VRC 615: A Phase I, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB-0115-AB (VRC01.23LS), Administered Intravenously or Subcutaneously to Healthy Adults
Phase: PHASE1
Conditions: HIV
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Protocol Title: VRC 615: A Phase I, Open-Label, Dose-Escalation Study of the Safety and 
Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB0115-00-AB 
(VRC01.23LS), Administered Intravenously or Subcutaneously to Healthy Adults. 
 
NCT: 05627258  
 
Documents: 
 IRB-approved Protocol (v3.0 October 16, 2023) – Statistical Analysis Considerations located 
in Section 6 of the Protocol 

Page 1 of 68
VACCINE RESEARCH CENTER
Protocol VRC 615
NIH 000889
A PHASE I, OPEN-LABEL, DOSE-ESCALATION STUDY OF THE SAFETY AND   
PHARMACOKINETICS OF A HUMAN MONOCLONAL ANTIBODY, VRC-
HIVMAB0115-00-AB (VRC01.23LS), ADMINISTERED INTRAVENOUSLY OR 
SUBCUTANEOUSLY TO HEALTHY ADULTS
Study Product Provided by:
National Institute of Allergy and Infectious Diseases (NIAID), 
Vaccine Research Center (VRC)
National Institutes of Health (NIH)
Bethesda, Maryland
Clinical Trial Sponsored by:
NIAID, VRC
Bethesda, Maryland
IND Sponsored by:
NIAID, VRC 
Bethesda, Maryland
IND 159753
NIH Principal Investigator:
Lesia K. Dropulic, M.D.
VRC/NIAID
BG NIHBC T40 RM 150 
9000 Rockville Pike
Bethesda, MD 20892
Phone: 301-412-2708
Email: dropulicl@nih.gov
Version 3.0
October 16, 2023

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 2 of 68
TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................................2
LIST OF TABLES...........................................................................................................................6
ABBREVIATIONS .........................................................................................................................7
PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE ...........................................10
PRÉCIS
....................................................................................................................................11
STATEMENT OF COMPLIANCE...............................................................................................12
1.
INTRODUCTION......................................................................................................13
1.1.
Next Generation HIV Envelope CD4 Binding Site Antibody Development: 
VRC01.23LS ..............................................................................................................14
1.2.
Previous Human Experience.......................................................................................14
1.3.
PARENTAL VRC01, VRC01LS SAFETY IN CLINICAL TRIALS .......................15
1.3.1.
VRC01........................................................................................................................15
1.3.2.
VRC01LS ...................................................................................................................15
1.4.
Rationale for the Study Design...................................................................................16
1.5.
Research-Specific Laboratory Assessments...............................................................16
1.5.1.
Pharmacokinetic (PK) Analysis..................................................................................17
1.5.2.
Anti-drug Antibody (ADA) Analysis.........................................................................17
1.5.3.
HIV Pseudovirus Neutralization.................................................................................17
1.5.4.
Allotype-Specific Effects............................................................................................17
2.
INVESTIGATIONAL PRODUCTS ..........................................................................18
2.1.
VRC01.23LS (VRC-HIVMAB0115-00-AB).............................................................18
2.1.1.
Overview.....................................................................................................................18
2.2.
NONCLINICAL STUDIES........................................................................................19
3.
STUDY OBJECTIVES ..............................................................................................20
3.1.
Primary Objectives .....................................................................................................20
3.2.
Secondary Objectives .................................................................................................20
3.3.
Exploratory Objectives...............................................................................................20
4.
STUDY DESIGN AND CLINICAL PROCEDURES...............................................21
4.1.
Study Population.........................................................................................................21
4.1.1.
Inclusion Criteria ........................................................................................................21

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4.1.2.
Exclusion Criteria.......................................................................................................22
4.2.
Inclusion of Vulnerable Subjects................................................................................23
4.2.1.
Pregnant Women ........................................................................................................23
4.2.2.
Participation of Children.............................................................................................23
4.2.3.
Participation of NIH Employees.................................................................................23
4.2.4.
Adult Subjects who Lack the Capacity to Consent ....................................................24
4.3.
Clinical Procedures.....................................................................................................24
4.3.1.
Recruitment and Retention Strategies ........................................................................24
4.3.2.
Screening ....................................................................................................................25
4.3.3.
Enrollment, Study Days and Visit Numbers...............................................................25
4.3.4.
Administration of VRC01.23LS.................................................................................26
4.3.5.
Post-Product Administration Follow-up.....................................................................26
4.3.6.
Solicited Adverse Events and Clinical Follow-up......................................................27
4.3.7.
Pharmacokinetics........................................................................................................27
4.3.8.
Follow-Up through End of Study ...............................................................................28
4.3.9.
Concomitant Medications...........................................................................................28
4.4.
Criteria for Dose-Escalation .......................................................................................28
4.5.
Criteria for Subject Discontinuation from Protocol Participation..............................29
4.6.
Criteria for Discontinuation of VRC01.23LS Administration ...................................29
4.7.
Criteria for Pausing and Resuming the Study.............................................................30
5.
SAFETY AND ADVERSE EVENTS........................................................................31
5.1.
Adverse Events...........................................................................................................31
5.2.
Serious Adverse Events..............................................................................................31
5.3.
Adverse Event Reporting to the IND Sponsor ...........................................................31
5.4.
IND Sponsor Reporting to the FDA...........................................................................32
5.5.
Reporting to the Institutional Review Board..............................................................32
5.5.1.
Unanticipated Problem (UP) Definition.....................................................................33
5.5.2.
Non-Compliance Definition .......................................................................................33
5.5.3.
Protocol Deviation Definition.....................................................................................34
5.5.4.
Death...........................................................................................................................34
5.5.5.
New Information.........................................................................................................34
5.5.6.
Suspension or Termination of Research Activities ....................................................35

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5.5.7.
Expedited Reporting to the IRB .................................................................................35
5.5.8.
Annual Reporting to the IRB......................................................................................35
6.
STATISTICAL CONSIDERATIONS .......................................................................36
6.1.
Overview.....................................................................................................................36
6.2.
Accrual and Sample Size Considerations...................................................................36
6.2.1.
Group Assignments ....................................................................................................36
6.2.2.
Sample Size Considerations .......................................................................................36
6.3.
Statistical Analysis......................................................................................................37
6.3.1.
Analysis Variables......................................................................................................37
6.3.2.
Baseline Characteristics..............................................................................................37
6.3.3.
Safety Analysis...........................................................................................................37
6.3.4.
Tolerability Evaluation...............................................................................................38
6.3.5.
Pharmacokinetics Analysis.........................................................................................38
6.3.6.
Interim Analyses.........................................................................................................39
6.3.7.
Missing Data...............................................................................................................39
7.
PHARMACY PROCEDURES...................................................................................40
7.1.
Study Product..............................................................................................................40
7.2.
VRC01.23LS Vialed Product Storage........................................................................40
7.3.
Temperature Excursions.............................................................................................40
7.4.
Preparation of VRC01.23LS for Administration........................................................41
7.4.1.
Thawing Instructions ..................................................................................................41
7.4.2.
Preparation for Intravenous Infusion..........................................................................41
7.4.3.
Preparation for Subcutaneous Injection......................................................................41
7.5.
Labeling of Study Product..........................................................................................41
7.6.
Study Product Accountability.....................................................................................42
7.7.
Study Product Disposition..........................................................................................42
8.
HUMAN SUBJECT PROTECTIONS AND ETHICAL OBLIGATIONS................43
8.1.
Informed Consent .......................................................................................................43
8.2.
Risk/Benefit Assessment ............................................................................................43
8.2.1.
Potential Risks ............................................................................................................43
8.2.2
Assessment of Potential Risks and Benefits...............................................................45
8.3.
Institutional Review Board.........................................................................................45

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8.4.
Subject Confidentiality...............................................................................................45
8.5.
Certificate of Confidentiality......................................................................................46
8.6.
Conflict of Interest......................................................................................................46
8.7.
Plan for Use and Storage of Biological Samples........................................................46
8.7.1.
Use of Samples, Specimens and Data.........................................................................46
8.7.2.
Storage and Tracking of Blood Samples and Other Specimens.................................47
8.7.3.
Disposition of Samples, Specimens and Data at Completion of the Protocol............47
8.7.4.
Loss or Destruction of Samples, Specimens or Data..................................................47
8.8.
Subject Identification and Enrollment of Study Subjects...........................................47
8.9.
Safety Monitoring.......................................................................................................47
9.
ADMINISTRATIVE AND LEGAL OBLIGATIONS ..............................................48
9.1.
Protocol Amendments and Study Termination...........................................................48
9.2.
Study Documentation and Storage .............................................................................48
9.3.
Clinical Monitoring, Data Collection and Data Sharing ............................................49
9.3.1.
Clinical Monitoring Plan ............................................................................................49
9.3.2.
Data Collection...........................................................................................................49
9.3.3.
Source Documents......................................................................................................49
9.3.4.
Data Sharing ...............................................................................................................49
9.4
Quality Assurance and Quality Control......................................................................50
9.5.
Language.....................................................................................................................50
9.6.
Policy Regarding Research-Related Injuries..............................................................50
10.
REFERENCES ...........................................................................................................51
APPENDIX I: SCHEDULE OF EVALUATIONS.......................................................................54
APPENDIX II: ASSESSMENT OF RELATIONSHIP TO STUDY PRODUCT AND 
TABLE FOR GRADING SEVERITY OF ADVERSE EVENTS.............................66

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LIST OF TABLES
Table 1: Non-Clinical Studies Summary.......................................................................................19
Table 2: VRC 615 Study Schema..................................................................................................21
Table 3: Plan for Dose-Escalation Reviews...................................................................................29
Table 4: Probability of Observing a Given Number of Events for Different True Event 
Rates................................................................................................................................37
Table 5: Two-sided 95% Confidence Intervals for Probability of an Event Based on 
Observed Event Rate.......................................................................................................37

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October 16, 2023
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ABBREVIATIONS
Abbreviation
Term
ADA
anti-drug antibody
ADL
activities of daily living
AE
adverse event
AIDS
Acquired Immunodeficiency Syndrome
ALT
alanine aminotransferase
AoU
Assessment of Understanding
ART
antiretroviral therapy
AST
aspartate aminotransferase
AUC
area under the curve
bnAb
broadly-neutralizing antibody
CFR 
Code of Federal Regulations
cGMP
current Good Manufacturing Practice
CL
clearance
Cmax
maximum concentration
CRS
cytokine release syndrome 
DP
drug product
DS
drug substance
ECL
electrochemiluminescence
ELISA
enzyme-linked immunosorbent assay
EOI
end of infusion; end of injection
F
bioavailability
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLT
Light green lithium heparin tube
GLP
Good Laboratory Practice
HA 
hyaluronan
HCL
hydrochloric acid
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HRPP
Human Research Protections Program
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IgG1
Immunoglobulin G1

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Abbreviation
Term
IND
investigational new drug application
IP
investigational product  
IRB
Institutional Review Board
IV
intravenous
kg
kilogram
LIMS
Laboratory Information Management System
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
mcg
microgram
mg
milligram
mL
milliliter
mM, mmol
millimole
MO
medical officer
MSD
Meso Scale Discovery
NHP
Non-human primate
NIAID
National Institute of Allergy and Infectious Diseases
NIH
National Institutes of Health
NIH CC
National Institutes of Health Clinical Center
OHRP
Office for Human Research Protections
PBS
phosphate buffered saline
PCR
polymerase chain reaction
PES
polyethersulfone
PI
Principal Investigator
PII
Personal Identifiable Information
PK
pharmacokinetic
PSRT
Protocol Safety Review Team
PT
preferred term
Q
Inter-compartmental clearance
QA
quality assurance
SAE
serious adverse event
SC
subcutaneous
SHIV
simian-human immunodeficiency virus
SOC
system organ class
SOE
Schedule of Evaluation
SST
Serum separator tube
SUSAR
serious and unexpected suspected adverse reaction

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Abbreviation
Term
T½
half-life
TCR
tissue cross reactivity
Tmax
time of maximal concentration (Cmax)
ULN
upper limit of normal
UNAIDS
Joint United Nations Programme on HIV/AIDS
UP
unanticipated problem
USP
United States Pharmacopeia
Vd
volume of distribution
VEC
Vaccine Evaluation Clinic
VIP
Vaccine Immunology Program
VRC
Vaccine Research Center
WBC
white blood cell
β-HCG
human chorionic gonadotropin
λz
terminal slope of concentration vs time profile

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PRINCIPAL INVESTIGATOR PROTOCOL SIGNATURE PAGE
VRC 615: A Phase I, Open-Label, Dose-Escalation Study of the Safety and   
Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB0115-00-AB 
(VRC01.23LS), Administered Intravenously or Subcutaneously to Healthy Adults
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 for 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.
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, for at least 2 years following submission of a marketing application to FDA 
(21 CFR 312.62).  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.
Lesia K. Dropulic, M.D_______________        NIH-Clinical Center Vaccine Evaluation Clinic
Name/Title of Principal Investigator 
    Study Site Name
___________________________________   __________________________________
Signature of Principal Investigator                 Date

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PRÉCIS
VRC 615:
A Phase I, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics 
of a Human Monoclonal Antibody, VRC-HIVMAB0115-00-AB (VRC01.23LS), 
Administered Intravenously or Subcutaneously to Healthy Adults.
Study 
Design:  
This first-in-human, open-label study will evaluate VRC01.23LS (VRC-
HIVMAB0115-00-AB) in a dose-escalation design to examine safety, tolerability, 
dose, and pharmacokinetics (PK) in healthy adults. The primary hypothesis is that 
subcutaneous (SC) and intravenous (IV) administrations of VRC01.23LS will be 
safe and well-tolerated in healthy adults. A secondary hypothesis is that 
VRC01.23LS will be detectable in human sera with a definable half-life.
Study
Products:
The VRC01.23LS broadly neutralizing monoclonal antibody (bnAb) targets the 
CD4 binding site in the HIV-1 envelope, is human in origin, and contains two 
amino acid modifications within the C-terminus of the heavy chain constant region 
designed to improve the antibody half-life in vivo. VRC01.23LS was developed 
by the VRC/NIAID/NIH and manufactured under cGMP regulations at the VRC 
Pilot Plant operated under contract by the Vaccine Clinical Materials Program 
(VCMP), Leidos Biomedical Research, Inc., Frederick. MD. 
Subjects:
Healthy adults, 18-60 years of age
Study 
Plan:
This open-label study will include 6 groups to evaluate VRC01.23LS administered 
alone or by repeat dosing as shown below in the Study Schema. Enrollment will 
begin with the 5 mg/kg dose groups, and enrollment for subsequent dose groups 
will proceed after dose-escalation safety reviews. Assessment of safety will 
include solicited reactogenicity, clinical observation, and monitoring of 
hematological and chemical parameters at clinical visits throughout the study.  
VRC 615 Study Schema
Dosing Schedule
Group
Subjects
VRC01.23LS 
Dose and Route
Day 0
Week 12
Week 24
1
3
5 mg/kg IV
X
2
3
5 mg/kg SC
X
3
3
20 mg/kg IV
X
4
3
40 mg/kg IV
X
5
5
5 mg/kg SC
X
X
X
6
5
20 mg/kg IV
X
X
X
Total
22*
*Enrollment up to a total of 40 subjects is permitted if additional subjects are 
necessary for safety or PK evaluations.
Study 
Duration:  
Study participation will be approximately 24 weeks after the last product 
administration. 

