Antibodies to Plasmodium vivax PvDBP recognize VAR2CSA and block adhesion of P. falciparum-infected red cells to chondroitin sulphate A

Background: During infection with Plasmodium falciparum in pregnancy, parasites express the surface antigen, VAR2CSA that mediates adherence of infected red cells to chondroitin sulphate A (CSA) in the placenta. For women in Africa, antibodies to VAR2CSA are acquired with successive exposures to P. falciparum in pregnancy and the presence of these VAR2CSA-specific antibodies has been associated with protection from placental malaria. In Colombia, we previously observed a high frequency of antibodies to VAR2CSA in non-pregnant populations and these antibodies can functionally inhibit binding of iRBCs to CSA. However, neither the origin of these VAR2CSA-specific antibodies nor their role in protecting against malaria is known. Here, we tested the hypothesis that acquisition of antibodies outside of pregnancy can arise due to exposure to P. vivax. Materials and Methods: 200 sera frommen and children living in malaria-endemic regions of Colombia and Brazil and mouse monoclonal antibodies (mAbs) that recognize the DBL domain of PvDBP were tested. Overlapping peptides were used to map epitopes. PvDBP-specific antibodies were affinity-purified from Colombian men and children with prior infection with P. vivax. IFA, flow cytometry and inhibition of binding of iRBCs to CSA were used to probe antigen expression and antibody function. Results and Conclusions: Over 50% of non-pregnant individuals exposed to P. vivaxhad antibodies that recognized VAR2CSA. PvDBP affinity-purified antibodies from human sera and a PvDBP mAb recognized VAR2CSA with an endpoint titre of 3 micrograms/mL and 0.9 micrograms/mL, respectively. The immunodominant peptide epitope within the DBL5 domain of VAR2CSA recognized by the mAb was also recognized by the human sera of vivax-exposed individuals. The monoclonal antibody recognized the surface of CS2 iRBC and inhibited binding to CSA by 33%, similar to the inhibition with sera from multigravid African women. These data show that exposure to PvDBP can induce antibodies that functionally recognize VAR2CSA and we thus identify a novel mechanism of cross-species immunity to falciparum malaria. This work also establishes the importance of structural epitopes shared between functionally unrelated proteins as targets of cross-species immunity and has important implications for development of a vaccine against pregnancy-associated malaria.