Afucosylated VAR2CSA-Specific IgG Reduces Risks of Placental Malaria

Abstract Background Antibody Fc regions have important roles in clearance of Plasmodium falciparum-infected erythrocytes. One such role is engagement with Fcγ receptors on host leukocytes. In the case of FcγRIIIa and b, this interaction is greatly enhanced when the IgG glycan is afucosylated. Methods In this study, we used a fucose-sensitive enzyme-linked immunosorbent assay (FEASI) to assess afucosylation in IgG specific for placental malaria protein VAR2CSA from n = 139 malaria-exposed pregnant Malawian women, correlating these data with mass spectrometry-based analysis. Furthermore, we measured the effect of afucosylation on Fc-mediated leukocyte functions, using both plasma and a monoclonal antibody, PAM2.8, with varying levels of afucosylation. Results There were significantly higher levels of VAR2CSA-specific IgG afucosylation in women with no placental malaria measured by FEASI (P < .0001), which correlated strongly with mass spectrometry analysis (R = 0.8, P < .0001). In addition, highly afucosylated IgG mediated significantly greater neutrophil phagocytosis of antigen-coated beads and induction of NK cell degranulation by infected erythrocytes. Conclusions Afucosylated IgG to VAR2CSA, measured by FEASI or mass spectrometry, was a correlate of protection from placental malaria, and afucosylated IgG activated NK cells and neutrophils. Naturally acquired or therapeutic afucosylated IgG antibody could have a role in protection from malaria infection.