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303 Preclinical Evaluation of Gene-Delivery-Based HIV-1 Vaccines in Nonhuman Primates
D. R. Casimiro*, T. Fu, L. Chen, R. Evans, X. Liang, A. Bett, R. Youil, D. Kaslow, D. Volkin, M. Davies, W. Hurni, P. Keller, E. Emini, and J. W. Shiver
Merck Res. Labs, West Point, PA, USA
Background: Immunization with the internal genes of HIV-1 leads to an effective induction of virus-specific cellular immune responses. The goal of the studies is to optimize the levels and quality of the T-cell responses using homologous or heterologous immunization regimens of DNA, DNA-adjuvant, and replication-defective adenovirus type 5 vectors (Ad5).
Methods: Rhesus macaques were immunized with DNA gag, DNA gag/adjuvant, Ad5-gag, and several combinations thereof. HIV-1-gag-specific immune responses in these animals were monitored using cytokine ELISpot, intracellular cytokine staining, in vitro bulk killing, and anti-p24 ELISA assays.
Results: Replication-incompetent adenoviruses are extremely potent vectors for eliciting long-lived HIV-1-specific T-cell responses in nonhuman primates. Characterization of antigen-specific T cells by intracellular IFN-gamma staining reveals a mixed CD4+/CD8+ population with a pronounced bias toward CD8+ T cells. In vitro killing of autologous cell lines by peripheral blood samples from Ad5 HIV-1 vaccinees indicate consistently high cytotoxic activities. The utility of the adenoviral vectors may be limited by pre-existing neutralizing activity to the viral vector itself. However, we find that by priming for HIV-1-specific immunity using DNA vaccines formulated with potent adjuvants (e.g., nonionic block polymers) and following with Ad5 vaccine boost, the levels of antigen-specific T cells are comparable to those in naïve animals receiving multiple, high doses of the Ad5 HIV-1 vaccines.
Conclusions: The successful development of an HIV-1 vaccine for either prophylactic or therapeutic application in infected patients will require the design of a vaccine vector delivery system that is potent and consistent in its ability to elicit such effective cellular immune responses. In these studies, cellular immune responses in nonhuman primates can be optimized using homologous prime/boost with Ad5 or DNA/adjuvant prime with Ad5 boost regimens. Further evaluation of the potential of these approaches for an HIV-1 vaccine awaits the outcome of ongoing human safety and immunogenicity clinical trials.
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