Study of Safety and Immunogenicity of HIV Vaccines in Healthy Volunteers

This is a Phase 1, single center, randomized, double-blind study designed to evaluate the
safety and immunogenicity of live, replication-competent recombinant Adenovirus type 4-HIV
vaccine regimens. The oral route will also contain a placebo control. The vaccine candidates
Ad4-mgag and Ad4-EnvC150 will be formulated as enteric-coated capsules to be delivered
orally, and as an aqueous formulation for intranasal administration. Determining the optimal
regimen and route will greatly accelerate investigations of these vectors as HIV vaccine
platforms.

Participants volunteering to receive the vaccine orally will be randomized to 1 of 4
treatment arms, and those volunteering to receive the vaccine via the intranasal route will
be randomized to 1 of 3 treatment arms. Participants will receive either 1 or both vaccines
or placebo, depending on group assignment. The study vaccines will be administered to
participants in 3 rounds of vaccination at 0, 2, and 6 months. All participants will receive
a booster vaccination with a bivalent HIV gp120 glycoprotein at 8 months. Intranasal vaccine
recipients with household contact(s) will receive the first vaccine in the NIH Special
Clinical Studies Unit or other appropriate unit and be followed on an inpatient basis to
allow for respiratory isolation. Intranasal vaccinees without household contact(s) may also
receive the vaccination as inpatients or may opt to receive the vaccine on an outpatient
basis if they agree to follow precautions for preventing the spread of adenovirus. Beginning
4 days after vaccination, inpatient participants will be tested daily for respiratory
shedding of Ad4 by nasopharyngeal wash. They will be discharged to home with close monitoring
on Day 7 or after 2 consecutive negative washes, whichever comes first; they may remain on
the unit longer if medically necessary. Prior to receiving the second dose of vaccine on an
outpatient basis, seroconversion to Ad4 will be confirmed in the intranasal vaccine
recipients. Those who have household contact(s) and have not seroconverted will continue to
receive subsequent doses as inpatients until they show seroconversion. Those who do not have
household contact(s) and those who have seroconverted may receive the remaining vaccinations
as inpatients or may opt to receive the doses on an outpatient basis if they agree to follow
precautions for preventing the spread of adenovirus. If they decline these options, they may
withdraw from the study and will be replaced. Oral capsule recipients will be vaccinated and
discharged to home.

In addition to clinical and laboratory monitoring of safety, the principal assessments will
be shedding of this viruses in rectal, cervicovaginal, throat, and nasal swabs, and
assessment of the antibody (mucosal and systemic) response to the HIV and to the Ad4 virus.

The candidate vaccines will also be administered to 2 groups of participants who have
previously received an unrelated HIV vaccine in another clinical study and/or are Ad4
seropositive. The aim for these groups is to explore the boost potential of the enteric
coated capsule and aqueous formulations of the Ad4-mgag and Ad4- EnvC150 vaccines when given
to subjects who have previously received another HIV vaccine and/or are Ad4 seropositive.

The adenovirus vaccines will not be retested for stability in 2018, and therefore will be out
of specifications on May 9th 2018. In an effort to capture as much information on
immunogenicity and adenoviral replication as possible, we will implemement the following
change beginning in 2018. The study will continue with enrollment into the remaining
treatment groups in a nonrandomized manner such that remaining participants receive both the
Ad4-mgag and Ad4-EnvC150 intranasally. These participants will receive 2 rounds of the
intranasal vaccine at Months 0 and 2 followed by a single dose of the booster vaccination at
Month 4.

All participants will be followed for a total of 6 months following the final dose of study
vaccine. Household and intimate contacts will also be enrolled and monitored for Adenovirus
and HIV antibodies for up to 8 months.

- 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. Able to provide proof of identity to the acceptance of the Principal Investigator or
designee during enrollment.

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

5. 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. A female must meet one of the following criteria:

1. No reproductive potential because of menopause (one year without menses) or
because of a hysterectomy, bilateral oophorectomy, or tubal ligation.

OR

2. Participant agrees to be heterosexually inactive or consistently practice
contraception at least 21 days prior to and 28 days following each vaccination.
Acceptable methods of contraception include the following:

- condoms, male or female, with a spermicide.

- diaphragm or cervical cap with spermicide.

- contraceptive pills, Norplant, or Depo-Provera.

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

- intrauterine device.

5. Male participants must agree to practice abstinence or effective birth control for at
least 21 days prior to and 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 vaccination other than the study agent for 30 days prior to and 30
days after administration of the Ad4-HIV vaccine.

4. Safety Laboratory Criteria within 8 weeks prior to enrollment:

Hematopoietic: -White blood cell count and Lymphocyte count +/- 25% of normal limits
for the NIH Clinical Center

- Platelet count of least 100,000/mm(3)

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

Renal: BUN <23 mg/dL; creatinine within normal limits for the NIH Clinical Center

Hepatic: Serum total bilirubin less than or equal to 2 mg/dL

Metabolic: ALT <2 times upper limit of normal range

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 Arms C and D.)

The following inclusion criterion applies only to intranasal vaccinees and not to capsule
vaccine recipients or household or intimate contacts:

1. Willing to be hospitalized at the Clinical Center under respiratory precautions for up
to 7 days or longer if medically indicated.

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 criterion applies 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 (within 6 months) history of chronic infection suggestive
of immunodeficiency.

7. Taking any medication which may affect immune function, except participants may be
taking low doses of nonprescription strength NSAIDS (including e.g. ibuprofen or
aspirin) or acetaminophen.

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, defer immunization but do not
exclude 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 or Hepatitis C viral load).

10. Female of child-bearing potential who is breast-feeding or planning pregnancy during
the 28 days following 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. Participants 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 immunocompromised or immunosuppressed individual.

3. An individual with chronic respiratory disease.

4. A woman who is currently pregnant or planning a pregnancy during the period of
immunization.

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

5. Participants caring for children <18 years of age.

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.