Cytomegalovirus vectors expressing Plasmodium knowlesi antigens induce immune responses that delay parasitemia upon sporozoite challenge

作者：Scott G. Hansen, Jennie Womack, Isabel Scholz, Andrea Renner, Kimberly A. Edgel, Guangwu Xu, Julia C. Ford, Mikayla Grey, Brandyce St. Laurent, John M. Turner, Shannon Planer, Al Legasse, Thomas L. Richie, João C. Aguiar, Michael K. Axthelm, Eileen D. Villasante, Walter R. Weiss, Paul T. Edlefsen, Louis J. Picker, Klaus Früh · 发表于：PLoS ONE · 年份：2019 · DOI：10.1371/journal.pone.0210252 · 被引用次数：45 · 研究领域：Mosquito-borne diseases and control、Cytomegalovirus and herpesvirus research、Malaria Research and Control

The development of a sterilizing vaccine against malaria remains one of the highest priorities for global health research. While sporozoite vaccines targeting the pre-erythrocytic stage show great promise, it has not been possible to maintain efficacy long-term, likely due to an inability of these vaccines to maintain effector memory T cell responses in the liver. Vaccines based on human cytomegalovirus (HCMV) might overcome this limitation since vectors based on rhesus CMV (RhCMV), the homologous virus in rhesus macaques (RM), elicit and indefinitely maintain high frequency, non-exhausted effector memory T cells in extralymphoid tissues, including the liver. Moreover, RhCMV strain 68-1 elicits CD8+ T cells broadly recognizing unconventional epitopes exclusively restricted by MHC-II and MHC-E. To evaluate the potential of these unique immune responses to protect against malaria, we expressed four Plasmodium knowlesi (Pk) antigens (CSP, AMA1, SSP2/TRAP, MSP1c) in RhCMV 68-1 or in Rh189-deleted 68-1, which additionally elicits canonical MHC-Ia-restricted CD8+ T cells. Upon inoculation of RM with either of these Pk Ag expressing RhCMV vaccines, we obtained T cell responses to each of the four Pk antigens. Upon challenge with Pk sporozoites we observed a delayed appearance of blood stage parasites in vaccinated RM consistent with a 75-80% reduction of parasite release from the liver. Moreover, the Rh189-deleted RhCMV/Pk vectors elicited sterile protection in one RM. Once in the b...