Phase I Study of HIV Adenoviral Vector Vaccine in Healthy Subjects Using Needle or Biojector Injection

Study Design:

VRC 015 will examine safety, tolerability and immune response to the VRC recombinant
adenoviral vector serotype 5 vector vaccine, VRC-HIVADV014-00-VP (rAd5), in uninfected
subjects who will be randomized to receive the injection either by needle or Biojector
injection. The study will include enrollment of rAd5 vaccine-naive subjects, as well as
enrollment of rollover subjects who received at least one rAd5 injection in a prior study
that included the rAd5 vaccine. The hypothesis is that the rAd5 vaccine will be safe and
immunogenic when administered by either needle or Biojector. The primary objectives are to
evaluate the safety and tolerability of the rAd5 vaccine at 10(10) PU dosage in the naive and
previously vaccinated, uninfected subjects when administered by needle or Biojectors. The
secondary objectives include evaluating the HIV-1-specific humoral and T-cell immune
responses and adenovirus serotype 5 (Ad5) antibody responses, and social impacts of
participation in an HIV vaccine study. Exploratory evaluations include epitope mapping and
other immunogenicity evaluations.

Product Description:

The VRC HIV rAd5 vaccine is a recombinant product composed of 4 adenoviral vectors (in a
3:1:1:1 ratio) that encode the HIV-1 Gag/Pol polyprotein from clade B and HIV-1 Env
glycoproteins from clades A, B, and C, respectively.

Subjects:

Group 1 will include healthy adults, ages 18-50 years old who are HIV vaccine-naive. Group 2
will include healthy adults, ages 18-55 years old, who are rollover enrollments from a prior
study of the VRC HIV rAd5 vaccine.

Study Plan:

Study Group 1 and Group 2 will be simultaneously enrolled. Both groups will be randomized in
1:1 ratio to receive the study injection by needle or Biojector. All study injections will be
at a dosage of 10(10) particle units (PU) of rAd5 vaccine delivered into deltoid muscle.

There are more than 100 past study participants who are potentially eligible for Group 2. The
study design is based on at least 10 rollover subjects, but allows for additional rollover
enrollment of up to 10 more (i.e., Group 2 total n=20) if there is greater than expected
interest in participation. The sample for immunogenicity studies collected at Week 4 after
vaccination from Group 2 subjects will be obtained by apheresis from those who are willing
and eligible for apheresis; otherwise peripheral blood mononuclear cells (PBMCs) will be
obtained from 80 mL blood collected by phlebotomy.

Study Duration:

Subjects will be evaluated at 5 or more clinical visits for 24 weeks after the study
injection and then followed by annual clinic telephone or mail contact for the subsequent 4
years.

- INCLUSION CRITERIA:

A participant must meet all of the following criteria:

1. 18 to 50 years old if enrolling into Group 1 or 18 to 55 years old if enrolling into
Group 2.

2. HIV vaccine naive if enrolling into Group 1, or receipt of the VRC HIV rAd5 vaccine in
a previous study without experiencing a serious adverse event attributed (i.e.,
definitely, probably, possibly, or probably not related) to the vaccine if enrolling
into Group 2.

3. Available for clinical follow-up through Week 24 of the study and committed to four
years of annual follow-up contact after Week 24.

4. Able to provide proof of identity to the satisfaction of the study clinician
completing the enrollment process.

5. Complete an Assessment of Understanding that includes understanding of the STEP Study
results prior to enrollment and verbalize understanding of all questions answered
incorrectly.

6. Able and willing to complete the informed consent process.

7. Willing to receive HIV test results and willing to abide by NIH guidelines for partner
notification of positive HIV results.

8. Willing to donate blood for sample storage to be used for future research.

9. Willing to discuss HIV infection risks, amenable to risk reduction counseling,
committed to maintaining behavior consistent with low risk of HIV exposure through the
last required protocol clinic visit, and assessed by the clinic staff as being at low
risk of HIV infection on the basis of behaviors in the 12 months before enrollment as
follows:

- Sexually abstinent OR

- Had two or fewer mutually monogamous relationships with partners believed to be
HIV-uninfected and who did not use injection drugs, crack cocaine or
methamphetamine OR

- Had two or fewer partners believed to be HIV-uninfected and who did not use
injection drugs, crack cocaine or methamphetamine and with whom he/she regularly
used condoms for vaginal or anal intercourse.

10. In good general health without clinically significant medical history.

11. Physical examination and laboratory results without clinically significant findings
and a body mass index (BMI) less than or equal to 40 within the 56 days prior to
enrollment.

Laboratory Criteria within 56 days prior to enrollment:

12. Hemoglobin greater than or equal to 11.5 g/dL for women; greater than or equal to 13.0
g/dL for men.

13. White blood cells (WBC) = 3,300-12,000 cells/mm(3).

14. Differential either within institutional normal range or accompanied by site physician
approval.

15. Total lymphocyte count greater than or equal to 800 cells/mm(3).

16. Alanine aminotransferase (ALT) less than or equal to 1.25 times the upper limit of
normal

17. Serum creatinine less than or equal to 1 time the upper limit of normal (less than or
equal to 1.3 mg/dL for females; less than or equal to 1.4 mg/dL for males).

