Protective immunity against severe malaria is associated with a repertoire of antibodies to conserved PfEMP1 variants

Abstract

Extreme diversity of the major P. falciparum antigen, PfEMP1, poses a barrier to identifying targets of protective immunity to malaria. To overcome this problem, we used DBLα protein microarrays covering PfEMP1 diversity to probe the immunomes of young malaria-exposed children in association with disease risk. Children with high group 2 DBLα antibodies had a 26-36% lower risk of uncomplicated malaria but individual DBLα variants were weakly associated with clinical immunity. High antibodies to DBLα groups 1 and 2, and 85 individual DBLα variants were associated with a 70-100% reduction in severe malaria. Low antibodies to 17 variants were strong predictors of severe malaria and these variants were linked to pathogenic domains. This suggests that while immunity to uncomplicated malaria requires a broad repertoire of antibodies, immunity to severe malaria targets a subset of conserved variants. These findings provide new insights into antimalarial immunity and potential biomarkers for disease risk.