Current SARS-CoV-2 vaccines take advantage of the viral spike protein required for infection in humans. Considering that spike proteins may contain both “self” and “nonself” sequences (sequences that exist in the human proteome and those that do not, respectively), nonself sequences are likely to be better candidate epitopes than self sequences for vaccines to efficiently eliminate pathogenic proteins and to reduce the potential long-term risks of autoimmune diseases. This viewpoint is likely important when one considers that various autoantibodies are produced in COVID-19 patients. Here, we comprehensively identified self and nonself short constituent sequences (SCSs) of 5 amino acid residues in the proteome of SARS-CoV-2. Self and nonself SCSs comprised 91.2% and 8.8% of the SARS-CoV-2 proteome, respectively. We identified potentially important nonself SCS clusters in the receptor-binding domain of the spike protein that overlap with previously identified epitopes of neutralizing antibodies. These nonself SCS clusters may serve as functional epitopes for effective, safe, and long-term vaccines against SARS-CoV-2 infection. Additionally, analyses of self/nonself status changes in mutants revealed that the SARS-CoV-2 proteome may be evolving to mimic the human proteome. Further SCS-based proteome analyses may provide useful information to predict epidemiological dynamics of the current COVID-19 pandemic.
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 overtaking 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 five 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.
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 Se-quence (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.
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