The development of effective malaria vaccines and immune biomarkers of malaria is a high priority for malaria control and elimination. Antigens expressed by merozoites of Plasmodium falciparum are likely to be important targets of human immunity and promising vaccine candidates, but very few antigens have been studied.
We developed an approach to assess human antibody responses to a comprehensive repertoire of merozoite proteins, to investigate whether they are targets of protective antibodies and potential vaccine candidates. We expressed 91 recombinant merozoite proteins, located on the merozoite surface or within invasion organelles, and screened them for quality and reactivity to human antibodies. Subsequently, antibodies to 46 proteins were studied in a longitudinal cohort of Papua New Guinean children to define antibody acquisition and associations with protective immunity. There was a high prevalence of antibodies to the majority of the 46 antigens. Antibodies were generally higher among older children and those with active parasitemia. High-level antibody responses to many merozoite antigens were prospectively associated with a reduced risk of symptomatic malaria. Overall, antibodies to rhoptry and microneme proteins that function in erythrocyte invasion were identified as being most strongly associated with protective immunity compared to other antigens.Additionally, antibodies to new or under-studied antigens were more strongly associated with protection than antibodies to current vaccine candidates that have progressed to phase 1 or 2 vaacine trials. Combinations of antibody responses were identified that were very strongly associated with protective immunity.
This study identifies antigens that are likely to be key targets of protective human immunity and facilitates the prioritization of antigens for further evaluation as malaria vaccine candidates and/or for use as biomarkers of immunity to malaria in surveillance and control.