VRC 603: A Phase I Dose-Escalation Study of the Safety of AAV8-VRC07 (VRC-HIVAAV070-00-GT) Recombinant AAV Vector Expressing VRC07 HIV-1 Neutralizing Antibody in Antiretroviral -Treated, HIV-1 Infected Adults With Controlled Viremia.

Design: This is a Phase I study of the safety and tolerability of AAV8-VRC07
(VRC-HIVAAV070-00-GT) expressing VRC07 human monoclonal antibody with broad HIV-1
neutralizing activity in HIV-1 infected adults. It is a dose-escalation study to examine
pharmacokinetics of VRC07 expression following intramuscular (IM) administration of
AAV8-VRC07 in subjects on anti-retroviral therapy (ART). The hypotheses are: 1) AAV8-VRC07
will be safe for human administration and will not elicit hypersensitivity or anti-drug
antibody (ADA) to VRC07; and 2) intramuscular delivery of AAV8-VRC07 will result in
production of biologically active VRC07 antibody at a concentration in serum that is
measurable and safe.

Description: AAV8-VRC07 was developed by VRC, NIAID, NIH, and manufactured by the Clinical
Vector Core, Center for Cellular and Molecular Therapeutics, The Children s Hospital of
Philadelphia (CHOP), Philadelphia, PA. It is composed of an AAV8 recombinant vector
expressing genes encoding the heavy and light chains of the VRC07 monoclonal antibody.
AAV8-VRC07 will be supplied at 2.84x10(13) vg/mL.

Subjects: HIV-1 infected adult volunteers (18 to 60 years old) on a stable antiretroviral
regimen for more than or equal to 3 months, with controlled viremia, under the care of a
physician, and without additional clinically significant medical conditions.

Study Plan: There are 3 dose escalation groups. Sequentially enrolled subjects will be
assigned to the dosage level being evaluated at the time of enrollment. All injections will
be administered intramuscularly (IM) by needle and syringe. Cumulative safety data will be
reviewed weekly by a Protocol Safety Review Team (PSRT) that includes an Independent Safety
Monitor (ISM) while injections are being administered. Safety, including reactogenicity and
unsolicited AEs, laboratory findings, pharmacokinetics, and VRC07 antibody levels in blood
will be assessed after the injection and summarized for an interim analysis at 4 weeks post
injection. The second subject in each dose group will be injected after the 4 weeks safety
assessment for the first subject. Decisions regarding dose escalation and subject enrollments
will be based on safety data and the VRC07 concentration in blood at 4 weeks after product
administration. The pharmacokinetics of VRC07 at each dose level will be evaluated to
determine the dose that would result in antibody production that achieves at least 50 mcg/mL
VRC07 concentration in serum at 4 weeks post injection with a target set point of more than
or equal to 5 mcg/mL at 12 weeks post injection.

- INCLUSION CRITERIA:

A volunteer must meet all of the following criteria:

Able and willing to complete the informed consent process.

18 to 60 years of age.

HIV-1 infected.

On a stable antiretroviral regimen for greater than or equal to 3 months.

Available for clinical follow-up through the last study visit.

Based on history and examination, must be in general good health with no evidence of
clinically significant lab abnormalities and without additional clinically significant
medical conditions as per exclusion criteria.

Willing to maintain or establish a relationship with a primary health care provider for
medical management of HIV infection while participating in the study.

Willing to have blood samples collected, stored indefinitely, and used for research
purposes.

Able to provide proof of identity to the satisfaction of the study clinician completing the
enrollment process.

Laboratory tests assessing subject health will be conducted within 84 days prior to
enrollment and values must meet the following criteria:

1. White blood cell count (WBC) 2,500-12,000/mm cubed;

2. WBC differential either within institutional normal range or accompanied by approval
of the Principal Investigator (PI) or designee;

3. Platelets = 125,000-400,000/mm cubed;

4. Hemoglobin greater than or equal to 10.0 gm/dL;

5. Creatinine less than or equal to 1.1 x upper limit of normal (ULN);

6. ALT less than or equal to 1.1 x ULN;

7. AST less than or equal to 1.1 x ULN; and,

8. VL less than or equal to 50 copies/mL and a CD4 count greater than or equal to
300/mcL.

Male-Specific Criteria:

Males must agree to use condoms for all sexual activity of any reproductive potential for
52 weeks after receiving the study product.

Female-Specific Criteria:

If a woman is sexually active with a male partner and has no history of hysterectomy, tubal
ligation or menopause, she must agree to use either a prescription birth control method or
a barrier birth control method from the time of study enrollment through study Week 52, or
to be monogamous with a partner who has had a vasectomy.

Negative beta-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day of
enrollment for women presumed to be of reproductive potential.

EXCLUSION CRITERIA:

A volunteer will be excluded if one or more of the following conditions apply:

Previous receipt of monoclonal antibody whether licensed or investigational.

Previous receipt of gene therapy product.

Ongoing AIDS-related opportunistic infection (including oral thrush).

Active injection drug use or active drug or alcohol use or dependence that, in the opinion
of the site investigator, would interfere with adherence to study requirements.

Evidence of pre-existing antibodies to AAV8 capsid.

Weight > 115 kg.

History of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis
within the 2 years prior to enrollment that has a reasonable risk of recurrence.

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.

Active liver disease such as chronic hepatitis.

Hypertension that is not well controlled by medication.

Woman who is breast-feeding or planning to become pregnant during the study participation.

Receipt of any investigational study agent within 28 days prior to enrollment.

Any other chronic or clinically significant medical condition that in the opinion of
investigator would jeopardize the safety or rights of the volunteer, including, but not
limited to: diabetes mellitus type I; OR clinically significant forms of asthma, autoimmune
disease, psychiatric disorders, heart disease, or cancer.