18. HIV-uninfected as evidenced by a negative FDA-approved HIV diagnostic blood test if
enrolling into Group 1 or negative HIV polymerase chain reaction (PCR) test if
enrolling into Group 2

19. Negative hepatitis B surface antigen (HbsAg).

20. Negative anti-HCV (hepatitis C virus antibody) and negative HCV PCR.

Female-Specific Criteria:

21. Negative beta-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on
day of enrollment for women presumed to be of reproductive potential.

22. A female participant must meet any of the following criteria:

No reproductive potential because of menopause [one year without menses] or because of a
hysterectomy, bilateral oophorectomy, or tubal ligation,

or

Participant agrees to be heterosexually inactive at least 21 days prior to enrollment and
through Week 24 of the study,

or

Participant agrees to consistently practice contraception at least 21 days prior to
enrollment and through Week 24 of the study by one of the following methods:

- condoms, male or female, with or without a spermicide

- diaphragm or cervical cap with spermicide

- intrauterine device

- contraceptive pills or patch, Depo-Provera or other FDA-approved contraceptive method

- male partner has previously undergone a vasectomy.

EXCLUSION CRITERIA:

A volunteer will be excluded if one or more of the following conditions apply:

Women:

1. Woman who is breast-feeding or planning to become pregnant during the 24 weeks of
study participation.

Volunteer has received any of the following substances:

2. Immunosuppressive medications, cytotoxic medications, inhaled corticosteroids, or
long-acting beta-agonists within the past three months.

[Note: The following will NOT exclude study participation:

- use of corticosteroid nasal spray for rhinitis;

- topical corticosteroids for an acute uncomplicated dermatitis;

- short-acting beta-agonists in controlled asthmatics; a short course (10 days or
less) of corticosteroids for a non-chronic condition completed at least 2 weeks
prior to enrollment in this study]

3. Blood products within 112 days (16 weeks) prior to HIV screening.

4. Immunoglobulin within 56 days (8 weeks) prior to HIV screening.

5. Investigational research agents within 28 days (4 weeks) prior to initial study
vaccine administration.

6. Live attenuated vaccines within 28 days (4 weeks) prior to initial study vaccine
administration.

7. Medically indicated subunit or killed vaccines, e.g. influenza, pneumococcal, or
allergy treatment with antigen injections, within 14 days (2 weeks) prior to study
vaccine administration.

8. Current anti-tuberculosis prophylaxis or therapy.

Volunteer has a history of any of the following clinically significant conditions:

9. Serious adverse reactions to vaccines such as anaphylaxis, urticaria (hives),
respiratory difficulty, angioedema, or abdominal pain.

10. Autoimmune disease or immunodeficiency.

11. Asthma that is unstable or required emergent care, urgent care, hospitalization or
intubation during the past two years or that requires the use of oral or intravenous
corticosteroids.

12. Diabetes mellitus (type I or II), with the exception of gestational diabetes.

13. Thyroid disease that is not well-controlled

14. A history of hereditary angioedema (HAE), acquired angioedema (AAE), or idiopathic
forms of angioedema.

15. Generalized idiopathic urticaria within the last 1 years.

16. Hypertension that is not well controlled by medication or is more than 145/95 at
enrollment.

17. Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or
platelet disorder requiring special precautions) or significant bruising or bleeding
difficulties with IM injections or blood draws.

18. Within the 12 months prior to enrollment: newly-acquired syphilis, gonorrhea,
non-gonococcal urethritis, herpes simplex virus type 2, chlamydia, pelvic inflammatory
disease, trichomonas, mucopurulent cervicitis, epididymitis, proctitis,
lymphogranuloma venereum, chancroid, or hepatitis B.

19. Malignancy that is active or treated malignancy for which there is not reasonable
assurance of sustained cure or malignancy that is likely to recur during the period of
the study.

20. Seizure disorder other than: 1) febrile seizures, 2) seizures secondary to alcohol
withdrawal more than 3 years ago, or 3) seizure that have not required treatment
within the last 3 years.

21. Asplenia, functional asplenia or any condition resulting in the absence or removal of
the spleen.

22. Psychiatric condition that precludes compliance with the protocol; past or present
psychoses; past or present bipolar disorder; disorder requiring lithium; or within
five years prior to enrollment, history of a suicide plan or attempt.

23. Any medical, psychiatric, social condition, occupational reason or other
responsibility that, in the judgment of the investigator, is a contraindication to
protocol participation or impairs a volunteer s ability to give informed consent.

24. Within the 12 months prior to enrollment, one or more of the following:

- excessive daily alcohol use

- frequent binge drinking

- chronic marijuana abuse

- any other illicit drug use