Maternal malaria and early-life infections shape humoral immunity to P. falciparum in infants

Maternally derived antibodies transferred across the placenta are hypothesized to protect infants against Plasmodium falciparum malaria in early life, but placental malaria may impair this transfer and alter the subsequent development of infant immunity. To test whether maternally derived and infant antibody responses are associated with protection from infection and clinical malaria, and how malaria exposure during pregnancy and infancy shapes these responses, we enrolled a birth cohort of infants in a birth cohort nested within a randomized trial of chemoprevention in Tororo, Uganda. We measured P. falciparum -specific antibody responses to 20 P. falciparum antigens and tetanus toxoid in 183 infants at birth, 6, and 12 months of age using a Luminex multiplex bead array. We also assessed the frequency and phenotype of peripheral T follicular helper cells and B cells using flow cytometry at 12 months of age. Placental malaria was associated with lower cord-blood antibody levels to tetanus toxoid (Benjamini-Hochberg [BH]-adjusted P = 0.0069), GEXP, HYP2 and SEA (BH-adjusted P = 0.05–0.1), and with higher levels to AMA1, while higher gestational age correlated with higher levels of antibodies to GEXP (BH-adjusted P = 0.033) and, more weakly, AMA1, GLURP, HSP40 and HYP2 (BH-adjusted P = 0.075). The maternal antibodies we measured in cord blood were not associated with protection in the first year of life, and neither was maternal malaria status. Infants generated antibodies against P. falciparum antigens in response to infection: levels of antibodies to ETRAMP5, GLURP, HYP2 and SBP1 were significantly higher in children with more parasitemic months in the preceding 6 months (BH-adjusted P < 0.05). No antibody, and no aggregate measure of repertoire breadth, was associated with subsequent protection. Interestingly, the number of parasitemic months in the first 6 months of life correlated with significantly decreased levels of antibodies to EBA140, H103, RH2 and RH4 at 1 year of age (BH-adjusted P < 0.05), whereas the number of symptomatic malaria episodes in that window was not. Early-life infections were not clearly associated with circulating follicular T cell or B cell phenotypic composition. These data suggest the infant antibody responses measured here are markers of exposure rather than correlates of protection against clinical malaria or parasitemia in the first year of life.