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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council for 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(s) 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(s) will be IRB-approved; 
an IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.

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1.
INTRODUCTION 
The human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) has 
remained a major global public health problem since the discovery of the virus in 1983. Reports 
by the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimate that since 2021 79.3 
million people have been infected with HIV since the start of the epidemic, contributing to 36.3 
million deaths from AIDS-related illnesses[1]. Despite these statistics, global incidences of new 
HIV infections have actually declined from peak rates in the mid-1990s; a reduction attributed in 
part to increased availability of antiretroviral therapy (ART) and the effective execution of 
prevention/treatment programs such as those that target mother-to-child transmission.   
Unfortunately, HIV infection is extremely complex and none of the current therapeutic or 
prophylactic regimens can completely prevent or cure an infection or induce a full recovery of 
the host immune system. The National Institute of Allergy and Infectious Diseases (NIAID), 
National Institutes of Health (NIH) is committed to the development of safe, effective methods 
to prevent and treat HIV infection and AIDS worldwide.  In this regard, the Vaccine Research 
Center (VRC), NIAID and Division of AIDS (DAIDS), NIAID, are collaborating to evaluate the 
potential clinical uses of HIV-specific broadly neutralizing human monoclonal antibodies (mAb) 
[2-4]. Thus, novel prevention and cure strategies are being investigated. 
In 2018, ibalizumab, which is a CD4-directed post attachment HIV-1 inhibitor, became the first 
licensed monoclonal antibody therapy indicated for heavily treatment-experienced adults with 
multi-drug resistant HIV-1 infection failing their current antiretroviral regimen [5].  The 
licensure of ibalizumab was the culmination of extensive studies over the previous two decades.  
Efforts to develop effective mAbs against HIV itself have resulted in scientific discoveries and 
innovations in the first twenty years of the 21st century that include sera screening strategies, 
pseudovirus neutralization assay development [6-8], and single B-cell isolation and screening 
techniques [2, 9-11], enabling identification and evaluation of mAbs against HIV-1 in clinical 
trials [12]; however, to date, an anti-HIV mAb effective for the prevention and/or treatment of 
HIV-1 infection has yet to be approved.  
In 2010, the VRC, NIAID, NIH Virology Laboratory reported the isolation and characterization 
of one of the earliest broadly neutralizing antibodies (bnAbs), VRC01, from a single B cell of an 
HIV-infected, long-term, slow progressor donor [2].  Since then, applying similar strategies to 
serum banks from HIV-infected subject cohorts, multiple researchers have identified and 
characterized diverse bnAbs [13-20] and, in many cases, have extended their investigations to 
clinical trials.  
Contemporaneous efforts and studies in anti-HIV mAb analysis, engineering, and functional and 
structural characterization have pinpointed previously unrecognized sites of vulnerability on the 
HIV envelope protein, informed efforts to develop broad and potent mAb therapeutics, and 
provided clarity and insight into requisite elements of an HIV-1 vaccine able to elicit potent and 
broad responses in recipients [15, 18, 21].
In parallel, the field of immunology has progressed in understanding of IgG subclasses, antibody 
domains, B cell ontogenies, and mAb-cell receptor interactions, including those with the 
neonatal Fc receptor (FcRn), which interacts with the fragment crystallizable (Fc) domain [22-
24].  For biotherapeutic mAbs, strong pH-dependent FcRn binding capability is valued for its 
potentiation of longer mAb half-life and increased transcytosis across mucosal membranes.  

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Rational design methods coupled with high-throughput protein screening identified a variant of 
bevacizumab, a mAb that inhibits vascular endothelial growth factor, with a M428L/N434S (LS) 
substitution in the Fc domain that provided an 11-fold improvement in FcRn affinity at pH 6 and 
an extended serum half-life [25].  At the VRC, engineering this LS mutation into bnAb VRC01 
produced VRC01LS, which demonstrated sustained levels in mucosal tissue relative to parental 
VRC01 in a simian-human immunodeficiency virus (SHIV) infection model [22] and in humans 
[26] (NCT02599896).
1.1.
Next Generation HIV Envelope CD4 Binding Site Antibody 
Development: VRC01.23LS 
At the VRC, advancing HIV mAb development efforts are typified by the generation and clinical 
evaluation of anti-HIV mAbs to the CD4 binding site (CD4bs) (VRC07-523LS, N6LS), the 
V2/V3 loop (CAP256V2LS), and the membrane proximal external region (10E8VLS) of the 
HIV-1 envelope protein.  
More recently, to advance the HIV antibody field, the VRC has undertaken systematic 
engineering of the “next-generation” anti-HIV envelope antibodies, by combining a structure-
based design and a matrix-based approach, with the aim to increase mAb breadth, potency, or 
both.  Beginning with previously well-characterized and clinically studied bnAbs, panels of 
sequence variations are systematically generated and tested.  Applying this approach to the CD4-
binding site targeting bnAb VRC01LS, VRC01.23LS has been identified as a lead candidate for 
clinical evaluation.  VRC01.23LS varies from parent VRC01LS by three sets of mutations: 

Heavy chain (HC,), G54W (glycine to tryptophan at HC residue 54), filling a 
hydrophobic pocket at the interface between VRC01LS and HIV-1 envelope (env) gp120, 

Extended HC Framework 3 (FR3) loop, adopted from VRC01 mAb class member 
VRC03, that increases contact surface area between the FR3 loop and a neighboring 
HIV-1 env gp120 protomer, and 

Deletion of the light chain (LC) N-terminal-most three amino acids to reduce potential 
steric clashes with the variable V5 region of HIV-1 env gp120. 
On a 208 HIV- pseudovirus cross-clade panel, in comparison to VRC01LS, VRC01.23LS 
exhibits overall ~8-fold greater neutralization potency with a geometric mean IC50 of 0.042 
μg/mL, and 94% breadth at IC50 of <1 μg/mL [27].  Serum concentrations of VRC01.23LS and 
VRC01LS in human FcRn knock-in mice were comparable [27].  Data from a study in 
cynomolgus macaques support the comparability of VRC01LS and VRC01.23LS PK.  
VRC01LS has a half-life (t1/2) of 71 ± 18 days in humans, and a comparable human t1/2 is 
expected for VRC01.23LS. Based on substantial PK data acquired from evaluating the LS 
mutation incorporated in multiple VRC mAbs, the LS modification has been retained in 
VRC01.23LS to increase pH-dependent FcRn binding and hence to increase antibody half-life in 
vivo.  
1.2.
Previous Human Experience
This study constitutes the first-in-human trial with VRC01.23LS; there is no previous experience 
with this mAb product in humans.  Similar to its VRC mAb antecedents, VRC01.23LS targets 

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the CD4-binding site on the HIV-1 envelope protein, and, therefore, previous human experience 
with the first mAb in this class, VRC01, and its offspring, VRC01LS, provide relevant 
experience.
1.3.
Parental VRC01, VRC01LS Safety in Clinical Trials 
VRC01LS, a parental mAb of VRC01.23LS, differs from its antecedent, VRC01, by the two-
amino acid mutations, LS, that increase binding to FcRn and extend mAb in vivo half-life.  The 
two mAbs are otherwise identical in sequence.
1.3.1.
VRC01
VRC01, the original VRC broadly neutralizing HIV-1 CD4bs mAb isolated from a subject, has 
been clinically evaluated in 15 trials, including Phase 1 studies VRC 601 (NCT01950325); VRC 
602 (NCT01993706); and HVTN 104 (NCT02165267) and Phase 2 studies HVTN 704/HPTN 
085(NCT02716675) and HVTN 703/HPTN 081 (NCT02568215). 
As of March 2019, VRC01 has been administered either IV or SC at doses up to 40 mg/kg to 
over 3260 HIV-uninfected healthy adults, 110 HIV-1-infected adults, 39 HIV-1 exposed infants 
and 6 HIV-1 infected infants.  There have been no serious adverse events (SAEs) related to 
VRC01, as assessed by the Sponsor.  
1.3.2.
VRC01LS
VRC HIV-1 human bnAb VRC01LS, the parent of VRC01.23LS, has been evaluated in five 
clinical trials.  As of August 30, 2021, 112 subjects have received one or more doses of 
VRC01LS.  VRC01LS IV and SC administrations have been well-tolerated in adults and 
children; there have been no SAEs related to VRC01LS.  Clinical information regarding 
VRC01LS is available under DAIDS IND 125494 (VRC 606, HVTN 116), DAIDS IND 140909 
(Dual bnAb protocol), DAIDS IND 130804 (VRC 607), and in Gaudinski et al [26].  
In the three prevention studies (VRC 606, HVTN 116, and P1112), 56 healthy adults and 21 
HIV-exposed infants have received VRC01LS in doses ranging from 5 to 40 mg/kg IV and 5 
mg/kg SC in adults and up to 100 mg/dose SC in infants.  VRC 606, a VRC01LS phase I dose 
escalation study, has been completed and results published [26] (NCT02599896).  HVTN 116, a 
phase I study to evaluate VRC01LS and VRC01 safety, tolerability, PK, and anti-viral activity in 
healthy adults has also been completed (NCT02797171).  A phase I study, IMPAACT P1112, 
evaluating the safety and PK of VRC01, VRC01LS, or another CD4bs mAb, VRC07-523LS, in 
HIV-1 exposed infants, has completed investigational product (IP) administration 
(NCT02256631).  
In the two therapeutic studies in HIV-positive subjects (VRC 607 and Dual bnAb treatment in 
children), seven HIV-viremic adults and 28 HIV-suppressed children have received VRC01LS at 
doses ranging from 10 to 40 mg/kg IV.  VRC 607/A5378, a phase I single dose study evaluating 
the safety and anti-viral effect of VRC01LS and VRC07-523LS in HIV-infected viremic adults, 
has been completed (NCT02840474).  VRC01LS continues to be studied in HIV-infected, virally 
suppressed children in a Phase1/2 study (Dual bnAb), administering VRC01LS and mAb 10-
1074 (NCT03707977).  

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Collectively, safety data from these studies indicate that VRC01LS is safe and well tolerated at 
doses ranging from 5 mg/kg to 40 mg/kg.  The overall safety profile is consistent with expected 
events for monoclonal antibodies, most commonly mild to moderate reactogenicity that occurs 
shortly after product administration and is self-limited.  There have been no unexpected safety 
trends identified and no SAEs related to VRC01LS.  
1.4.
Rationale for the Study Design
Animal and in vitro models of HIV infection have suggested bNAbs reactive to antigenically 
diversified Env proteins expressed by quasispecies of circulating virus may hold significant 
promise as immunoprophylactic and/or therapeutic agents to prevent the subversive effects of 
HIV on the immune system. Based on substantial PK data, acquired by evaluating the LS 
mutations in multiple, next-generation VRC mAbs and confirming the effect on mAb half-life, 
the LS modification has been retained in VRC01.23LS to increase pH-dependent FcRn binding 
and hence to increase antibody half-life in vivo.  VRC01.23LS varies from parent VRC01LS by 
three sets of mutations as described in 1.1. VRC01.23LS aims to be a next-generation CD4bs 
antibody with increased potency and breadth relative to parental VRC01LS, while maintaining 
its extended half-life and safety.  In clinical trials, multiple VRC01-class antibodies, including 
VRC01, VRC01LS, VRC07-523LS, and N6LS, have demonstrated favorable safety proﬁles [16, 
20, 27-29].  
This study is the first-in-human trial to evaluate the safety, tolerability, dose, and PK of 
VRC01.23LS administered intravenously or subcutaneously.  The dosages selected for 
evaluation of VRC01.23LS are based on prior experience with other CD4-binding site mAbs, 
VRC01 and VRC01LS, which were shown in several clinical trials (VRC 601, VRC 602) to be 
safe and well-tolerated at 5-40 mg/kg dosages given intravenously and at a 5 mg/kg dosage given 
subcutaneously in both HIV-infected and -uninfected adult populations [28, 29] .  This study will 
involve the evaluation of VRC01.23LS administered alone or by repeat dosing. 
While Groups 1 through 4 will receive a single dose of VRC01.23LS by SC injection or IV 
infusion, Groups 5 and 6 will receive three-repeat doses of VRC01.23LS at 12-week intervals 
(i.e., on Weeks 0, 12, and 24). A 12-week interval for repeat-dosing is based on predicted half-
life and has been used in clinical trials with VRC01LS and VRC07-523LS [30].  Aligning the 
antibody dose levels and administration interval with that used in prior studies of other HIV-1 
bNAbs will allow for a direct comparison of the serum concentration of each bNAb at identical 
time-points.  This in turn will support PK profile comparisons and characterization of the bNAbs 
currently in development by the VRC.  The PK of VRC01.23LS administered using different 
regimens, dosages, and routes will be evaluated in healthy adults aged 18 to 60 years.     
1.5.
Research-Specific Laboratory Assessments
The research assays described in this section are designed to characterize the investigational 
product rather than assess the health of the subjects.  Laboratory assessments in this Phase 1 
study will include PK analysis, evaluation for anti-drug antibody (ADA) development following 
product exposure, and ex vivo analysis to assess the neutralization activity of VRC01.23LS post-
injection/infusion.  Other assays may also be completed from stored samples at a later date, if 
additional assessments are needed. 

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The VRC’s Vaccine Immunology Program (VIP), Gaithersburg, MD, will process blood and 
store coded samples, and will either perform sample testing or ship coded samples to designated 
research laboratories at the VRC or other approved collaborators.  Some immunogenicity assays 
may be performed by VRC laboratories in Bethesda, MD, or by approved contract laboratories or 
research collaborators.  See Appendix I for schedules, volumes and tube types to be used for 
research sample collection.  Tube types for clinical laboratory evaluations and research 
collections are selected according to institutional requirements and are shown in the Schedule of 
Evaluations to estimate blood volumes.  Different tube types and sizes may be used to meet site 
requirements. Samples will be transported according to approved site procedures.
1.5.1.
Pharmacokinetic (PK) Analysis 
The VRC01.23LS concentration for the PK analysis will be measured by a Meso Scale 
Discovery (MSD) or similar assay [22].
1.5.2.
Anti-drug Antibody (ADA) Analysis 
A three-level algorithm will be used to screen, confirm, and functionally characterize ADA to 
VRC01.23LS in clinical serum and/or plasma samples. Analysis will be conducted according to 
the Food and Drug Administration (FDA) guidance [31]. Screening and confirmation will 
involve a MSD electrochemiluminescence (ECL) bridging or similar assay [22]. The ADA assay 
will be conducted on batched samples collected at baseline, 4-weeks and 8-weeks in the single 
administration groups, with additional 28- and 32-weeks samples in multiple administration 
groups and may be tested at the last study visit if needed. It may also be assessed at other time-
points if there is a clinical indication, or the PK analysis shows a substantial decrease in the 
VRC01.23LS concentration. 
1.5.3.
HIV Pseudovirus Neutralization  
For all study groups, subject sera will be evaluated to assess the functional capacity of passively 
administered VRC01.23LS to neutralize pseudotyped HIV viruses using an in vitro cell-based 
virus neutralization assay, such as previously described for VRC01, VRC01LS, and VRC07-
523LS [28-30, 32, 33]. 
1.5.4.
Allotype-Specific Effects
Exploratory evaluation to detect theoretical immunoglobulin G1 (IgG1) allotype-specific effects 
may be performed in cases when PK measures suggest a reduced VRC01.23LS antibody half-life 
or an ADA response [34-36]. Coded stored samples will be used for evaluation of the genetic 
sequence of the immunoglobulin heavy chain constant region allotype. 

