Protective immunity to clinical malaria is modified by the genetic diversity of <i>P. falciparum</i> antigens

Abstract Prioritising malaria vaccine targets requires understanding immunity to genetically and structurally diverse parasite antigens, influencing antibody measurements and durability. We measured total IgG levels to 25 Plasmodium falciparum antigens and assessed their association with protection and antigen features. Antibodies were quantified in two longitudinal cohorts of Papua New Guinean children (5–14 years; n=647) experiencing high or moderate transmission. Associations between antibody levels and time to first clinical malaria episode were evaluated using Cox regression and Bayesian antibody-kinetics models, incorporating antigen genetic diversity and structural properties. In high-transmission settings, antibody levels were elevated and stable, with the strongest protection observed for conserved, low-diversity antigens dominated by the 3D7 variant and enriched for intrinsically disordered and alpha-helical regions. In moderate transmission, antibody levels were variable, decayed over time, and reflected recent exposure. These findings identify antigen diversity as a key modifier of malaria immunity and underscore the importance of antigen features.