Evaluating the Safety and Efficacy of the VRC01 Antibody in Reducing Acquisition of HIV-1 Infection Among Men and Transgender Persons Who Have Sex With Men

This study will evaluate the safety, tolerability, and efficacy of the VRC01 antibody in
preventing HIV-1 infection in men and transgender (TG) persons who have sex with men, in
North America, South America, and Switzerland.

Participants will be randomized to receive VRC01 mAb by intravenous (IV) infusion at a dose
of 10 mg/kg or 30 mg/kg every 8 weeks, or to receive control infusions every 8 weeks. All
participants will receive the VRC01 antibody or placebo by IV infusion at Weeks 0 (study
entry), 8, 16, 24, 32, 40, 48, 56, 64, and 72. For 3 days following each infusion,
participants will be asked to record and report any symptoms to study researchers.

In addition to the infusion visits, participants will attend study visits at Weeks 4, 8 + 5
days, 12, 20, 28, 36, 44, 52, 60, 68, 76, 80, 88, 96, and 104. All study visits will include
blood collection and HIV testing and counseling. Select study visits will include a medical
history review, physical exam, urine collection, pregnancy testing for participants capable
of becoming pregnant, risk reduction counseling, and an interview/questionnaire.

Inclusion Criteria:

General and Demographic Criteria

- Age of 18 to 50 years

- Access to a participating clinical research site (CRS) and willingness to be followed
for the planned duration of the study

- Ability and willingness to provide informed consent

- Assessment of understanding: volunteer demonstrates understanding of this study and
completes a questionnaire prior to first infusion with verbal demonstration of
understanding of all questionnaire items answered incorrectly

- Agrees not to enroll in another study of an investigational research agent for the
duration of the participant's trial participation

- Good general health as shown by medical history, physical exam, and screening
laboratory tests

HIV-Related Criteria

- Willingness to receive HIV test results

- Willingness to discuss HIV infection risks and amenable to HIV risk reduction
counseling

- Persons born Male or identifying as Transgender (TG) (male-to-female or
female-to-male, see HVTN 704/HPTN 085 SSP) who, in the 6 months prior to
randomization, experienced 1 or both of the following HIV risk criteria:

- Condomless anal intercourse with 1 or more male or transgender partner(s)

- Anal intercourse with 2 or more male or transgender partners

- Male-to-female and female-to-male TG volunteers are eligible. Receipt of hormonal
therapy does not make a TG volunteer ineligible.

- Volunteers who have been in a mutually monogamous relationship with an HIV-1
seronegative partner for greater than 1 year are excluded.

Laboratory Inclusion Values:

Hematology

- Hemoglobin (Hgb) greater than or equal to 10.5 g/dL for volunteers who were born
female, greater than or equal to 13.0 g/dL for volunteers who were born male (greater
than or equal to 12.0 g/dL for transgender women taking feminizing hormones [e.g.,
anti-androgens, estrogens])

- Platelets greater than or equal to 100,000 cells/mm^3

Chemistry

- Alanine aminotransferase (ALT) less than 2.5 times the institutional upper limit of
normal and creatinine less than or equal to 1.25 times the institutional upper limit
of normal

Virology

- HIV uninfected, as defined in the SSP, within 30 days prior to enrollment

Urine

- Negative, trace, or 1+ (30 g/L for semi-quantitative) urine protein by dipstick

Reproductive Status

- Volunteers capable of becoming pregnant: negative serum or urine beta human chorionic
gonadotropin (β-HCG) pregnancy test performed at the screening visit and prior to
infusion on the day of initial infusion. Persons who are NOT capable of becoming
pregnant due to having undergone total hysterectomy or bilateral oophorectomy
(verified by medical records) are not required to undergo pregnancy testing.

- Reproductive Status: A volunteer who is capable of becoming pregnant must agree to
consistently use effective contraception (see the protocol and SSP for more
information) for sexual activity that could lead to pregnancy from at least 21 days
prior to enrollment through the last required protocol clinic visit.

- Volunteers capable of becoming pregnant must also agree not to seek pregnancy through
alternative methods, such as artificial insemination or in vitro fertilization until
after the last required protocol clinic visit

Exclusion Criteria:

General

- Investigational research agents received within 30 days before first infusion

- Body mass index (BMI) greater than or equal to 40

- Pregnant or breastfeeding

- Any reactive, indeterminate, or positive HIV test, even if subsequent testing
indicates that the individual is not HIV infected, except as permitted by the HVTN
704/HPTN 085 Protocol Safety Review Team (PSRT).

Vaccines

- HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received
control/placebo in an HIV vaccine trial, the HVTN 704/HPTN 085 PSRT will determine
eligibility on a case-by-case basis.

Immune System

- Serious adverse reactions to VRC01 formulation components such as sodium citrate,
sodium chloride, and L-arginine hydrochloride, including history of anaphylaxis and
related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal
pain.

- Autoimmune disease, including Type I diabetes mellitus (Not excluded from
participation: Volunteer with mild, stable and uncomplicated autoimmune disease that
does not require consistent immunosuppressive medication and that, in the judgment of
the site investigator, is likely not subject to exacerbation and likely not to
complicate reactogenicity and AE assessments)

- Immunodeficiency syndrome

Clinically Significant Medical Conditions

- Clinically significant medical condition, physical examination findings, clinically
significant abnormal laboratory results, or past medical history with clinically
significant implications for current health. A clinically significant condition or
process includes but is not limited to:

- Any contraindication to repeated infusions or blood draws, including inability to
establish venous access;

- A condition that requires active medical intervention or monitoring to avert
grave danger to the volunteer's health or well-being during the study period; or

- A condition or process for which signs or symptoms could be confused with
reactions to VRC01.

- Any medical, psychiatric, occupational, or other condition that, in the judgment of
the investigator, would interfere with, or serve as a contraindication to, protocol
adherence, assessment of safety or infusion reactions, or a volunteer's ability to
give informed consent

- Psychiatric condition that precludes compliance with the protocol. Specifically
excluded are persons with psychoses within the past 3 years, ongoing risk for suicide,
or history of suicide attempt or gesture within the past 3 years.

- Asthma, other than mild, well-controlled asthma

- Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or
platelet disorder requiring special precautions)

- Malignancy (Not excluded from participation: Volunteer who has had malignancy excised
surgically and who, in the investigator's estimation, has a reasonable assurance of
sustained cure, or who is unlikely to experience recurrence of malignancy during the
period of the study)

- Seizure disorder: History of seizure(s) within past three years. Also exclude if
volunteer has used medications in order to prevent or treat seizure(s) at any time
within the past 3 years.

- History of hereditary angioedema, acquired angioedema, or idiopathic angioedema

- History of receiving transplantation of life-saving organs or tissues (includes heart,
kidney, pancreas, lungs, liver, and intestines)

- Known hepatic or renal dysfunction