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2.
INVESTIGATIONAL PRODUCTS
This protocol will evaluate the investigational product, VRC-HIVMAB0115-00-AB 
(VRC01.23LS), in healthy adults. 
2.1.
VRC01.23LS (VRC-HIVMAB0115-00-AB) 
2.1.1.
Overview
VRC-HIVMAB0115-00-AB (VRC01.23LS) is manufactured under current Good Manufacturing 
Practices (cGMP) by VRC/NIAID/NIH at the VRC Pilot Plant operated under contract by the 
Vaccine Clinical Materials Program, Leidos Biomedical Research, Inc., Frederick, MD.
VRC01.23LS is a recombinant human immunoglobulin G1 (IgG1) antibody, targeting the HIV 
envelope CD4 binding site. 

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2.2.
NONCLINICAL STUDIES 
A summary of non-clinical studies conducted with VRC01.23LS is presented in the table below. 
More information related to non-clinical evaluations of VRC01.23LS can be found in the IB.
Table 1: Non-Clinical Studies Summary
Study Purpose
Study Outcome
In Vitro Neutralization Activity
On a 208 HIV-pseudovirus cross-clade panel, in 
comparison to VRC01, VRC01.23LS exhibits an overall 
~8-fold greater neutralization potency with a geometric 
mean IC50 of 0.042 μg/mL, and 94% breadth at IC50 of <1 
μg/mL.
VRC01.23LS Serum Levels in 
Mice
In human FcRn transgenic mice, VRC01.23LS exhibited a 
serum half-life (t1/2) comparable to that of parental 
VRC01LS.
Non-human primate (NHP) PK
Three cynomolgus monkeys received a single IV dose of 
10 mg/kg VRC01.23LS.  Two of the monkeys exhibited 
PK comparable to that of parental VRC01LS.  One 
monkey exhibited depletion beginning on day 20, 
suggesting induction of an ADA response.  No signs of 
toxicity were observed.
Tissue Cross Reactivity (TCR) 
Study
In a GLP TCR study evaluating a panel of 38 normal 
human tissues obtained from at least 3 adult donors per 
tissue, VRC01.23LS did not exhibit specific cell 
membrane binding in any human tissue, which was 
expected and was consistent with similar lack of binding 
observed for VRC01 and VRC01LS. 
Autoreactivity by assessment of 
binding to a human epithelial 
cell line (HEp-2) by indirect 
immunohistochemistry
VRC01.23LS demonstrated no evidence of autoreactivity 
as assessed by HEp-2 cell binding.
Autoreactivity by assessment of 
anti-phospholipid reactivity 
VRC01.23LS was considered not reactive in the 
cardiolipin binding assay when compared to an anti-HIV 
neutralizing mAb (4E10), known to react with 
phospholipids.

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3.
STUDY OBJECTIVES 
3.1.
Primary Objectives

To evaluate the safety and tolerability of VRC01.23LS in healthy adults when 
administered SC as a single dose at 5 mg/kg.

To evaluate the safety and tolerability of VRC01.23LS in healthy adults when 
administered IV as a single dose at 5, 20, or 40 mg/kg.

To evaluate the safety and tolerability of VRC01.23LS in healthy adults when 
administered by repeat SC dosing at 5 mg/kg, for a total of 3 injections in 12-week 
intervals.

To evaluate the safety and tolerability of VRC01.23LS in healthy adults when 
administered by repeat IV dosing at 20 mg/kg, for a total of 3 infusions in 12-week 
intervals.
3.2.
Secondary Objectives

To evaluate the pharmacokinetics of VRC01.23LS at each dose level and route of 
administration throughout the study. 
3.3.
Exploratory Objectives

To determine whether anti-drug antibody (ADA) to VRC01.23LS is detectable in 
recipients at specific timepoints throughout the study.

To assess the neutralization potential of VRC01.23LS at timepoints throughout the 
study. 

To assess for IgG1 allotypes and allotype-specific effects on PK as appropriate.

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4.
STUDY DESIGN AND CLINICAL PROCEDURES
This is an open-label, dose-escalation study to examine the safety, tolerability, dose, and PK of  
VRC01.23LS in healthy adults as shown in the study schema (Table 2). 
Table 2: VRC 615 Study Schema
VRC 615 Study Schema
Dosing Schedule
Group Subjects
VRC01.23LS 
Dose and Route
Day 0
Week 12
Week 24
1
3
5 mg/kg IV
X
2
3
5 mg/kg SC
X
3
3
20 mg/kg IV
X
4
3
40 mg/kg IV
X
5
5
5 mg/kg SC
X
X
X
6
5
20 mg/kg IV
X
X
X
Total
22*
*Enrollment up to a total of 40 subjects is permitted if additional 
subjects are necessary for safety or PK evaluations.
The study will be conducted at a single site, the Vaccine Evaluation Clinic located at the NIH 
Clinical Center (NIH CC).
Enrollment will begin with the 5 mg/kg dose groups (Groups 1, 2 and 5) with no more than one 
subject per day at the 5 mg/kg dose for the first 3 subjects.  Enrollments into the subsequent dose 
groups (Groups 3, 4, and 6) will proceed after dose-escalation reviews as described in 4.4.  
4.1.
Study Population
Subjects will be screened to confirm eligibility requirements for participation using the VRC 500 
screening protocol. The screening and education process required prior to enrollment is designed 
to ensure that subjects comprehend the purpose, details and risks/benefits of the study. All 
inclusion and exclusion criteria must be met for eligibility.
4.1.1.
Inclusion Criteria
A subject must meet all of the following criteria:
1. Willing and able to complete the informed consent process.
2. Able to provide proof of identity to the satisfaction of the study clinician completing the 
enrollment process. 
3. Available for clinical follow-up through the last study visit. 
4. 18 to 60 years of age.
5. In good general health without clinically significant medical history.

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6. Physical examination without clinically significant findings within the 56 days prior to 
enrollment.
7. Adequate venous access if assigned to an IV group or adequate abdominal subcutaneous 
tissue if assigned to SC group.
8. Willing to have blood samples collected, stored indefinitely, and used for research 
purposes.
Laboratory Criteria within 56 days prior to enrollment:
9. White blood cell count (WBC): 2,500-12,000/mm3.
10. WBC differential either within institutional normal range or accompanied by the Principal 
Investigator (PI) or designee approval.
11. Platelets: 125,000 – 500,000/mm3.
12. Hemoglobin within institutional normal range or accompanied by PI or designee approval.
13. Creatinine: ≤ 1.1 x Upper Limit of Normal (ULN).
14. ALT: ≤ 1.25 x ULN.
15. AST: ≤ 1.25 x ULN. 
16. Negative for HIV infection by an FDA approved method of detection.
Female-Specific Criteria:
17. Agrees to use an effective means of birth control from 21 days prior to enrollment through 
the duration of study participation.
18. 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 subject will be excluded if one or more of the following conditions apply:
1. Woman who is breast-feeding or planning to become pregnant during study participation.
2. Weight > 115 kg.
3. Any history of a severe allergic reaction with generalized urticaria, angioedema or 
anaphylaxis prior to enrollment that has a reasonable risk of recurrence during the study.
4. Hypertension that is not well controlled. 
5. Receipt of any investigational study product within 28 days prior to enrollment (Note: 
Emergency Use Authorization of a COVID-19 vaccine is not exclusionary).
6. Receipt of an investigational HIV vaccine or anti-HIV monoclonal antibody.
7. Receipt of any live attenuated vaccine within 28 days prior to enrollment.
8. Receipt of any vaccine within 2 weeks prior to enrollment.

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9. 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.
10. Any other chronic or clinically significant medical condition that in the opinion of the 
investigator would jeopardize the safety or rights of the volunteer, including but not limited 
to: diabetes mellitus type I, chronic hepatitis; OR clinically significant forms of: drug or 
alcohol abuse, asthma, infectious disease, autoimmune disease, psychiatric disorder, heart 
disease, or cancer.
4.2.
Inclusion of Vulnerable Subjects
4.2.1.
Pregnant Women
This is a first-in-human trial in healthy subjects, ≥18 years of age. Because the effects of the 
vaccine on the fetus are not known, pregnant women will not be eligible for the trial. Women of 
childbearing potential must utilize a highly effective method of contraception and will be 
required to have a negative urine or serum pregnancy test within 24 hours prior to each product 
administration. 
Pregnancy, if it occurs during study participation, will be recorded in the study database. These 
participants will not continue to receive any further study product administrations, Error! 
Reference source not found. research sample collections, or research procedures.   Pregnant 
participants will continue to be followed for clinical safety and to collect the pregnancy outcome. 
Any follow-up procedures and/or data collected will be for clinical/safety outcome purposes 
only. Pregnancy will be reported as described in Section 5.6.
4.2.2.
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.
4.2.3.
Participation of NIH Employees
NIH employees and members of their immediate families may participate in this protocol. We 
will follow the Guidelines for the Inclusion of Employees in NIH Research Studies and will give 
each employee a copy of the “NIH FAQs for NIH Staff Who are Considering Participation in 
NIH Research” published by Office of Human Research Subjects Protections on Research 
Involving NIH Staff as Subjects, Policy 404. 
For NIH employee subjects, consent will be obtained by an individual who is independent of the 
employee’s team.  If an NIH staff member seeks to enroll in research taking place within their 
own work unit or conducted by any of their supervisors, the employee will be:

Informed that neither participation nor refusal to participate as a research subject will 
have an effect, either beneficial or adverse, on the subject’s employment, training or 
position at the NIH,

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
When possible, consent should be obtained by an individual in a non-supervisory 
relationship with the subject, and

When consent is conducted, a third party (e.g. a consent monitor) will be included 
through the Bioethics Consultation Service or another party independent of the research 
team or, if a consent monitor is not available, the consent process will be observed by 
another qualified investigator on the study who is independent of the NIH staff member’s 
work unit and not a supervisor to the NIH staff member.  If no such person exists, 
consent observation may be performed by any qualified investigator on the study.  
Protocol study staff will be trained on obtaining potentially sensitive and private 
information from co-workers or subordinates. 
4.2.4.
Adult Subjects who Lack the Capacity to Consent
Adults who are unable to provide initial informed consent are not eligible to enroll. Also, adults 
who permanently lose the capacity to provide on-going consent after initial consent and during 
the study will be discontinued from protocol participation as it is described in Section 4.5
4.3.
Clinical Procedures
Evaluation of study product safety will include laboratory studies, medical history, and physical 
assessment by clinicians, and subject self-assessment on a diary card for 7 days after product 
administration.  The study schedule is provided in the Schedule of Evaluations, Appendix I.  
Total blood volume drawn from each subject will comply with the NIH CC Guidelines, which is 
available on the NIH intranet at the following link: 
http://cc-internal.cc.nih.gov/policies/PDF/M95-9.pdf.  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 during study conduct.
The study will be conducted at the Vaccine Evaluation Clinic (VEC) located at the NIH CC.  All 
nursing staff in the VEC are assessed annually for nursing competency including medication 
administration, peripheral vascular access device care and maintenance, and clinical emergency 
response. The VEC Clinic is equipped with basic cardiac life support equipment and emergency 
medications.  An advanced clinician (nurse practitioner, physician assistant or physician) is 
available in the clinic during administration of all investigational study products and throughout 
the post-administration monitoring period.
4.3.1.
Recruitment and Retention Strategies 
Study enrollments will be conducted at the NIH Clinical Center.  Study subjects will be recruited 
through the VRC’s screening protocol, VRC 500 (NCT 01375530).  The on-site and off-site 
Institutional Review Board (IRB)-approved advertising will be implemented.  
Per recruitment plan described in the VRC 500 protocol, efforts will be made to include women 
and minorities in proportions similar to that of the community from which they are recruited. The 
recruitment team utilizes a variety of mechanisms to recruit participants including flyer 
distribution within and outside of the NIH, social media, community tabling events, print and 
radio ads, listserv emails, posting information on the NIAID/ VRC website, and 
ResearchMatch.org to effectively recruit potential volunteers.

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4.3.1.1.
Costs
There are no costs to subjects for their participation in this trial.
4.3.1.2.
Compensation
Subjects will be compensated for time and inconvenience in accordance with the standards for 
compensation of the NIH CC Clinical Research Volunteer Program.  Compensation for a study 
visit that includes IV product administration is $430; a study visit that includes SC product 
administration is $375. If enrollment occurs on a different day than study product administration, 
then visit compensation will be $85.  Compensation will be $200 for scheduled follow-up visits 
that include venipuncture, $85 for clinic visits that do not include venipuncture, and $25 for 
timely completion of all 7 days of the electronic diary card.  The total amount of compensation 
varies depending upon the group and the visits completed. 
4.3.2.
Screening 
All screening procedures for this study are described and will be completed through the Vaccine 
Research Center’s screening protocol, VRC 500 (NIH 11-I-0164) used for all VRC IND studies 
conducted at the NIH Clinical Center.  The Recruitment Plan per NIH Policy 302 for all VRC 
studies can be found in the NIH IRB approved VRC 500 protocol.  Subjects will be recruited 
through Institutional Review Board (IRB)-approved advertising.  Screening evaluations 
performed to determine eligibility for study participation will include medical history review, 
physical exam, and the clinical laboratory tests as detailed in the Schedule of Evaluations, 
Appendix I). No screening procedures will be done under protocol VRC 615. 
Additional assessments of health may be conducted at screening based on clinical judgment.  
Screening evaluations for specific eligibility criteria must be completed within the time interval 
specified prior to enrollment for the given parameter and may be repeated, as needed, to confirm 
eligibility. 
Blood samples for research can be drawn at any time during the screening period and are not 
subject to a time interval. Informed consent documents will be reviewed.  Counseling related to 
potential risks of the study product, pregnancy prevention, and HIV risk-reduction will be 
performed.  An Assessment of Understanding (AoU) will be completed in association with 
enrollment into VRC 615.  Screening records will be maintained to document the reason why an 
individual was screened but not enrolled. 
Subjects who are not up to date on standard vaccinations may receive these, if available, during 
their participation in the screening protocol or at a later date during study participation as 
described in Sections 4.3.4 and 4.3.9.
4.3.3.
Enrollment, Study Days and Visit Numbers
In this study, enrollment is defined as the assignment of a study identification number and study 
group schedule in the clinical database.  A clinician will discuss the target dates and timing of the 
study product administration(s) and sample collections before completing an enrollment to help 
ensure that the subject can comply with the projected schedule.  Informed consent must be 
obtained prior to enrollment.

