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.

主要恶性疟原虫的极端多样性抗原PfEMP1对识别针对疟疾的免疫靶标构成障碍。在这里，我们使用了包含数百种PfEMP1DBLα域变体的蛋白质微阵列，以覆盖巴布亚新几内亚（PNG）寄生虫的多样性。探查疟疾暴露的PNG儿童纵向队列的血浆显示，第2组DBLα抗体与未发生疟疾的较低风险适度相关，而个别变异仅与临床免疫性弱相关。相比之下，针对85个第1组和第2组DBLα变体的抗体可使严重疟疾减少70％–100％。其中，有17种变异是严重疟疾的有力预测指标。对来自PNG样品的全长PfEMP1序列的分析表明，这17个变体与致病性CIDR域相关。这表明，对简单的疟疾的免疫需要广泛的抗体库，而对严重疟疾的免疫则以保守变异体的子集为目标。这些发现为了解抗疟疾免疫力和潜在的疾病风险抗体生物标志物提供了见识。