Functional and structural modifications of influenza antibodies during pregnancy.

Pregnancy represents a unique tolerogenic immune state which may alter susceptibility to infection and vaccine response. Here, we characterized humoral immunity to seasonal influenza vaccine strains in pregnant and non-pregnant women. Although serological responses to influenza remained largely intact during late pregnancy, distinct modifications were observed. Pregnant women had reduced hemagglutinin subtype-1 (H1)- IgG, IgG1, IgG2, and IgG3, hemagglutination inhibition, and group 1 and 2 stem IgG titers. Intriguingly, H1-specific avidity and FcγR1 binding increased, and influenza antibodies had distinct Fc and Fab glycans characterized by increased di-galactosylation and di-sialylation. H1-specific Fc-functionality (i.e. monocyte phagocytosis and complement deposition) was moderately reduced in pregnancy. Multivariate antibody analysis revealed two distinct populations (pregnant vs. non-pregnant) segregated by H1 FcγR1 binding, H1-IgG levels, and Fab and Fc glycosylation. Our results demonstrated a structural and functional modulation of influenza humoral immunity during pregnancy that was antigen-specific and consistent with reduced inflammation and efficient placental transport.

Fc Glycan-Mediated Regulation of Placental Antibody Transfer.

Despite the worldwide success of vaccination, newborns remain vulnerable to infections. While neonatal vaccination has been hampered by maternal antibody-mediated dampening of immune responses, enhanced regulatory and tolerogenic mechanisms, and immune system immaturity, maternal pre-natal immunization aims to boost neonatal immunity via antibody transfer to the fetus. However, emerging data suggest that antibodies are not transferred equally across the placenta. To understand this, we used systems serology to define Fc features associated with antibody transfer. The Fc-profile of neonatal and maternal antibodies differed, skewed toward natural killer (NK) cell-activating antibodies. This selective transfer was linked to digalactosylated Fc-glycans that selectively bind FcRn and FCGR3A, resulting in transfer of antibodies able to efficiently leverage innate immune cells present at birth. Given emerging data that vaccination may direct antibody glycosylation, our study provides insights for the development of next-generation maternal vaccines designed to elicit antibodies that will most effectively aid neonates.