The pairs of overlapping epitope forming clusters and their HLA allele binders were also utilized to analyze the world population coverage by the screened epitopes on the basis of HLA allele distributed worldwide amongst different ethnic human population. The identified Ag-Patches, in other words, act as the source of multiple CTL and HTL epitopes and hence are the potential stretch of SARS-CoV-2 proteins which can be utilized to elicit T Cell immune response. These CTL and HTL epitope clusters further led us to identify the antigenic patches (Ag-Patches) of the SARS-CoV-2 proteins from where the overlapping epitopes clusters were arising. We further performed multiple sequence alignment for all the screened epitopes leading us to obtain clusters of overlapping epitopes from the proteins of SARS-CoV-2. The schematic of antigen presentation, the identification of antigenic patches (Ag-Patches) by the reverse epitomics “Overlapping-epitope-clusters-to-patches” method and Multi-Patch Vaccine designing is shown in Figure 1A and 1B. Hence, the MPVs would provide more effective and specific solution with larger human population coverage for vaccine development against SARS-CoV-2. The larger the number of epitopes covered larger would be the number of HLA alleles targeted and hence larger human population with ethnic distribution of HLA alleles will be covered. Moreover the Ag-Patch based MPVs will cover larger number of overlapping epitopes in comparison to the limited number of epitopes covered by epitope based MEVs ( Srivastava et al., 2020a Srivastava et al., 2020b). The proteasome and lysosomal chop down processing of MPVs by the Antigen Presenting cells would release larger number of epitopes in their intact form for which the MEVs would have a challenge. In comparison to the epitope based MEVs, the Ag-Patches based MPVs will provide a more natural antigenic vaccine candidate. MPVs would involve Ag-Patches from entire proteome of SARS-CoV-2 and hence would be more effective than subunit or single protein vaccine. The designed MPVs are supposed to be more effective than both the subunit or single antigenic protein based vaccines and the Multi-Epitope Vaccines (MEVs). Further we utilized these identified Ag-Patches from SARS-CoV-2 proteome to design Multi-Patch Vaccine candidates against SARS-CoV-2. In our present study we have identified 73 CTL (Cytotoxic T-Lymphocyte) and 49 HTL (Helper T-Lymphocyte) such Ag-Patches from the structural and non-structural proteins of SARS-CoV-2 virus proteome. These Ag-Patches, once administered as vaccine candidates, are expected to be chopped down to produce cluster of overlapping multiple epitope. These antigenic patches are termed here as Ag-Patch or Ag-Patches. This method of identifying antigenic patches (Ag-Patches) from a protein is termed here as “Overlapping-epitope-clusters-to-patches” method. The term “reverse epitomics” would involve search for antigenic patches from the overlapping multiple epitope clusters. In the present study, we have performed the reverse epitomics analysis to identify antigenic patches from SARS-CoV-2 proteins by novel “overlapping-epitope-clusters-to-patches” method. The crucial step in the process of antigen presentation is the cleavage of the antigenic protein molecules to provide small length peptides which acts as epitopes at later stage after their presentation on the surface of APC ( Melief et al., 2005 Kahan et al., 2003, Tenzer et al., 2005, Antoniou et al., 2003). The ‘Transporter associated with antigen processing’ (TAP) and further the HLA allele (human leukocyte antigen) molecules facilitate the epitope presentation ( Figure 1A). The chop down processing of antigen by proteasome and lysosome into small size peptide epitopes of different length like (7,9,13,15… amino acid) pave the way for epitope formation and eventual presentation. The long term adaptive immunity crucially involves presentation of antigen as epitope on the surface of Antigen Presenting Cells (APC). The outbreak has raised an urgent need of a specific and efficient vaccine against the SARS-CoV-2 virus. More than 26,415,380 people have already got infected and 870,286 have died worldwide, resulting the ongoing mortality rate to be ∼3.295% (cases/deaths*100) ( WHO Coronavirus Disease (COVID-19) Dashboard, 5 th September, 2020 WHO Weekly Epidemiological Update, 31 st August 2020). The disease has already spread to more than 216 countries and territories worldwide. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes the highly communicable disease COVID-19, the ongoing 2019-2020 disease outbreak which has turned into a pandemic.
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