Evaluating the Safety, Pharmacokinetics, and Anti-Viral Activity of VRC01 and VRC01LS in the Serum and Mucosa of Healthy, HIV-Uninfected Adults

This study will evaluate two experimental human monoclonal antibodies (mAbs):
VRC-HIVMAB060-00-AB (VRC01) and VRC-HIVMAB080-00-AB (VRC01LS). VRC01LS is designed to have a
longer half-life than VRC01. The purpose of this study is to evaluate the safety,
pharmacokinetics, and antiviral activity of VRC01 and VRC01LS in the serum and mucosa of
healthy, HIV-uninfected adults.

This study will enroll healthy, HIV-uninfected adults into five groups. At various time
points during the study, participants in Groups 1, 2, and 4 will receive intravenous (IV)
infusions of VRC01, and participants in Groups 3 and 5 will receive IV infusions of VRC01LS.
Participants in Groups 1, 2, and 3 will attend 13 to 14 study visits over about 1 to 1 ½
years; participants in Groups 4 and 5 will attend 7 to 9 study visits over about 6 months to
1 year. At certain time points, study visits will include physical examinations, blood
collection, urine collection, and interviews and questionnaires. At other time points,
depending on group assignment and gender, visits will also include collection of
cervicovaginal secretions, rectal secretions, and semen; and cervical, vaginal, and rectal
biopsies.

Inclusion Criteria:

General and Demographic Criteria:

- Age of 18 to 50 years

- Weight less than or equal to 115 kg

- Access to a participating HIV Vaccine Trials Network (HVTN) 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;
completes a questionnaire prior to enrollment with verbal demonstration of
understanding of all questionnaire items answered incorrectly

- Agrees not to enroll in another study of an investigational research agent until
completion of the last study visit

- 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

- Assessed by the clinic staff as being at "low risk" for HIV infection [low risk
guidelines are found on the protocol home page on the HVTN Members' site
(https://members.hvtn.org/protocols/hvtn116)] and committed to maintaining behavior
consistent with low risk of HIV exposure through the last required protocol clinic
visit

Laboratory Inclusion Values:

Hemogram/CBC

- Hemoglobin greater than or equal to 11.0 g/dL for volunteers who were born female,
greater than or equal to 13.0 g/dL for volunteers who were born male

- White blood cell count equal to 2,500 to 12,000 cells/mm^3

- Total lymphocyte count greater than or equal to 800 cells/mm^3

- Remaining differential either within institutional normal range or with site physician
approval

- Platelets equal to 125,000 to 550,000/mm^3

Chemistry

- Chemistry panel: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and
alkaline phosphatase less than 1.25 times the institutional upper limit of normal;
creatinine less than or equal to institutional upper limit of normal

Virology

- Negative HIV-1 and -2 blood test: U.S. volunteers must have a negative Food and Drug
Administration (FDA)-approved enzyme immunoassay (EIA). Non-U.S. sites may use locally
available assays that have been approved by HVTN Laboratory Operations.

- Negative hepatitis B surface antigen (HBsAg)

- Negative anti-hepatitis C virus antibodies (anti-HCV), or negative HCV polymerase
chain reaction (PCR) if the anti-HCV is positive

Urine

- Normal urine:

- Negative urine glucose, and

- Negative or trace urine protein, and

- Negative or trace urine hemoglobin (if trace hemoglobin is present on dipstick, a
microscopic urinalysis with red blood cells levels within institutional normal
range)

Reproductive Status:

- Volunteers who were born female: negative serum or urine beta human chorionic
gonadotropin (β-HCG) pregnancy test performed prior to initial biopsy for groups 1-3
and prior to initial infusion for groups 4-5 on the day of enrollment. Persons who are
NOT of reproductive potential due to having undergone bilateral oophorectomy (verified
by medical records), are not required to undergo pregnancy testing.

Reproductive Status:

United States:

A volunteer who was born female must:

- Agree to consistently use effective contraception (see the protocol 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. Effective
contraception is defined as using the following methods:

- Condoms (male or female) with or without a spermicide,

- Diaphragm or cervical cap with spermicide,

- Intrauterine device (IUD),

- Hormonal contraception, or

- Any other contraceptive method approved by the HVTN 116 Protocol Safety Review
Team (PSRT)

- Successful vasectomy in the male partner (considered successful if a volunteer
reports that a male partner has [1] documentation of azoospermia by microscopy,
or [2] a vasectomy more than 2 years ago with no resultant pregnancy despite
sexual activity postvasectomy);

- Or not be of reproductive potential, such as having had a bilateral oophorectomy, or
tubal ligation;

- Or be sexually abstinent.

South Africa:

A volunteer who was born female must:

- Agree to consistently use effective contraception (see the protocol 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. Effective
contraception for participants in South Africa is defined as using 2 methods of birth
control.

ONE barrier contraceptive method:

- Condoms (male or female)

- Diaphragm or cervical cap

PLUS ONE of the following methods:

- Intrauterine device (IUD),

- Hormonal contraception, or

- Successful vasectomy in the male partner (considered successful if a volunteer reports
that a male partner has [1] documentation of azoospermia by microscopy, or [2] a
vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity
postvasectomy), or

- Any other contraceptive method approved by the HVTN 116 PSRT

Or not be of reproductive potential, such as having had a bilateral oophorectomy, or tubal
ligation;

Or be sexually abstinent.

