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.

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.

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.

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.