Breadth of Fc-mediated effector function correlates with clinical immunity following human malaria challenge

• Published in: Immunity (Cambridge, Mass.) Vol. 57; no. 6; pp. 1215 - 1224.e6
• Main Authors: Nkumama, Irene N., Ogwang, Rodney, Odera, Dennis, Musasia, Fauzia, Mwai, Kennedy, Nyamako, Lydia, Murungi, Linda, Tuju, James, Fürle, Kristin, Rosenkranz, Micha, Kimathi, Rinter, Njuguna, Patricia, Hamaluba, Mainga, Kapulu, Melissa C., Frank, Roland, Osier, Faith H.A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.06.2024
• Subjects: Adult; antibodies; Antibodies, Protozoan - immunology; CHMI; Erythrocytes - immunology; Erythrocytes - parasitology; Fc-mediated effector function; Female; growth inhibition activity; Humans; Immunoglobulin Fc Fragments - immunology; malaria; Malaria Vaccines - immunology; Malaria, Falciparum - immunology; Malaria, Falciparum - parasitology; Male; merozoite; Merozoites - immunology; naturally acquired immunity; plasmodium falciparum; Plasmodium falciparum - immunology; Young Adult; naturally acquired immunity; growth inhibition activity; merozoite; plasmodium falciparum; antibodies; malaria; Fc-mediated effector function; CHMI
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2024.05.001

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. [Display omitted] •Used a human malaria infection study to investigate functional correlates of immunity•IgG Fc-dependent mechanisms are correlated with acquired immunity, but GIA is not•The breadth of IgG Fc-effector function is associated with protective immunity Malaria vaccine development targeting blood-stage infections requires a correlate of protection. Nkumama et al. leverage a controlled human malaria infection model to study mechanisms of acquired immunity. They show that the breadth of IgG Fc-mediated effector functions targeting merozoites and rings is the strongest predictor of protection and is superior to GIA. These findings present important considerations for vaccine development.