Malaria in pregnant mothers is a major public health problem. Women in endemic areas acquire resistance to malaria after years of exposure, but their susceptibility increases significantly during pregnancy, particularly first pregnancy. The hallmark of pregnancy malaria is sequestration of parasites in the placenta. Placental isolates of P. falciparum uniformly bind to chondroitin sulfate A (CSA) expressed on the surface of syncytiotrophoblast. Over successive pregnancies, women develop antibodies that inhibit parasite adhesion to CSA. Women who acquired immunity are at reduced risk of becoming infected and even when they become infected they can control the level of parasitemia resulting in improved outcomes, including increased birth weight and reduction in maternal anemia. Naturally acquired antibodies that inhibit parasite adhesion to CSA are broadly reactive, sera donated by mothers in Asia and Africa cross-react with placental parasites collected on either continent, indicating that the antigen(s) or epitope(s) targeted by these protective antibodies are conserved. VAR2CSA is a member of the PfEMP1 family preferentially expressed by placental parasites and laboratory isolates selected for adhesion to CSA. Importantly, VAR2CSA is expressed on the surface of CSA-binding parasites, and women acquire antibodies against VAR2CSA over successive pregnancies, as they become resistant to pregnancy malaria, properties that placed VAR2CSA as the leading candidate for a PM vaccine. Because the protein encoded by var2csa is a large molecular weight protein (m.w.300 kD) consisting of 6 DBL domains, major effort by numerous labs focused on identifying the best domain or domain combination as an alternative to the full length protein. Using functional genomic tools, additional conserved protein named PfCSA-L (encoded by the gene PF10_0013) was identified as a PM vaccine candidate. Like VAR2CSA, the protein is expressed on the surface of IE and a recombinant form of the protein binds to CSA. These data establish VAR2CSA and PfCSA-L as leading candidates for inclusion in a pregnancy malaria vaccine.
