The Natural History and Burden of Malaria During the First Year of Life in a High Transmission Setting in Uganda

Infants under one year of age are considered partially protected from malaria due to maternal antibodies and fetal hemoglobin. However, emerging evidence suggests that malaria burden in this age group may be underestimated. We enrolled a cohort of 855 infants in Busia District, Uganda to characterize and identify risk factors for malaria incidence and parasite prevalence during the first year of life. The study was conducted from 2021-2025, prior to malaria vaccine roll-out. Infants born to HIV-uninfected women were enrolled at 4-8 weeks of age and followed 7 days/week in a dedicated study clinic to 1 year of age. Routine visits every 4 weeks included assessments for parasitemia by microscopy and quantitative PCR. Over 706.7 person-years of follow-up, 662 malaria episodes occurred; 71% occurred prior to 9 months of age. Overall prevalence of microscopic parasitemia was 7.9% and combined prevalence of microscopic and submicroscopic parasitemia was 21.8%. Sickle cell trait (HbAS) conferred 39% protection against symptomatic malaria but had no association with risk of parasitemia. Modern housing construction and higher maternal education were independently associated with reduced malaria risk. District-wide distribution of alpha-cypermethrin plus chlorfenapyr long-lasting insecticide-treated nets in October 2023 was followed by an 80% reduction in malaria incidence and significant declines in parasitemia prevalence. These findings underscore the urgent need for age-appropriate preventive interventions targeting young infants, such as earlier vaccine administration and/or monoclonal antibodies, alongside sustained investment in next-generation vector control, and attention to socioeconomic determinants of malaria risk.