Decreased Fc fucosylation aligns with enhanced RSV-specific antibody functionality in adults compared to young children

Background: Respiratory syncytial virus (RSV) is a major cause of severe respiratory tract infections in infants and older adults. While RSV vaccines have recently been approved for older adults and pregnant women, and newborns can be protected through monoclonal antibody immunization, vaccine development for infants remains challenging. Understanding immunological differences between target groups is essential for improving vaccination strategies, but no clear correlates of protection have been identified yet. Antibody Fc-mediated effector functions may play an important role. Here, we aim to delineate RSV-specific antibody features underlying differences in antibody functionality between children and adults. Methods: In an observational cohort of 24-month old children and adults (n = 46 per group), we assessed RSV-specific IgG/IgA levels, IgG subclasses, avidity, Fc glycosylation, neutralization, and antibody-dependent NK cell activation, cellular phagocytosis, and complement deposition using a systems serology approach including (multiplex) bead-based immunoassays, mass-spectrometry, and in vitro cellular assays. Results: Here we show that, compared to children, antibodies from adults display enhanced functionality. Furthermore, RSV-specific antibodies display differences in avidity and glycosylation patterns between the two groups, which might relate to differences in the number of previous exposures. Importantly, our data strongly suggest that IgG Fc afucosylation drives the enhanced capacity of RSV-specific antibodies to activate NK cells in adults. Conclusions: Our data provide a detailed overview of similarities and differences between RSV-specific antibodies in children and adults. This information will support the ongoing quest for correlates of protection and the design of future vaccination strategies in different target populations.