Progress in crystallizable fragment effector functions and its application in the evaluation of vaccines

Antibodies serve as critical effector molecules in mediating vaccine-induced protection. While antibody-mediated immunity has traditionally been attributed primarily to neutralization, where the fragment antigen-binding (Fab) domain blocks viral entry by preventing the interaction between viruses and host cells, accumulating evidence underscores the pivotal role of the crystallizable fragment (Fc) domain in orchestrating broader immune responses. By interacting with Fc receptors or complement receptors on effector cells such as natural killer cells, macrophages, neutrophils, and dendritic cells, the Fc domain activates multiple innate immune pathways and elicits a spectrum of non-neutralizing antiviral effector functions. These include antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), antibody-dependent complement deposition (ADCD), and complement-dependent cytotoxicity (CDC). Although the evaluation of Fc-mediated functions is more complex than the measurement of neutralizing antibody titers, the contribution of such functions to vaccine efficacy is increasingly recognized. This review provides a comprehensive overview of Fc-mediated immune effector mechanisms, highlights their critical roles in antiviral vaccine-induced protection, and summarizes recent advances in Fc function assays, with the aim of supporting the rational design and immunogenicity evaluation of next-generation viral vaccines.