Impacts of receptor binding and immunity on SARS-CoV-2 fitness landscape: a modeling study

Despite numerous studies investigating SARS-CoV-2 ACE2 binding affinity and its transmissibility, their relationship concerning varying immunity remains unclear. Daily ACE2 binding and immune escape in SARS-CoV-2 were calculated by summing the effects of all amino acid mutations in the receptor binding domain for each viral sequence per day, based on deep mutational scanning data. We developed an infectious disease transmission model that decomposed the effective reproduction number into viral infectiousness, host protection, and contact patterns. Viral infectiousness was used to represent a component of the fitness determined by both ACE2 binding and the immunity of infected hosts. By fitting the model to daily reported cases, immune escape, vaccine rollout, and population mobility, both viral infectiousness and effective immunity (i.e. the protection against the circulating variants) among infected individuals were quantified. A rugged fitness landscape, spanned by ACE2 binding and hosts’ effective immunity, was observed with peaks corresponding to individual VOCs (alpha, delta, and omicron (BA.1* and BA.2*)). We found that higher effective immunity was associated with a lower level of virus fitness peak initially; and lower effective immunity with weaker receptor binding was associated with an optimal virus fitness. The finding helps understand SARS-CoV-2 evolution and predict future dominant variants.