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Day 0 is defined as the day of first VRC01.23LS administration.  Day 0 may occur on the same 
day as enrollment or up to 6 weeks after enrollment.  This period may be increased with PI 
approval.  If Day 0 does not coincide with enrollment, then the enrollment day may be referred 
to by a negative number of days (i.e., Day -1 to Day -42).  For calculating elapsed days following 
Day 0, each subsequent calendar date is labeled by the next sequential “Study Day” as shown in 
the Schedule of Evaluations (Appendix I).  Since there may be more than one research sampling 
timepoint of interest per study day, each sample collection timepoint has its own “Visit 
Number.”  For this reason, there may be more than one visit number recorded on the same 
calendar date.
Medical history and Day 0 evaluations prior to the first study product administration are the 
baseline for subsequent safety assessments.
4.3.4.
Administration of VRC01.23LS
All study product administrations will be completed according to the assigned group. Licensed 
vaccines should be avoided within 2 weeks before and after product administration. Prior to 
administering study product, a clinician should consult with an advanced practitioner if licensed 
vaccination occurred or is scheduled within that time frame.
On the day of and prior to each product administration, vital signs (temperature, blood pressure, 
heart rate and respiratory rate), and weight will be recorded, a targeted physical examination may 
be conducted as needed, and women of childbearing potential must have a negative pregnancy 
test.  
4.3.4.1. IV Administration
If a subject is assigned to an IV administration group, the IV access will be placed in an arm vein 
in an aseptic manner.  A different site may be used for collection of PK blood samples; however, 
the same site may be used after flushing the line if another site is not available.  VRC01.23LS  
will be administered with approximately 100 mL of normal saline IV over about 15-30 minutes, 
with a target of 30 minutes.  Infusions lasting longer than 30 minutes are allowed.  If the subject 
experiences side effects during the infusion, the rate of infusion may be slowed or stopped to 
alleviate the symptoms.  At the end of product administration, the IV administration set must be 
flushed with about 30 mL (or appropriate volume) of normal saline under the same infusion rate 
to ensure the entire dose is given.
4.3.4.2.
SC Administration 
If a subject is assigned to a SC administration group, the SC administration site(s) to be used 
must be assessed as acceptable by the clinician and the subject. The preferred SC administration 
site is the abdomen, but the upper arm or thigh may be used. Given the weight criterion in this 
study, the maximum volume needed to administer a 5 mg/kg SC dose is not expected to exceed 
5.75 mL. The SC dose will be administered by standard needle in a maximum volume of about 
2.5 mL per injection site. Up to three (3) SC injection sites may be used if deemed necessary by 
the clinician. SC administration sites should be at least 2 inches apart.

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4.3.5.
Post-Product Administration Follow-up
Following completion of IV product administration in Groups 1, 3, 4, and 6, subjects will be 
observed for at least 2 hours in the clinic.  Following completion of SC product administration in 
Groups 2 and 5, subjects will be observed for at least 1 hour in the clinic.
Prior to discharge from the clinic, subjects will be assessed for local and systemic reactogenicity, 
and vital signs will be recorded.  Any subject who is assessed as being unwell or has ongoing 
reactogenicity symptoms will be asked to remain in the clinic until evaluation and discharge by a 
study clinician.  This includes the possibility of an overnight inpatient stay to evaluate for safety.
4.3.6.
Solicited Adverse Events and Clinical Follow-up
Each subject will be given a 7-day diary (paper and electronic-based available), a thermometer, 
and a measuring tool. The subjects will use the diary to record their highest temperature, local 
and systemic symptoms, and concomitant medications taken for 7 days after any product 
administration. Subjects will be provided training on diary completion and proper usage of the 
thermometer to measure temperature and the measuring device to measure injection site 
reactogenicity.  Completion of diary card training will be noted in the source documents. The 
web-based diary for this study is entered in the electronic database provided by Emmes 
Corporation via a NIAID approved contractual agreement. No personal identifiable information 
(PII) is entered in this database. The secure web-based electronic method is preferred for diary 
completion, but subjects will have the option to use a paper diary. The paper diary, if used, will 
be transcribed into the study database and stored in the subject file for monitoring purposes.  
When neither paper nor electronic diary is available from the subject, the study clinician will 
document the source of reactogenicity information recorded in the study database.
The signs and symptoms solicited by diary will include systemic events of temperature, feeling 
unusually tired/unwell, muscles aches (outside the injection site), headache, chills, nausea and 
joint pain; and local event at the product administration site of pain/tenderness, swelling, redness, 
bruising, and pruritus. Subjects will record their highest measured temperature daily for 
assessment of fever and largest measured diameter of redness, swelling, and bruising at the 
injection site, if applicable.  Subject diaries will be reviewed by a clinician 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.
Diary card data will be available in real-time for subjects who use the electronic diary. Subjects 
using a paper diary will be encouraged to contact the clinic as soon as possible for any moderate 
or severe side effects that they experience in the 7 days post product administration. A clinician 
may contact the subject by phone if any moderate or severe side effect is reported. 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 (ADL) (such as 
those consistent with Grade 2 or higher impairment). Additionally, other clinical concerns may 
prompt a 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 each administration.  Throughout the study, clinicians will also assess subjects for 
any changes in symptoms.  Any new or concerning symptoms will be fully assessed to include 
specialty consultation at the NIH Clinical Center as indicated clinically. 

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4.3.7.
Pharmacokinetics  
PK samples will be collected as close as reasonably possible to the target timepoints.  However, 
actual time of collection is critical for PK analysis and will be recorded for all samples.  The PK 
timepoints are shown in the Schedule of Evaluations (Appendix I).
4.3.8.
Follow-Up through End of Study
The Schedule of Evaluations (Appendix I) provides details on the study schedule and the 
allowable windows for completing study visits.  Study follow-up will continue via clinical visits 
through 24 weeks after the final product administration. The visit schedule is based on intervals 
of time after product administration. Out of window study visits will be discouraged and 
recorded as protocol deviations but may be permitted at the discretion of the PI in the interest of 
obtaining safety and PK evaluations following exposure to the investigational study product. 
Any subject who receives investigational product will be required to follow the product 
administration schedule for a complete safety and research evaluation through study duration. 
If product administration is discontinued for a Group 5 or 6 subject assigned to receive repeat 
product administrations, then the study schedule may be modified, and the subject will be 
followed for 24 weeks after the last product administration received.  Schedule 5 of the SOE 
outlines this altered schedule.  Briefly, subjects will be followed according to the assigned group 
visit schedule until the 12th week after their last product administration and will then complete 
the protocol according to Schedule 5 starting at Visit 11 for those who receive only one product 
administration or Visit 17 for those who receive two product administrations. 
Additional visits and blood draws may be scheduled during the study if needed to assess subject 
safety or for sample collection for immunological testing.  Any evaluation for an AE or possible 
exacerbation of a pre-existing condition may be evaluated at study team discretion as a “protocol 
related” evaluation.
After study completion, subjects may be invited to participate in one of the VRC sample 
collection protocols (VRC 200 or VRC 900) for follow-up sample collection.
4.3.9.
Concomitant Medications 
Only routine prescription medications will be entered in the database at the time of enrollment.  
Subsequently, concomitant medications are only updated or recorded in the study database if 
there is an occurrence of an adverse event (AE) that requires expedited reporting, a change to 
pre-existing condition treatment, or the development of a new chronic condition that requires 
ongoing medical management.  Receipt of an FDA-approved vaccine at any time during the 
study will be recorded in the database.  Clinicians should work with subjects regarding the 
timing of licensed vaccines relative to study product administration as indicated in4.3.4.  
Otherwise, concomitant medication changes throughout the study will be recorded in the 
subject’s chart as needed for general medical documentation but will not be recorded in the 
database. 

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4.4.
Criteria for Dose-Escalation 
This study will include a series of interim safety reviews to assess product safety in a stepwise 
manner. The activation of additional dose groups will proceed in a staged manner that is 
governed by the outcome of the planned interim PSRT data reviews. The PSRT must assess the 
data as showing no significant safety concerns before proceeding with group activation. 
Table 3: Plan for Dose-Escalation Reviews
Data Review 
Objective
Minimum Evaluable 
Safety Data*
Favorable 
Review Outcome
Review #1

Dose-escalation from 
5 to 20 mg/kg IV

All post-administration safety data from Day 0 
through at least the “Day 7” visit in at least 3 
5-mg/kg IV recipients from Group 1.  

Proceed with enrollment 
into Groups 3 and 6.
Review #2

Dose-escalation from 
20 to 40 mg/kg IV

All post-administration safety data from Day 0 
through at least the “Day 7” visit in at least 3 
20 mg/kg IV recipients from Groups 3 or 6.  

Proceed with enrollment 
into Group 4.
Group 2 and Group 5 enrollment (5 mg/kg SC) does not depend on dose-escalation reviews for 
the IV doses. 
If there are discontinuations from the study before there are sufficient data to conduct the dose-
escalation review, then additional subjects may be enrolled to have the requisite data on at least 3 
subjects at the dose level and route being evaluated. Additionally, AEs assessed as related to the 
study product at the time of a dose-escalation review may be judged by the PSRT to warrant 
adding additional subjects to a particular group. Consultation with the IRB or FDA as per study 
pause criteria may occur if indicated.
4.5.
Criteria for Subject Discontinuation from Protocol Participation
Subjects who receive at least one dose of VRC01.23LS will be encouraged to stay on the study 
and complete safety evaluations.  A subject may be discontinued from protocol participation for 
the following reasons:

Subject voluntarily withdraws;

Pregnancy;

The IND Sponsor or regulatory authorities stop the study; 

The PI assesses that it is not in the best interest of the subject to continue participation 
in the study; or

Severe non-compliance as determined by the PI.

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4.6.
Criteria for Discontinuation of VRC01.23LS Administration
Under certain circumstances, a subject may be prohibited from receiving further study product 
administrations. These include:

Grade 3 adverse event assessed as related to VRC01.23LS (with the exception of self-
limited Grade 3 solicited reactogenicity that resolve during the solicited 
reactogenicity period);

Grade 4 adverse event assessed as related to VRC01.23LS; 

SAE assessed as related to VRC01.23LS; 

Immediate hypersensitivity reaction associated with VRC01.23LS;

Intercurrent illness that is not expected to resolve prior to the next scheduled study 
product administration and for which PI (or designee) believes is in the best interest 
of the subject to restrict further exposure; 

Repeated failure to comply with protocol requirements.
Subjects who receive at least one dose of VRC01.23LS but are discontinued from further study 
product administrations will continue with follow-up as shown in the Schedule 5 of the Schedule 
of Evaluations with the exception that research sample collections will be discontinued for 
pregnant women or others in which it is contraindicated.    
4.7.
Criteria for Pausing and Resuming the Study 
The study team will closely monitor and review study data as they become available to make 
determinations regarding the presence and severity of adverse events (AEs).  Study product 
administrations and new enrollments will be paused if any of the following criteria are met: 

One (or more) subject experiences a serious adverse event (SAE) that is assessed as 
related (possible, probably, or definitely) to the study product, or

Two (or more) subjects experience the same Grade 3 or higher AE that is assessed 
as related (possible, probably, or definitely) to study agent (other than self-limited 
Grade 3 AEs that resolve during the solicited reactogenicity period).
In the event of a pause, the IND Sponsor Medical Officer (MO) and the PSRT will be promptly 
notified. 
Plan for Review of Pauses and Resuming Rules:  
Study product administration and enrollments would resume only if review of the AEs that 
caused the pause results 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 Medical Officer (MO), with 
participation by the PI, will conduct the review and make the decision to resume, 
amend or close the study. The IRB and FDA will be notified accordingly.

Pauses for Grade 3 or higher related AEs: The IND Sponsor MO, in consultation 
with the PI, will conduct the review and make the decision to resume, amend or close 

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the study for the Grade 3 or higher AEs that meet 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 Grade 3 or higher pause reviews and of the IND Sponsor’s 
decisions.

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5.
SAFETY AND ADVERSE EVENTS
5.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  

Solicited AEs (i.e., reactogenicity parameters as defined in 4.3.6) will be recorded 
without attribution assessments by the subject on paper or electronic diary for 7 days after 
each product administration. 

Unsolicited AEs will be recorded in the study database with attribution assessments from 
product administration through the Day 28 post-product administration visit. 

SAEs (as detailed in 5.2) and new chronic medical conditions will be recorded as AEs 
through the last expected study visit or contact.
Appendix II describes how the relationship between an AE and the study product will be 
assessed. Also available in Appendix II is the link to the DAIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events, Corrected Version 2.1 [July 2017], which will be used to 
determine the severity grades of AEs in this protocol with several modifications as noted.
5.2.
Serious Adverse Events
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 adverse event or life-threatening suspected adverse reaction.  An adverse event 
or suspected adverse reaction is considered "life-threatening" if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at immediate risk of death.  It 
does not include an adverse event or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death.  “Life-threatening” refers to an AE that at occurrence 
represents an immediate risk of death to a subject. It does not include an adverse event or 
suspected adverse reaction that, had it occurred in a more severe form, might have caused death. 
Similarly, a hospital admission for an elective procedure is not considered a SAE. 
5.3.
Adverse Event Reporting to the IND Sponsor
AEs that meet SAE criteria 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: 

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
Results in death

Is life threatening

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 SAE, may be reported on an expedited basis.
An investigator will communicate an initial SAE report within 24 hours of site awareness of 
occurrence to the IND Sponsor by data entry into the database, which triggers an alert to the IND 
Sponsor MO.  Within 3 working days, a written summary by the investigator should be 
submitted to the IND Sponsor.  
In order for the IND Sponsor to comply with regulations mandating sponsor notification of 
specified SAEs to the FDA within 7 and/or 15 calendar days, the investigator must submit 
additional information as soon as it is available.
5.4.
IND Sponsor Reporting to the FDA
The IND Sponsor is responsible for making the determination of which SAEs are “serious and 
unexpected suspected adverse reactions” (SUSARs) 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 IB 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; IND Safety Reports will also be provided to the IRB.
The IND Sponsor will also submit an IND Annual Report of the progress of the investigation to 
the FDA as defined in 21 CFR 312.32.
5.5.
Reporting to the Institutional Review Board
The following information is consistent with NIH IRB Policy 801: Reporting Research Events. 
Reportable Event - An event that occurs during the course of human subject research that 
requires notification to the IRB.
For the purposes of this policy, reportable events include the following:

Unanticipated Problems (UPs) involving risks to subjects or others,

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
Non-compliance (including major protocol deviations and noncompliance that is not 
related to a protocol deviation),

Deaths related or possibly related to research activities, and

New information that might affect the willingness of subjects to enroll or continue 
participation in the study.
5.5.1.
Unanticipated Problem (UP) Definition
An unanticipated problem (UP) is defined as any incident, experience, or outcome that meets all 
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.
A UP must be reported within 7 calendar days of an investigator becoming aware of the actual or 
suspected UP.
5.5.2.
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 affects 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 

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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.
5.5.3.
Protocol Deviation Definition
A protocol deviation is 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 within 7 calendar days of an investigator becoming aware of 
an actual or suspected deviation.  Although PDs 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.  
Researchers are responsible for monitoring their studies throughout the year for adherence to the 
IRB-approved protocol.  The purpose of this monitoring is to identify major deviations and to 
look for trends in minor deviations that may indicate a systemic issue in how the study is being 
conducted that could potentially negatively impact the rights, safety, or welfare of participants or 
the study’s ability to produce scientifically valid results.  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.
5.5.4.
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.
5.5.5.
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. 

