#41: Mechanistic Immune Correlates of Protection Following Vaccination Against Rift Valley Fever Virus

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Abstract Background Rift Valley fever virus (RVFV) is a zoonotic arbovirus endemic to large areas of Africa and the Arabian peninsula that causes a significant annual burden of disease in ruminant animals, and is associated with periodic outbreaks in human populations. RVFV causes a wide spectrum of disease in infected patients ranging from a self-limiting febrile illness to hepatitis, encephalitis, hemorrhagic fever, and death. Despite the significant economic and public health impact of RVFV, there are no currently available vaccines or therapeutics available for RVFV. Methods Previous work has established that vaccination with an attenuated strain of RVFV, RVFV-ΔNSs, confers protection against subsequent lethal challenge in a murine model of infection. To characterize mechanistic immune correlates of protection, we vaccinated C57BL/6 mice with RVFV-ΔNSs then depleted vaccinated mice of various memory lymphocyte subsets, including CD4+, CD8+, CD4+/CD8+ T-cells before challenging mice with a lethal dose of WT RVFV. To assess for the role of antibodies in providing protection, we depleted mice of their B cells prior to vaccination with RVFV-ΔNSs, confirmed the lack of RVFV specific antibodies, and then challenged them with lethal WT RVFV. To determine the minimal immunologic factors required for protection, we vaccinated a series of donor mice, transferred either immunoglobulins or splenocytes to naïve recipient mice, then challenged them with WT RVFV. Results Vaccination with RVFV-ΔNSs protected mice from subsequent challenge, and this protection was not abrogated by depletion of CD4+, CD8+, or combined CD4+ and CD8+ lymphocytes, suggesting that RVFV-specific T-cells are dispensable for protection in the presence of virus specific antibodies. Vaccinated mice depleted of CD20+ B-cells were also protected against WT challenge, suggesting that B-cells/antibodies are also dispensable for protection in the presence of an intact T-cell response. Passive transfer of antibodies from vaccinated mice to recipient mice protected them against subsequent WT challenge, demonstrating that antibodies are sufficient for protection. Adoptive transfer of total splenocytes protected mice against subsequent WT challenge, indicating that lymphocytes are also sufficient to mediate protection. Conclusions In this study we defined the mechanistic immune correlates of protection following vaccination with attenuated RVFV-ΔNSs against WT RVFV in a murine model. Here, we have shown that both humoral and cellular immunity are sufficient to mediate protection in recipient animals, and can compensate for each other when one is missing. These results further our understanding of the protective immunologic response to infection by RVFV, and will help inform further vaccine development efforts against this important emerging pathogen.