Immune Response to an HIV DNA Plasmid Vaccine Prime Followed by Adenovirus Boost in HIV-uninfected Individuals

The worldwide HIV/AIDS epidemic may only be controlled through development of a safe and
effective vaccine that will prevent HIV infection. DNA vaccines are inexpensive to construct,
readily produced in large quantities, and stable for long periods of time. This study will
evaluate the safety and immunogenicity of an experimental multiclade HIV vaccine,
VRC-HIVDNA016-00-VP, followed by a similarly structured adenovirus-vectored vaccine boost,
VRC-HIVADV014-00-VP, in HIV uninfected adults. The DNA plasmids in both the vaccines code for
proteins from HIV subtypes A, B, and C, which together represent 90% of new HIV infections in
the world. The study's primary objective is to investigate the ability of a 6-plasmid DNA
prime followed by a rAd5 boost to elicit HIV-specific cellular immune responses at mucosal
surfaces.

This study will last 12 months and participants will visit the clinic 15 times. Participants
will receive three injections of the VRC-HIVDNA016-00-VP vaccine at Months 0, 1, and 2
followed by an injection of VRC-HIVADV014-00-VP at Month 6. All injections will be given in
the upper arm. At study visits participants will have a physical, medical history taken,
blood collection, and risk reduction counseling. At some visits, rectal biopsies (via
anoscopy or, optionally, by flexible sigmoidoscopy), saliva, semen, cervical and/or vaginal
fluid samples will also be collected. Pregnancy testing for women will be done prior to each
vaccination and study procedure.

Participants will be contacted by study staff once a year for 5 years after the initial study
visit for follow-up health and safety monitoring.

Inclusion Criteria:

- Access to participating HVTN CRS and willingness to be followed for the planned
duration of the study

- Ability and willingness to provide informed consent

- Assessment of understanding: participant demonstrates understanding of this study and
the Step Study results; completes a questionnaire prior to first vaccination with
verbal demonstration of understanding of all questionnaire items answered incorrectly

- Willingness to receive HIV test results

- 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 clinic visit, and willing to continue annual follow-up contact after the
last required clinic visit, for a total of 5 years following enrollment

- Agrees not to enroll in another study of an investigational research agent prior to
completion of last required protocol clinic visit (excludes annual follow-up contact
for safety surveillance)

- Assessed by clinic staff as being at "low risk" for HIV infection. More information on
this criterion can be found in the protocol.

- Good general health as shown by medical history, physical exam, and screening
laboratory tests. More information on this criterion can be found in the protocol.

- Neutralizing antibody titers of Ad5 less than 1:18

- Hemoglobin equal to or greater than 11.0 g/dL for participants who were born female,
12.5 g/dL for participants who were born male

- White blood cell (WBC) count = 3,300 to 12,000 cells/mm^3

- Total lymphocyte count equal to or greater than 800 cells/mm^3

- Remaining differential either within institutional normal range or accompanied by site
physician approval

- Platelets = 125,000 to 550,000/mm^3

- Prothrombin time (PT) less than 1.5 and partial thromboplastin time (PTT) less than
1.25 greater than upper limits of normal

- Alanine transaminase (ALT) is less than 2.5 times the institutional upper limit of
normal

- Negative HIV-1 and 2 blood test: participants must have a negative FDA-approved enzyme
immunoassay (EIA)

- For participants born female, normal Pap smear or ASCUS with no evidence of high risk
HPV within 3 years prior to enrollment

- Participants who were born female: negative serum or urine beta human chorionic
gonadotropin (β-HCG) pregnancy test performed on the day of initial vaccination prior
to vaccination

- Participants who were born female must agree to consistently use effective
contraception from at least 21 days prior to enrollment through the last required
clinic visit for sexual activity that could lead to pregnancy; or not be of
reproductive potential; or be sexually abstinent. More information on this criterion
can be found in the protocol.

- Participants who were born female must also agree not to seek pregnancy through
alternative methods such as artificial insemination or in vitro fertilization until
after the last required clinic visit

- If born male, must be fully circumcised (as documented at a screening examination)

Exclusion Criteria:

- Excessive daily alcohol use or frequent binge drinking or chronic marijuana abuse or
any other use of illicit drugs within the past 12 months

- A history of newly acquired syphilis, gonorrhea, non-gonococcal urethritis, herpes
simplex virus type 2 (HSV2), Chlamydia, pelvic inflammatory disease (PID),
trichomonas, mucopurulent cervicitis, epididymitis, proctitis, lymphogranuloma
venereum, chancroid, or hepatitis B in the past 12 months

- HIV vaccine(s) received in a prior HIV vaccine trial. For potential participants who
have received control/placebo in an HIV vaccine trial, the HVTN 076 PSRT will
determine eligibility on a case-by-case basis.

- Experimental vaccine(s) received within the last 5 years in a prior vaccine trial.
More information on this criterion can be found in the protocol.

- Immunosuppressive medications received within 168 days before first vaccination (eg,
oral/parenteral corticosteroids, and/or cytotoxic medications). People taking
corticosteroid nasal spray for allergic rhinitis and topical corticosteroids for mild,
uncomplicated dermatitis are not excluded.

- Abnormality of the colorectal mucosa, or significant colorectal symptom(s), which in
the opinion of the clinician represents a contraindication to biopsy (including but
not limited to presence of any unresolved injury, infectious or inflammatory condition
of the local mucosa, and presence of hemorrhoids)

- 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 vaccination (e.g., measles, mumps,
and rubella [MMR]; oral polio vaccine [OPV]; varicella; yellow fever)

- Influenza vaccine or any vaccines that are not live attenuated vaccines received
within 14 days prior to first vaccination or scheduled within 14 days after
vaccination (e.g., influenza, tetanus, pneumococcal, hepatitis A or B)

- Investigational research agents received within 30 days before first vaccination

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

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

- Current anti-tuberculosis (TB) prophylaxis or therapy

- Clinically significant medical condition, physical examination findings, clinically
significant abnormal laboratory results, or past medical history with clinically
significant implications for current health. More information on this criterion can be
found in the protocol.

- 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, protocol adherence, assessment of safety or reactogenicity, or a
participant's ability to give informed consent

- Serious adverse reactions to vaccines including anaphylaxis and related symptoms such
as hives, respiratory difficulty, angioedema, and/or abdominal pain. Participants who
had a nonanaphylactic adverse reaction to pertussis vaccine as a child are not
excluded.

- Autoimmune disease

- Immunodeficiency

- Active syphilis infection. (Not excluded: syphilis fully treated over 6 months prior
to enrollment)

- Reports one or more perianal HSV outbreaks within 30 days prior to enrollment

- Positive gonorrhea or Chlamydia urine nucleic acid amplification test (NAAT)

- Participants reporting receptive anal intercourse in the last 12 months: positive
rectal gonorrhea or Chlamydia test by NAAT or culture

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

- History of partial or complete hysterectomy

- History of valvular heart disease

- Diabetes mellitus type 1 or type 2, including cases controlled with diet alone

- 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 protocol.

- Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or
platelet disorder requiring special precautions)

- Malignancy. (Not excluded: a participant with a surgical excision and subsequent
observation period that in the investigator's estimation has a reasonable assurance of
sustained cure or is unlikely to recur during the period of the study.)

- Seizure disorder. (Not excluded: a participant with a history of seizures who has not
required medications or had a seizure for 3 years.)

- Asplenia: any condition resulting in the absence of a functional spleen

- Psychiatric condition that precludes compliance with the protocol

- Pregnant or breastfeeding

- If born male, has been circumcised within 90 days prior to first vaccination or
displays evidence that surgical site is not fully healed.