PREMALSTRUCT · Structural analysis of the CSA binding interactions involved during pregnancy associated malaria

Adhesion of Plasmodium falciparum-infected erythrocytes (PE) to placental chondroitin-4-sulfate (CSA) has been linked to the severe disease outcome of pregnancy-associated malaria (PAM). After multiple pregnancies, women acquire protective antibodies that block CSA-binding and cross-react with geographically diverse placental isolates suggesting that surface molecule(s) expressed by PAM-infected erythrocytes have conserved epitopes and that a PAM vaccine may be possible. Recent evidence strongly suggests that var2CSA, a member of the P. falciparum Erythrocyte Membrane protein 1 (PfEMP1) family, may have an important role in PAM and immunity. Although var2CSA and to some extent var1CSA are the main candidates for a pregnancy malaria vaccine, experimental evidence implies that antigenic polymorphism and the lack of a small animal in vivo experimental model may pose a challenge for vaccine development. To date, efforts to develop a truly prophylactic PAM vaccine have been hindered by the difficulty in identifying immunogens that elicit broadly neutralizing and adhesion-blocking antibodies. Accordingly, a small number of highly specialized and experienced malaria research groups from Europe (6 groups) and endemic countries (2 groups) have decided to give highest priority to decipher the molecular basis for the CSA binding to the parasite ligands in order to define the common features within the different CSA-binding domains and the cross-reactive epitopes that are likely to be the targets of natural protective antibodies. This knowledge will not only be very helpful in the design of novel PfEMP1-CSA based antigens capable of inducing broad and potent neutralising antibodies to a wide variety of strains, but also to identify molecules with inhibitory capacity that could be considered for therapeutic strategies as anti-adhesive drugs.