Protective Immunity against Severe Malaria in Children Is Associated with a Limited Repertoire of Antibodies to Conserved PfEMP1 Variants.

Extreme diversity of the major Plasmodium falciparum antigen, PfEMP1, poses a barrier to identifying targets of immunity to malaria. Here, we used protein microarrays containing hundreds of variants of the DBLα domain of PfEMP1 to cover the diversity of Papua New Guinean (PNG) parasites. Probing the plasma of a longitudinal cohort of malaria-exposed PNG children showed that group 2 DBLα antibodies were moderately associated with a lower risk of uncomplicated malaria, whereas individual variants were only weakly associated with clinical immunity. In contrast, antibodies to 85 individual group 1 and 2 DBLα variants were associated with a 70%–100% reduction in severe malaria. Of these, 17 variants were strong predictors of severe malaria. Analysis of full-length PfEMP1 sequences from PNG samples shows that these 17 variants are linked to pathogenic CIDR domains. This suggests that whereas immunity to uncomplicated malaria requires a broad repertoire of antibodies, immunity to severe malaria targets a subset of conserved variants. These findings provide insights into antimalarial immunity and potential antibody biomarkers for disease risk. • Group 1 and 2 DBLα domains are serodominant in PNG children exposed to malaria • Antibodies against individual DBLα are weakly associated with risk of clinical malaria • Antibodies against specific conserved DBLα are strongly associated with severe malaria • Protective DBLα antibodies are potential biomarkers for severe disease risk Identifying targets of antimalarial immunity is essential for vaccine development but compromised by the enormous diversity of malaria parasite surface antigens. Tessema et al. show that severe malaria immunity targets a subset of antigenically conserved parasite proteins, whereas clinical immunity requires a broad repertoire of antibodies to diverse proteins. [ABSTRACT FROM AUTHOR]