Breadth of Fc-mediated effector function delineates grades of clinical immunity following human malaria challenge

Abstract

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 growth inhibition assay was not. The breadth of Fc-mediated effector function clearly discriminated grades of clinical immunity following challenge. These findings present a paradigm shift in the understanding of the mechanisms that underpin immunity to malaria and have important implications for vaccine development.

Full-length merozoite surface protein 1 ofPlasmodium falciparumis a major target of protective immunity following controlled human malaria infections

“…The finding that the entire MSP1 molecule was the target of functional antibodies was not surprising and is supported by early and more recent studies (Jäschke et al, 2017;Woehlbier et al, 2006). The most striking results were that anti-MSP1FL antibodies almost completely recapitulated our recent data identifying Fc-mediated mechanisms targeting merozoites as strong correlates of protective immunity (Nkumama et al, 2022;Odera et al, 2021). These data are consistent with the fact that MSP1 is the most abundant protein on the surface of merozoites (Gilson et al, 2006).…”

“…However, most studies focused on the conserved C-terminal subunit representing ~20% of the molecule (Ellis et al, 2010;Fowkes et al, 2010;Malkin et al, 2007;Ogutu et al, 2009;Richards et al, 2013). Furthermore, although the functional immunological correlate for these and other studies has widely been invasion-inhibition, recent data call this into question in favour of Fc-mediated effector mechanisms (Nkumama et al, 2022;Reiling et al, 2019).…”

“…We categorized the level of Fc-mediated functions of the study participants as either high or low (coded 1 or 0, respectively) based on function specific thresholds. We then summed the breadth scores across the five functions (Nkumama et al, 2022). Non-treated volunteers had higher breadth scores compared to treated volunteers, with 78% (67/86) versus 29% (16/56), respectively (Fig.…”

“…We recently conducted a controlled human malaria infection study in semi-immune Kenyan adults (CHMI-SIKA) (Kapulu et al, 2022) where we showed that antibody-dependent phagocytosis of ring-stage parasites (Musasia et al, 2022) and activity of NK cells against merozoites (Odera et al, 2021) were important functional correlates of protection. Furthermore, additional analyses incorporating the full-panel of Fc-dependent and non-Fc mechanisms revealed that the breadth of effector functions targeting merozoites was most strongly associated with protection (Nkumama et al, 2022).…”

“…Two independent lines of evidence led us to investigate full-length merozoite surface protein 1 (MSP1 FL) as a target of important Fc-mediated mechanisms. First, it is the most abundant protein on the merozoite surface (Gilson et al, 2006) and we have recently shown that the breadth of effector functions was strongly correlated with antibody binding to whole merozoites (Nkumama et al, 2022). Second, an independent and recent vaccine trial using MSP1 FL showed that the vaccine was safe, highly immunogenic and induced opsonizing antibodies that fixed complement and triggered neutrophil respiratory burst (Blank et al, 2020).…”