Fc effector functions in RNA viral infections: mechanisms of antiviral immunity and implications for vaccine design

Neutralizing antibodies (NAbs) have long been the principal correlate of antiviral protection. Evidence now indicates that antibody Fc-mediated effector functions play indispensable and context-dependent roles in antiviral immunity. Through interactions between the fragment crystallizable (Fc) domain and Fc receptors (FcRs) or complement components, antibodies mediate a broad spectrum of effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular and neutrophil phagocytosis (ADCP and ADNP), and complement activation, contributing to viral control beyond direct neutralization. In this review, we integrate recent evidence on Fc effector biology across major viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza virus, human immunodeficiency virus (HIV), Ebola virus (EBOV), and dengue virus (DENV). We discuss how Fc-FcR interactions shape antiviral immune outcomes, modulate vaccine efficacy, and influence the balance between protective immunity and immunopathology, including antibody-dependent enhancement (ADE). We focus on the experimental strategies used to assess Fc-mediated functions and on the inherent limitations of in vitro assays and animal models in defining their physiological relevance in humans. We explore how different vaccine platforms and immunization strategies shape Fc effector profiles, specifically through antibody subclass selection, Fc glycosylation patterns, and engagement with Fcγ receptors. We also summarize emerging approaches to Fc engineering and glycan modification that aim to enhance antibody efficacy while limiting adverse immune activation. This review summarizes current understanding of Fc effector functions in antiviral immunity and discusses their relevance for the design of next-generation vaccines and antibody-based therapies.