Effects of sex, parity, and sequence variation on seroreactivity to candidate pregnancy malaria vaccine antigens

Background. Plasmodium falciparum-infected erythrocytes adhere to chondroitin sulfate A ( CSA) to sequester in the human placenta, and pregnancy malaria ( PM) is associated with the development of disease in and the death of both mother and child. A PM vaccine appears to be feasible, because women become protected as they develop antibodies against placental infected erythrocytes ( IEs). Two IE surface molecules, VAR1CSA and VAR2CSA, bind CSA in vitro and are potential vaccine candidates. Methods. We expressed all domains of VAR1CSA and VAR2CSA as mammalian cell surface proteins, using a novel approach that allows rapid purification, immobilization, and quantification of target antigen. For serum samples from East Africa, we measured reactivity to all domains, and we examined the effects of host sex and parity, as well as the effects of parasite antigenic variation. Results. Serum samples obtained from multigravid women had a higher reactivity to all VAR2CSA domains than did those obtained from primigravid women or from men. Conversely, serum samples obtained from men had consistently higher reactivity to VAR1CSA domains than did those obtained from gravid women. Seroreactivity was strongly influenced by antigenic variation of VAR2CSA Duffy binding-like domains. Conclusions. Women acquire antibodies to VAR2CSA over successive pregnancies, but they lose reactivity to VAR1CSA. Serum reactivity to VAR2CSA is variant specific, and future studies should examine the degree to which functional antibodies, such as binding-inhibition antibodies, are variant specific.