Antibodies to Intercellular Adhesion Molecule 1-Binding Plasmodium falciparum Erythrocyte Membrane Protein 1-DBLβ Are Biomarkers of Protective Immunity to Malaria in a Cohort of Young Children from Papua New Guinea

Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) mediates parasite sequestration to the cerebral microvasculature via binding of DBLβ domains to Intercellular Adhesion Molecule 1 (ICAM1) and is associated with severe cerebral malaria. In a cohort of 187 young children from Papua New Guinea (PNG), we examined baseline antibody levels to the ICAM1-binding PfEMP1 domain, DBLβ3_{PF11_0521}, in comparison to four control antigens including NTS-DBLα and CIDR1 domains from another group A variant and a group B/C variant. Antibody levels for the group A antigens were strongly associated with age and exposure. Antibody responses to DBLβ3_{PF11_0521} were associated with a 37% reduced risk of high-density clinical malaria in the follow up period (adjusted incidence risk ratio, aIRR = 0.63 [95% CI: 0.45-0.88; p = 0.007]) and a 25% reduction in risk of low-density clinical malaria (aIRR = 0.75 [95% CI: 0.55-1.01; p = 0.06]), whilst there was no such association for other variants. Children who experienced severe malaria also had significantly lower antibody levels to DBLβ3_{PF11_0521} and the other group A domains than other children. Furthermore, a subset of PNG DBLβ sequences had ICAM1-binding motifs, formed a distinct phylogenetic cluster and were similar to sequences from other endemic areas. PfEMP1 variants associated with these DBLβ were enriched for DC4 and DC13 head-structures implicated in EPCR-binding and severe malaria, suggesting conservation of dual binding specificity. These results provide further support for the development of specific classes of PfEMP1 as vaccine candidates, and as biomarkers for protective immunity against clinical P. falciparum malaria.