SUMMARY The development of a sterilizing vaccine against malaria remains one of the highest priorities for global health research. While experimental vaccines targeting the malaria parasite prior to entering the blood stage have shown great promise, it has so far not been possible to elicit the longterm immunity required to maintain protection over time. We propose to apply a fundamentally new vaccine tool to malaria vaccine research: persistent effector memory T cell-eliciting vaccines based on cytomegalovirus (CMV). By taking advantage of the natural ability of CMV to elicit and maintain high frequency, non-exhausted, life-long cellular immunity we demonstrated that CMV-based vaccines protect against highly virulent pathogens such as simian immune- deficiency virus and mycobacterium tuberculosis. Our work has renewed hope for AIDS eradication and we are now in clinical development of CMV/HIV vaccines. In preliminary work we now also show that CMV-based malaria vaccines containing a limited set of malaria antigens reduce the parasite burden prior to blood stage development. The central goal of this proposal is to further improve this protection in order to generate sterilizing immunity. We will apply the unique immunological characteristics of CMV-based vaccines by designing CMV-vaccines that recruit different types of cytotoxic T cells to eliminate the parasite liver stage. Specifically, we will address the role of conventional, MHC-I restricted CD8+ T cells versus unconventional MHC-II and MHC-E-restricted CD8+ T cells in protection. We will additionally broaden the spectrum of parasite antigens by including a new set of vaccine targets for the pre-erythrocytic stage of malaria. These new vaccine targets were selected based on systematic evaluation of T cell immunity in humans and validation in murine malaria models. Finally we will extend the immune responses and protective effects elicited by heterologous prime/boost immunization by boosting with CMV-vectors eliciting MHC-I restricted CD8+ T cells recognizing both immunodominant and subdominant epitopes. We anticipate that this project will validate CMV as new method to vaccinate against malaria.