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BACKGROUND: The targets and mechanisms of human immunity to malaria are poorly understood, which poses a major barrier to malaria vaccine development. Antibodies play a key role in human immunity and may act by inhibiting receptor-binding functions of key merozoite invasion ligands. Antibodies to the major invasion ligand and vaccine candidate, EBA-175, have been linked with protection, but how these antibodies function has not been established. METHODS: We developed two new assays that quantify the ability of antibodies to inhibit binding of EBA-175 to its erythrocyte receptor, glycophorin A, using either native or recombinant EBA-175. Binding-inhibitory antibodies were evaluated in a longitudinal cohort study of Papua New Guinean children and related to risk of malaria, age, infection status, and markers of parasite exposure. RESULTS: Binding-inhibitory assays were reproducible and the two assays had a high level of agreement. Inhibitory antibodies were common among children and were acquired in association with markers of increasing parasite exposure and were high in those children with active infection. Inhibitory antibodies correlated with total IgG levels to the EBA-175 binding domain (region II). Importantly, binding-inhibitory antibodies were significantly associated with protection from symptomatic malaria when measured using either binding inhibition assay. CONCLUSION: Findings suggest that naturally-acquired binding-inhibitory antibodies are an important functional mechanism that contributes to protection against malaria and further supports the potential of EBA-175 as a vaccine candidate. Identifying vaccines and approaches that induce potent binding-inhibitory antibodies may be a valuable strategy in the development of highly efficacious malaria vaccines.
This work was supported by the National Health and Medical Research Council of Australia (Program Grant to JB; Postgraduate Research Fellowship to JR; and Infrastructure for Research Institutes Support Scheme Grant); the Australian Research Council (Future Fellowship to JB); the Victorian State Government Operational Infrastructure Support, University of Melbourne (Melbourne International Fee Remission Scholarship and Melbourne International Research Scholarship to VI) and Monash University (Australian Postgraduate Award to AJG and Medicine, Nursing and Health Science International Honours Scholarship to VI).
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