Project Grant R01AI185725

MECHANISMS OF COMPROMISED CD8 T CELL RESPONSES TO VACCINATION IN MALARIA EXPERIENCED HOSTS - MALARIA, CAUSED BY PLASMODIUM SPECIES, IS AN UNRESOLVED GLOBAL HEALTH BURDEN. ALTHOUGH INSECTICIDE TREATED BED NETS AND ANTIMALARIAL DRUGS HAVE REDUCED THE INCIDENCE AND SEVERITY OF MALARIA IN SOME REGIONS, INFECTIONS ARE ON THE RISE WITH 247,000,000 CASES AND >600,000 FATALITIES IN 2021. OF ADDITIONAL CONCERN, FRONT LINE ARTESMININ DRUG THERAPIES ARE THREATENED BY EMERGING DRUG RESISTANT PARASITES. THUS, EFFECTIVE VACCINES REMAIN A CRITICAL GOAL TO COMBAT THE GLOBAL THREAT OF MALARIA. DUE TO LOGISTICS AND THE DEVELOPMENT OF CONTROLLED HUMAN MALARIA INFECTION (CHMI) CHALLENGE IN HUMANS, MOST INITIAL CLINICAL TRIALS OF CANDIDATE VACCINES ARE CARRIED OUT IN MALARIA NAIVE INDIVIDUALS RATHER THAN IN MALARIA ENDEMIC REGIONS. UNQUESTIONABLY, THE MOST SUCCESSFUL OF THESE CANDIDATES ARE RADIATION ATTENUATED SPOROZOITES (RAS). RAS VACCINATION, ORIGINALLY DESCRIBED IN MICE, ELICITS PRE-ERYTHROCYTIC (LIVER-STAGE) IMMUNITY THAT CAN COMPLETELY PREVENT DEVELOPMENT OF SYMPTOMATIC BLOOD-STAGE INFECTION AFTER EXPOSURE TO VIRULENT SPOROZOITES IN HUMANS3. RAS VACCINATION (BY THE I.V. ROUTE WITH CRYOPRESERVED RAS) IN MALARIA NAIVE INDIVIDUALS CAN BE UP TO 100% EFFECTIVE AND IMMUNITY CAN LAST FOR AT LEAST A YEAR. HOWEVER, A MAJOR HURDLE FOR PROGRESS IN MALARIA VACCINES IS THE FINDING OF SUBSTANTIALLY REDUCED EFFICACY OF RAS VACCINATION IN MALARIA ENDEMIC REGIONS TO ADDRESS THIS KNOWLEDGE GAP, WE GENERATED A MOUSE MODEL WHERE PRIOR EXPOSURE TO NON-LETHAL P. YOELII 17XNL (PY) BLOOD-STAGE INFECTION COMPROMISES P. BERGHEI ANKA (PB) RAS-INDUCED PROTECTIVE IMMUNITY AGAINST VIRULENT PB SPOROZOITE CHALLENGE (PLEASE SEE FIG. 1 FOR EXPERIMENTAL DESIGN SCHEMATIC). WE FURTHER SHOW THAT PRIOR MALARIA EXPOSURE RESULTS IN A PROLONGED (>12 MONTH) REDUCTION IN THE CAPACITY TO MAKE MALARIA-SPECIFIC CD8 T CELL RESPONSES AGAINST RAS IMMUNIZATION. IN CONSIDERING HOW SUCH DURABLE IMMUNE DYSFUNCTION COULD OCCUR, WE NOTED THAT ONE LONG-TERM SIGNATURE OF MALARIA EXPOSURE IN HUMANS AND MICE IS THE ESSENTIALLY LIFELONG PERSISTENCE OF HEMOZOIN (HZ) IN SPECIFIC TISSUES (LIVER, SPLEEN, BONE MARROW). HZ IS A NON-DEGRADABLE BIOCRYSTAL FORMED DURING BLOOD-STAGE INFECTION AS PLASMODIUM METABOLIZES HEMOGLOBIN IN INFECTED RBC. IMPORTANTLY, WE DETERMINED THAT INJECTION OF SYNTHETIC HZ AND EQUILIBRATION IN TISSUES ALSO COMPROMISED CD8 T CELL RESPONSES TO RAS IMMUNIZATION. THE GOAL OF THIS RO1 IS TO GAIN MECHANISTIC INSIGHT INTO HZ-MEDIATED T CELL DYSFUNCTION IN AN EFFORT TO IMPROVE THE EFFICACY OF MALARIA VACCINES IN ENDEMIC AREAS. AIM 1. DETERMINE HOW HZ DISRUPTS ANTIGEN-PRESENTING FUNCTIONS REQUIRED FOR CD8 T CELL PRIMING AFTER RAS IMMUNIZATION. AIM 2: DEFINE THE EXTENT TO WHICH HZ COMPROMISES RAS- INDUCED LIVER T RESIDENT MEMORY (TRM) AND CIRCULATING T CELL MEMORY (TCIRCM) PROTECTIVE FUNCTIONS. AIM 3. IDENTIFY TRANSLATABLE IMMUNIZATION REGIMENS TO OVERCOME HZ-MEDIATED DISRUPTION OF CD8 T CELL PRIMING AND LIVER STAGE IMMUNITY AFTER RAS VACCINATION.