biostudies-literatureNkumama INEPANational Institute for Health Research (NIHR)Wellcome Trust1215-1224.e6https://www.ebi.ac.uk/biostudies/studies/S-EPMC7616646biostudies-literatureUnknown57(6)Malaria is a life-threatening disease of global health importance, particularly in sub-Saharan Africa. The growth inhibition assay (GIA) is routinely used to evaluate, prioritize, and quantify the efficacy of malaria blood-stage vaccine candidates but does not reliably predict either naturally acquired or vaccine-induced protection. Controlled human malaria challenge studies in semi-immune volunteers provide an unparalleled opportunity to robustly identify mechanistic correlates of protection. We leveraged this platform to undertake a head-to-head comparison of seven functional antibody assays that are relevant to immunity against the erythrocytic merozoite stage of Plasmodium falciparum. Fc-mediated effector functions were strongly associated with protection from clinical symptoms of malaria and exponential parasite multiplication, while the gold standard GIA was not. The breadth of Fc-mediated effector function discriminated clinical immunity following the challenge. These findings present a shift in the understanding of the mechanisms that underpin immunity to malaria and have important implications for vaccine development.ImmunityBreadth of Fc-mediated effector function correlates with clinical immunity following human malaria challenge.PMC7616646107499/Z/15/Z226669/Z/22/ZEP-C-15-00310749916/136/33107769/Z/10/ZMwai KCHMI-SIKA study teamFrank RRosenkranz MMusasia FTuju JOsier FHAFurle KOgwang RKapulu MCOdera DNyamako LNkumama INMurungi LNjuguna PKimathi RHamaluba MfalseBreadth of Fc-mediated effector function correlates with clinical immunity following human malaria challenge.Malaria is a life-threatening disease of global health importance, particularly in sub-Saharan Africa. The growth inhibition assay (GIA) is routinely used to evaluate, prioritize, and quantify the efficacy of malaria blood-stage vaccine candidates but does not reliably predict either naturally acquired or vaccine-induced protection. Controlled human malaria challenge studies in semi-immune volunteers provide an unparalleled opportunity to robustly identify mechanistic correlates of protection. We leveraged this platform to undertake a head-to-head comparison of seven functional antibody assays that are relevant to immunity against the erythrocytic merozoite stage of Plasmodium falciparum. Fc-mediated effector functions were strongly associated with protection from clinical symptoms of malaria and exponential parasite multiplication, while the gold standard GIA was not. The breadth of Fc-mediated effector function discriminated clinical immunity following the challenge. These findings present a shift in the understanding of the mechanisms that underpin immunity to malaria and have important implications for vaccine development.2024-01-01T00:00:00Z2024 Jun2026-06-03T05:27:32.353Z2025-04-04T08:23:14.308ZS-EPMC76166463878871110.1016/j.immuni.2024.05.001