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Vaccine-induced immunity to Ebola virus infection in nonhuman primates (NHPs) is marked by potent antigen-specific cellular and humoral immune responses (1,2); however, the immune mechanism of protection remains unknown. Here we define the immune basis of protection conferred by a highly protective recombinant adenovirus virus serotype 5 (rAd5) encoding Ebola virus glycoprotein (GP) (1,3) in NHPs. Passive transfer of high-titer polyclonal antibodies from vaccinated Ebola virus-immune cynomolgus macaques to naive macaques failed to confer protection against disease, suggesting a limited role of humoral immunity. In contrast, depletion of [CD3.sup.+] T cells in vivo after vaccination and immediately before challenge eliminated immunity in two vaccinated macaques, indicating a crucial requirement for T cells in this setting. The protective effect was mediated largely by [CD8.sup.+] cells, as depletion of [CD8.sup.+] cells in vivo using the cM-T807 monoclonal antibody (mAb), which does not affect [CD4.sup.+] T cell or humoral immune responses, abrogated protection in four out of five subjects. These findings indicate that [CD8.sup.+] cells have a major role in rAd5-GP-induced immune protection against Ebola virus infection in NHPs. Understanding the immunologic mechanism of Ebola virus protection will facilitate the development of vaccines for Ebola and related hemorrhagic fever viruses in humans., Viral vector vaccines have shown efficacy for the delivery of Ebola virus genes and immune protection against infection in NHPs, but the mechanism of immune protection has not been defined [...]