Age-related Changes in Malaria Clinical Phenotypes During Infancy are Modified by Sickle Cell Trait.

BACKGROUND Young infants are protected against Plasmodium falciparum malaria. Mechanisms driving this protection remain unclear due to a poor understanding of malaria clinical phenotypes during infancy. METHODS We enrolled a birth cohort of 678 infants in Busia, Uganda, an area of high malaria transmission. We followed infants through 12 months of age, and quantified protection against parasitemia and clinical disease. RESULTS Symptomatic malaria incidence increased from 1.2 to 2.6 episodes per person year between 0-<6 months and 6-12 months of age, while the monthly probability of asymptomatic parasitemia given infection decreased from 32% to 21%. Sickle cell trait (HbAS) was protective against symptomatic malaria (incidence rate ratio (IRR) = 0.57 comparing HbAS vs. HbAA, 95% CI 0.44-0.74, p<0.001), but age modified this relationship (Pint=<0.001), with non-linear protection that waned between 0-9 months of age before increasing. Increasing age was associated with higher parasite densities at the time of infection, and, in infants with HbAS, a reduced ability to tolerate high parasite densities without fever. CONCLUSIONS Age-dependent changes in HbAS protective efficacy in infancy were accompanied by differential loss of anti-parasite and anti-disease protection among HbAS and HbAA infants. This provides a framework for investigating mechanisms underlying infant protection against malaria.