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314 Enhanced Vaccine Technologies for the Induction of Potent Neutralizing Antibodies and Cellular Immune Responses against HIV
S. W. Barnett*1, I. K. Srivastava1, L. Stamatatos2, D. Montefiori3, S. Engelbrecht4, E. Janse Van Rensburg4, G. R. Otten1, D. O'Hagan1, J. Polo1, J. B. Ulmer1, and J. J. Donnelly1
1Chiron Corp., Emeryville, CA, USA; 2The Aaron Diamond AIDS Res. Ctr., New York, NY, USA; 3Duke Univ., Durham, NC, USA; and 4Univ. of Stellenbosch and Tygerberg Hosp., South Africa
Protection against HIV infection will require potent and broadly reactive pre-existing neutralizing antibodies in vaccinated individuals exposed to a virus challenge. Although cellular immune responses are desirable to control viremia in those who get infected, protection against infection has not been demonstrated for vaccine approaches that rely exclusively on the induction of these responses. For this reason, we have chosen to explore the use of prime-boost approaches that employ novel V-deleted envelope antigens from primary R5 subtype B (HIV-1SF162) and subtype C (HIV-1TV1) strains. These antigens were delivered by enhanced DNA [polylactide co-glycolide (PLG) microparticle formulations or electroporation] or alphavirus replicon particle-based vaccine approaches, followed by booster immunizations with Env proteins in MF59 adjuvant. Both native and V-deleted monomeric (gp120) and oligomeric (o-gp140) forms of protein from the SF162 strain were tested as boosters. All protein preparations were highly purified and extensively characterized by biophysical and immunochemical methodologies. Results from rabbit and primate immunogenicity studies indicated that, whereas neutralizing antibody responses could be consistently induced against the parental non-V2-deleted SF162 virus, the induction of responses against heterologous HIV strains required deletion of the V2 loop of the immunogens. Moreover, using these prime-boost vaccine regimens, potent HIV antigen-specific CD4+ and CD8+ T-cell responses were also demonstrated. Based on these findings, V2-deleted SF162 envelope DNA and protein vaccines were chosen for advancement toward clinical evaluation.
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