Dissecting compromised efficacy of liver-stage malaria immunizations in hosts with a history of blood-stage malaria

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PROJECT SUMMARY/ABSTRACT Highly effective vaccines are needed to help control the global disease burden of malaria. Candidate vaccines targeting the liver-stage of malaria have shown promising efficacy when trialed in malaria-naïve humans, but performed disappointingly when tested in the target population for malaria vaccines: individuals living malaria- endemic regions. Blood-stage malaria produces diverse immunosuppressive effects, some of which outlast the clearance of infection. This proposal uses a murine model to explore the hypothesis that blood-stage malaria infections produce lasting alterations in the host immune environment that prevent future immunizations from generating optimally protective responses. In a novel murine infection-immunization-rechallenge model developed to address this topic, immunization with radiation-attenuated malaria sporozoites produced inferior protection in mice with a history of blood-stage malaria, compared to blood-stage-naïve comparators. The proposed work uses a series of experimentally tractable mouse models to dissect the mechanistic basis of compromised immunization efficacy in hosts with a history of blood-stage malaria. Aim 1 will test whether a parasite-produced hemoglobin derivative is a key driver of the impaired immunization responses observed after resolution of blood-stage malaria. Aim 2 will determine whether ineffective CD8 T-cell priming due to reductions in antigen presentation explains the poor responses of mice with a history of blood stage malaria to immunization. This project is designed to simultaneously advance knowledge of malaria immunity and prepare the investigator for further independent research in malaria pathogenesis and immunity by incorporating diverse approaches in immunology and rodent models of malaria.