up visits to check on your health. 
We will ask you to report the outcome of the pregnancy to us, which will be reported to the 
antiretroviral pregnancy registry (http://www.apregistry.com). 
As a precaution, we ask all male participants to use condoms for vaginal sex that could lead to 
pregnancy during the first year of the study.  We also ask all participants to use condoms to 
prevent spreading of HIV and other sexually transmitted infections.
POSSIBLE BENEFITS
This study will not provide you with any direct health benefit.  You and others may benefit in the 
future from what we learn from the study.
STOPPING STUDY PARTICIPATION
A study sponsor, a regulatory agency or the study investigators may stop the study.  If this 
happens you will be told the reason why.
You may choose to stop participating in the study at any time.  If you get a dose of AAV8-
VRC07, production of VRC07 may continue in your body for some time.  Therefore, we will ask 
you to keep follow-up visits so we can monitor your health.  We may stop collection of samples 
that are for research purposes only.
ALTERNATIVES
This study is not designed to treat or prevent any disease. You may choose to not participate in 
this study. You may be eligible for other studies.
CONFLICT OF INTEREST
The NIH research staff is checked yearly for conflicts of interest.  You may ask the research 
team for more information on this process.  This study may have investigators who are not NIH 
employees.  Non-NIH investigators are expected to follow the principles of the Protocol 
Review Guide but are not required to report their personal financial holdings to the NIH.
The NIH, including some members of the VRC scientific staff, developed the study product 
used in this research study.  The results of this study could play a role in whether the FDA will 
approve the study product for sale at some time in the future.  If approved, the future sale of 
the study product could lead to payments to NIH and some NIH scientists.  By U.S. law, 
government scientists are required to receive such payments for their inventions.  You will not 
receive any money from the development or sale of the study product.
Manufacturing process of the investigational agent used in this trial is currently not available as 
a stock option by any commercial entity. 
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COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The 
amount of compensation, if any, is guided by NIH policies and guidelines.
You will get compensation for your time and inconvenience based on VRC policy to help you 
with transportation costs and other expenses that may occur because of your study participation.  
It is possible that you may have some expenses not covered by the compensation provided. 
The compensation is $200 for scheduled visits with blood drawing and oral swabs.  For the 
enrollment visit that includes study injection(s) and blood draw, compensation depends on the 
number of injections given: $315 for 1-2 injection(s), $450 for 3-5 injections, $600 for 6-8 
injections, and $750 for 9-11 injections.  Compensation for timely completion of all 7 days of an 
online diary will be $25 total.  Clinic visits that do not include research or safety blood sample 
collection will be $100.
Total compensation for completion of the study and all follow-up visits over 5 years is estimated 
to range from $6,915 to $7,350.  Actual compensation is based on the number and type of study 
visits you complete and the number of injections you get.  Your compensation may need to be 
reported to the internal revenue service (IRS) as taxable income.
If you are unable to finish the study, you will receive compensation for the visits and for the 
parts you completed. You usually will get the compensation about 2 weeks after each completed 
visit by direct deposit into a bank account that you specify to the Volunteer Payment Office.   
With few exceptions, study compensation is considered taxable income that is reportable to the 
Internal Revenue Service (IRS). A “Form 1099-Other Income” will be sent to you if your total 
payments for research participation are $600 or more in a calendar year. If you have unpaid debt 
to the federal government, please be aware that some or all of your compensation may be 
automatically reduced to repay that debt on your behalf.
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
This study does not offer reimbursement for, or payment of, travel, lodging or meals. 
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
There are no costs to you for participating in this study.  You or your health insurance will 
have to pay for all medical costs for medical care that you get outside this study.  It is possible 
that you may have some expenses that are not covered by the study compensation provided.  
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CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include:
•
The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.
•
National Institutes of Health Intramural Institutional Review Board
•
The study Sponsor VRC or their agent(s) 
•
Qualified representatives from Center for Cellular and Molecular Therapeutics, The 
Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA, the research organization 
that produced AAV8-VRC07.
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section 
of this document on sharing of specimens and data, and as further outlined in the following 
sections.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
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2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or 
your involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self 
or others including, for example, child abuse and neglect, and by signing below you consent to 
those disclosures. Other permissions for release may be made by signing NIH forms, such as the 
Notice and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy 
Act allows release of information from your medical record without your permission, for 
example, if it is requested by Congress. Information may also be released for certain research 
purposes with due consideration and protection, to those engaged by the agency for research 
purposes, to certain federal and state agencies, for HIV partner notification, for infectious disease 
or abuse or neglect reporting, to tumor registries, for quality assessment and medical audits, or 
when the NIH is involved in a lawsuit.  However, NIH will only release information from your 
medical record if it is permitted by both the Certificate of Confidentiality and the Privacy Act.
RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Joseph 
Casazza, M.D., Ph.D., 
 Other researchers you may call 
are: Study Coordinator, Laura Novik, RN, 
at 
15 or 
 You may also call the NIH Clinical Center Patient Representative at 301-496-2626, or the 
NIH Office of IRB Operations at 301-402-3713, if you have a research-related complaint or 
concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
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Adult Research Participant: I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: 
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language 
facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language 
facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 18I0030
IRB EFFECTIVE DATE: 2/18/2025