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249 DNA Vaccine Induction of T-Cell Responses prior to Infection Augments the Efficacy of Immunotherapy during HAART Post-Infection
D. Fuller1, M. S. Wu1, P. Rajakumar2, T. Allen3, S. Capuano2, J. T. Fuller1, T. Shipley1, R. Rudersdorf3, A. Sette4, J. R. Haynes1, D. I. Watkins3, and M. Murphey-Corb*2
1Powderject Vaccines, Madison, WI, USA; 2Univ. of Pittsburgh, PA, USA; 3Univ. of Wisconsin, Madison, USA; and 4Epimmune, San Diego, CA, USA
Immunization with vaccines that induce HIV-specific T-cell immunity during highly active antiretroviral therapy (HAART) offers a viable strategy for immunotherapy against HIV. We examined the effects of administering a DNA vaccine as adjunct immunotherapy to HAART in SIV-infected macaques. Thirty-two rhesus macaques were immunized either both before and after infection or only after infection with DNA encoding SIVmac239gag and SIVmac239tat. Sixteen MamuA*01-positive macaques in this group were additionally immunized with DNA encoding 18 MamuA*01-restricted SIVmac239 CTL epitopes fused to a hepatitis core antigen gene. Control groups consisted of 8 macaques, including 4 MamuA*01, immunized with sham DNA vaccines before and after infection. Therapy with daily injections of 20 mg/kg PMPA was initiated 14 days post-infection with the heterologous primary isolate, SIV/DeltaB670. Vaccinations were administered at monthly intervals using the PowderJect gene delivery system to deliver the DNA to the skin. Plasma virus loads and SIV-specific T-cell responses were evaluated during the course of the experiment by real time PCR and by tetramer-staining, proliferation assay, and ELISPOT, respectively. Following the third immunization post-infection/PMPA, mean virus loads in all vaccinated groups were significantly lower than mock-vaccinated controls, with the lowest mean virus loads in animals that were vaccinated both before and after infection. Seven of 8 animals immunized both before and after infection had no detectable virus in plasma, whereas only 3 of 8 monkeys immunized only after infection were plasma virus-free. Plasma virus remained persistently detectable in 6 of 8 mock-vaccinated control monkeys. The magnitude of the CD8+ and CD4+ T-cell immune responses were consistent with the plasma virus loads in each group, with higher responses observed in those animals primed prior to infection. Analysis of the effect of vaccination after removing PMPA is in progress. These interim data indicate that vaccinating uninfected, at-risk individuals with a DNA vaccine may enhance the effectiveness of adjunct immunotherapy to HAART in the event an infection occurs.
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