Olsen, R.W.Ecklu-Mensah, G.Bengtsson, A.Ofori, M.F.Lusingu, J.P.A.Castberg, F.C.Hviid, L.Adams, Y.Jensen, A.T.R.2019-07-092019-07-092018-02DOI: 10.1128/IAI.00622-17http://ugspace.ug.edu.gh/handle/123456789/31324Cerebral 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 PfEMP1 that facilitate dual binding to host ICAM-1 and EPCR. The PfEMP1 subtype is characterized by the presence of a particular motif (DBLβ_motif) in the constituent ICAM-1-binding DBLβ domain. The rate of natural acquisition of DBLβ_motif-specific IgG and the ability to induce such antibodies by vaccination are unknown, and the aim of this study was to provide such data. We used ELISA to measure DBLβ-specific IgG in plasma from Ghanaian children with malaria. The ability of human immune plasma and DBLβ-specific rat anti-sera to inhibit the interaction between ICAM-1 and DBLβ was assessed using ELISA and in vitro assays of IE adhesion under flow. Acquisition of DBLβ_motif-specific IgG coincided with age-specific susceptibility to CM. Broadly cross-reactive antibodies inhibiting the interaction between ICAM-1 and DBLβ_motif domains were detectable in immune plasma and in sera of rats immunized with specific DBLβ_motif antigens. Importantly, antibodies against the DBLβ_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 DBLβ_motif antigens can induce cross-reactive antibodies that inhibit the interaction between ICAM-1 and a broad range of DBLβ_motif domains. These findings raise hope that a vaccine designed specifically to prevent CM is feasible.enDBLβ cross-reactive antibodiesICAM-1-binding motifPfEMP1Plasmodium falciparumAdhesion inhibitionArticle