Safety and Immunogenicity of Ad4-HIV Envelope Vaccine Vectors in Healthy Volunteers

This is a Phase 1 study to evaluate the immunogenicity and safety of adenovirus serotype 4
(Ad4)-based HIV vaccines when administered via the intranasal route to healthy human
volunteers. It is hypothesized that the vaccines will be safe for human administration and
will elicit immune responses to the HIV components. All study activities will be carried out
at the NIH.

Each study vaccinee will receive 10^8 viral particles of either Ad4-Env150KN or
Ad4-Env145NFL, administered as an intranasal spray at months 0 and 2. An intramuscular
protein booster vaccination with the heterologous soluble trimeric protein
VRC-HIVRGP096-00-VP (Trimer 4571) with alum will be administered to all vaccinees at month 6.
Specimens to evaluate immunogenicity will be taken at baseline and at specified time points
through month 12. The HIV-specific immune responses will be assessed by cellular immune
function assays (intracellular cytokine analysis, flow cytometry-based killing assays), as
well as measures of humoral immunity (enzyme-linked immunosorbent assay [ELISA] and
neutralization assays).

The overall goal will be to compare the safety and immunogenicity of the Ad-HIV vaccine
regimens. Participants who have previously received another HIV vaccine and/or are Ad4
seropositive will be enrolled into an exploratory arm to be analyzed separately.

Household contacts willing to participate and all intimate contacts (current and/or those
expected within the first 4 weeks after vaccination) will also be enrolled and monitored for
transmission of the vaccine virus by serology.

- INCLUSION CRITERIA:

All participants (vaccinees, household contacts, and intimate contacts) must meet all of
the following criteria:

1. Age 18 to 49 years for vaccinees. Age 18 to 65 years for household and intimate
contacts.

2. Negative FDA-approved HIV test.

3. Available and willing to participate in follow-up visits and tests for the duration of
the study.

4. Willing to have samples stored for future research.

The following inclusion criteria apply to vaccinees and intimate contacts, but not to
household contacts:

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

2. Willing to discuss HIV infection risks with the study clinicians, assessed as low risk
for HIV infection, amenable to HIV risk reduction counseling, and committed to
maintaining behavior consistent with low risk of HIV exposure through the last
required clinic visit in the protocol schedule.

3. Negative beta-HCG pregnancy test for females presumed to be of reproductive potential.

4. Female vaccinees and male intimate contacts must meet one of the following criteria:

-The female vaccinee has no reproductive potential because of menopause (1 year
without menses) or because of a hysterectomy, bilateral oophorectomy,
medically-documented ovarian failure, or tubal ligation.

or

-The female vaccinee and her male intimate contact(s) agree to be heterosexually
inactive or consistently practice contraception at least 21 days prior to each
vaccination through 28 days following each vaccination. Acceptable methods of
contraception include any of

the following:

- condoms, male or female, with a spermicide.

- diaphragm or cervical cap with spermicide.

- contraceptive pills, Norplant, or Depo-Provera (and is not on any medications
that would interfere with the effectiveness of these contraceptive agents).

- male partner has previously undergone a vasectomy for which there is
documentation.

- intrauterine device.

5. Male vaccinees and female intimate contacts must agree to consistently practice
abstinence or effective birth control (described above) and for 28 days following each
vaccination.

The following inclusion criteria apply only to vaccinees and not to household or intimate
contacts:

1. Willing to receive HIV test results and abide by NIH guidelines for partner
notification of positive HIV results.

2. Physical examination and laboratory results without clinically significant findings
within the 8 weeks prior to enrollment.

3. Willing to avoid other investigational and/or HIV vaccinations, other than the study
agent, from screening through the end-of-study visit.

4. Safety laboratory criteria within 8 weeks prior to enrollment:

- Hematopoietic:

- White blood cell count and lymphocyte count within 25% of both the lower
limit and upper limit of normal for the NIH CC (ranges: 2.985-12.55 K/uL for
white blood cells and 0.885 4.675 K/uL for lymphocytes).

- Platelet count of least 150,000/mm3.

- Hemoglobin >11.2 g/dL for females and >13.0 g/dL for males.

