Marked heterogeneity in malaria infection risk in a Malian longitudinal cohort

Variation in malaria infection risk, a product of disease exposure and immunity, is poorly understood. We genotypically profiled over 13,000 blood samples from a six-year longitudinal cohort in Mali to characterize malaria infection dynamics with unprecedented detail. We generated Plasmodium falciparum amplicon sequencing data from 464 participants (aged 3 months -25 years) across the six-month 2011 transmission season and profiled a subset of 120 participants across the subsequent five annual transmission seasons. We measured infection risk as the molecular force of infection (molFOI, number of genetically distinct parasites acquired over time). We found that molFOI varied extensively among individuals (0-55 in 2011) but was independent of age and consistent within individuals over multiple seasons. Reported bednet usage was nearly universal. The HbS allele associated with lower molFOI, and functional antibody signatures correlated with both low and high molFOI participants, identifying candidate immune correlates of protection and risk, respectively. The large inter-individual variability in molFOI and consistency of intra-individual infection risk over time remains largely unexplained, but should be considered in clinical trials and implementation of malaria interventions. Factors contributing to heterogeneity in infection risk should be further studied to inform development of future malaria interventions.