PROTECTIVE EFFICACY OF MERCK AD5 PRIME/BOOST AGAINST MUCOSAL CHALLENGE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To address some of the lingering questions surrounding the failed STEP HIV vaccine study in humans by assessing the antiviral immune responses and the efficacy of the vaccine regimen in rhesus macaques. PROGRESS: In the wake of the STEP trial, questions remain as to why the vaccine regimen failed to protect against or control virus replication. The limited breadth of vaccine-induced T-cell responses has been suggested as a possible reason for the failure. To address this, we vaccinated eight Indian Rhesus macaques using the STEP trial protocol. Macaques were immunized intramuscularly with a 1:1:1 ratio of three separate Ad5 vectors expressing gag, pol or nef derived from SIVmac239 and administered on weeks 0, 4 and 26 of the study. Using cryopreserved cells collected at four weeks post-immunization, we detected very few vaccine-induced T cell responses (1-2 epitopes/open reading frame) consistent with the STEP trial results. However, one week after the third immunization, we detected vaccine-induced CD8+ and CD4+ T-cell responses against an average of 11 epitopes in IFN-¿ ELISPOT assays (1-5 epitopes/open reading frame). Impressively, the magnitude of these CD8+ and CD4+ T-cell responses ranged up to 3,600 spot forming cells (SFC)/million PBMC and 955 SFC/million PBMC depleted of CD8+ cells. Our results suggest that the time points chosen to perform immune assays may influence the breadth of responses and the perceived immunogenicity of vaccine regimens. We are now challenging the vaccinated animals, along with eight na¿ve controls, with repeated limiting-doses of SIVsmE660, a virus heterologous to the vaccine immunogens. PUBLICATIONS: None.