Immunogenicity of Duffy Binding-Like Domains That Bind Chondroitin Sulfate A and Protection against Pregnancy-Associated Malaria

<jats:title>ABSTRACT</jats:title> <jats:p> Sequestration of <jats:italic>Plasmodium falciparum-</jats:italic> infected erythrocytes in the placenta is implicated in pathological outcomes of pregnancy-associated malaria (PAM). <jats:italic>P. falciparum</jats:italic> isolates that sequester in the placenta primarily bind chondroitin sulfate A (CSA). Following exposure to malaria during pregnancy, women in areas of endemicity develop immunity, and so multigravid women are less susceptible to PAM than primigravidae. Protective immunity to PAM is associated with the development of antibodies that recognize diverse CSA-binding, placental <jats:italic>P. falciparum</jats:italic> isolates. The epitopes recognized by such protective antibodies have not been identified but are likely to lie in conserved Duffy binding-like (DBL) domains, encoded by <jats:italic>var</jats:italic> genes, that bind CSA. Immunization of mice with the CSA-binding DBL3γ domain encoded by <jats:italic>var1CSA</jats:italic> elicits cross-reactive antibodies that recognize diverse CSA-binding <jats:italic>P. falciparum</jats:italic> isolates and block their binding to placental cryosections under flow. However, CSA-binding isolates primarily express <jats:italic>var2CSA</jats:italic> , which does not encode any DBLγ domains. Here, we demonstrate that antibodies raised against DBL3γ encoded by <jats:italic>var1CSA</jats:italic> cross-react with one of the CSA-binding domains, DBL3X, encoded by <jats:italic>var2CSA</jats:italic> . This explains the paradoxical observation made here and earlier that anti-rDBL3γ sera recognize CSA-binding isolates and provides evidence for the presence of conserved, cross-reactive epitopes in diverse CSA-binding DBL domains. Such cross-reactive epitopes within CSA-binding DBL domains can form the basis for a vaccine that provides protection against PAM. </jats:p>