Pilot Award

Malaria is the leading cause of morbidity and mortality among children in Uganda. The clinical presentation of malaria is modulated by the natural development of acquired immunity, which develops slowly, wanes rapidly, and is poorly understood. A more thorough understanding of natural immunity to malaria and its development during early childhood is needed to inform development of an effective vaccine. Several lines of evidence from both human and animal model studies suggest that naturally acquired malaria-specific T-cells, particularly those targeting antigens expressed during the pre-erythrocytic (liver-stage) of infection, can confer protection from subsequent episodes of clinical malaria. We are in a unique position to study the development of naturally acquired T-cell responses to P. falciparum, due to our collaboration with UCSF investigators who will soon launch an NIH P01-funded randomized controlled trial which will enroll 400 children in an area of Uganda with extremely high malaria transmission. In this trial, children will be randomized to receive chemoprevention (which pre-empts the erythrocytic stage of infection but does not impact liver-stage infection) or the current standard of no chemoprevention. This trial therefore provides an unprecedented opportunity to study the natural development of malaria-specific T cell responses in groups of children who will differ only in their exposure to the erythrocytic stage of P. falciparum infection. We aim to perform a cross-sectional assessment of the prevalence of T cell immune responses to pre-erythrocytic and erythrocytic-stage malarial antigens among children randomized to receive chemoprevention vs. no intervention. We will also use multiparameter flow cytometry to compare the functional quality of T cell responses to liver-stage antigens in the two study arms, to test our hypothesis that children who receive chemoprevention develop qualitatively superior T-cell responses to pre-erythrocytic antigens compared to children not given chemoprevention, in whom progression to erythrocytic stage infection occurs.