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

Placental malaria (PM) causes mortality and severe morbidity in areas with stable <i>Plasmodium falciparum</i> transmission. The selective placental accumulation of <i>P. falciparum</i>-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 <i>P. falciparum</i> 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 <i>P. vivax</i>-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 (FV2_BIC) or Chinese hamster ovary cells (FV2_CHO) as well as the corresponding native antigen (IT4VAR04) on the IE surface. We also measured levels of IgG specific for GLURP (<i>P. falciparum-</i>specific) and PvDBP (<i>P. vivax</i>-specific). FV2_CHO-specific IgG levels were lower than FV2_BIC-reactive IgG levels. Furthermore, only FV2_CHO-specific IgG was restricted to women exposed to <i>P. falciparum</i> during pregnancy. Levels of PvDBP-specific IgG were significantly higher among <i>P. vivax</i>-exposed pregnant women but did not correlate with FV2-specific IgG levels. Finally, FV2_CHO-specific IgG was markedly Fc-afucosylated in contrast to FV2_BIC-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.