Project Grant F31AI202961

MALARIA TREATMENT OUTCOMES AND HUMAN-TO-MOSQUITO TRANSMISSION IN EASTERN TANZANIA - PROJECT SUMMARY/ABSTRACT MALARIA REMAINS A MAJOR GLOBAL HEALTH CHALLENGE, AND DRUG POLICY DEPENDS ON ACCURATE FINDINGS FROM THERAPEUTIC EFFICACY STUDIES (TES). CURRENT WHO GENOTYPING STANDARDS FOR CLASSIFYING TREATMENT FAILURE RELY ON LIMITED GENETIC MARKERS, WHICH CAN MISESTIMATE FAILURE RATES. AMPLICON SEQUENCING COMBINED WITH BAYESIAN ALGORITHMS OFFERS A MORE SENSITIVE APPROACH, BUT ITS APPLICATION SO FAR TO TES IS LIMITED. ADDITIONALLY, THERAPEUTIC EFFICACY STUDIES RARELY EXAMINE MALARIA TRANSMISSION IN PARTICIPANTS POST-TREATMENT, LEAVING CRITICAL GAPS IN UNDERSTANDING HOW DRUG RESISTANCE OR OTHER PREDICTORS INFLUENCE ONWARD SPREAD. THIS PROJECT LEVERAGES SAMPLES FROM THE 3ACT KIBINDU TES AND TACT-MQ ADD-ON STUDY IN EASTERN TANZANIA TO ADDRESS TWO KEY QUESTIONS: 1) CAN EXPANDED BASELINE GENOTYPING USING DAY 0 AND DAY 1 SAMPLES IMPROVE DETECTION OF TREATMENT FAILURE COMPARED TO CURRENT METHODS? 2) ARE MOLECULAR MARKERS OF DRUG RESISTANCE, PATIENT CHARACTERISTICS, OR SEASONALITY ASSOCIATED WITH EXPERIMENTALLY OBSERVED HUMAN-TO-MOSQUITO TRANSMISSION FOLLOWING TREATMENT? WE HYPOTHESIZE THAT INCORPORATING DAY 1 PARASITE GENOTYPES IN THE BASELINE POPULATION FOR TREATMENT FAILURE DETERMINATION WILL REVEAL ADDITIONAL VARIANTS, INCREASING SENSITIVITY FOR DETECTING TREATMENT FAILURE. WE FURTHER HYPOTHESIZE THAT RECRUDESCENT PARASITES ASSOCIATED WITH TREATMENT FAILURE WILL BE ASSOCIATED WITH TRANSMISSION TO MOSQUITOES. THE FELLOWSHIP WILL PROVIDE RIGOROUS INTERDISCIPLINARY TRAINING IN GENOMIC DATA ANALYSIS, BAYESIAN MODELING, AND INTEGRATION OF GENETIC, EPIDEMIOLOGIC, AND ECOLOGICAL DATA. THE RESEARCH PROPOSED HERE WILL ENHANCE TES METHODOLOGY, HELPING TO REDUCE GLOBAL MALARIA BURDEN AND THE RISK OF MALARIA FOR US TRAVELERS. ADDITIONALLY, IT WILL HELP PRESERVE THE EFFICACY OF FIRST-LINE MALARIA THERAPIES USED IN THE UNITED STATES BY UNDERSTANDING FACTORS THAT LEAD TO THE SPREAD OF DRUG-RESISTANT MALARIA. BY COMBINING INNOVATIVE RESEARCH WITH STRUCTURED TRAINING, THIS PROJECT WILL ADVANCE TES METHODOLOGY, INFORM MOLECULAR SURVEILLANCE STRATEGIES, AND PREPARE THE APPLICANT FOR AN INDEPENDENT RESEARCH CAREER FOCUSED ON MODELING DRIVERS OF INFECTIOUS DISEASE TRANSMISSION.