- Volunteers who were born female 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

Mucosal Specimen Collection

- Volunteers 21 years of age and older who were born female: Pap smear (verified by
medical records) is required within:

- the 3 years prior to enrollment with the latest result reported as normal or
ASCUS (atypical squamous cells of undetermined significance), OR

- the 5 years prior to enrollment, with the latest result reported as normal, or
ASCUS with no evidence of high risk HPV.

- If no Pap smear was done within the last 3 years (or within the last 5 years, if
high risk HPV testing was performed), the volunteer must be willing to undergo a
Pap smear with the result reported (verified by medical records) as normal or
ASCUS prior to sample collection.

- Willing to have mucosal secretions and tissue biopsies collected

- Willing to abstain from sexual intercourse for the required period after each biopsy
collection

Exclusion Criteria:

General

- Blood products received within 120 days before first infusion, unless eligibility for
earlier enrollment is determined by the HVTN 116 PSRT

- Investigational research agents received within 30 days before first infusion

- Intent to participate in another study of an investigational research agent or any
other study that requires non-HVTN HIV antibody testing during the planned duration of
the HVTN 116 study

- Pregnant or breastfeeding

- Active duty U.S. military personnel with the potential of being deployed during the
study

Vaccines and Other Injections

- HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received
control/placebo in an HIV vaccine trial, the HVTN 116 PSRT will determine eligibility
on a case-by-case basis.

- Non-HIV experimental vaccine(s) received within the last 6 months in a prior vaccine
trial. Exceptions may be made for some vaccines and vaccine trials. For volunteers who
have received an experimental vaccine(s) less than 6 months ago, eligibility for
enrollment will be determined by the HVTN 116 PSRT on a case-by-case basis.

- Live attenuated vaccines other than influenza vaccine received within 10 days before
first infusion or scheduled within 10 days after first infusion (e.g., measles, mumps,
and rubella [MMR]; oral polio vaccine [OPV]; varicella; yellow fever)

- Previous receipt of humanized or human mAbs whether licensed or investigational

Immune System

- Immunosuppressive medications received within 30 days before first infusion. (Not
exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; or [3]
topical corticosteroids for mild, uncomplicated dermatitis)

- Serious adverse reactions to VRC01 and VRC01LS 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 (Not exclusionary: mild, well-controlled psoriasis)

- Immunodeficiency

Clinically Significant Medical Conditions

- Untreated or incompletely treated syphilis infection

- 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:

- A process that would affect the immune response,

- A process that would require medication that affects the immune response,

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

- A condition that requires regular use of any anticoagulant medications (not
including aspirin or NSAIDs),

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

- A condition or process for which signs or symptoms could be confused with
reactions to study product, or

- Any condition specifically listed among the exclusion criteria below.

- 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 reactogenicity, 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.

- Current anti-tuberculosis (TB) prophylaxis or therapy

- Asthma other than mild, well-controlled asthma. (Symptoms of asthma severity as
defined in the most recent National Asthma Education and Prevention Program (NAEPP)
Expert Panel report).

- Exclude a volunteer who:

- Uses a short-acting rescue inhaler (typically a beta 2 agonist) daily, or

- Uses moderate/high dose inhaled corticosteroids, or

- In the past year has either of the following:

- Greater than 1 exacerbation of symptoms treated with oral/parenteral
corticosteroids;

- Needed emergency care, urgent care, hospitalization, or intubation for asthma.

- Diabetes mellitus type 1 or type 2, including cases controlled with diet alone. (Not
excluded: history of isolated gestational diabetes.)

- Thyroidectomy, or thyroid disease unless well controlled (normal T3/T4/TSH) with
medication

- Hypertension:

- If a person has been found to have elevated blood pressure or hypertension during
screening or previously, exclude for blood pressure that is not well controlled.
Well-controlled blood pressure is defined as consistently less than or equal to
140 mm Hg systolic and less than or equal to 90 mm Hg diastolic, with or without
medication, with only isolated, brief instances of higher readings, which must be
less than or equal to 150 mm Hg systolic and less than or equal to 100 mm Hg
diastolic. For these volunteers, blood pressure must be less than or equal to 140
mm Hg systolic and less than or equal to 90 mm Hg diastolic at enrollment.

- If a person has NOT been found to have elevated blood pressure or hypertension
during screening or previously, exclude for systolic blood pressure greater than
or equal to 150 mm Hg at enrollment or diastolic blood pressure greater than or
equal to 100 mm Hg at enrollment.

- 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.

- Asplenia: any condition resulting in the absence of a functional spleen

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

- For those undergoing rectal biopsies, a rectal condition, such as an active infection
or inflammation of the colorectal area (e.g., an HSV-2 outbreak or inflamed
hemorrhoids or colitis/diarrhea), internal hemorrhoids, or any other condition noted
during screening rectal exam via anoscope or in medical history that in the opinion of
the clinician represents a contraindication to mucosal sampling

- For those undergoing vaginal and cervical biopsies, any condition noted during pelvic
exam via speculum or in medical history that in the opinion of the clinician
represents a contraindication to mucosal sampling

- An active genital tract condition, such as an active infection or inflammation of the
genital tract (e.g., genital sores or ulcers, penile or abnormal vaginal discharge,
genital warts that are symptomatic or requiring treatment) or any other condition that
in the opinion of the clinician represents a contraindication to mucosal sampling

- Hysterectomy

- Menopause