Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) kills thousands of people worldwide every day, thus necessitating rapid development of countermeasures. Immunoinformatics analyses carried out here in search of immunodominant regions in recently identified SARS-CoV-2 unannotated open reading frames (uORFs) have identified eight linear B-cell, one conformational B-cell, 10 CD4+ T-cell, and 12 CD8+ T-cell promising epitopes. Among them, ORF9b B-cell and T-cell epitopes are the most promising followed by M.ext and ORF3c epitopes. ORF9b40-48 (CD8+ T-cell epitope) is found to be highly immunogenic and antigenic with the highest allele coverage. Furthermore, it has overlap with four potent CD4+ T-cell epitopes. Structure-based B-cell epitope prediction has identified ORF9b61-68 to be immunodominant, which partially overlaps with one of the linear B-cell epitopes (ORF9b65-69). ORF3c CD4+ T-cell epitopes (ORF3c2-16, ORF3c3-17, and ORF3c4-18) and linear B-cell epitope (ORF3c14-22) have also been identified as the candidate epitopes. Similarly, M.ext and 7a.iORF1 (overlap with M and ORF7a) proteins have promising immunogenic regions. By considering the level of antigen expression, four ORF9b and five M.ext epitopes are finally shortlisted as potent epitopes. Mutation analysis has further revealed that the shortlisted potent uORF epitopes are resistant to recurrent mutations. Additionally, four N-protein (expressed by canonical ORF) epitopes are found to be potent. Thus, SARS-CoV-2 uORF B-cell and T-cell epitopes identified here along with canonical ORF epitopes may aid in the design of a promising epitope-based polyvalent vaccine (when connected through appropriate linkers) against SARS-CoV-2. Such a vaccine can act as a bulwark against SARS-CoV-2, especially in the scenario of emergence of variants with recurring mutations in the spike protein.
Highlights
Even 18 months after the official declaration of the SARS-CoV-2 pandemic by the World Health Organization, the world is losing thousands of lives, and nearly half a million people around the globe are being infected by the virus every day
Using comparative genomics and ribosomeprofiling techniques, a recent experimental study has confirmed the translation of 23 additional unannotated open reading frame proteins along with the proteins expressed by canonical ORFs [36]
A CD8+ T-cell epitope binds with more than three human leukocyte antigen (HLA) I alleles and has immunogenicity and antigenicity scores above 0.25 and 0.4, respectively, it is not considered a potent epitope if the IC50 value is not less than 500 nM for at least one of its HLA I-binding partners
Summary
Even 18 months after the official declaration of the SARS-CoV-2 pandemic by the World Health Organization (https://www.who. int/), the world is losing thousands of lives, and nearly half a million people around the globe are being infected by the virus every day (https://www.worldometers.info/coronavirus/). Reports indicate that the number of mutations in the spike protein has increased to 1.4-fold in a time span of 6 months [9, 10]. This is indicative of challenges in using the existing spike protein antigen-based vaccines [11] when new variants emerge. Experimental investigations in recent times have revealed immunodominant epitopes present in the canonical proteins of SARS-CoV-2 [13,14,15,16,17,18,19,20,21,22,23,24,25]. To the best of our knowledge, there is no systematic investigation carried out to identify immunodominant regions in the uORF proteins of SARS-CoV-2
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