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There is intense interest in induction and characterization of strain-transcending neutralizing Ab against antigenically variable human pathogens. We have recently identified the human malaria parasite Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) as a target of broadly neutralizing Abs, but there is little information regarding the functional mechanism(s) of Ab-mediated neutralization. In this study, we report that vaccine-induced polyclonal anti-PfRH5 Abs inhibit the tight attachment of merozoites to erythrocytes and are capable of blocking the interaction of PfRH5 with its receptor basigin. Furthermore, by developing anti-PfRH5 mAbs, we provide evidence of the following: 1) the ability to block the PfRH5-basigin interaction in vitro is predictive of functional activity, but absence of blockade does not predict absence of functional activity; 2) neutralizing mAbs bind spatially related epitopes on the folded protein, involving at least two defined regions of the PfRH5 primary sequence; 3) a brief exposure window of PfRH5 is likely to necessitate rapid binding of Ab to neutralize parasites; and 4) intact bivalent IgG contributes to but is not necessary for parasite neutralization. These data provide important insight into the mechanisms of broadly neutralizing anti-malaria Abs and further encourage anti-PfRH5-based malaria prevention efforts.

Original publication

DOI

10.4049/jimmunol.1302045

Type

Journal article

Journal

J Immunol

Publication Date

01/01/2014

Volume

192

Pages

245 - 258

Keywords

Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Protozoan, Carrier Proteins, Epitope Mapping, Epitopes, Erythrocytes, Humans, Kinetics, Malaria Vaccines, Malaria, Falciparum, Merozoites, Mice, Neutralization Tests, Plasmodium falciparum, Protein Binding, Rabbits