Plasmodium falciparum clearance from the placenta by antibodies to VAR2CSA

Abstract

Placental malaria is caused by sequestration of Plasmodium falciparum-infected erythrocytes (IE) in the placenta. Parasite antigen VAR2CSA, expressed on the surface of IE, enables binding of IE to chondroitin sulfate A (CSA) in the placenta, which leads to inflammation and increased risks of poor pregnancy outcomes. Antibodies (Ab) to VAR2CSA, found at higher levels in multigravid women, are associated with improved pregnancy outcomes. However, the precise link between Ab to VAR2CSA and its direct protective effect of IE clearance, i.e., absence of placental malaria at delivery, has not been established. The relative importance of antibodies to individual Duffy binding-like (DBL) domains and the full-length VAR2CSA (FV2) in parasite clearance is also unknown. In this study, we tested whether higher levels of Ab to FV2, to individual domains/variants, and a larger overall antibody repertoire throughout pregnancy correlated with absence of placental malaria in pregnant women living in high or low malaria transmission settings. We further examined if higher levels of high avidity FV2 Ab, inhibitory antibodies and opsonizing antibodies were associated with parasite clearance. Our data showed that in the high transmission setting, women without placental malaria produced significantly higher levels of Ab to FV2 (p=0.0047), DBL3 (p=0.014; 0.023), DBL4 (p=0.037; 0.025), DBL5 (p=0.037; 0.048) and DBL6 (p=0.03) early on than women with placental malaria. The same group of women also produced larger proportions of high avidity antibodies (p=0.0009) and had larger antibody repertoires to domains (p=0.003) and variants (p=0.021) than women with placental malaria. While no difference was found in the levels of antibody mediating inhibition of binding at 5 and 8 month of pregnancy (MoP), women without placental malaria had higher levels of opsonizing antibodies (p=0.027) at 8 MoP than women with placental malaria. No association was found between antibody levels and absence of placental malaria in women living in the low transmission setting. These data provide the first evidence that antibodies to VAR2CSA are important in parasite clearance from the placenta. Also, antibodies involved in opsonic phagocytosis may be a useful functional correlate of protection. Lastly, frequent malaria infections are required for the development of protective antibodies.