Naturally Acquired Antibodies Target the Glutamate-Rich Protein on Intact Merozoites and Predict Protection Against Febrile Malaria

[[[ Background: ]]] Plasmodium species antigens accessible at the time of merozoite release are likely targets of biologically functional antibodies. [[[ Methods: ]]] Immunoglobulin G (IgG) antibodies against intact merozoites were quantified in the plasma of Ghanaian children from a longitudinal cohort using a novel flow cytometry-based immunofluorescence assay. Functionality of these antibodies, as well as glutamate-rich protein (GLURP)-specific affinity-purified IgG from malaria hyperimmune Liberian adults, was assessed by the opsonic phagocytosis (OP) assay. [[[ Results: ]]] Opsonic phagocytosis activity was strongly associated (hazard ratio [HR] = 0.46; 95% confidence interval [CI] = .30-.73; P = .0008) with protection against febrile malaria. Of the antimerozoite-specific antibodies, only IgG3 was significantly associated with both OP and protection (HR = 0.53; 95% CI = .34-.84; Pcorrected = .03) against febrile malaria. Similarly, GLURP-specific antibodies previously shown to be protective against febrile malaria in this same cohort were significantly associated with OP activity in this study. GLURP-specific antibodies recognized merozoites and also mediated OP activity. [[[ Conclusions: ]]] These findings support previous studies that found OP of merozoites to be associated with protection against malaria and further shows IgG3 and GLURP antibodies are key in the OP mechanism, thus giving further impetus for the development of malaria vaccines targeting GLURP.