A Molecular Analysis of Memory B Cell and Antibody Responses Against Plasmodium falciparum Merozoite Surface Protein 1 in Children and Adults From Uganda

Abstract

Memory B cells (MBCs) and plasma antibodies against <i>Plasmodium falciparum</i> (<i>Pf</i>) merozoite antigens are important components of the protective immune response against malaria. To gain understanding of how responses against <i>Pf</i> develop in these two arms of the humoral immune system, we evaluated MBC and antibody responses against the most abundant merozoite antigen, full-length <i>Pf</i> merozoite surface protein 1 (PfMSP1_FL), in individuals from a region in Uganda with high <i>Pf</i> transmission. Our results showed that PfMSP1_FL-specific B cells in adults with immunological protection against malaria were predominantly IgG⁺ classical MBCs, while children with incomplete protection mainly harbored IgM⁺ PfMSP1_FL-specific classical MBCs. In contrast, anti-PfMSP1_FL plasma IgM reactivity was minimal in both children and adults. Instead, both groups showed high plasma IgG reactivity against PfMSP1_FL, with broadening of the response against non-3D7 strains in adults. The B cell receptors encoded by PfMSP1_FL-specific IgG⁺ MBCs carried high levels of amino acid substitutions and recognized relatively conserved epitopes on the highly variable PfMSP1 protein. Proteomics analysis of PfMSP1₁₉-specific IgG in plasma of an adult revealed a limited repertoire of anti-MSP1 antibodies, most of which were IgG₁ or IgG₃. Similar to B cell receptors of PfMSP1_FL-specific MBCs, anti-PfMSP1₁₉ IgGs had high levels of amino acid substitutions and their sequences were predominantly found in classical MBCs, not atypical MBCs. Collectively, these results showed evolution of the PfMSP1-specific humoral immune response with cumulative <i>Pf</i> exposure, with a shift from IgM⁺ to IgG⁺ B cell memory, diversification of B cells from germline, and stronger recognition of PfMSP1 variants by the plasma IgG repertoire.