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5.5.6.
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 or IC leadership, or any regulatory agency must be 
reported within 7 calendar days of an investigator becoming aware.
5.5.7.
Expedited Reporting to the 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 PDs;

SAEs that are actual or suspected UPs;

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 or IC leadership, or any regulatory agency. 
5.5.8.
Annual Reporting to the IRB
The following will be reported to the IRB in summary at the time of Continuing Review:

Summary of UPs and non-compliance;

AEs, including SAEs, that are not UPs, as a narrative summary statement indicating 
whether these events were within the expected range;

Minor PDs (aggregate summary);

Any trends or events which in the opinion of the investigator should be reported.
5.6.
Reporting of Pregnancy
Pregnancy is not an adverse event, but pregnancy, if it occurs during the time of study 
participation, will be recorded in the study database, and notification on the pregnancy will be 
distributed to the study team and to the IND Sponsor. Subjects will be followed for clinical 
safety and to collect the pregnancy outcome as described in Section 4.2.1. Congenital 
abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (Section 
Error! Reference source not found.) will be reported as SAEs. Pregnancy outcome will be 
reported to the IND Sponsor and to regulatory agencies.

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6.
STATISTICAL CONSIDERATIONS
6.1.
Overview
This is a phase I, open-label, dose-escalation study in healthy adults to assess the safety, 
tolerability, dose, and PK of VRC01.23LS (VRC-HIVMAB0115-00-AB), a human monoclonal 
antibody with broad HIV-1 neutralizing activity. 
6.2.
Accrual and Sample Size Considerations
Recruitment will target about 22 healthy adults, 18 to 60 years of age, with 3 subjects in each of 
the single dose groups (Groups 1 through 4) and 5 subjects in the repeat dose groups (Groups 5 
and 6) as shown in Table 2. The permitted accrual is 40 subjects in total to allow for additional 
enrollments in the event that an enrolled subject does not complete the minimum evaluations 
needed to meet the protocol criteria for the group dose safety or dose-escalation evaluation. Dose 
escalation rules are described in 4.4.
6.2.1.
Group Assignments
The Advantage eClinical system (The Emmes Company LLC, Rockville, MD) will be used to 
assign subjects to a dose group in active accrual at the time of enrollment.  If an enrolled subject 
discontinues from the study before he/she has received study product, a new eligible subject may 
be enrolled into the same group.  If a replacement subject is needed in the case of a subject 
withdrawal, the replacement subject will be assigned to the same group as the dropout subject.
6.2.2.
 Sample Size Considerations
The goal of the safety evaluation is to identify safety concerns associated with product 
administration. The ability of the study to detect SAEs can be expressed by the true event rate 
above which at least 1 SAE would likely be observed and the true event rate below which no 
events would likely be observed. For this study, group sizes are targeted to be n=3 or n=5, and 
within this section, an event is defined as a subject experiencing at least one event.
For n=3, there is at least a 90% chance of observing at least 1 event if the true rate is 0.536 or 
more and at least a 90% chance of observing no events if the true rate is 0.035 or less. For n=5, 
there is at least a 90% chance of observing at least 1 event if the true rate is 0.369 or more and at 
least a 90% chance of observing no events if the true rate is 0.021 or less.
Probabilities of observing 0, 1 or more, and 2 or more events among group sizes n=3 and n=5 are 
presented in Table 4 for a range of possible true event rates. These calculations provide a more 
complete picture of the sensitivity of this study design to identify potential safety problems with 
product administration. 

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Table 4: Probability of Observing a Given Number of Events for Different True Event 
Rates
N=3
N=5
True 
event rate
Pr 
(0 events)
Pr 
(1+ events)
Pr 
(2+ events)
Pr 
(0 events)
Pr 
(1+ events)
Pr 
(2+ events)
0.01
0.970
0.030
<0.001
0.951
0.049
0.001
0.05
0.857
0.143
0.007
0.774
0.226
0.023
0.10
0.729
0.271
0.028
0.590
0.410
0.081
0.20
0.512
0.488
0.104
0.328
0.672
0.263
0.30
0.343
0.657
0.216
0.168
0.832
0.472
0.40
0.216
0.784
0.352
0.078
0.922
0.663
Table 5 displays the two-sided 95% confidence intervals (CIs) for the probability of an event 
based on observed events for n=3 and n=5 using the exact method. For example, if none of the 
subjects experience a particular safety event, the 95% two-sided upper confidence bound for the 
true rate of such events in the population is 0.708 for n=3 and 0.522 for n=5.
Table 5: Two-sided 95% Confidence Intervals for Probability of an Event Based on 
Observed Event Rate
Observed event rate
95% CI for N=3
Observed event rate
95% CI for N=5
0/3
0.000, 0.708
0/5
0.000, 0.522
1/3
0.008, 0.906
1/5
0.005, 0.716
2/3
0.094, 0.992
2/5
0.053, 0.853
3/3
0.292, 1.000
3/5
0.147, 0.947
-
-
4/5
0.284, 0.995
-
-
5/5
0.478, 1.000
6.3.
Statistical Analysis 
6.3.1.
Analysis Variables
The analysis variables will consist of baseline, pharmacokinetics, and safety variables to support 
analyses of the primary and secondary objectives. Continuous variables will be summarized 
using descriptive statistics, and categorical variables will be summarized using counts and 
percentages.
6.3.2.
Baseline Characteristics 
Descriptive statistics will be used to summarize baseline characteristics, inclusive of 
demographics and safety laboratory measurements.
6.3.3.
Safety Analysis
Subjects who receive at least one administration will be considered in the safety analyses. 
Solicited Adverse Events: Solicited AE data will be collected for 7 days after each product 
administration. When summarizing the number and percentage of subjects experiencing each 

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solicited sign or symptom, subjects with multiple occurrences of the same event will be counted 
once, and only the maximum severity level will be presented. Solicited AEs will be summarized 
by route and dose level for each administration. 
Adverse Events: All reportable AEs will be recorded and coded by Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class (SOC) and preferred term (PT). The 
number and percentage of subjects with each unsolicited AE will be summarized by group 
(Groups 1 through 6). Subjects with multiple occurrences of the same event will be counted 
once; only the maximum severity level will be presented in severity summaries, and the strongest 
relationship level will be presented in relationship summaries. 
A by-subject listing of all unsolicited AEs will provide details including severity, relationship to 
treatment type, seriousness, new medical condition status, onset and end date, onset study day, 
duration, and outcome.
Local laboratory values: By-subject listings will present laboratory data measured during the 
course of the study and may include change from baseline values and reference ranges for 
abnormal findings. 
Additional listings may be included, such as disposition and administration status, concomitant 
medications, protocol deviations, or vital signs.
6.3.4.
Tolerability Evaluation 
The tolerability of an investigational medicinal product represents the degree to which overt 
adverse effects can be tolerated by the subject [32]. Since VRC 615 is the first trial of 
VRC01.23LS in healthy adults, the tolerability evaluation will include mostly descriptive 
summaries of the frequency of solicited AE reports with an onset in the 3 days following each 
administration and subject withdrawals or discontinuations based upon subject discomfort or 
AEs. This early assessment of tolerability will inform the parameters to solicit or routinely assess 
in future studies to further characterize the tolerability profile in a larger subject cohort.
6.3.5.
Pharmacokinetics Analysis
Blood samples for PK evaluations will be collected at time points based on participant study 
groups defined in the Schedule of Evaluations (Appendix I).
Individual Subject Pharmacokinetic Analysis:
Population pharmacokinetic analyses will be performed on the VRC01.23LS pharmacokinetic 
data following product administration to determine compartmental PK parameters as previously 
described [37-39].  One, two and three compartment pharmacokinetic models will be considered. 
Based on prior pharmacokinetic studies of bnAbs, including VRC01LS, it is anticipated that a 
two-compartment model will adequately characterize the data.  The population analysis will 
generate estimates for initial and final volumes of distribution (Vd1 and Vd2), inter-
compartmental clearance (Q), CL and bioavailability (F).  Given the small subject numbers, the 
population PK analysis will include only a limited covariate analysis to assess clinical factors as 
fixed effects associated with VRC01.23LS PK parameters.  Specifically dose level, repeat dosing 
and allotype will be assessed as applicable. 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 

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assessed using bootstrap analysis and Monte Carlo simulations will be utilized to assess dosing 
strategies to archive target VRC01.23LS concentrations. 
Population Pharmacokinetic Analyses:
Population pharmacokinetic analyses will be performed on the VRC01.23LS pharmacokinetic 
data following product administration to determine compartmental PK parameters as previously 
described [26, 37, 40].  One, two and three compartment pharmacokinetic models will be 
considered.  Based on prior pharmacokinetic studies of bNAbs, including VRC01LS, it is 
anticipated that a two-compartment model will adequately characterize the data.  The population 
analysis will generate estimates for initial and final volumes of distribution (Vd1 and Vd2), inter-
compartmental clearance (Q), CL and bioavailability (F).  Given the small subject numbers, the 
population PK analysis will include only a limited covariate analysis to assess clinical factors as 
fixed effects associated with VRC01.23LS PK parameters.  Specifically dose level, repeat dosing 
and allotype will be assessed as applicable.  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 and Monte Carlo simulations will be utilized to assess 
dosing strategies to archive target VRC01.23LS concentrations
6.3.6.
Interim Analyses
Preliminary PK analyses may be done as the data for each dose level is obtained.  This may be 
performed before a dose group’s PK data is complete and may only generate a subset of the final 
PK parameters.  The interim analyses may be used to inform decisions about the dose levels to 
be administered in future studies. 
6.3.7.
Missing Data
Missing data will be assumed to be missing completely at random. Analyses will include all 
samples available at each study time point. Based on experience from previous trials, we expect 
missing data to be rare. Regardless, in the event of missing data, we will report the occurrence 
and extent of missingness. We will also provide plausible explanations for the missingness 
mechanism, should such information be available.

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7.
PHARMACY PROCEDURES
The dose groups and VRC01.23LS dosing schedule are shown in Table 1. 
7.1.
Study Product 
VRC01.23LS (VRC-HIVMAB0115-00-AB) is a clear, colorless to yellow liquid, sterile aqueous 
buffered solution that is essentially free of visible particles (some opaque or translucent particles 
may be present) and is filled into 10 mL single-dose vials.  Each vial contains a 6.25 ± 0.1 mL 
volume of VRC01.23LS at a concentration of 100 ± 10 mg/mL in formulation buffer composed 
of 20 mM Acetate Phosphate, 25 mM NaCl, 150 mM Arginine HCl, 5% Sucrose, 0.2%  
Polysorbate 80, pH 5.8.
7.2.
VRC01.23LS Vialed Product Storage
VRC-HIVMAB0115-00-AB (VRC01.23LS) vials are stored until use at -35°C to -15°C in a 
qualified, continuously monitored, temperature-controlled freezer. Following thaw, unopened 
VRC01.23LS vials may be stored for up to 24 hours at ambient temperature (up to 27°C) and up 
to 14 days at 2°C to 8°C.  Product may not be stored in direct sunlight.  If stored at 2°C to 8°C, 
vials must be equilibrated to 15°C to 27°C for a minimum of 60 minutes and may be held at this 
temperature for up to 8 hours prior to product preparation.  Vials should not the refrozen after 
thaw. 
7.3.
Temperature Excursions
The site pharmacist must promptly report any storage temperature excursions outside of the 
normal allowance for the investigational products to the IND Sponsor. In the case of storage or 
shipping/handling temperature excursions outside of the normal allowance for the storage device, 
the following procedure is to be followed:
1. Quarantine the affected product in a separate area.  If the excursion results in thawed 
material, it must not be refrozen. Thawed vials must be quarantined at 5°C ± 3°C. 
2. Report the excursion to the IND sponsor’s authorized representative (SAR) or designee, 
any other parties required by site procedures, and via email to 
VRCProductinquiries@nih.gov.  Quarantine the product and do not use until the IND 
Sponsor’s authorized representative or designee informs the site pharmacist whether 
continued clinical use of the product is acceptable.
3. Inquiries sent to VRCProductinquiries@nih.gov will prompt an automatic email reply to 
the notifier that includes the Clinical Excursion Reporting Form (CERF) as an 
attachment.  
4. Fill out the CERF as completely as possible, either electronically or manually.  
5. Email the completed form and relevant attachments (e.g., temperature charts) to 
VRCProductinquiries@nih.gov, replying to the previous email.  
6. After receipt and evaluation of the reported information, the Sponsor or manufacturer’s 
designee will notify the site pharmacist whether continued clinical use of the product is 
acceptable.

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7.4.
Preparation of VRC01.23LS for Administration 
This section describes how the site pharmacist will prepare the study products for administration 
and how the clinician will administer each product.  Clinician instructions on how to select an 
administration site are in Sections 4.3.4.1 and 4.3.4.2  
7.4.1.
Thawing Instructions
Prior to each dose preparation, the pharmacist will calculate the dose per Study Schema and 
retrieve the minimum number of vials required to prepare each dose.  Thaw and equilibrate the 
vials at 15°C to 27°C for a minimum of 60 minutes.  If thawed vials are removed from 
refrigerator at 2°C to 8°C, equilibrate at 15°C to 27°C for a minimum of 30 minutes and may be 
held at this temperature for up to 8 hours prior to product preparation.  Vials should be gently 
swirled for approximately 30 seconds while avoiding foaming.  Vials should not be shaken.
7.4.2.
Preparation for Intravenous Infusion
To prepare the IV infusion, the calculated dosing volume must be mixed with 100 mL 0.9% 
Sodium Chloride Injection USP (equivalent to DEHP-free and Latex-free B.Braun PAB® REF# 
S8004-5264).  It is acceptable that the prefilled infusion bag may have varying amount of overfill 
depending on the manufacturer, pharmacy may follow the institutional practice to account for the 
overfill to ensure the final concentration is maintained between the range of 2.15 mg/mL to 31.5 
mg/mL.  Purge all air from the IV bag before adding VRC01.23LS into the bag.  A primary 
infusion set attached with in-line filter must be used for IV product administrations and comply 
with the following specifications: DEHP-free, Latex-free primary infusion set (equivalent to BD 
Alaris Pump Infusion Set REF# 2426-0007), 1.2-micron polyethersulfone (PES) filter membrane 
(equivalent to B.Braun REF# 473994 filter extension set). The entire administration set must 
then be primed by the final solution.
The prepared IV bags may be stored for up to 4 hours at 2ºC to 8ºC or at ambient temperature 
(up to 27°C), including dose administration time.
7.4.3.
Preparation for Subcutaneous Injection 
To prepare the subcutaneous injection, the calculated dosing volume must be withdrawn from the 
thawed vial(s) into 1 to 3 syringes using 5-micron filter needle(s).  A new filter needle must be 
used for measuring the required volume up to 2.5 ml for each syringe.  The filter needle must be 
discarded prior to dispensing and replaced with a needle suitable for subcutaneous injection at 
the time of dose administration.  The prepared syringe may be stored at 2ºC to 8ºC or at ambient 
temperature (up to 27°C) for up to 4 hours, including dose administration time.
7.5.
Labeling of Study Product
Vials of both study products 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.

