Examining the Role of Genetics in Determining the Immune Response to an HIV Vaccine in HIV-Uninfected Adult Twins

Genetics may play a role in the immune response to HIV vaccines. It remains unknown,
however, exactly what the genetic influence on the immune response may be. This study will
examine how genes affect the strength of an immune response produced by HIV vaccines and how
genes influence different immune responses. In this study, participants will receive two HIV
vaccines—a DNA HIV vaccine (VRC-HIVDNA016-00-VP) and a recombinant adenoviral serotype 5
(rAd5) vector HIV vaccine (HIVADV014-00-VP). Both of these vaccines are experimental, but
have been used in previous clinical trials without any serious side effects. Comparing
immunological responses in HIV vaccine trials can be complicated by various genetic and
environmental factors. This study will enroll pairs of twins who grew up in common childhood
environments. This will provide researchers with participants who have similar backgrounds
so that the role of genetics can be examined while controlling for other environmental
variables. The purpose of this study is to examine how genes may influence the immune
response to a DNA HIV vaccine followed by a rAd5 HIV vaccine.

This study will enroll pairs of healthy, HIV-uninfected monozygotic and dizygotic adult
twins. Participants will receive the DNA vaccine at baseline and Months 1 and 2, and the
rAd5 vaccine at Month 6. Both vaccines will be injected into the upper arm. At all
vaccination study visits, participants will undergo a medical history and medication history
review, physical exam, and blood collection. Participants will also complete questionnaires
and a social impact assessment. They will receive counseling on HIV testing, 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, additional study visits will occur at
Weeks 2, 6, and 10; 1, 3, and 7 days after the Month 6 visit; and Months 7, 9, 12, and 18.
Various study procedures, including a physical exam, blood collection, and counseling, will
be repeated at these visits. At the end of 18 months, participants will be contacted by
study researchers once a year for 3 ½ years for follow-up health monitoring.

Inclusion Criteria:

- Pairs of MZ and DZ twins who shared common childhood environments

- If born male, participant must be fully circumcised (as documented at screening
examination). Circumcision must have been performed at least 90 days prior to first
vaccination and surgical site must be fully healed.

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

- 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 HIV exposure through the
last required study visit, and 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" for 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.

- Ad5 nAb titer less than 1:18

- Hemoglobin greater than or equal to 11.3 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 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 2.5 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

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

- Agree not to participate in any other study requiring blood draws more than 10 mLs
total or additional investigational drugs 56 days before study entry or during the
study

- 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

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, chlamydia, pelvic inflammatory disease (PID), trichomonas,
mucopurulent cervicitis, epididymitis, proctitis, lymphogranuloma venereum,
chancroid, or hepatitis B in the 12 months 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 or allergy treatment with antigen
injections received within 14 days before the first study vaccination

- Current anti-tuberculosis preventive therapy or treatment

- Clinically significant medical condition, abnormal physical examination findings,
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 as a child 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 isolated gestational diabetes are not excluded.

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

- History of hereditary angioedema, acquired angioedema, or idiopathic forms of
angioedema

- Idiopathic urticaria within the 2 years before study entry

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

- 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 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