VAR2CSA-reactive IgG in Brazilian women exposed to Plasmodium falciparum or P. vivax infection during pregnancy.

Placental malaria (PM) causes mortality and severe morbidity in areas with stable Plasmodium falciparum transmission. The selective placental accumulation of P. falciparum-infected erythrocytes (IEs) is mediated by VAR2CSA, a PfEMP1-type parasite ligand that binds exclusively to placenta-restricted CSA. VAR2CSA-specific IgG is therefore generally restricted to women exposed to P. falciparum infection during pregnancy. However, widespread acquisition of VAR2CSA-reactive IgG outside pregnancy among Colombian and Brazilian individuals has been reported, supposedly due to cross-reactivity between VAR2CSA and the P. vivax-specific antigen PvDBP. Here, we measured levels and Fc-afucosylation of VAR2CSA-reactive IgG in plasma from pregnant Brazilian women at delivery, using full-length VAR2CSA (FV2) expressed in baculovirus-transfected insect cells (FV2BIC) or Chinese hamster ovary cells (FV2CHO) as well as the corresponding native antigen (IT4VAR04) on the IE surface. We also measured levels of IgG specific for GLURP (P. falciparum-specific) and PvDBP (P. vivax-specific). FV2CHO-specific IgG levels were lower than FV2BIC-reactive IgG levels. Furthermore, only FV2CHO-specific IgG was restricted to women exposed to P. falciparum during pregnancy. Levels of PvDBP-specific IgG were significantly higher among P. vivax-exposed pregnant women but did not correlate with FV2-specific IgG levels. Finally, FV2CHO-specific IgG was markedly Fc-afucosylated in contrast to FV2BIC-reactive IgG. Our findings caution against using levels of IgG reacting with recombinant proteins expressed in insect cells as a measure of exposure to VAR2CSA during pregnancy, at least in South America. Furthermore, our data do not support the hypothesis that exposure to PvDBP induces IgG that cross-reacts with VAR2CSA and contributes to protection against PM.