Journal
JOURNAL OF IMMUNOLOGY
Volume 192, Issue 1, Pages 245-258Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1302045
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Funding
- Wellcome Trust [089455/2/09/z, 092873/z/10/z, 098051]
- Medical Research Council [U117532067, G1000527]
- European Community [242095-EVIMalaR]
- Medical Research Council [G1000527, 1369217, MC_U117532067] Funding Source: researchfish
- MRC [G1000527, MC_U117532067] Funding Source: UKRI
- Wellcome Trust [092873/Z/10/Z] Funding Source: Wellcome Trust
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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.
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