Evaluating Heterologous-Insert Prime-Boost HIV Vaccine Regimens in HIV-Uninfected Adults

One approach to developing a preventive HIV vaccine includes the use of a prime-boost
vaccine strategy. This type of strategy involves two vaccines, given sequentially at
different time points. The goal is to stimulate different parts of the immune system and
enhance the body's overall immune response to HIV. In this study, participants will receive
two HIV vaccines 3 months apart. Heterologous-insert prime-boost vaccine regimens, which use
the same gene from different HIV-1 subtypes, may be more effective than traditional
homologous insert prime-boost vaccine regimens at eliciting immune responses directed at
epitopes that are highly prevalent, possibly leading to a more effective immune system
response to the vaccine. The purpose of this study is to assess the safety and
immunogenicity of a heterologous-insert prime-boost HIV vaccine regimen that uses inserts
from different HIV-1 subtypes and different adenovirus vectors.

This study will enroll healthy, HIV-uninfected people. Participants will be randomly
assigned to one of five study groups:

- Group 1 will receive the recombinant adenovirus serotype 35 (rAd35) Env A vaccine at
baseline and the recombinant adenovirus serotype 5 (rAd5) Env A vaccine at Month 3.

- Group 2 will receive the rAd35 Env A vaccine at baseline and the rAd5 Env B vaccine at
Month 3.

- Group 3 will receive the rAd35 Env A vaccine at baseline and at Month 3.

- Group 4 will receive the rAd5 Env A vaccine at baseline and at Month 3.

- Group 5 will receive the rAd5 Env A vaccine at baseline and the rAd5 Env B vaccine at
Month 3.

All vaccines will be injected into the upper arm. At both vaccination study visits,
participants will undergo a physical exam, a medical and medication history review, a blood
and urine collection, and questionnaires. Participants will receive counseling on HIV risk
reduction and pregnancy prevention. After receiving the vaccine, participants will remain in
the clinic for at least 30 minutes for observation and monitoring of side effects. For 3
days after each vaccination, participants will record their temperature and side effects in
a symptom log. In addition to the vaccine study visits, other study visits will occur at
Week 2, two weeks after the Month 3 visit, and at Months 4, 6, and 9, at which time various
study procedures will be repeated.

Participants will be contacted by study researchers once a year for 5 years for follow-up
safety monitoring. Safety monitoring will not involve visiting a clinic except if a
confirmatory HIV test is needed. Questions will assess health and adverse events.

The primary objective of this study is to assess the safety and tolerability, as well as the
ability, of a heterologous-insert prime-boost vaccine regimen using env inserts from
different HIV-1 clades to increase T-cell responses. In addition, this study is evaluating
the effectiveness of a heterologous-insert prime-boost and vector prime-boost vaccine
regimen at increasing T-cell responses. The study will also compare the degree of
polyfunctionality of insert specific T cells after vaccination within heterologous and
homologous vector vaccine regimens.

Inclusion Criteria:

- Assessed by clinic staff as being "low risk" for HIV infection

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

- Able and willing to provide informed consent

- Assessment of understanding, including the completion of a questionnaire before the
first vaccination and demonstration of understanding for all questionnaire items
answered incorrectly

- Willing to receive HIV test results

- Willing 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 study visit

- Willing to continue annual follow-up contact after the final study visit for a total
of 5 years after study entry

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

- Assessed by the clinic staff as having a low risk of HIV infection on the basis of
sexual behaviors in the 12 months before study entry. More information on this
criterion can be found in the protocol.

- Adenovirus 5 nAb titer less than 1:18

- Adenovirus 35 nAb titer less than 1:12

- Hemoglobin greater than or equal to 11.0 g/dL for participants who were born female
and greater than or equal to 13.0 g/dL for participants who were born male

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

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

- Remaining differential either within site's normal range or with site physician
approval

- Platelet level between 125,000 to 550,000/mm^3

- Alanine aminotransferase (ALT) less than or equal to 1.25 times the site's upper
limit of normal

- Negative HIV-1 and -2 blood test

- Negative Hepatitis B surface antigen (HBsAg)

- Negative anti-Hepatitis C virus antibodies (anti-HCV), or negative HCV polymerase
chain reaction (PCR) if the anti-HCV test is positive

- Normal urine test results

- Participants who were born female must have a negative pregnancy test result before
the first study vaccination

- Participants who were born female must agree to use an effective form of
contraception from at least 21 days before study entry until the last study visit.
More information on this criterion can be found in the protocol.

- Participants who were born female must agree not to seek pregnancy through
alternative methods (e.g., artificial insemination, in vitro fertilization) until
after the last study visit

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

Exclusion Criteria:

- Excessive daily alcohol use, frequent binge drinking, chronic marijuana abuse, or use
of any other illicit drugs in the 12 months before study entry

- 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 12 months before study entry

- Received non-HIV experimental vaccines in a previous vaccine trial in the 5 years
before study entry

- Received HIV vaccines in a prior HIV vaccine trial

- Immunosuppressive medications received within 168 days before the first study
vaccination

- Blood products received within 120 days before the first study vaccination

- Immunoglobulin received within 60 days before the first study vaccination

- Live attenuated vaccines received within 30 days before the first study vaccination
or scheduled within 14 days after injection

- Investigational research agents received within 30 days before the first study
vaccination

- Intent to participate in another investigational drug study

- Any vaccines that are not live attenuated vaccines and were received within 14 days
before the first study vaccination

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

- Current anti-tuberculosis (TB) prophylaxis or therapy

- Clinically significant medical condition, abnormal physical examination findings,
clinically significant abnormal laboratory results, or past medical history that may
affect current health

- Any medical, psychiatric, occupational, or other condition that would interfere with
participation in the study

- Serious adverse reactions to vaccines, including anaphylaxis and related symptoms
(e.g., hives, respiratory difficulty, angioedema, abdominal pain). A person who had
an adverse reaction to the pertussis vaccine is not excluded.

- Autoimmune disease or immunodeficiency

- Active syphilis infection

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

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

- Surgical removal of the thyroid or thyroid disease requiring medication in the 12
months before study entry

- Angioedema in the 3 years before study entry or angioedema requiring medication in
the 2 years before study entry

- High blood pressure that is not well controlled or high blood pressure of 150/100 mm
Hg or greater at study entry. More information on this criterion can be found in the
protocol.

- Body mass index (BMI) greater than or equal to 40, or BMI greater than or equal to 35
and two or more of the following conditions: age greater than 45, systolic blood
pressure greater than 140 mm Hg, diastolic blood pressure greater than 90 mm Hg,
current smoker, or known hyperlipidemia

- Bleeding disorder (e.g., factor deficiency, coagulopathy, platelet disorder requiring
special precautions)

- Cancer. People with surgically removed cancer, that in the opinion of the
investigator, is unlikely to recur during the study period are not excluded.

- Seizure disorder. People with a history of seizures who have not required medications
or had a seizure within the 3 years before study entry are not excluded.

- Absence of the spleen

- Psychiatric condition that makes study compliance difficult (e.g., people with
psychoses in the 3 years before study entry, ongoing risk for suicide, history of
suicide attempt in the 3 years before study entry)

- Pregnant or breastfeeding

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