Immune correlates for VEEV replicon vaccine protection against Ebolavirus

Abstract

Abstract The progress of filovirus vaccines has advanced greatly due in part to the urgent need to develop countermeasures for the unprecedented Ebolavirus (EBOV) outbreak in West Africa. While a variety of vaccination approaches have been moved into clinical trials, the understanding of what constitutes a protective response after vaccination is still under investigation. Our approach to addressing immune correlates has involved the use of various mouse models to first test whether or not protection is afforded in the absence of a cell population. To this end, wild type (wt), β2m−/− and μMT−/− mouse models were used to assess the protective efficacy of vaccination with a Venezuelan Equine Encephalitis Virus replicon bearing the EBOV glycoprotein (GP). Vaccinated β2m−/− mice, despite lacking CD8 T cells, enjoyed full protection against mouse-adapted (ma) EBOV exposure. Vaccinated μMT−/− mice, on the other hand, succumbed to maEBOV exposure, similar to unvaccinated control mice. A flow cytometry analysis of T cell responses in Wt, β2­m−/− and μMT−/− mice revealed all mice mounted CD4 T cell responses, whereas only wt mice generated CD8 T cell responses. Antibody responses to EBOV GP were predictably lacking in μMT−/− mice after vaccination, but were present at high titers in wt and β2m−/− mice. We were able to achieve protection in vaccinated μMT−/−, but not unvaccinated μMT−/− mice, given serum from vaccinated wt mice before and after maEBOV exposure. These data indicate that T cell responses in this model can contribute to protection when given antibody help. Ultimately, antibody responses appear to be the best protective correlate in this model, though we also provide evidence that T cell responses can be essential in certain conditions.