TY - JOUR

T1 - Neutralization of Plasmodium falciparum Merozoites by Antibodies against PfRH5

AU - Douglas, Alexander D

AU - Williams, Andrew Richard

AU - Knuepfer, Ellen

AU - Illingworth, Joseph J

AU - Furze, Julie M

AU - Crosnier, Cécile

AU - Choudhary, Prateek

AU - Bustamante, Leyla Y

AU - Zakutansky, Sara E

AU - Awuah, Dennis K

AU - Alanine, Daniel G W

AU - Theron, Michel

AU - Worth, Andrew

AU - Shimkets, Richard

AU - Rayner, Julian C

AU - Holder, Anthony A

AU - Wright, Gavin J

AU - Draper, Simon J

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

U2 - 10.4049/jimmunol.1302045

DO - 10.4049/jimmunol.1302045

M3 - Journal article

C2 - 24293631

VL - 192

SP - 245

EP - 258

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 1

ER -