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7.6.
Study Product Accountability
The study pharmacist will be responsible for maintaining an accurate record of the study group 
codes, inventory, and an accountability record of all study products.  Electronic documentation 
as well as paper copies may be used.
7.7.
Study Product Disposition
Empty vials, including equipment used to prepare VRC01.23LS, and the unused portion of a vial 
will be discarded in a biohazard containment bag for incineration or decontamination by 
autoclave and disposed in accordance with the institutional or pharmacy policy.  Partially used 
vials will not be administered to other subjects or used for in vitro experimental studies.  Any 
unopened vials that remain at the end of the study will be returned or discarded at the discretion 
of the sponsor in accordance with policies that apply to investigational agents.  

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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.
Informed Consent
The study informed consent (ICF) is provided as a separate hard copy which describes the 
investigational product to be used and all aspects involved in protocol participation. 
The PI or designee is responsible for obtaining written informed consent from the subject after 
adequate explanation of the aims, methods, anticipated risks and benefits of the study before any 
protocol- specific procedures or study product is administered. The Assessment of 
Understanding (AoU) must be completed before the study ICF is signed.
The study informed consent form (ICF) describes the investigational product to be used and all 
aspects involved in protocol participation. It is provided to potential participants for their review 
in advance, typically as a hard copy during screening as described in 4.3.2. Volunteers will have 
ample time to ask questions and discuss this study with NIH staff, and with their family, friends, 
and personal health care providers prior to signing the informed consent.
The informed consent process is conducted in person, with only relevant parties present, to 
protect the privacy of the subject. The study clinicians that are listed as Associate Investigators 
on the study are authorized to obtain consent and to respond to volunteers’ questions as needed. 
Steps to reduce coercion or undue influence for volunteers who are NIH employees are described 
in the protocol 4.2.3. 
The acquisition of informed consent will be documented in the subject’s medical records, as 
required by 21 CFR 312.62, and the ICF will be signed and personally dated by the subject and 
the person who conducted the informed consent discussion.  The signed ICF will be scanned into 
the electronic medical record and a copy will be provided to the subject. 
8.2.
Risk/Benefit Assessment 
8.2.1.
Potential Risks
Risks of VRC01.23LS and mAb Administration
The side effects of mAbs are mild but may include reactions at the injection site (pain, redness, 
bruising, swelling), 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 infections [41]; 
however, this is not expected to be a risk for a mAb targeted to a viral antigen.
Administration of mAbs may cause immune reactions such as acute anaphylaxis, serum sickness, 
and the generation of antibodies. However, these reactions are rare and more often associated 
with mAb targeted to human proteins or with the use of murine monoclonal antibodies which 
would have a risk of human anti-mouse antibodies [41].  It is expected that that VRC01.23LS  

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will have a low risk of such side effects since it is directed against a viral antigen and is human in 
origin. 
Published experience with other human mAb directed against cell surface targets on lymphocytes 
have shown that infusion of a mAb may be associated with cytokine release, causing a reaction 
known as “cytokine release syndrome” (CRS) [42]. Most infusion-related events occur within 
the first 24 hours after beginning administration.  Severe reactions, such as anaphylaxis, 
angioedema, bronchospasm, hypotension and hypoxia, are infrequent and more often associated 
with mAbs targeted to human proteins or when a non-human mAb, such as a murine mAb, is 
used [41].  Specifically, with regard to the rare CRS reactions, these generally occur within the 
first few hours of beginning the infusion and are more common with the first mAb infusion 
received.  This is because the cytokine release is associated with lysis of the cells targeted by the 
mAb and the burden of target cells is greatest at the time of the first mAb treatment.  With 
licensed therapeutic mAbs, CRS is managed by temporarily stopping the infusion, administration 
of histamine blockers, and restarting the infusion at a slower rate [43].
Delayed allergic reactions to other mAbs may include a serum sickness type of reaction, which is 
characterized by urticaria, fever, lymph node enlargement, and joint pains.  These symptoms 
may not appear until several days after the exposure to the mAb and are noted to be more 
common with chimeric types of mAbs [41].
There are several FDA-licensed mAbs for which reactions related to the rate of IV infusion have 
been described.  Some symptoms may be treated by slowing or stopping the infusion. Supportive 
treatment may also be indicated for some signs and symptoms.  
Participation in this study may limit a subject’s eligibility for other future mAb studies.
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. In 
this study, an IV line that can be used for the collection of blood may be left in place for several 
hours on the days when there are frequent PK blood draws.  Problems from use of an IV for 
blood drawing are generally mild and may include pain, bruising, minor swelling or bleeding at 
the IV site and rarely, infection, vein irritation (called phlebitis), or blood clot. 
Risks of IV Infusions or SC Injections 
General risks of methods that use a needle include stinging, discomfort, pain, soreness, redness, 
bruising, swelling or a tiny cut at the needle insertion site.
Risks of New Diagnoses
It is possible that the standard medical tests performed as part of this research protocol will result 
in new diagnoses. Depending upon the medical findings and consequences of being provided 
with the new medical information about health status, the study subject may view this aspect of 
study participation as either a risk or a benefit. Any such information will be shared and 
discussed with the subject and, if requested by the subject, will be forwarded to the subject’s 
primary health care provider for further workup and management.

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8.2.2
Assessment of Potential Risks and Benefits
The potential risks associated with participation of healthy volunteers in this study and receiving 
VRC01.23LS has been informed by results of previous VRC trials evaluating similar HIV mAbs 
with a favorable safety profile, as described in 1.2 and in the IB. In addition, a protocol specific 
risk management plan with a risk register has been established for this trial and assesses potential 
risks and strategies to mitigate risk, such as gradual initial enrollment in each dose group with a 
dose escalation plan (4.4) and study pause (4.5) and product discontinuation criteria (4.6) to 
minimize risk to subjects.
There are no direct benefits to study subjects from study participation. However, the study may 
benefit others as there is a potential benefit from knowledge gained in this study that would 
further inform the clinical development of HIV mAbs for the prevention or treatment of HIV 
infection.
8.3.
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 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 AEs per 
IRB policy.
The investigator will be responsible for obtaining IRB approval of the annual Continuing Review 
throughout the duration of the study.
8.4.
Subject Confidentiality
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the Sponsor(s) and their representatives.  This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants.  Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence.  No information concerning the study, or the data will 
be released to any unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the Sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study.  The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study.  At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or Sponsor 
requirements.

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Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored by The Emmes Company, LLC, the Data 
Coordinating Center.  This will not include the participant’s contact or identifying information.  
Rather, individual participants and their research data will be identified by a unique study 
identification number.  The study data entry and study management systems used by the clinical 
site and by Emmes research staff will be secured and password protected.  At the end of the 
study, all study databases will be de-identified and archived.
8.5.
Certificate of Confidentiality 
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure.  It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level.  By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
8.6.
Conflict of Interest
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership has established policies and procedures for 
all study group members to disclose all conflicts of interest and will establish a mechanism for 
the management of all reported dualities of interest.
8.7.
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.
8.7.1.
Use of Samples, Specimens and Data
Samples, specimens and data collected under this protocol may be used to conduct protocol-
related safety and immunology evaluations, exploratory laboratory evaluations related to the 
biological target of the study product, exploratory laboratory evaluations related to study product 
or infectious disease research in general and for research assay validation. 
Genetic testing may be performed in accordance with the genetic testing information that is 
included in the study ICF.  Genetic testing, including allotyping, may be done on collected 
specimens in an effort to evaluate for allotype-specific effects on pharmacokinetics.

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8.7.2.
Storage and Tracking of Blood Samples and Other Specimens
All research samples use coded labels that only the VRC Clinic can link to the subject.  Samples 
are stored at the Vaccine Immunology Program laboratory (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 
or GlobalTrace).
8.7.3.
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.  If the samples and/or data will be shared in an identified format, then IRB approval 
must be sought prior to any sharing of samples/data from this protocol. The research use of  
unlinked or de-identified samples are exempt from prospective IRB review and approval.  
The samples will be stored in the VIP laboratory or in a VRC laboratory(ies). Data will be 
archived by the VRC in compliance with requirements for retention of research records.
8.7.4.
Loss or Destruction of Samples, Specimens or Data
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.
8.8.
Subject Identification and Enrollment of Study Subjects
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 60 years of age at enrollment.
8.9.
Safety Monitoring
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 
PSRT, comprised of the PI, Associate Investigators, Study Coordinator, Protocol Specialists, 
other Study Clinicians, and MO will review the summary study safety data reports on a weekly 
basis through 4 weeks after the last subject receives the last product administration and will 
continue to monitor the safety data reports on a monthly basis through completion of the last 
study visit. 

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9.
ADMINISTRATIVE AND LEGAL OBLIGATIONS
9.1.
Protocol Amendments and Study Termination
Protocol amendments may be made only with the prior approval from the IND Sponsor.  
Agreement from the PI and MO must be obtained for all amendments to the protocol and the 
informed consent document. All study amendments will be submitted to the IRB for approval.
The IND Sponsor, NIH IRB, Office of Human Research Protections, study PI, 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.
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, the 
investigators, the IND Sponsor and regulatory authorities, as appropriate. If the study is 
prematurely terminated or suspended, the PI will promptly inform study participants, the IRB, 
and Sponsor and will provide the reason(s) for the termination or suspension. Study participants 
will be contacted, as applicable, and be informed of changes to the study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants 

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the Sponsor, IRB, Office for Human Research Protections (OHRP), and, 
as applicable, the FDA.
9.2.
Study Documentation and Storage
The PI will delegate the study responsibilities to the study team, and a list of appropriately 
qualified persons to whom trial duties have been delegated will be maintained.
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. Long-term 
storage of source documents may be in the form of electronic files. 
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).

Study files containing the protocol with all amendments, IBs, copies of all 
correspondence with the IRB and the VRC.
In addition, all original source documentation must be maintained and be readily available.

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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 VRC 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 VRC in writing of the new responsible person and/or the new location.
9.3.
Clinical Monitoring, Data Collection and Data Sharing
9.3.1.
Clinical Monitoring Plan
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
ICH GCP, and with applicable regulatory requirement(s). 
Monitoring for this study will be performed by a designated CRO.  Details of clinical site 
monitoring are documented in a Clinical Monitoring Plan (CMP).  The CMP describes in detail 
who will conduct the monitoring, at what frequency monitoring will be done, at what level of 
detail monitoring will be performed, and the distribution of monitoring reports.
9.3.2.
Data Collection
Clinical research data will be collected in a secure electronic web-based clinical data 
management system (CDMS) through a contract research organization, The Emmes Company 
LLC (Rockville, MD).  Extracted, anonymized data will be sent to the PSRT for safety review 
and to Protocol Statistician for statistical analysis.
9.3.3.
Source Documents
The site will maintain appropriate medical and research records for this trial, in compliance with 
ICH E6 GCP, regulatory and institutional requirements for the protection of confidentiality of 
subjects. Source data are all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, medical 
records, laboratory reports, pharmacy records and other research records maintained for the 
clinical trial. 
9.3.4.
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 completion date.

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9.4
 Quality Assurance and Quality Control
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. The VEC’s Quality Management Plan will 
be used to perform quality management for this trial.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
QC checks will be run on the database. Any missing data or data anomalies will be 
communicated to the site for clarification/resolution.
Study monitors will verify that the clinical trial is conducted, and data are generated, and 
biological specimens are collected, documented (recorded), and reported in compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. The Principal Investigator will 
provide direct access to all trial related source data/documents, and reports for the purpose of 
monitoring and auditing by the sponsor, and inspection by local and regulatory authorities.
9.5.
Language
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood. 
9.6.
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 National Institutes of Health, the NIH CC, or the U.S. Federal 
Government will provide no long-term medical care or financial compensation for research-
related injuries.

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10.
REFERENCES
1.
UNAIDS. Fact sheet: 2021 statistics. 2021; Available from: 
https://www.unaids.org/sites/default/files/media_asset/UNAIDS_FactSheet_en.pdf.
2.
Wu, X., et al., Rational design of envelope identifies broadly neutralizing human 
monoclonal antibodies to HIV-1. Science, 2010. 329(5993): p. 856-61.
3.
Rudicell, R.S., et al., Enhanced Potency of a Broadly Neutralizing HIV-1 Antibody In 
Vitro Improves Protection against Lentiviral Infection In Vivo. J Virol, 2014. 88(21): p. 
12669-82.
4.
Kwon, Y., et al., Structure-guided modification and optimization of antibody VRC07. 
Retrovirology, 2012. 9(Suppl 2): p. O34.
5.
Beccari, M.V., et al., Ibalizumab, a Novel Monoclonal Antibody for the Management of 
Multidrug-Resistant HIV-1 Infection. Antimicrob Agents Chemother, 2019. 63(6).
6.
Mascola, J.R. and D.C. Montefiori, The role of antibodies in HIV vaccines. Annu Rev 
Immunol, 2010. 28: p. 413-44.
7.
Montefiori, D.C., Measuring HIV neutralization in a luciferase reporter gene assay. 
Methods Mol Biol, 2009. 485: p. 395-405.
8.
Sarzotti-Kelsoe, M., et al., Optimization and validation of the TZM-bl assay for 
standardized assessments of neutralizing antibodies against HIV-1. J Immunol Methods, 
2014. 409: p. 131-46.
9.
Scheid, J.F., et al., Sequence and structural convergence of broad and potent HIV 
antibodies that mimic CD4 binding. Science, 2011. 333(6049): p. 1633-7.
10.
Scheid, J.F., et al., A method for identification of HIV gp140 binding memory B cells in 
human blood. J Immunol Methods, 2009. 343(2): p. 65-7.
11.
Corti, D., et al., Analysis of memory B cell responses and isolation of novel monoclonal 
antibodies with neutralizing breadth from HIV-1-infected individuals. PLoS One, 2010. 
5(1): p. e8805.
12.
Graham, B.S. and D.M. Ambrosino, History of passive antibody administration for 
prevention and treatment of infectious diseases. Curr Opin HIV AIDS, 2015. 10(3): p. 
129-34.
13.
Walker, L.M., et al., Broad and potent neutralizing antibodies from an African donor 
reveal a new HIV-1 vaccine target. Science, 2009. 326(5950): p. 285-9.
14.
Pietzsch, J., et al., Anti-gp41 antibodies cloned from HIV-infected patients with broadly 
neutralizing serologic activity. J Virol, 2010. 84(10): p. 5032-42.
15.
Mouquet, H., et al., Memory B cell antibodies to HIV-1 gp140 cloned from individuals 
infected with clade A and B viruses. PLoS One, 2011. 6(9): p. e24078.
16.
Mouquet, H., et al., Complex-type N-glycan recognition by potent broadly neutralizing 
HIV antibodies. Proc Natl Acad Sci U S A, 2012. 109(47): p. E3268-77.
17.
Huang, J., et al., Broad and potent neutralization of HIV-1 by a gp41-specific human 
antibody. Nature, 2012. 491(7424): p. 406-12.
18.
Huang, J., et al., Identification of a CD4-Binding-Site Antibody to HIV that Evolved 
Near-Pan Neutralization Breadth. Immunity, 2016. 45(5): p. 1108-1121.
19.
van Gils, M.J., et al., An HIV-1 antibody from an elite neutralizer implicates the fusion 
peptide as a site of vulnerability. Nat Microbiol, 2016. 2: p. 16199.

