title: Neutralization of Plasmodium falciparum merozoites by antibodies against PfRH5.
abstract: 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.
authors.affiliation: Jenner Institute, University of Oxford, Oxford OX3 7DQ, United Kingdom;
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Douglas
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Williams
authors.forename: Ellen
authors.initials: E
authors.lastname: Knuepfer
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Illingworth
authors.forename: Julie M
authors.initials: JM
authors.lastname: Furze
authors.forename: Cécile
authors.initials: C
authors.lastname: Crosnier
authors.forename: Prateek
authors.initials: P
authors.lastname: Choudhary
authors.forename: Leyla Y
authors.initials: LY
authors.lastname: Bustamante
authors.forename: Sara E
authors.initials: SE
authors.lastname: Zakutansky
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Awuah
authors.forename: Daniel G W
authors.initials: DG
authors.lastname: Alanine
authors.forename: Michel
authors.initials: M
authors.lastname: Theron
authors.forename: Andrew
authors.initials: A
authors.lastname: Worth
authors.forename: Richard
authors.initials: R
authors.lastname: Shimkets
authors.forename: Julian C
authors.initials: JC
authors.lastname: Rayner
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Holder
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Wright
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Draper
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D057134:Antibodies, Neutralizing / Q000276:immunology* / Q000378:metabolism; D000913:Antibodies, Protozoan / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology; D006801:Humans; D007700:Kinetics; D017780:Malaria Vaccines / Q000276:immunology; D016778:Malaria, Falciparum / Q000276:immunology; D052940:Merozoites / Q000276:immunology*; D051379:Mice; D009500:Neutralization Tests; D010963:Plasmodium falciparum / Q000254:growth & development / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D011817:Rabbits
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000913:Antibodies, Protozoan; D002352:Carrier Proteins; D000939:Epitopes; D017780:Malaria Vaccines; C531020:RH5 protein, Plasmodium falciparum