Safety of and Immune Response to a Prime-Boost Vaccine Regimen in HIV-Uninfected Vaccine-Naive Adults

Some of the first HIV vaccines were designed to trigger neutralizing antibody responses as a
way to prevent HIV infection. Unfortunately, the first versions of these vaccines were not
able to achieve their desired response. An alternative strategy to the antibody approach is
the stimulation of HIV-specific CD8 T-lymphocyte (CTL) responses. CTL responses were
previously demonstrated to play an important role in the control of simian immunodeficiency
virus (SIV), the HIV equivalent seen in rhesus macaque monkeys. Additionally, other studies
suggest CTLs play an important role in viral control during chronic infection. Based on this
information, several groups have shifted their focus to the development of CTL-based
vaccines, some of which have entered advanced clinical trials.

A DNA/rMVA vaccine strategy is structured to bring about both T-cell and antibody responses.
The primary vaccination is DNA based and will express only HIV proteins as a way to produce
an HIV-focused immune response. An rMVA vaccine strategy expresses both HIV and MVA proteins
and may amplify the focused response of a DNA vaccination. Participants in this study will
receive either a combined DNA/rMVA vaccine strategy, in which they receive both types of
vaccines; an rMVA vaccine strategy, in which they receive only the rMVA vaccine; or a
placebo. The DNA and rMVA are physically two different vaccinations given at separate times,
but in the DNA/rMVA group, they will be used together to make up one preventive regimen.
Both vaccine components express noninfectious virus-like particles.

This study is a multicenter, randomized study that is conducted in two parts and comprised
of five groups. In all groups, participants will receive four injections. In Part A, Groups
1 and 2 will be compared. In Group 1, participants will receive two shots of the DNA vaccine
and two shots of the rMVA vaccine. In Group 2, participants will receive four placebo
injections. In Part B, Groups 3, 4, and 5 will be compared. In Group 3, the combination
vaccine strategy will be used again; in Group 4, a single-vaccine strategy of three
injections of the rMVA vaccine and one injection of placebo will be given; and in Group 5,
participants will again receive four placebo injections. The study will last for a total of
12 months for participants, including enrollment and follow-up.

Inclusion Criteria:

- Access to a participating HIV Vaccine Trials Network (HVTN) clinical research center
and willing to be followed for the planned duration of the study

- Ability and willingness to provide informed consent

- Assessment of understanding: completion of a questionnaire prior to first
vaccination; demonstration of understanding for all questionnaire items answered
incorrectly

- Willingness to receive HIV test results

- Good general health as shown by medical history, physical exam, and screening
laboratory tests

- Certain specified laboratory values. More information on this criterion can be found
in the study protocol.

- If pregnancy is possible, must agree to use contraception from at least 21 days prior
to enrollment through the last protocol visit for sexual activity that could lead to
pregnancy. More information on this criterion can be found in the study protocol.

- Willingness to discuss HIV infection risks, amenable to HIV risk reduction
counseling, committed to maintaining behavior consistent with low risk of HIV
exposure through the last required protocol clinic visit, and willing to continue
annual follow-up contact after the last required protocol clinic visit for a total of
5 years following enrollment

- Assessed by clinic staff as being at "low risk" of HIV infection on the basis of
sexual behaviors within the 12 months prior to enrollment. More information on this
criterion can be found in the study protocol.

Exclusion Criteria:

- HIV vaccine(s) or other experimental vaccines, received in a prior HIV vaccine trial.
More information on this criterion can be found in the study protocol.

- Receipt of smallpox vaccination

- Excessive alcohol use, frequent binge drinking, chronic marijuana abuse, or use of
any other illicit drugs, such as cocaine or methamphetamine, within the past 12
months

- History of newly acquired or newly diagnosed syphilis; history of newly acquired
gonorrhea, nongonococcal urethritis, herpes simplex virus type 2 (HSV2), chlamydia,
pelvic inflammatory disease (PID), trichomonas, mucopurulent cervicitis,epididymitis,
proctitis, lymphogranuloma venereum, chancroid, or hepatitis B within the past 12
months

- Immunosuppressive medication received within 168 days before first vaccination.
Certain medications are excluded from this criterion; more information can be found
in the study protocol.

- Blood products received within 120 days before first vaccination

- Immunoglobulin received within 60 days before first vaccination

- Live attenuated vaccines other than influenza vaccine received within 30 days before
first vaccination or scheduled within 14 days after injection

- Influenza vaccine or any vaccines that are not live attenuated and were received
within 14 days prior to first vaccination or that are scheduled within 14 days after
injection

- Allergy treatment with antigen injections within 30 days before first vaccination or
scheduled within 14 days after injection

- Intent to participate in another study of an investigational research agent during
the planned duration of this study

- Current anti-tuberculosis (TB) prophylaxis or therapy

- Clinically significant medical condition. More information on this criterion can be
found in the study protocol.

- Any medical, psychiatric, or social condition or occupational or other responsibility
that in the opinion of the investigator might interfere with the study protocol

- Serious adverse reactions to vaccines. More information on this criterion can be
found in the study protocol.

- Allergy to eggs and/or egg products

- History of or known active cardiac disease. More information on this criterion can be
found in the study protocol.

- Participants who have two or more of the following cardiac risk factors: (1)
participant report of history of elevated blood cholesterol defined as fasting
low-density lipoprotein (LDL) greater than 160 mg/dL; (2) first degree relative
(e.g., mother, father, sister, or brother) who had coronary artery disease before the
age of 50 years; (3) current smoker; or (4) body mass index greater than or equal to
35.

- Electrocardiogram (ECG) with clinically significant findings. More information on
this criterion can be found in the study protocol.

- Autoimmune disease

- Immunodeficiency

- Asthma other than mild, well-controlled asthma. More information on this criterion
can be found in the study protocol.

- Diabetes mellitus, type 1 or type 2, including cases controlled with diet alone.
Those with a history of isolated gestational diabetes are not excluded.

- Thyroidectomy or thyroid disease requiring medication during the last 12 months

- Angioedema within the last 3 years if episodes are considered serious or have
required medication within the last 2 years

- Hypertension. More information on this criterion can be found in the study protocol.

- Body mass index greater than or equal to 40

- Bleeding disorder diagnosed by a doctor

- Malignancy. Participants with surgical excisions and subsequent observation periods,
that in the investigator's estimation have a reasonable assurance of sustained cure
or are unlikely to recur during the period of study, are not excluded.

- Seizure disorder, unless the participant has not required medication or had a seizure
within the last 3 years.

- Asplenia

- Pregnant or breastfeeding