ABSTRACT Despite decades of eradication efforts, malaria remains a global cause of morbidity and mortality, with the greatest burden caused by Plasmodium falciparum and largely affecting young children in Sub-Saharan Africa. One malaria vaccine has recently been approved by the World Health Organization; however, improved vaccines are needed and are likely essential for malaria eradication. Unfortunately, our understanding of protective immunity to malaria remains limited. Within the human host, the parasite propagates through several life cycle stages in various organs, expressing multitudes of antigens at each stage, many of which remain uncharacterized. To add to the challenge, many surface-exposed antigens are studded with amino acid polymorphisms that result in immune system evasion, and some epitopes elicit immune responses that are not actually protective. Serum profiling of multiple genetically diverse antigens will improve our understanding of protective immunity to malaria and drive the design of better vaccines. Limited attention has been given to isotype composition of the antibody response to malaria, and IgA, though previously underrecognized, appears to be a prominent component. While most seroprofiling studies examine antibody responses to whole proteins, study of antibody responses to peptides that comprise the proteins allows for discernment of precise antibody binding sites on the protein surface, which can inform vaccine design. This research will focus on IgA and IgG antibody responses to malaria infection in two groups: (1) infants and children living in Mali, West Africa who were followed for three to four years and (2) infants living in Malawi, Southern Africa, who were followed from birth to two years. Both groups were in settings with high malaria transmission and had active and passive surveillance for malaria infections. Antibody reactivity to peptides representing hundreds of P. falciparum proteins including antigenic variants will be measured following first and repeated malaria infections on PepSeq, a novel peptide library platform that has not previously been used in malaria. Epitopes recognized by serum IgA and IgG after malaria infection will be identified, and a longitudinal study design will allow for the study of the magnitude, kinetics, and isotype ratio (IgA/IgG) of the antibody response to malaria. In summary, this work will answer critical questions about the IgA response to malaria infection, identify epitopes and proteins for exploration as vaccine candidate antigens, and provide new data on the antibody response to antigenic variants. Overall, the findings will improve our understanding of the immune response to malaria and inform vaccine design.

PROJECT NARRATIVE After decades of effort, one malaria vaccine has been approved by the World Health Organization, but improved malaria vaccines with higher efficacy are needed. Antibody responses to infections in infants and young children living in Sub-Saharan Africa who experience multiple malaria infections may hold the key to understanding how immunity to malaria develops. This research will investigate antibody responses against multiple malaria proteins after early childhood malaria infection with the goal of identifying proteins that could be developed into malaria vaccines.