Vector order determines protection against pathogenic simian immunodeficiency virus infection in a triple component vaccine by balancing CD4+ and CD8+ T-cell responses

An effective AIDS vaccine should elicit strong humoral and cellular immune responses while maintaining low levels of CD4(+) T-cell activation to avoid the generation of target cells for viral infection. The present study investigated two prime-boost regimens, both starting vaccination with single-cycle immunodeficiency virus, followed by two mucosal boosts with either recombinant adenovirus (rAd) or fowlpox virus (rFWPV) expressing SIVmac239 or SIVmac251 gag/pol and env genes, respectively. Finally, vectors were switched and systemically administered to the reciprocal group of animals. Only mucosal rFWPV immunizations followed by systemic rAd boost significantly protected animals against a repeated low-dose intrarectal challenge with pathogenic SIVmac251, resulting in a vaccine efficacy (i.e., risk reduction per exposure) of 68%. Delayed viral acquisition was associated with higher levels of activated CD8(+) T cells and Gag-specific gamma interferon (IFN-gamma)-secreting CD8(+) cells, low virus-specific CD4(+) T-cell responses, and low Env antibody titers. In contrast, the systemic rFWPV boost induced strong virus-specific CD4(+) T-cell activity. rAd and rFWPV also induced differential patterns of the innate immune responses, thereby possibly shaping the specific immunity. Plasma CXCL10 levels after final immunization correlated directly with virus-specific CD4(+) T-cell responses and inversely with the number of exposures to infection. Also, the percentage of activated CD69(+) CD8(+) T cells correlated with the number of exposures to infection. Differential stimulation of the immune response likely provided the basis for the diverging levels of protection afforded by the vaccine regimen.