More antibodies are not always better: Fc effector functions play a critical role in SARS-CoV-2 infection and...

Traditional vaccinology has primarily focused on neutralizing antibody titers as the main correlate of vaccine efficacy, often overlooking the multifaceted roles of antibody Fc effector functions in orchestrating protective immune responses. Fc-mediated immune responses play a pivotal role in immune modulation and pathogen clearance. Emerging evidence from natural infections and vaccine studies highlights the critical contribution of Fc effector functions in determining the quality and durability of immunity. This work explores the limitations of current vaccine evaluation paradigms that prioritize neutralization over Fc effector mechanisms. It also describes findings from a study showing an unexpected role for SARS-CoV-2 anti-spike antibodies: both convalescent plasma and patient-derived monoclonal antibodies (mAbs) lead to maximum phagocytic capacity by monocytes at low concentrations, whereas at higher concentrations the phagocytic capacity was reduced. Given that the severity of COVID-19 disease and antibody titers are strongly positively correlated, this work challenges the paradigm that high antibodies offer better protection against severe disease. It is proposed that humoral and cellular responses elicited by vaccination should never be higher than those produced by natural infection. By integrating antibody Fc effector functions into vaccine development, a paradigm shift is proposed that emphasizes synergic antibody responses. Such an approach could transform vaccine efficacy assessment, enhance protection against dangerous pathogens, and drive innovation in vaccine design.