Determinants of success and failure of antibody-based strategies against respiratory viruses: insights from RSV and SARS-CoV-2

Respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS−CoV−2) represent two extremes in the outcome of antibody−based interventions. The long−acting monoclonal antibody nirsevimab has achieved durable, population−level protection against RSV in infants, reducing hospitalizations by 70–90% with no evidence of antigenic escape. In contrast, all neutralizing monoclonal antibodies against SARS−CoV−2 became obsolete within three years due to rapid viral evolution, particularly in the spike receptor−binding domain. This review dissects the mechanistic determinants underlying this divergence. We propose four key principles that govern antibody efficacy against respiratory viruses: (i) targeting a structurally conserved epitope with high fitness cost for escape; (ii) achieving sufficient antibody concentrations in the airway epithelial lining fluid; (iii) the vulnerability of single−epitope strategies against mutable viral targets; and (iv) the auxiliary but non−substitutable role of Fc effector functions. By comparing RSV and SARS−CoV−2, we illustrate how these principles align in successful interventions and fail in others. Finally, we discuss emerging strategies—particularly inhaled delivery and mRNA−encoded antibodies—that may overcome current limitations and enable durable protection against antigenically variable respiratory pathogens.