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 53 of 68
20.
Lee, J.H., et al., A Broadly Neutralizing Antibody Targets the Dynamic HIV Envelope 
Trimer Apex via a Long, Rigidified, and Anionic β-Hairpin Structure. Immunity, 2017. 
46(4): p. 690-702.
21.
Doria-Rose, N.A., et al., New Member of the V1V2-Directed CAP256-VRC26 Lineage 
That Shows Increased Breadth and Exceptional Potency. J Virol, 2016. 90(1): p. 76-91.
22.
Ko, S.Y., et al., Enhanced neonatal Fc receptor function improves protection against 
primate SHIV infection. Nature, 2014. 514(7524): p. 642-5.
23.
Ward, E.S. and R.J. Ober, Chapter 4: Multitasking by exploitation of intracellular 
transport functions the many faces of FcRn. Adv Immunol, 2009. 103: p. 77-115.
24.
Nimmerjahn, F. and J.V. Ravetch, Antibody-mediated modulation of immune responses. 
Immunol Rev, 2010. 236: p. 265-75.
25.
Zalevsky, J., et al., Enhanced antibody half-life improves in vivo activity. Nat Biotechnol, 
2010. 28(2): p. 157-9.
26.
Gaudinski, M.R., et al., Safety and pharmacokinetics of the Fc-modified HIV-1 human 
monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults. 
PLoS Med, 2018. 15(1): p. e1002493.
27.
Kwon, Y.D., et al., A matrix of structure-based designs yields improved VRC01-class 
antibodies for HIV-1 therapy and prevention. MAbs, 2021. 13(1): p. 1946918.
28.
Ledgerwood, J.E., et al., Safety, pharmacokinetics and neutralization of the broadly 
neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin Exp 
Immunol, 2015.
29.
Lynch, R.M., et al., Virologic effects of broadly neutralizing antibody VRC01 
administration during chronic HIV-1 infection. Sci Transl Med, 2015. 7(319): p. 
319ra206.
30.
Gaudinski, M.R., et al., Safety and pharmacokinetics of broadly neutralising human 
monoclonal antibody VRC07-523LS in healthy adults: a phase 1 dose-escalation clinical 
trial. Lancet HIV, 2019.
31.
FDA. Immunogenicity Testing of Therapeutic Protein Products —Developing and 
Validating Assays for Anti-Drug Antibody Detection. 2019; Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/immunogenicity-testing-therapeutic-protein-products-developing-and-
validating-assays-anti-drug.
32.
Huang, J., et al., Identification of a CD4-Binding-Site Antibody to HIV that Evolved 
Near-Pan Neutralization Breadth. Immunity, 2016. 45(5): p. 1108-1121.
33.
Li, M., et al., Human immunodeficiency virus type 1 env clones from acute and early 
subtype B infections for standardized assessments of vaccine-elicited neutralizing 
antibodies. J Virol, 2005. 79(16): p. 10108-25.
34.
Allen, J.C. and H.G. Kunkel, Antibodies to genetic types of gamma globulin after 
multiple transfusions. Science, 1963. 139(3553): p. 418-9.
35.
Jefferis, R. and M.P. Lefranc, Human immunoglobulin allotypes: possible implications 
for immunogenicity. MAbs, 2009. 1(4): p. 332-8.
36.
Kickler, T.S., et al., The expression of IgG allotypes on platelets and immunization to IgG 
allotypes in multitransfused thrombocytopenic patients. Blood, 1990. 76(4): p. 849-52.
37.
Gaudinski, M.R., et al., Safety and pharmacokinetics of broadly neutralising human 
monoclonal antibody VRC07-523LS in healthy adults: a phase 1 dose-escalation clinical 
trial. Lancet HIV, 2019. 6(10): p. e667-e679.

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Protocol VRC 615, Version 3.0
October 16, 2023
Page 54 of 68
38.
Gaudinski, M.R., et al., Safety and pharmacokinetics of the Fc-modified HIV-1 human 
monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults. 
PLoS Med, 2018. 15(1): p. e1002493.
39.
Ledgerwood, J.E., et al., Safety, pharmacokinetics and neutralization of the broadly 
neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin Exp 
Immunol, 2015. 182(3): p. 289-301.
40.
Ledgerwood, J.E., et al., Safety, pharmacokinetics and neutralization of the broadly 
neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin Exp 
Immunol, 2015. 182(3): p. 289-301.
41.
Hansel, T.T., et al., The safety and side effects of monoclonal antibodies. Nature reviews. 
Drug discovery, 2010. 9(4): p. 325-38.
42.
Bugelski, P.J., et al., Monoclonal antibody-induced cytokine-release syndrome. Expert 
review of clinical immunology, 2009. 5(5): p. 499-521.
43.
Vogel, W.H., Infusion reactions: diagnosis, assessment, and management. Clin J Oncol 
Nurs, 2010. 14(2): p. E10-21.

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 55 of 68
APPENDIX I: SCHEDULE OF EVALUATIONS

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 56 of 68
Schedule 1: IV Group 1 (5 mg/kg), 3 (20 mg/kg), and 4 (40 mg/kg)  
Visit Number
01
01R
02
02A
02B
02C
02D
02E
02F
03
04
05
06
07
08
11
12
13
Time After Infusion
Pre
EOI
1hr
2hr
4hr
24hr
48hr
Wk1
Wk2
Wk3
Wk4
Wk8
Wk12
Wk16
Wk20
Wk24
1Day of Study
-56 to -1
-42 to 0 D0
D0
D0
D0
D0
D1
D2
D7
D14
D21
D28
D56
D84
D112
D140
D168
Clinical
Tube*
Screen
Enroll
Day of Administration
VRC 500 Screening Consent
X
VRC 615 AoU; Consent
X
2Physical examination 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete medical history at screen; then 
interim med hx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
3VRC01.23LS Administration
X
Begin 7-day Diary Card
X
CBC / differential
EDTA
3
3
3
3
3
3
3
ALT, creatinine
GLT
4
4
4
4
4
4
4
CMP: Total bili, BUN, albumin, protein, calcium, Na, 
K, Cl, CO2, glucose, AST, ALP
GLT
X
X
X
4Pregnancy Test: urine or serum
X
X
X
X
X
X
4Pregnancy Prevention Counseling
X
X
X
X
X
X
HIV Ab/Ag combo test
EDTA
3
3
HIV Risk-Reduction Counseling
X
X
X
Research Samples
PK 
SST
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
PBMCs
EDTA
20
20
Serum
SST
24
8
8
8
8
8
8
8
8
8
8
Daily Volume (mL)
10
0
55
4
4
4
4
31
12
22
19
12
19
12
19
12
12
12
Cumulative Volume (mL)
10
10
65
69
73
77
81
112
124
146
165
177
196
207
227
239
251
263
Visit windows: Schedule visits 02A through 13 with respect to day 0: 
Visit A (+10 min); Visits B and C (±10 min); Visit D (+2 hrs); Visits E, F (± 6 hrs); Visits 03, 04, 05, 06 (± 2 days), and Visits 07, 08, 11, 12, 13 (±7 days).
Not applicable to Schedule 1: Visits 02G, 09, 10
*Tube types and blood volumes are shown to meet current institutional requirements and projected blood volumes. Different tubes for clinical evaluations may be used to 
meet site requirements. Different volumes and tubes may be used for research blood samples when tubes as shown are not available, or as otherwise instructed by the IND 
Sponsor. Collected blood volumes will stay within the NIH CC blood draw limits for each subject.
1Day 0=day of first product administration.  Day 0 is preferably scheduled within 14 days after enrollment but may be scheduled up to 42 days after enrollment to allow for 
the possibility of study pauses or scheduling difficulty with the approval of the PI. Day 0 evaluations prior to product administration are the baseline for assessing subsequent 
AEs.  
(Footnotes continue to next page)

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 57 of 68
2 Screening includes physical exam with vital signs (blood pressure, temperature, pulse, respiratory rate), height and weight. At other visits, if medically indicated, perform 
a targeted exam. Otherwise only vital signs are required, except at Visit 02 when the current weight is also obtained to use for ordering the study product, dosed based on 
“mg/kg.”
3 The PK blood draw “visits,” defined by hours after an infusion, are relative to the exact time of the end of infusion (EOI).  The exact start and end times of product 
administration and the time of PK blood draw(s) are recorded to ensure accurate PK analysis.  In all IV groups, subjects will be observed in clinic for at least 2 hours 
following completion of product administration. 
4 Pregnancy test results must be negative for women of reproductive potential before each product administration. Complete a Pregnancy Prevention Form when pregnancy 
test is given. 

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 58 of 68
Schedule 2: SC Group 2 (5 mg/kg)
Visit Number
01
01R
02
02A
02E
02F
02G
03
04
05
06
07
08
11
12
13
Time After Infusion
Pre
EOI
24hr
48hr
72hr
Wk1
Wk2
Wk3
Wk4
Wk8
Wk12 Wk16 Wk20 Wk24
1Day of Study
-56 to -1
-42 to 0
D0
D0
D1
D2
D3
D7
D14
D21
D28
D56
D84
D112
D140
D168
Clinical
Tube*
Screen
Enroll Day of Injection
VRC 500 Screening Consent
X
VRC 615 AoU; Consent
X
2Physical examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete medical history at screen; 
then interim med hx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
3VRC01.23LS Administration
X
Begin 7-day Diary Card
X
CBC / differential
EDTA
3
3
3
3
3
3
3
ALT, creatinine
GLT
4
4
4
4
4
4
4
CMP: Total bili, BUN, albumin, protein, 
calcium, Na, K, Cl, CO2, glucose, AST, ALP
GLT
X
X
X
4Pregnancy test: urine or serum
X
X
X
X
X
X
4Pregnancy Prevention Counseling 
X
X
X
X
X
X
HIV Ab/Ag combo test
EDTA
3
3
HIV Risk-Reduction Counseling
X
X
X
Research Samples
PK 
SST
4
4
4
4
4
4
4
4
4
4
4
4
4
PBMCs
EDTA
20
20
Serum
SST
24
8
8
8
8
8
8
8
8
8
8
8
Daily Volume (mL)
10
0
55
0
31
12
12
22
19
12
19
12
19
12
12
12
Cumulative Volume (mL)
10
10
65
65
96
108
120
142
161
173
192
204
223
235
247
259
Visit windows: Schedule visits 02A through 13 with respect to day 0:
Visit A (+10 min); Visits E, F, G (± 6 hrs.); Visits 03, 04, 05, 06 (± 2 days); Visits 07, 08, 11, 12, 13 (±7 days). 
Not applicable to Schedule 2: Visits 02B, 02C, 02D, 09, 10
* Tube types and blood volumes are shown to meet current institutional requirements and projected blood volumes. Different tubes for clinical evaluations may be 
used to meet site requirements. Different volumes and tubes may be used for research blood samples when tubes as shown are not available, or as otherwise instructed 
by the IND Sponsor. Collected blood volumes will stay within the NIH CC blood draw limits for each subject.
1 Day 0=day of first product administration.  Day 0 is preferably scheduled within 14 days after enrollment but may be scheduled up to 42 days after enrollment to 
allow for the possibility of study pauses or scheduling difficulty with the approval of the PI.  Day 0 evaluations prior to product administration are the baseline for 
assessing subsequent AEs.  
(Footnotes continue to next page)

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 59 of 68
2 Screening includes physical exam with vital signs (blood pressure, temperature, pulse, respiratory rate), height and weight. At other visits, if medically indicated, 
perform a targeted exam. Otherwise only vital signs are required, except at Visit 02 when the current weight is also obtained to use for ordering the study product, 
dosed based on “mg/kg.”
3 The PK blood draw “visits,” defined by hours after an injection, are relative to the exact time of the end of injection (EOI).  The exact start and end times of product 
administration and the time of PK blood draw(s) are recorded to ensure accurate PK analysis.  In all SC groups, subjects will be observed for at least 1 hour after 
product administration. 
4 Pregnancy test results must be negative for women of reproductive potential before each product administration. Complete a Pregnancy Prevention Form when 
pregnancy test is given. 

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 60 of 68
Schedule 3: SC Group 5 (5 mg/kg by repeat dosing)
Visit Number
01
01R
02 02A 02E 02F 02G
03
04
06
07
08
08A
08E
08G
09
10
11
12
13
13A
13E
Time After Infusion
Pre
D0
EOI
D0 24hr 48hr 72hr 1wk Wk2 Wk4 Wk8
Pre
Wk12
EOI
Wk12
24hr 72hr Wk13 Wk14 Wk16 Wk20
Pre
Wk24
EOI
Wk24
24hr
1Day of Study
-56 to -1 -42 to 0 D0
D0
D1
D2
D3
D7
D14 D28 D56
D84
D84
D85
D87
D91
D98 D112 D140 D168 D168
D169
Clinical
Tube*
Screen
Enroll
Day of 
injection
Day of 
injection
Day of 
injection
VRC 500 Screening Consent
X
VRC 615 AoU; Consent
X
2Physical examination 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete med history at screen; then 
interim med hx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
3VRC01.23LS Administration
X
X
X
Begin 7-day Diary Card
X
X
X
Phone contact; clinic visit if indicated
X
X
CBC / differential
EDTA
3
3
3
3
3
3
3
3
3
3
3
3
ALT, creatinine
GLT
4
4
4
4
4
4
4
4
4
4
4
4
CMP: Total bili, BUN, albumin, protein, 
calcium, Na, K, Cl, CO2, glucose, AST, ALP 
GLT
X
X
X
X
X
X
4Pregnancy Test: urine or serum
X
X
X
X
X
X
X
4Pregnancy Prevention Counseling
X
X
X
X
X
X
X
HIV Ab/Ag combo test
EDTA
3
3
3
HIV Risk-Reduction Counseling
X
X
X
X
X
X
Research Samples
PK
SST
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
PBMCs
EDTA
20
20
Serum
SST
24
8
8
8
8
8
8
8
8
8
8
8
8
8
Daily Volume (mL)
10
0
55
0
31
12
12
22
19
19
12
19
0
0
19
22
19
19
12
19
0
0
Cumulative Volume (mL)
10
10
65
65
96
108 120 142 161 180 192
211
211
211
230
252
271
290
302
321
321
321
Visit windows: Schedule visits 02A through 08 with respect to day 0; visits 08A through 13 with respect to visit 08; visits 13A through 21 with respect to visit 13:
Visit A (+10 min); Visits 02E, 02F, 02G, 08G (± 6 hrs.); Visits 08E, 13E (+ 1 day); Visits 03, 04, 09, 10 (± 2 days); Visits 06, 07, 08, 11, 12, 13  (± 7 days, with 
not less than 21 days between injections).
Not applicable to Schedule 3: Visits B, C, D, 05 
*Tube types and blood volumes are shown to meet current institutional requirements and projected blood volumes. Different tubes for clinical evaluations may be used to 
meet site requirements. Different volumes and tubes may be used for research blood samples when tubes as shown are not available, or as otherwise instructed by the IND 
Sponsor. Collected blood volumes will stay within the NIH CC blood draw limits for each subject.

