Safety and Effectiveness of HIV-1 DNA Plasmid Vaccine and HIV-1 Recombinant Adenoviral Vector Vaccine in HIV-Uninfected, Circumcised Men and Male-to-Female (MTF) Transgender Persons Who Have Sex With Men

In 2007, the Joint United Nations Programme on HIV/AIDS estimated that 33.2 million people
were living with HIV/AIDS globally. The U.S. HIV prevalence data reported in October 2008 by
the Centers for Disease Control and Prevention estimate that 1.1 million adults and
adolescents were living with diagnosed or undiagnosed HIV infection in the United States at
the end of 2006. Nearly half of all U.S. HIV infections (48.1%) were found in men who have
sex with men (MSM). Given the difficulty of maintaining behaviors that prevent HIV
transmission over a lifetime and the occurrence of nonconsensual sex, the need for a safe and
effective vaccine is clear. The primary purpose of this study is to determine the safety and
efficacy of a VRC DNA/rAd5 vaccine regimen in healthy, at-risk, circumcised men and MTF
transgender persons who have sex with men.

Participants will be randomly assigned to one of two arms. Participants in Arm 1 will receive
a recombinant DNA plasmid vaccine injection at study entry and on Days 28 and 56, followed by
a recombinant adenoviral serotype vector vaccine injection on Day 168. Participants in Arm 2
will receive placebo injections at study entry and on Days 28, 56, and 168.

Participants who do not become HIV infected will be actively followed for a minimum of 24
months and will continue to be followed by the study for long-term safety surveillance for a
total of 5 years following enrollment. Participants will be contacted annually during the
period of long-term safety surveillance.

Participants who are found to be HIV infected prior to receiving their first injection or who
receive their first injection but were HIV infected prior to study start will be followed on
a modified schedule.

Participants who become HIV infected will be followed for 6 months post-diagnosis.

At most study visits, participants will undergo a physical exam and blood draw.

NOTES:

As of April 2013, all vaccinations in this study have been stopped. Participants have been
notified of whether they received the study vaccines or placebo. Participants diagnosed with
HIV infection will attend study visits for 6 months for health monitoring. Participants who
are not diagnosed with HIV infection will attend planned study visits for 24 months and will
be followed by the study clinic at least annually for a total of 5 years following study
enrollment.

As of June 2017, this study has been closed. Therefore, to avoid further burden on study
participants, further participant follow-up for the study is suspended.

Inclusion Criteria:

- HIV-1 and -2 negative

- Good general health

- Fully circumcised

- Experienced one or both of the following HIV risk criteria in the 6 months before
study entry:

1. Unprotected anal intercourse with one or more male or MTF transgender partner(s)

2. Anal intercourse with two or more male or MTF transgender partners

- Alanine aminotransferase (ALT) 2.5 or less times the upper limit of normal (ULN)

- Ad5 neutralizing antibody (nAb) titer less than 1:18

- Have access to a participating study site and are willing to be followed during the
study

- Demonstrate understanding of the study

- Willing to receive HIV test results

- Willing to discuss HIV infection risks and amenable to risk-reduction counseling

- Agrees not to enroll in another study of an investigational research agent before
unblinding of this study

- NOTE: MTF transgender volunteers who have undergone gender reassignment surgery (GRS)
are eligible to participate if they provide documentation from a health care provider
confirming that they were fully circumcised prior to GRS. MTF transgender volunteers
who have not undergone GRS are eligible to participate if they meet all enrollment
criteria. Receipt of hormonal therapy does not make a transgender volunteer
ineligible.

Exclusion Criteria:

- HIV vaccines in prior HIV vaccine trial. Participants who can provide documentation
that they received a placebo in a prior HIV trial may be eligible.

- Used antiretroviral (ARV) drugs for the purpose of HIV-1 prophylaxis for greater than
or equal to 50% of days during the 3 months prior to first vaccination or for 30
consecutive days within the 60 days prior to first vaccination

- Circumcised within 90 days prior to first vaccination or displays evidence that
surgical site is not fully healed

- Immunosuppressive medications within 168 days prior to first study vaccination.
Participants who have used corticosteroid nasal sprays for allergic rhinitis; topical
corticosteroids for mild, uncomplicated dermatitis; or oral/parenteral corticosteroids
for nonchronic conditions are not excluded.

- Blood products within 90 days prior to first study vaccination

- Immunoglobulin within 90 days prior to first study vaccination

- Live attenuated vaccines other than influenza vaccine within 30 days prior to first
study vaccination

- Investigational research agents within 90 days prior to first study vaccination

- Influenza vaccine or any vaccines that are not live attenuated within 14 days prior to
first study vaccination

- Allergy treatment with antigen injections within 30 days prior to first study
vaccination or that are scheduled within 14 days after first vaccination

- Clinically significant medical condition, physical examination findings, abnormal
laboratory results, or past medical history that, in the judgment of the investigator,
has significant implications for current health

- Any medical, psychiatric, or job-related responsibility that would interfere with the
study. More information about this criterion can be found in the protocol.

- Any concern that, in the opinion of the investigator, may interfere with a
participant's completion of the post-vaccination symptom log

- History of serious adverse reactions to vaccinations, including anaphylaxis or allergy
to any of the vaccine's components

- Current anti-tuberculosis prophylaxis or therapy

- Autoimmune disease. People with mild, stable, and uncomplicated autoimmune disease
that does not require immunosuppressive medication and that, in the judgment of the
site investigator, is likely not subject to exacerbation and likely not to complicate
reactogenicity and adverse event assessments are not excluded.

- Immunodeficiency

- Bleeding disorder

- History of malignancy

- Seizure disorder. People with a history of seizures who have had no seizures within
the 3 years prior to study entry are not excluded.

- Asthma other than mild, well-controlled asthma

- Hereditary angioedema (HAE), acquired angioedema (AAE), or idiopathic angioedema