Cell Host & Microbe
Volume 26, Issue 5, 13 November 2019, Pages 579-590.e5
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Clinical and Translational Report
Protective Immunity against Severe Malaria in Children Is Associated with a Limited Repertoire of Antibodies to Conserved PfEMP1 Variants

https://doi.org/10.1016/j.chom.2019.10.012Get rights and content
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Highlights

  • 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

Summary

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.

Keywords

malaria
severe malaria
Plasmodium falciparum
PfEMP1
var genes
diversity
antibodies
immunity
vaccine
biomarker

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Present address: School of Medicine, Deakin University, Locked Bag 20000, Geelong 3220, VIC, Australia

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