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.