IgG and IgM responses to PfEMP1 domains associated with semi-immunity to clinical malaria in Burkinabe children under five

Background Malaria remains a major global health burden, with children under five years in sub-Saharan Africa disproportionately affected. While immunity develops with repeated exposure, the specific correlates of protection in early childhood are not well defined. To address this, we assessed IgG and IgM antibody responses to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) domains in plasma samples from 80 Burkinabe children (aged 0–60 months) collected before (pre-malaria season) and during peak malaria transmission. Methods Using AlphaScreen, we measured antibody responses to 271 PfEMP1 (3D7) domains expressed via wheat germ cell-free synthesis. Results Pre-season analysis showed that 96% of domains were IgG-reactive and IgG breadth increased with age, whereas 71% were IgM-reactive, but IgM breadth showed no age trend. IgG responses to 132 domains (49%) remained significantly associated with reduced risk of clinical malaria after false discovery rate (FDR) correction, including many non-adhesion domains. Five (5) IgM responses were nominally protective, but none remained significant after FDR correction. Fc-dependent opsonic phagocytosis assay using a subset of the top-ranked domains revealed that opsonic phagocytosis activity correlated with protection for only one antigen, suggesting that PfEMP1-specific antibodies may mediate protection through mechanisms beyond phagocytosis in children under 5 years old. Conclusions This study provides the first comprehensive characterization of IgG and IgM responses to a large panel of PfEMP1 domains in young children, revealing broad antibody recognition and selective opsonic phagocytosis activity. Findings from the study deepen our understanding of early-life immunity to malaria and help identify PfEMP1 regions of interest for future vaccine development.