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

Abstract

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 levels of antibody to the ICAM1-binding PfEMP1 domain, DBLβ3, 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 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% confidence interval {CI}, 0.45 to 0.88; = 0.007]) and a 25% reduction in risk of low-density clinical malaria (aIRR = 0.75 [95% CI, 0.55 to 1.01; = 0.06]), while there was no such association for other variants. Children who experienced severe malaria also had significantly lower levels of antibody to DBLβ3 and the other group A domains than those that experienced nonsevere malaria. Furthermore, a subset of PNG DBLβ sequences had ICAM1-binding motifs, formed a distinct phylogenetic cluster, and were similar to sequences from other areas of endemicity. PfEMP1 variants associated with these DBLβ domains were enriched for DC4 and DC13 head structures implicated in endothelial protein C receptor (EPCR) binding and severe malaria, suggesting conservation of dual binding specificities. These results provide further support for the development of specific classes of PfEMP1 as vaccine candidates and as biomarkers for protective immunity against clinical malaria.

Acquisition of IgG to ICAM-1-Binding DBLβ Domains in the Plasmodium falciparum Erythrocyte Membrane Protein 1 Antigen Family Varies between Groups A, B, and C

“…2). Overall, these findings are in agreement with the previously reported dominance of responses to group A PfEMP1 over other PfEMP1 groups (12, 13, 37). However, when the assays were repeated with plasma obtained from children with acute malaria, we found higher overall IgG reactivity to ICAM-1-binding DBLβ domains from groups B and C rather than group A (Fig.…”

Longitudinal analysis of naturally acquired PfEMP1 CIDR domain variant antibodies identifies associations with malaria protection

“…DBLβ domains have been associated with reduced risk of clinical malaria, with parasite densities of ≥10,000 parasites/μl (44). We also observed early acquisition of IgG specific for CIDRα1.8 domains.…”

From genomic to LC-MS/MS evidence: Analysis of PfEMP1 in Benin malaria cases

“…In addition, the proportion of peptides corresponding to DBLβ was higher in the severe malaria patients compared to the uncomplicated malaria patients. These strengthen the hypothesis that DBLβ is involved in the disease development, as demonstrated with antibodies against DBLβ in Tanzania [48] and Papua New Guinea [49]. However, the technical limitation of bottom-up approach in LC-MS/MS does not allow for an optimal sequence coverage for precise PfEMP1 variants identification.…”