Sequestration of P. falciparum-infected erythrocytes (IEs) in the microvasculature contributes to the pathogenesis of severe malaria in children. This mechanism is mediated by PfEMP1 expressed on the IE surface, a major target of naturally acquired antibodies. However, little is known regarding the association between PfEMP1-specific antibodies and protective immunity against severe malaria.
In a case-control study of young children in Papua New Guinea presenting with severe (SM) or uncomplicated malaria (UM) (n=805), antibody levels were quantified to antigens expressed on the IE surface, using isolates with a virulent phenotype, and to recombinant PfEMP1 domains. We used genetically-modified isolates with suppressed PfEMP1 expression to quantify PfEMP1 as a target of antibodies. Functional antibody responses were quantified using an opsonic phagocytosis assay with monocytes.
Antibodies to the IE surface and recombinant PfEMP1 domains were higher in UM and boosted following infection. We found that PfEMP1 was the major target of antibodies among children with SM and UM, and PfEMP1-specific antibodies were associated with reduced risk of SM. Antibodies mediated opsonic phagocytosis of IEs, which were associated with reduced risk of SM and targeted PfEMP1.
Findings highlight the significance of PfEMP1-specific antibodies in mediating protective immunity against severe malaria in children.