Fc-Mediated Antibody Effector Functions During Respiratory Syncytial Virus Infection and Disease

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections and hospitalization in infants under 1 year of age and there is currently no market-approved vaccine available. For protection against infection, young children mainly depend on their innate immune system and maternal antibodies. Traditionally, antibody-mediated protection against viral infections is thought to be mediated by direct binding of antibodies to viral particles, resulting in virus neutralization. However, in the case of RSV, virus neutralization titers do not provide an adequate correlate of protection. The current lack of understanding of the mechanisms by which antibodies can protect against RSV infection and disease or, alternatively, contribute to disease severity, hampers the design of safe and effective vaccines against this virus. Importantly, neutralization is only one of many mechanisms by which antibodies can interfere with viral infection. Antibodies consist of two structural regions: a variable fragment (Fab) that mediates antigen binding and a constant fragment (Fc) that mediates downstream effector functions via its interaction with Fc-receptors on (innate) immune cells or with C1q, the recognition molecule of the complement system. The interaction with Fc-receptors can lead to killing of virus-infected cells through a variety of immune effector mechanisms, including antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Antibody-mediated complement activation may lead to complement-dependent cytotoxicity (CDC). In addition, both Fc-receptor interactions and complement activation can exert a broad range of immunomodulatory functions. Recent studies have emphasized the importance of Fc-mediated antibody effector functions in both protection and pathogenesis for various infectious agents. In this review article, we aim to provide a comprehensive overview of the current knowledge on Fc-mediated antibody effector functions in the context of RSV infection, discuss their potential role in establishing the balance between protection and pathogenesis, and point out important gaps in our understanding of these processes. Furthermore, we elaborate on the regulation of these effector functions on both the cellular and humoral side. Finally, we discuss the implications of Fc-mediated antibody effector functions for the rational design of safe and effective vaccines and monoclonal antibody therapies against RSV.