Natural and Vaccine-Induced Acquisition of Cross-Reactive IgG-Inhibiting ICAM-1-Specific Binding of a Plasmodium falciparum PfEMP1 Subtype Associated Specifically with Cerebral Malaria

Cerebral malaria (CM) is a potentially deadly outcome of Plasmodium falciparum malaria that is precipitated by sequestration of infected erythrocytes (IEs) in the brain. The adhesion of IEs to brain endothelial cells is mediated by a subtype of parasite-encoded erythrocyte membrane protein 1 (PfEMP1) that facilitates dual binding to host intercellular adhesion molecule 1 (ICAM-1) and endothelial protein receptor C (EPCR). The PfEMP1 subtype is characterized by the presence of a particular motif (DBL beta_motif) in the constituent ICAM-1-binding DBL beta domain. The rate of natural acquisition of DBL beta_motif-specific IgG antibodies and the ability to induce such antibodies by vaccination are unknown, and the aim of this study was to provide such data. We used an enzyme-linked immunosorbent assay (ELISA) to measure DBL beta-specific IgG in plasma from Ghanaian children with malaria. The ability of human immune plasma and DBL beta-specific rat antisera to inhibit the interaction between ICAM-1 and DBL beta was assessed using ELISA and in vitro assays of IE adhesion under flow. The acquisition of DBL beta_motif-specific IgG coincided with age-specific susceptibility to CM. Broadly cross-reactive antibodies inhibiting the interaction between ICAM-1 and DBL beta_motif domains were detectable in immune plasma and in sera of rats immunized with specific DBL beta_motif antigens. Importantly, antibodies against the DBL beta_motif inhibited ICAM-1-specific in vitro adhesion of erythrocytes infected by four of five P. falciparum isolates from cerebral malaria patients. We conclude that natural exposure to P. falciparum as well as immunization with specific DBL beta_motif antigens can induce cross-reactive antibodies that inhibit the interaction between ICAM-1 and a broad range of DBL beta_motif domains. These findings raise hope that a vaccine designed specifically to prevent CM is feasible.