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LB5 Merck's HIV Vaccine
Program: Research Approaches and Critical Issues
John Shiver
Merck Research Laboratories, West Point, PA, USA
Recent studies of HIV-1 infection in humans and of SIV infection in monkeys demonstrate that resolution of acute viremia and control of the persistent virus infection is largely mediated by the antiviral CD4+ and CD8+ cellular immune response. These data suggest that an HIV vaccine based solely on eliciting anti-HIV cellular immune responses may have utility to prevent or control HIV infection in humans. Several of the most significant issues associated with this vaccine development include (1) selection of and optimization of assays that allow quantitative measurement of CD4+ and CD8+ T cell responses; (2) identification of the appropriate HIV gene products and vaccine approaches for eliciting anti-HIV cellular immunity; and (3) determining cross-clade reactivities of T cell responses. We have employed gamma-interferon ELIspot and intracellular cytokine staining assays to measure T cell responses in healthy HIV-1 infected human subjects. Our results suggest that the antigens most commonly recognized by T cells from these individuals are derived from gag, pol, and nef. To determine the relative abilities of various vaccine approaches to elicit cellular immunity against viral antigens, we used the modified vaccinia Ankara (MVA) pox virus, several plasmid DNA formulations, and a replication defective adenoviral vector encoding the HIV-1 or SIV gag genes to immunize rhesus monkeys, either alone or as "prime/boost" combinations. Our results demonstrate that the adenoviral vector is the most potent vehicle for eliciting CD8+ T cell immune responses. The adenoviral vaccine also provided the greatest degree of protection against challenge with the pathogenic SHIV89.6P virus. This was accomplished using SIV gag alone as vaccine antigen without an env component. These studies provide guidance for the development of new vaccine candidates for human clinical trials.
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