Dose, Safety, Tolerability, and Immunogenicity of an HIV-1 Vaccine, VRC-HIVRGP096-00-VP, With Alum in Healthy Adults

Design:

This is a Phase I, open-label, dose escalation study to evaluate the dose, safety,
tolerability, and immunogenicity of VRC-HIVRGP096-00-VP (Trimer 4571) with aluminum hydroxide
suspension (alum) as adjuvant in a three-injection regimen. The hypotheses are that the
vaccine will be safe and tolerable and will induce detectable immune responses. The primary
objective is to evaluate the safety and tolerability of the investigational vaccine at three
doses administered with alum. Secondary objectives are to evaluate humoral and cellular
immunogenicity of the investigational vaccine regimens.

Study Products:

VRC-HIVRGP096-00-VP (Trimer 4571) was developed by the Vaccine Research Center (VRC),
National Institute of Allergy and Infectious Diseases (NIAID). The soluble HIV-1 envelope
product consists of an HIV-1 envelope (Env) trimer variant, derived from clade A, strain
BG505, with stabilizing mutations and engineered disulfide bonds, specifically recognized by
broadly neutralizing antibodies and resists gp120 conformational change caused by CD4
binding. Injections will be administered intramuscularly (IM) and subcutaneously (SC) in a 1
mL volume by needle and syringe. The product is provided at a 500 mcg/mL concentration in 3
mL glass vials filled to 1.2 +/- 0.10 mL. Adjuvant is an aluminum hydroxide suspension (alum)
provided in a sterile, pyrogen-free suspension at a concentration of 5 mg/mL in 3 mL glass
vials filled to 0.7 +/- 0.10 mL.

Subjects:

Healthy adults ages 18 to 50.

Study Plan:

Subjects will receive VRC-HIVRGP096-00-VP at doses of 100 mcg or 500 mcg, both with 500mcg
alum field mixed, administered via IM or SC injections. A dose escalation evaluation will
occur to ensure the safety data support proceeding to the higher dose. Subjects will be
evaluated for safety and immune responses through blood collection at specified timepoints
throughout the study. The study schema is below:

Group 1: Subjects = 3; Route = IM; Dose (mcg) = 100; Day** 0, Week** 8, Week** 20

Group 2: Subjects = 3; Route = SC; Dose (mcg) = 100; Day** 0, Week** 8, Week** 20

Group 3: Subjects = 5; Route = IM; Dose (mcg) = 500; Day** 0, Week** 8, Week** 20

Group 4: Subjects = 5; Route = SC; Dose (mcg) = 500; Day** 0, Week** 8, Week** 20

Total = *16 Subjects

**500 mcg of alum will be field mixed with Trimer 4571 for all groups

*Up to 25 subjects may be enrolled if needed to evaluate safety or immunogenicity.

Duration:

Subjects will be followed for 40 weeks.

- INCLUSION CRITERIA:

A subject must meet all of the following criteria:

1. Able and willing to complete the informed consent process.

2. 18-50 years old, inclusive, on day of enrollment.

3. Available for clinic follow-up through the last study visit.

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

5. Willing to donate blood for sample storage to be used for future research.

6. In good general health without clinically significant medical history.

7. Physical examination and laboratory results without clinically significant findings.

8. Body Mass Index (BMI) less than or equal to 40.

9. Assessed as low risk for HIV acquisition by agreeing to discuss HIV infection risks,
agreeing to risk reduction counseling, and agreeing to avoid behavior associated with
high risk of HIV exposure through the end of study.

10. Screening laboratory values within 56 days prior to enrollment that meet the following
criteria:

- Hemoglobin within the institutional normal limits

- White blood cell (WBC) count between 2,500-12,000/mm^3

- WBC differential absolute cell counts either within institutional normal range or
accompanied by site PI or Associate Investigator (AI) approval, except
neutrophils and lymphocytes must specifically be within the range of greater than
or equal to 0.75 x the lower limit of normal (LLN) and lees than or equal to 1.25
x the upper limit of normal (ULN) for neutrophil and lymphocyte absolute counts

- Platelets = 125,000-500,000/m^3

- Alanine aminotransferase (ALT) less than or equal to 1.25 x ULN based on the
institutional normal range

- Serum creatinine less than or equal to 1.1 x ULN based on the institutional
normal range

- Negative for HIV infection by an FDA approved method of detection

Woman-specific (if presumed to be of childbearing potential):

11. Agrees to use effective means of birth control from at least 21 days prior to
enrollment through the end of the study.

12. Negative beta-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on
day of enrollment.

EXCLUSION CRITERIA:

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

Woman-specific:

1. Breast-feeding or planning to become pregnant through the end of study.

Subject has received any of the following:

2. An investigational HIV vaccine.

3. Systemic glucocorticoid use equal or greater than prednisone 20mg/day within 4 weeks
prior to enrollment, or other medication use likely to impair vaccine response.

4. Blood products within 16 weeks prior to enrollment.

5. Live attenuated vaccines within 4 weeks prior to enrollment.

6. Inactivated vaccines within 2 weeks prior to enrollment.

7. Investigational research agents within 4 weeks prior to enrollment.

8. Current allergen immunotherapy with antigen injections, unless on maintenance
schedule.

9. Current anti-TB prophylaxis or therapy.

Subject has any of the following:

10. Serious reactions to vaccines that preclude receipt of study injections as determined
by the principal investigator or designee.

11. Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema.

12. Hypertension that is not well controlled.

13. Evidence of significant autoimmune disease or immunodeficiency.

14. Idiopathic urticaria within the past year.

15. 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.

16. Seizure disorder other than: 1) febrile seizures, 2) seizures secondary to alcohol
withdrawal more than 3 years ago, or 3) seizures that have not required treatment
within the last 3 years.

17. Asplenia or functional asplenia.

18. Any other chronic or clinically significant condition that in the opinion of the
investigator would jeopardize the safety or rights of the study subject including but
not limited to: diabetes mellitus type I, chronic hepatitis; OR clinically significant
forms of: drug or alcohol abuse, asthma, psychiatric disorders, heart disease, or
cancer.