- Renal: Blood urea nitrogen (BUN) <23 mg/dL; creatinine within normal limits for
the NIH CC (females: 0.51-0.95 mg/dL; males: 0.67-1.17 mg/dL).

- Hepatic: Serum direct bilirubin within normal limits for the NIH CC (0.0 to 0.3
mg/dL).

- Metabolic: Alanine aminotransferase (ALT) 1.5 times upper limit of normal range
(females: <49.5 U/L; males: <61.5 U/L).

- Endocrine: Serum glucose within normal range.

5. Additional laboratory criteria:

- Immunologic: No history of hypogammaglobulinemia.

- Serologic: Ad4 neutralizing antibody 80% inhibitory dilution <1:100. (This
criterion does not apply to participants in Arm B.)

6. Willing to follow precautions for preventing the spread of adenovirus in the
community.

7. Males must agree not to donate sperm for 28 days following each study vaccination.

EXCLUSION CRITERIA:

A participant (vaccinees, household contacts, and intimate contacts) will be excluded if
they have the following:

1. Any condition that, in the investigator s judgement, places the subject at undue risk by
participating in the study.

The following exclusion criteria apply to vaccinees and intimate contacts, but not to
household contacts:

1. History of any prior disease or therapy which would affect immune or pulmonary
function.

2. Prior malignancy, except curatively-treated basal cell or squamous cell carcinoma of
the skin or carcinoma in situ of the cervix.

3. History of radiation therapy or cytotoxic/cancer chemotherapy.

4. History of diabetes mellitus.

5. Immunodeficiency or autoimmune disease.

6. Acute infection or a recent history (within 6 months) of chronic infection suggestive
of immunodeficiency.

7. Taking any glucocorticoids or other immunosuppressive medications.

8. Chronic respiratory disorders including asthma, emphysema, interstitial lung disease,
pulmonary hypertension, recurrent pneumonia, or recent or ongoing respiratory tract
infection. If a respiratory disorder is transient, the study vaccination may be
deferred without excluding the participant.

9. Active hepatitis B or C infection (i.e., hepatitis B or C positive serology with the
presence of virus antigen or DNA). Ongoing viral replication will be confirmed by a
hepatitis B antigen test or hepatitis C viral load.

10. Female of childbearing potential who is breast-feeding or planning pregnancy during
the period from enrollment through 28 days following the last study vaccination.

The following exclusion criteria apply only to vaccinees and not to household or intimate
contacts:

1. Any medical, psychiatric, or social condition, or occupational or other responsibility
that, in the judgment of the investigator, would interfere with or serve as a
contraindication to receipt of live virus vaccine, protocol adherence, or a
participant s ability to give informed consent.

2. Psychiatric condition that precludes compliance with the protocol; past or present
psychoses; past or present bipolar disorder requiring therapy that has not been well
controlled on medication for the past two years; disorder requiring lithium; or
suicidal ideation occurring within five years prior to enrollment.

3. Individuals that live in the same house or apartment with any of the following will be
excluded:

1. An individual under 18 years of age.

2. An elderly individual (>65 years of age).

3. An immunocompromised or immunosuppressed individual.

4. An individual with chronic respiratory disease.

5. A woman who is currently pregnant or breastfeeding or planning a pregnancy during
the period of vaccination.

4. Healthcare worker who has direct contact with immunodeficient, unstable, elderly, or
pediatric patients.

5. Individuals caring for children <18 years of age or elderly individuals.

6. Receipt of any of the following:

- Antiviral medications within 30 days prior to vaccination.

- Blood products within 120 days prior to HIV screening.

- Immunoglobulin within 60 days prior to HIV screening.

- Investigational research drugs or any other investigational agent that in the
judgement of the Principal Investigator might interact with the study vaccine
within 30 days prior to initial study vaccine administration.

- Allergy treatment with antigen injections within 30 days of study vaccine
administration.

7. History of Guillain-Barr(SqrRoot)(Copyright) syndrome.

8. Indeterminate HIV Western blot test.

9. Prior receipt of an Ad5-based vaccine.

10. Refusal of any of the individual s intimate contacts to enroll as such on this study.