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 61 of 68
1Day 0=day of first product administration.  Day 0 is preferably scheduled within 14 days after enrollment but may be scheduled up to 42 days after enrollment to allow for 
the possibility of study pauses or scheduling difficulty with the approval of the PI.  Day 0 evaluations prior to product administration are the baseline for assessing 
subsequent AEs.  (Footnotes continue to next page)
2 Screening includes physical exam with vital signs (blood pressure, temperature, pulse, respiratory rate), height and weight. At other visits, if medically indicated, perform 
a targeted exam. Otherwise only vital signs are required, except at all product administration visits (02, 08, 13) when the current weight is also obtained to use for ordering 
the study product, dosed based on “mg/kg.”
3 The PK blood draw “visits,” defined by hours after an injection, are relative to the exact time of the end of injection (EOI).  The exact start and end times of product 
administration and the time of PK blood draw(s) are recorded to ensure accurate PK analysis.  In all SC groups, subjects will be observed for at least 1 hour after product 
administration.
4 Pregnancy test results must be negative before each study product administration.  Complete a Pregnancy Prevention Form when pregnancy test is given. 
*The study schedule for subjects who discontinue product administration will be modified as follows: 

Subjects who receive only one product administration will follow Schedule 3 through Visit 07, and then move to Schedule 5. 

Subjects who receive two product administrations will follow Schedule 3 through Visit 12 and then move to Schedule 5.

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 62 of 68
Schedule 3 (continued): SC Group 5 (5 mg/kg by repeat dosing)
Visit Number*
13G
14
15
16
17
18
19
20
21
Time After Infusion
72 hr
Wk25
Wk26
Wk28
Wk32
Wk36
Wk40
Wk44
Wk48
Day of Study
D171
D175
D182
D196
D224
D252
D280
D308
D336
Clinical
Tube^
Physical examination if medically indicated, otherwise 
only vitals
X
X
X
X
X
X
X
X
X
Interim medical history
X
X
X
X
X
X
X
X
X
CBC / differential
EDTA
3
3
3
3
ALT, creatinine
GLT
4
4
4
4
CMP: Total bili, BUN, albumin, protein, calcium, Na, K, Cl, 
CO2, glucose, AST, ALP 
GLT
X
1Pregnancy test: urine or serum
X
X
X
1Pregnancy Prevention Counseling
X
X
X
HIV Ab/Ag combo test
EDTA
3
HIV risk-reduction counseling
X
Research Samples
PK samples
SST
4
4
4
4
4
4
4
4
4
Serum
SST
8
8
8
8
8
8
8
8
8
Daily Volume (mL)
19
22
19
19
19
12
12
12
12
Cumulative Volume (mL)
340
362
381
400
412
424
436
448
460
Visit windows: Schedule visits 13G through 21 with respect to visit 13. 
Visit 13G (± 6 hrs), Visits 14-17 (±2 days), and Visits 18-21 (±7 days). 
1 Complete a Pregnancy Prevention Form when pregnancy test is given.
*The study schedule for subjects who discontinue product administration will be modified as follows: 

Subjects who have only received one product administration will follow Schedule 3 through Visit 07, and then move to Schedule 5. 

Subjects who have received two product administrations will follow Schedule 3 through Visit 12 and then move to Schedule 5.

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 63 of 68
Schedule 4: IV Group 6 (20 mg/kg by repeat dosing)
Visit Number
01
01R
02
02A 02B 02C 02D 02E
02F
03
04
06
07
08
08A
08B
08E
08F
09
10
11
12
13
13A
13B
Time After Infusion
Pre
D0
EOI
D0
1hr
2hr
4hr
24hr
48h
Wk1
Wk2
Wk4
Wk8
Pre
Wk12
EOI
Wk12
1hr
24hr
48hr
Wk13 Wk14 Wk16 Wk20
Pre
Wk24
EOI
Wk24
1hr
1Day of Study
-56 to -1
-42 to 0
D0
D0
D0
D0
D0
D1
D2
D7
D14
D28
D56
D84
D84
D84
D85
D86
D91
D98
D112
D140
D168
D168 D168
Clinical
Tube* Screen Enroll
Day of infusion
Day of 
infusion
Day of 
infusion
VRC 500 Screening Consent
X
VRC 615 AoU; Consent
X
2Physical examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete med history at screen; 
then interim med hx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
3VRC01.23LS Administration
X
X
X
Begin 7-day Diary Card
X
X
X
Phone contact; clinic visit if 
indicated
X
CBC / differential 
EDTA
3
3
3
3
3
3
3
3
3
3
3
3
ALT, creatinine
GLT
4
4
4
4
4
4
4
4
4
4
4
4
CMP: Total bili, BUN, albumin, protein, 
calcium, Na, K, Cl, CO2, glucose, AST, ALP
GLT
X
X
X
X
X
X
 4Pregnancy Test: urine or serum
X
X
X
X
X
X
X
 4Pregnancy Prevention 
Counseling
X
X
X
X
X
X
X
HIV Ab/Ag combo test
EDTA
3
3
3
HIV Risk-Reduction Counseling
X
X
X
X
X
X
Research Samples
PK 
SST
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
PBMCs
EDTA
20
20
Serum
SST
24
8
8
8
8
8
8
8
8
8
8
8
8
Daily Volume (mL)
10
0
55
4
4
4
4
31
12
22
19
19
12
19
4
4
0
19
22
19
19
12
19
4
4
Cumulative Volume (mL)
10
10
65
69
73
77
81
112 124 146 165 184 196
215
219
223
223
242
264
283
302
314
333
337
341
Visit windows: Schedule visits 02A through 08 with respect to Day 0; visits 08A through 13 with respect to Visit 08. 
Visits A (+10 min); Visits B and C (±10 min); Visit D (+2 hrs.); Visits 02E, 02F (± 6 hrs.); Visit 08E (+1 day), Visit 08F (+ 2 days), Visits 03, 04, 09, 10 (± 2 days); Visits 
06, 07, 08, 11, 12, 13 (±7 days, with not less than 21 days between infusions). 
Not applicable to Schedule 4: Visit G, 05, 08C, 08D, 08G, 13B, 13C, 13D
*Tube types and blood volumes are shown to meet current institutional requirements and projected blood volumes. Different tubes for clinical evaluations may be used to 
meet site requirements. Different volumes and tubes may be used for research blood samples when tubes as shown are not available, or as otherwise instructed by the IND 
Sponsor. Collected blood volumes will stay within the NIH CC blood draw limits for each subject. (Footnotes continue to next page)

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 64 of 68
1 Day 0=day of first product administration.  Day 0 is preferably scheduled within 14 days after enrollment but may be scheduled up to 42 days after enrollment to allow 
for the possibility of study pauses or scheduling difficulty with the approval of the PI. Day 0 evaluations prior to product administration are the baseline for assessing 
subsequent AEs.  
2 Screening includes physical exam with vital signs (blood pressure, temperature, pulse, respiratory rate), height and weight. At other visits, if medically indicated, perform 
a targeted exam. Otherwise only vital signs are required, except at all product administration visits (02, 08, 13) when the current weight is also obtained to use for ordering 
the study product, dosed based on “mg/kg.”
3 The PK blood draw “visits,” defined by hours after an infusion, are relative to the exact time of the end of infusion.  Exact start and end times of product administration 
and the time of PK blood draw(s) are recorded to ensure accurate PK analysis.  In all IV groups, subjects will be observed for at least 2 hours after the product administration.
4 Pregnancy test results must be negative for women of reproductive potential before each product administration. Complete a Pregnancy Prevention Form when pregnancy 
test given. 
**The study schedule for subjects who discontinue product administration will be modified as follows: 

Subjects who receive only one product administration will follow Schedule 4 through Visit 07, and then move to Schedule 5. 

Subjects who receive two product administrations will follow Schedule 4 through Visit 12 and then move to Schedule 5.

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 65 of 68
Schedule 4 (continued): IV Group 6 (20 mg/kg by repeat dosing)
Visit Number*
13E
13F
14
15
16
17
18
19
20
21
Time After Infusion
24hr
48hr
Wk25
Wk26
Wk28
Wk32
Wk36
Wk40
Wk44
Wk48
Day of Study
D169
D170
D175
D182
D196
D224
D252
D280
D308
D336
Clinical
Tube
Physical examination if medically indicated, otherwise only vitals
X
X
X
X
X
X
X
X
X
Interim medical history
X
X
X
X
X
X
X
X
X
Phone contact; clinic visit if indicated
X
CBC / differential
EDTA
3
3
3
3
ALT, creatinine
GLT
4
4
4
4
CMP: Total bili, BUN, albumin, protein, calcium, Na, K, Cl, CO2, 
glucose, AST, ALP
GLT
X
Pregnancy Test: urine or serum
X
X
X
Pregnancy Prevention Counseling when pregnancy test given
X
X
X
HIV Ab/Ag combo test
EDTA
3
HIV Risk-Reduction Counseling
X
Research Samples
PK 
SST
4
4
4
4
4
4
4
4
4
Serum
SST
8
8
8
8
8
8
8
8
8
Daily Volume (mL)
0
19
22
19
19
12
12
12
12
12
Cumulative Volume (mL)
341
360
382
401
420
432
444
456
468
480
Visit windows: Schedule visits 13E through 21 with respect to visit 13. 
Visit 13E (+1 day); Visit 13F (+2 days), Visits 14-17 (±2 days), and Visits 18-21 (±7 days).
* The study schedule study schedule for subjects who discontinue product administration will be modified as follows: 

Subjects who receive only one product administration will follow Schedule 4 through Visit 7, and then move to Schedule 5. 

Subjects who receive two product administrations will follow Schedule 4 through Visit 12 and then move to Schedule 5.

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 66 of 68
Schedule 5: For Subjects in Groups 5 and 6 Discontinued from Further Product Administration(s)
Visit Number
08
11
12
13
16
17
18
Time After Infusion
Wk12
Wk16
Wk20
Wk24
Wk28
Wk32
Wk36
Day of Study
D84
D112
D140
D168
D196
D224
D252
Clinical
Tube*
Physical examination if medically indicated, otherwise only vitals
X
X
X
X
X
X
X
Interim medical history
X
X
X
X
X
X
X
Pregnancy Test: urine or serum
X
X
X
Pregnancy Prevention Counseling when pregnancy test given
X
X
X
Research Samples
PK 
SST
4
4
4
4
4
4
4
Serum
SST
8
8
8
8
8
8
8
Daily Volume (mL)
12
12
12
12
12
12
12
Cumulative Volume (mL), Group 5
211
223
235
247
If starting at Visit 8
Cumulative Volume (mL), Group 6
215
227
239
251
Cumulative Volume (mL), Group 5
321
333
345
357
If starting at Visit 13
Cumulative Volume (mL), Group 6
333
345
357
369
Visit windows: ±7 days for all visits shown. 
*Tube types and blood volumes are shown to meet current institutional requirements and projected blood volumes. Different tubes for clinical evaluations 
may be used to meet site requirements. Different volumes and tubes may be used for research blood samples when tubes as shown are not available, or as 
otherwise instructed by the IND Sponsor. Collected blood volumes will stay within the NIH CC blood draw limits for each subject.
Group 5 or 6 subjects who do not receive the 2nd or 3rd product administrations will continue participation under this modified schedule:  

If only one product administration received, subjects will follow their originally assigned study schedule through Visit 7 and then move to Schedule 5 for 
Visits 8-13. Their final study visit will be Visit 13.

If two product administrations received, subjects will follow their originally assigned study schedule through Visit 12 and then move to Schedule 5 for 
Visits 13-18. Their final study visit will be Visit 18.

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 67 of 68
APPENDIX II: ASSESSMENT OF RELATIONSHIP TO STUDY PRODUCT AND TABLE 
FOR GRADING SEVERITY OF ADVERSE EVENTS

Product: VRC01.23LS (VRC-HIVMAB0115-00-AB)
Protocol VRC 615, Version 3.0
October 16, 2023
Page 68 of 68
Assessment of Causality Relationship of an Adverse Event to Study Product: 
The relationship between an adverse event (AE) and the product will be assessed by the 
investigator on the basis of his or her clinical judgment and the definitions below. 

Definitely Related. The AE and administration of study product are related in time, and a 
direct association can be demonstrated. 

Probably Related. The AE and administration of study product are reasonably related in 
time, and the AE is more likely explained by study product than other causes. 

Possibly Related. The AE and administration of study product are reasonably related in 
time, but the AE can be explained equally well by causes other than study product. 

Not Related. There is not a reasonable possibility that the AE is related to the study 
product. 
For purposes of preparing data reports in which AE attributions are limited to “Related” or “Not 
Related”, in this protocol, the “Definitely, Probably and Possibly” attributions will be mapped to 
the “Related” category. The definitions that apply when these two categories alone are used are 
as follows: 

Related – There is a reasonable possibility that the AE may be related to the study 
product. 

Not Related – There is not a reasonable possibility that the AE is related to the study 
product.
Table for Grading Severity of Adverse Events:
For consistency with other studies of VRC mAb products, the U.S. Department of Health and 
Human Services, National Institutes of Health, National Institute of Allergy and Infectious 
Diseases, Division of AIDS. DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Corrected Version 2.1. [July 2017]. Available from:
https://rsc.tech-res.com/docs/default-source/safety/division-of-aids-(daids)-table-for-grading-the-
severity-of-adult-and-pediatric-adverse-events-corrected-v-2-1.pdf 
The table will be used as posted at the link above with the following exemptions:

Weight loss will be recorded as an adverse event only if it is considered deleterious to 
the participant’s health.

For severity grading of the solicited bruising parameter at the product administration 
site, the definitions based on size of the largest diameter and listed for the “Injection 
Site Erythema or Redness” will be used. The severity grade definition for “Bruising” 
provided under the Dermatologic Clinical Conditions will be used only for 
unsolicited adverse events involving bruising at other body locations. 

Creatinine changes will be graded on the basis of the upper limit of normal provided 
by the grading table and not change from baseline.

Creatinine clearance changes will be graded according to mL/min provided by the 
grading table and not change from baseline.

Subclinical CMP results for sodium, potassium, chloride, bicarbonate, BUN, and 
glucose will not be considered an AE unless grade 2 or greater.