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

Abstract

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.

The convalescent sera option for containing COVID-19

“…This suggests that antibody declines with time and/or that few patients make high-titer responses. It is also possible that non-neutralizing antibodies are produced that contribute to protection and recovery, as described for other viral diseases (24)(25)(26). There are reports that convalescent serum was used for therapy of patients with COVID-19 in China during the current outbreak (27).…”

Deployment of convalescent plasma for the prevention and treatment of COVID-19

“…virus), thereby neutralizing its infectivity directly, while other antibody-mediated pathways such as complement activation, antibody-dependent cellular cytotoxicity and/or phagocytosis may also contribute to its therapeutic effect. Non-neutralizing antibodies that bind to the pathogen -but do not interfere with its ability to replicate in in vitro systems -may also contribute to prophylaxis and/or enhance recovery (13,14). Importantly, passive antibody administration offers the only short-term strategy to confer immediate immunity to susceptible individuals.…”

Potential antiviral options against SARS-CoV-2 infection

“…This may suggest that antibody levels decline with time and/or that only a subset of patients produces high-titer responses. It is also possible that non-neutralizing antibodies and cellular responses not connected to antibody production are contributing to protection and recovery, as described for other viral diseases (Gunn et al, 2018;Jenks et al, 2019;van Erp et al, 2019).…”