PROJECT SUMMARY/ABSTRACT Malaria continues to result in more than 400,000 deaths annually, mainly in young African children. Effective immunity to malaria develops in endemic populations, but only after many repeated infections. Intermittent preventive treatment in pregnancy (IPTp) and childhood (IPTc) have emerged as strategies to decrease childhood morbidity and mortality, but there is concern that preventing malaria exposure early in life will delay the development of antimalarial immunity. However, data from our group suggests that interventions that selectively block the blood stage of malaria infection during this critical time may actually enhance antimalarial immunity. In this proposal, we will test the hypothesis that preventing blood-stage malaria antigenic exposure in utero and in young children with IPT enhances protective immunity to malaria by limiting malaria-induced immunoregulatory mechanisms. To test this hypothesis, we will take advantage of a unique opportunity to study children born to mothers enrolled in a funded clinical trial of different IPTp regimens in an area of eastern Uganda with very high malaria transmission intensity. In this parent study, 2757 pregnant women will be randomized to receive IPTp with sulfadoxine-pyrimethamine (SP, the poorly effective, current standard of care), the highly effective drug dihydroartemisinin-piperaquine (DP), or both SP+DP. We will leverage this parent study to enroll a birth cohort of 924 children who will be randomized at birth to receive no IPTc, IPTc with monthly DP to 1 year of age, or IPTc with monthly DP to 2 years of age. Children will be followed up to 4 years of age. This unique study design will allow us to determine whether effective prevention of blood-stage malaria exposure with DP-based IPT both in pregnancy and in infancy has lasting benefits for young children compared with the current standard of care. Our specific aims will be (1) to compare the incidence of malaria from birth up to 4 years of age among children born to mothers randomized to receive monthly IPTp with SP, DP, or DP+SP, (2) To compare the incidence of malaria from 2 up to 4 years of age among children randomized to receive no IPTc in infancy, monthly DP for the first year of life, or monthly DP for the first two years of life, and (3) To determine whether prevention of malaria with effective IPT leads to lower regulatory responses and enhanced innate and adaptive immune responses. By determining whether effective prevention of malaria with IPT during pregnancy and infancy leads to long-term, lasting benefits on infant health, this study could critically inform policy guidelines, including extending the use of IPT to settings where malaria transmission is year-round. These studies will also significantly improve our understanding of how preventing malaria early in life affects infant immune development and the acquisition of antimalarial immunity.

NARRATIVE Malaria remains a major cause of pediatric deaths and morbidity in Africa. Intermittent preventive treatment in pregnancy (IPTp) and childhood (IPTc) have emerged as strategies to decrease childhood morbidity and mortality. The primary objective of this proposal will be to determine whether effective prevention of malaria with IPTp and IPTc can also enhance protective immunity to malaria in young children.