Safety and Efficacy of a Three-Dose Regimen of an Adenoviral HIV Vaccine (MRKAd5 HIV-1 Gag/Pol/Nef) in HIV Uninfected South African Adults

A Multicenter Double-Blind Randomized Placebo-Controlled Phase IIB Test-of-Concept Study to Evaluate the Safety and Efficacy of a Three-Dose Regimen of the Clade B-based Merck Adenovirus Serotype 5 HIV-1 Gag/Pol/Nef Vaccine in HIV-1 Uninfected Adults in South Africa

The purpose of this study is to determine the safety, efficacy, and tolerability of a three-dose regimen of an adenovirus-based HIV-1 vaccine in healthy South African adults.

The HIV epidemic is a major global health challenge. The Joint United Nations Program on HIV/AIDS (UNAIDS) reported that in 2004, 3 million people worldwide died of AIDS and an estimated 5 million people acquired HIV. Studies in animal models and observational data from humans suggest that cell-mediated immune responses may be key to controlling HIV infection. MRKAd5 HIV-1 gag/pol/nef, a clade B-based adenovirus serotype 5 HIV-1 vaccine, has been shown to elicit T-cell mediated immune responses. The vaccine appears to be safe and generally well tolerated in previous Phase 1 and 2 studies in HIV-uninfected people. The purpose of this study is to evaluate the safety and efficacy of the MRKAd5 HIV-1 gag/pol/nef vaccine in HIV-uninfected participants from South Africa, where clade C is predominant. The study will address whether a clade B-based vaccine designed to elicit T-cellular immunity will demonstrate efficacy in reducing acquisition of infection, or reducing HIV viral load in persons who become infected in a non-clade B region.

This study will last about 42 months for HIV-uninfected participants; for those who become HIV infected, visits continue for 18 months after diagnosis. Participants will be randomly assigned to receive 3 doses of either vaccine or placebo. All participants will receive their injections at study entry and at Months 1 and 6. Participants will be asked to complete a post-vaccination symptom log for the 3 days following each vaccination to monitor body temperature and symptoms known to be associated with the vaccine. At all study visits, participants will be asked about any adverse events they may have experienced. There will be at least 14 study visits over the first 4 years of the study. A physical exam, medication history, risk reduction counseling, and blood collection will occur at every visit. Participants will be asked to complete a social impact questionnaire at Weeks 12, 78, and 208; an outside testing and belief questionnaire at Weeks 30, 78, 130, 182, and 208; and a circumcision status assessment at Week 208. Participants will undergo HIV testing to check their HIV status approximately every 3 months.

Participants who become HIV infected during the study will have eight study visits at Weeks 4, 8, 12, 16, 20, 26, 52, and 78 post-diagnosis. A physical exam, risk reduction counseling, blood and urine collection, and a pregnancy test will occur at all visits. Genital secretion collection may also occur at some visits. Participants who become HIV infected and need to begin anti-HIV therapy will be discontinued from this study, but encouraged to enroll in the study HVTN 802.

As of September 17, 2007 enrollment and vaccinations for this study were suspended. Participants already enrolled have been asked to continue attending follow-up visits with this study.

Participants who were not diagnosed with HIV infection during their participation in the study will be eligible to enroll in a substudy. The purpose of the substudy is to expand HIV testing and to gather data on behavioral risk factors for HIV infection among participants in the original study. Participants in the substudy will attend a study visit, which will include a physical examination, HIV risk reduction counseling, blood collection, and a behavioral risk questionnaire. Some participants may have an HIV test as part of this visit; these participants will attend a second study visit 2 weeks later to receive their HIV test results. Upon completion of the substudy, researchers will contact participants to provide further information about the substudy results.

As of 9/19/07, clinical research sites were notified that HVTN 503 has been suspended; therefore, enrollment is discontinued and all participants will be unblinded and encouraged to continue follow-up visits.

Inclusion Criteria:

• HIV-1 and -2 negative
• Good general health
• ALT less than 2.6 times the upper limit of normal (ULN)
• Sexually active within the 6 months prior to study entry
• Have access to a participating HIV Vaccine Trials Unit (HVTU) and are willing to be followed during the study
• Demonstrate understanding of the study
• Willing to receive HIV test results
• Female participants must be willing to use acceptable forms of contraception, or not be of reproductive potential. More information about this criterion can be found in the protocol.

Exclusion Criteria:

• Adenovirus 5 titer greater than 200, once enrollment of participants in this stratum has been completed
• HIV vaccines in prior HIV trial. Participants who can provide documentation that they received a placebo in a prior HIV trial may be eligible.
• Immunosuppressive medications within 168 days prior to first study vaccination. Participants who have used corticosteroid nasal sprays for allergic rhinitis or topical corticosteroids for mild, uncomplicated dermatitis are not excluded.
• Blood products within 90 days prior to first study vaccination
• Immunoglobulin within 90 days prior to first study vaccination
• Live attenuated vaccines within 30 days prior to first study vaccination
• Investigational research agents within 30 days prior to first study vaccination
• Medically indicated subunit or killed vaccines within 5 days prior to first study vaccination OR scheduled to receive such vaccines within 14 days after first study vaccination
• Allergy treatment with antigen injections within 30 days prior to first study vaccination
• Clinically significant medical condition, abnormal physical exam findings, abnormal laboratory results, or past medical history that may affect current health. More information about this criterion can be found in the protocol.
• Any medical, psychiatric, or job-related responsibility that would interfere with the study. More information about this criterion can be found in the protocol.
• Any concern that, in the opinion of the investigator, may interfere with a participant's completion of the post-vaccination symptom log
• History of anaphylaxis or allergy to any of the vaccine's components
• Autoimmune disease
• Immunodeficiency
• Bleeding disorder
• Cancer
• Seizure disorder
• Pregnancy or breastfeeding