Understanding how immunity to malaria develops in children

What is it about?

Malaria is one of the leading causes of childhood morbidity and mortality globally. After many episodes of infection, children living in malaria-endemic areas develop some degree of immunity to malaria. Antibodies play an important role in immunity to P. falciparum malaria and are typically directed towards surface antigens expressed by the merozoite and infected erythrocyte forms during the blood-stage of infection. The importance of specific surface antigens as immune targets remains unclear, and the relative importance in immunity of antibodies to the merozoite form or the infected erythrocyte forms is unknown. We evaluated antibodies and protective associations in two cohorts of children in Papua New Guinea. We used genetically-modified P. falciparum to evaluate the importance of PfEMP1 (an important antigen on the surface of IEs) and a P. falciparum isolate with a virulent phenotype (associated with the development of severe malaria). Our findings suggested that PfEMP1 was by far the dominant target of antibodies to the IE surface, including functional antibodies that promoted opsonic phagocytosis by monocytes. Antibodies were acquired with increasing age, and were higher among children exposed to a higher force-of-infection as determined using molecular detection approaches. Interestingly, we found that antibodies to IE surface antigens were consistently associated with reduced risk of malaria in both younger and older children. However, protective associations for antibodies to merozoite surface antigens were only observed in older children. This suggests that antibodies to IE surface antigens, particularly PfEMP1, play an earlier role in acquired immunity to malaria, whereas greater exposure is required for protective antibodies to merozoite antigens.

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Why is it important?

These findings have implications for developing vaccines for malaria by understanding what responses contribute to malaria immunity and how these responses develop. Merozoite antigens have been the main focus of vaccines against blood stages and several vaccines have entered clinical trials, but with limited success. Our studies suggest that antibodies to merozoite antigens play a role in naturally-acquired immunity, but these responses are slow to develop. Therefore, a vaccine would aim to generate high level antibodies to key merozoite targets to mediate protective immunity. However, antibodies to infected erythrocytes (or other stages) might also be needed to obtain high levels of protective immunity