IMPLICATIONS OF ASYMPTOMATIC PLASMODIUM FALCIPARUM INFECTIONS FOR FUTURE SYMPTOMATIC MALARIA INFECTION AND ONWARD TRANSMISSION IN WESTERN KENYA

Abstract

Despite efforts to reduce the malaria burden in high transmission areas like Western Kenya, malaria has persisted, making it important to identify remaining malaria reservoirs. Asymptomatic infections could be sustaining transmission, but their role as a reservoir has not been quantified. Furthermore, the relationship between asymptomatic malaria and future symptomatic infection is poorly understood. Using a 29-month cohort of 268 participants residing in Western Kenya, this dissertation aimed to (1A) investigate the hazard of symptomatic P. falciparum when exposed to asymptomatic malaria versus no infection; (1B) establish the odds of symptomatic infection when exposed to new compared to previously acquired infections; and (2) estimate the relative contributions of asymptomatic and symptomatic human infections to successful onward mosquito transmission events. With a frailty Cox model, aim 1A found that infection with asymptomatic malaria compared to being uninfected greatly increased the short-term, 1-month hazard of symptomatic malaria [hazard ratio: 2.61, 95% CI: 2.05 to 3.33], regardless of parasite density or participant age, but the association weakened as the follow-up period was expanded. Next, using amplicon deep sequencing to determine genetically distinct malaria infections (haplotypes) acquired over time, aim 1B identified that, compared to infections with only recurrent haplotypes, incident infections with only new haplotypes had higher odds of symptomatic malaria [odds ratio (OR): 3.24, 95% CI: 1.20 to 8.78] but infections with both new and recurrent haplotypes had comparable odds of symptomatic malaria [OR: 0.64, 95% CI: 0.15 to 2.65]. Using amplicon deep sequencing of human and mosquito samples as well as probabilistic modelling, aim 2 observed that, compared with symptomatic infections, asymptomatic infections more than doubled the odds of transmission to a mosquito [OR 2.66, 95% CI: 2.05 to 3.47] and were the likely source of 94.6% (95% CI: 93.1 to 95.8%) of mosquito infections. These findings indicate that asymptomatic infections increase the 1-month hazard of symptomatic malaria, are more common in incident infections with previously seen haplotypes, and are major contributors to mosquito infections. Taken together, this research provides a rationale to include asymptomatic infections as a part of malaria reduction interventions in high transmission regions.Doctor of Philosoph