Background: Different quickly-developed vaccines are introduced against COVID-19 with inconclusive results especially against some recent variants. Eventually, somewhere COVID-19 cases decline and in some countries it revived with some new mutant-variants (i.e. D614G, Delta and Omicron).
Objectives: Proposing a universal vaccination strategy by screening globally-conserved SARS-CoV-2 spike-epitopes.
Methods: Presently, several conserved (186-countries) sequences including multiple-variants (ClustalX2) epitopic-regions (SVMTriP and IEDB) and in-silico mutants of SARS-CoV-2 spike-protein-fragments (Cut1-4) were screened for their stability against proteases, antigenicity (VaxiJen V2.0 and for glycosylation effects NetOGlyc-NetNGlyc), MHCI/II reactivity (IEDB-TOOLS) and CD4+ responses by molecular-docking (Haddock2.4/PatchDock). We also examined Molecular-Dynamic-Simulation (myPresto verson-5) of MHC-II 3LQZ with 3-Cuts and T-cell 2-molecules (1KGC/4JRX) with SM3-Cut. The MD-simulation was run with 5000-cycles after 300 k-heating/1-atm pressure adjustment for the system-equilibration. Finally, 1000 fs production was run.
Results: The cut4-mutant (SRLFRKSNLKPFERD) showed the highest combined-score 48.23548 and Immunogenicity-Score of 92.0887. The core-sequence SRLFRKSNL showed the highest Median-Percentile-Rank (7-HLA-allele) of 19. CD4+ immunogenicity also confirms the representation of the CUT4TM2 epitope SRLFRKSNL by MHC Class II. The epitope YNYKYRLFR from CUT4 showed an IC50 of ∼30 nM with allele HLA-DRB1*11:01 and HLA-DRB5*01:01 with plenty H-bonding. Cut4 double-mutants strongly interact with the exposed T-cell surface and are facilitated by its receptors. The MD-simulation data suggest that TM2 has a maximum RMSD value of 1.7 Å, DM2 is at 1.55 Å and SM3 is at 1.5 Å. These variations correspond to structural adjustments and involve binding/unbinding chemical interactions. The RMSD plot shows that 1KGC T-cell molecule is at 2.2 Å and the 4JRX is at 1.2 Å, which increases with the simulation time.
Conclusions: Screening of conserved SARS-CoV-2 spike fragments helps to find the most stable antigenic-determinant which with some mutations showed better antigenicity. Further studies are necessary to develop global vaccination strategies against COVID-19.
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| http://dx.doi.org/10.1016/j.intimp.2022.108847 | DOI Listing |
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