Neutralization of Plasmodium falciparum merozoites by antibodies against PfRH5

• Published in: The Journal of immunology (1950) Vol. 192; no. 1; pp. 245 - 258
• Main Authors: Douglas, Alexander D, Williams, Andrew R, Knuepfer, Ellen, Illingworth, Joseph J, Furze, Julie M, Crosnier, Cécile, Choudhary, Prateek, Bustamante, Leyla Y, Zakutansky, Sara E, Awuah, Dennis K, Alanine, Daniel G W, Theron, Michel, Worth, Andrew, Shimkets, Richard, Rayner, Julian C, Holder, Anthony A, Wright, Gavin J, Draper, Simon J
• Format: Journal Article
• Language: English
• Published: United States 01.01.2014
• Subjects: Amino Acid Sequence; Animals; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - metabolism; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - metabolism; Antibodies, Protozoan - immunology; Antibodies, Protozoan - metabolism; Carrier Proteins - immunology; Carrier Proteins - metabolism; Epitope Mapping; Epitopes - chemistry; Epitopes - immunology; Erythrocytes - immunology; Erythrocytes - parasitology; Humans; Kinetics; Malaria Vaccines - immunology; Malaria, Falciparum - immunology; Merozoites - immunology; Mice; Neutralization Tests; Plasmodium falciparum; Plasmodium falciparum - growth & development; Plasmodium falciparum - immunology; Protein Binding - immunology; Rabbits
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1302045

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.