Nonself Mutations in the Spike Protein Suggest an Increase in the Antigenicity and a Decrease in the Virulence of the Omicron Variant of SARS-CoV-2

Despite extensive worldwide vaccination, the current COVID-19 pandemic caused by SARS-CoV-2 continues. The Omicron variant is a recently emerged variant of concern and is now taking over the Delta variant. To characterize the potential antigenicity of the Omicron variant, we examined the distributions of SARS-CoV-2 nonself mutations (in reference to the human proteome) as 5 amino acid stretches of short constituent sequences (SCSs) in the Omicron and Delta proteomes. The number of nonself SCSs did not differ much throughout the Omicron, Delta, and Reference Sequence (RefSeq) proteomes but markedly increased in the receptor binding domain (RBD) of the Omicron spike protein compared to those of the Delta and RefSeq proteins. In contrast, the number of nonself SCSs decreased in non-RBD regions in the Omicron spike protein, compensating for the increase in the RBD. Several nonself SCSs were tandemly present in the RBD of the Omicron spike protein, likely as a result of selection for higher binding affinity to the ACE2 receptor (and hence higher infectivity and transmissibility) at the expense of increased antigenicity. Taken together, the present results suggest that the Omicron variant has evolved to have higher antigenicity and less virulence in humans despite increased infectivity and transmissibility.