The purpose of this study is to see if different doses of an experimental HIV vaccine are safe and to study how the immune system responds to the vaccine. The vaccine will be tested in healthy, HIV uninfected volunteers. AVX101 contains only one of the many substances that HIV needs to make more copies of itself; therefore, the vaccine cannot cause HIV or AIDS.

This study will evaluate the safety and immunogenicity of an alphavirus replicon HIV subtype C gag vaccine. This vaccine utilizes a propagation-defective replicon vector system derived from an attenuated strain of Venezuelan Equine Encephalitis (VEE) virus. The vaccine replicon expresses the gag gene from a South African subtype C isolate of HIV-1.

This study will evaluate the AVX101 vaccine in healthy, HIV uninfected volunteers in both the United States and South Africa. Participants will be randomized to receive either vaccine or placebo at study entry and again at Months 1 and 3. The study will involve four groups of participants in both the US and South Africa, with successive groups receiving increasing doses of the vaccine. Twelve US participants (US Group 1) will be randomized to receive either vaccine or placebo. After a review of initial safety data from this group, 12 South African participants (SA Group 1) will be randomized to receive the same vaccine dose as US Group 1 or placebo, while 12 US participants (US Group 2) will be randomized to receive the next higher vaccine dose or placebo. Review of safety data from SA Group 1 and US Group 2 will inform the decision to begin enrollment into SA Group 2 and US Group 3. This process of review and dose escalation will continue until the study has enrolled participants into all four SA and US Groups or until dose escalation is stopped due to safety concerns.

Participants will have nine study visits over 12 months. Study visits will include clinical evaluation, urine and blood tests, and HIV tests. After each injection, participants will be asked to record their temperature and any symptoms each day for 7 days and report them to the clinic staff.

• Pushko P, Parker M, Ludwig GV, Davis NL, Johnston RE, Smith JF. Replicon-helper systems from attenuated Venezuelan equine encephalitis virus: expression of heterologous genes in vitro and immunization against heterologous pathogens in vivo. Virology. 1997 Dec 22;239(2):389-401.
• Pushko P, Bray M, Ludwig GV, Parker M, Schmaljohn A, Sanchez A, Jahrling PB, Smith JF. Recombinant RNA replicons derived from attenuated Venezuelan equine encephalitis virus protect guinea pigs and mice from Ebola hemorrhagic fever virus. Vaccine. 2000 Aug 15;19(1):142-53.
• Davis NL, Caley IJ, Brown KW, Betts MR, Irlbeck DM, McGrath KM, Connell MJ, Montefiori DC, Frelinger JA, Swanstrom R, Johnson PR, Johnston RE. Vaccination of macaques against pathogenic simian immunodeficiency virus with Venezuelan equine encephalitis virus replicon particles. J Virol. 2000 Jan;74(1):371-8. Erratum in: J Virol 2000 Apr;74(7):3430.
• Strauss JH, Strauss EG. The alphaviruses: gene expression, replication, and evolution. Microbiol Rev. 1994 Sep;58(3):491-562. Review. Erratum in: Microbiol Rev 1994 Dec;58(4):806.

Inclusion Criteria

• HIV negative
• Willing to receive HIV test results
• Good general health
• Acceptable methods of contraception for females of reproductive potential
• Hepatitis B surface antigen negative
• Anti-hepatitis C virus antibody (anti-HCV) negative or negative HCV PCR if anti-HCV is positive
• Access to participating site and available for follow-up during the 12 month study

Exclusion Criteria

• HIV vaccines or placebos in prior HIV vaccine trial
• Measurable anti-VEE antibody
• High risk for HIV infection according to HVTN Risk Criteria
• Immunosuppressive medications within 168 days prior to first study vaccine administration
• Blood products within 120 days prior to first study vaccine administration
• Immunoglobulin within 60 days prior to first study vaccine administration
• Live attenuated vaccines within 30 days prior to first study vaccine administration
• Investigational research agents within 30 days prior to first study vaccine administration
• Subunit or killed vaccines within 14 days prior to first study vaccine administration
• Current tuberculosis prophylaxis or therapy
• Active syphilis
• Serious adverse reaction to vaccines. A person who had an adverse reaction to pertussis vaccine as a child is not excluded.
• Autoimmune disease or immunodeficiency
• Unstable asthma
• Type 1 or Type 2 Diabetes Mellitus
• Thyroid disease requiring treatment
• Serious angioedema within the past 3 years
• Uncontrolled hypertension
• Bleeding disorder
• Malignancy unless it has been surgically removed and, in the opinion of the investigator, is not likely to recur during the study period
• Seizure disorder requiring medication within the past 3 years
• Asplenia
• Mental illness that would interfere with compliance with the protocol
• Other conditions that, in the judgement of the investigator, would interfere with the study
• Pregnant or breast-feeding