Self and Nonself Short Constituent Sequences of Amino Acids in the SARS-CoV-2 Proteome for Vaccine Development

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.