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

Respiratory syncytial virus (RSV) is a major cause of severe respiratory tract infections in infants and older adults. While vaccines have recently been approved for older adults and pregnant women, vaccine development for infants remains challenging due to the risk of vaccine-enhanced disease. 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. In a cohort of 24-month old children and adults (n=46 per group), we assessed RSV-specific IgG/IgA levels, IgG subclasses, avidity, Fc glycosylation, and neutralization, antibody-dependent NK cell activation (ADNKA), cellular phagocytosis (ADCP), and complement deposition (ADCD). Compared to children, antibodies from adults showed enhanced functionality. Furthermore, RSV-specific antibodies displayed 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 enhanced ADNKA capacity of RSV-specific antibodies. Our data provide a detailed overview of similarities and differences between the 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.