Vector Order Determines Protection against Pathogenic Simian Immunodeficiency Virus Infection in a Triple-Component Vaccine by Balancing CD4 ⁺ and CD8 ⁺ T-Cell Responses

Abstract

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 either with recombinant adenovirus (rAd) or fowlpox virus (rFWPV) expressing SIVmac239 or SIVmac251 and 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 IFN-γ 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 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 this vaccine regimen. A failed phase II AIDS vaccine trial led to the hypothesis that CD4 T cell activation can abrogate any potentially protective effects delivered by vaccination or promote acquisition of the virus because CD4 T helper cells, required for an effective immune response, also represent the target cells for viral infection. We compared two vaccination protocols that elicited similar levels of Gag-specific immune responses in rhesus macaques. Only the animal group that had a low level of virus-specific CD4 T cells in combination with high levels of activated CD8 T cells was significantly protected from infection. Notably, protection was achieved despite the lack of appreciable Env-antibody titers. Moreover, we show that both, the vector and the route of immunization affected the level of CD4 T cell responses. Thus, mucosal immunization with FWPV-based vaccines should be considered as potent prime in prime-boost vaccination protocols.

Vaccination of Macaques with DNA Followed by Adenoviral Vectors Encoding Simian Immunodeficiency Virus (SIV) Gag Alone Delays Infection by Repeated Mucosal Challenge with SIV

“…The challenge virus represented an early passage of this prototype propagated on primary rhesus monkey PBMCs. Details of this particular stock have been previously described (42, 43).…”

Non-Human Primate-Derived Adenoviruses for Future Use as Oncolytic Agents?

“…Unexpectedly, a defect in the pathway had no effect on the generation of CD8 + T cell memory upon adenoviral infection [ 50 ]. This might be explained by the association of CD4 + T cell responses with virus-induced CXCL10 production, rather than CD8 + T cell responses [ 66 ]. Hence, a more detailed characterization of the specific CD4 + T cell responses induced by human- and NHP-derived adenoviruses might provide some insight in the generation of (anti-tumor) immune memory formation.…”

Mucosal Vaccine Approaches for Prevention of HIV and SIV Transmission

“…High doses may also induce greater levels of anti-vector antibodies that obviate vector boosting by the same route. Prime-boosting with heterologous vectors may therefore be more effective [76–78]. Another approach found effective for priming HIV-specific B and T cells without inducing anti-vector immunity in vaccination regimens has been to use DNA as the priming vehicle [79, 80].…”