A bioinformatic analysis of T-cell epitope diversity in SARS-CoV-2 variants: association with COVID-19 clinical severity in the United States population

Abstract

Long-term immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires the identification of T-cell epitopes affecting host immunogenicity. In this computational study, we explored the CD8⁺ epitope diversity estimated in 27 of the most common HLA-A and HLA-B alleles, representing most of the United States population. Analysis of 16 SARS-CoV-2 variants [B.1, Alpha (B.1.1.7), five Delta (AY.100, AY.25, AY.3, AY.3.1, AY.44), and nine Omicron (BA.1, BA.1.1, BA.2, BA.4, BA.5, BQ.1, BQ.1.1, XBB.1, XBB.1.5)] in analyzed MHC class I alleles revealed that SARS-CoV-2 CD8⁺ epitope conservation was estimated at 87.6%-96.5% in spike (S), 92.5%-99.6% in membrane (M), and 94.6%-99% in nucleocapsid (N). As the virus mutated, an increasing proportion of S epitopes experienced reduced predicted binding affinity: 70% of Omicron BQ.1-XBB.1.5 S epitopes experienced decreased predicted binding, as compared with ~3% and ~15% in the earlier strains Delta AY.100-AY.44 and Omicron BA.1-BA.5, respectively. Additionally, we identified several novel candidate HLA alleles that may be more susceptible to severe disease, notably HLA-A*32:01, HLA-A*26:01, and HLA-B*53:01, and relatively protected from disease, such as HLA-A*31:01, HLA-B*40:01, HLA-B*44:03, and HLA-B*57:01. Our findings support the hypothesis that viral genetic variation affecting CD8 T-cell epitope immunogenicity contributes to determining the clinical severity of acute COVID-19. Achieving long-term COVID-19 immunity will require an understanding of the relationship between T cells, SARS-CoV-2 variants, and host MHC class I genetics. This project is one of the first to explore the SARS-CoV-2 CD8⁺ epitope diversity that putatively impacts much of the United States population.

Keywords: CD8 T cell epitope; COVID-19; HLA; SARS-CoV-2; T cell epitope; bioinformatics; vaccine design.

Figure 1

Nucleotide (NT) variations of spike, membrane, and nucleocapsid over time between B.1 (colored black), Alpha (orange), five Delta (blue), and nine Omicron (red) variants when compared against the original Wuhan strain.

Figure 2

Spike (A), membrane (B), and nucleocapsid (C) epitope differences between variants of interest (B.1 labeled black, Alpha in orange, Delta in blue, and Omicron in red) when compared against the ancestral Wuhan strain. Predicted binding of SARS-CoV-2 S, M, and N epitopes was generated using the IEDB database TepiTool for the 27 most common HLA-A and HLA-B alleles.

Figure 3

Membrane epitopes lost (regions colored red) and gained (colored blue) in Delta (top) and Omicron (bottom) when compared against the ancestral Wuhan strain. Protein characteristics were generated using UniProt’s Feature Viewer (38).

Figure 4

Spike epitopes gained (top) and lost (bottom) when compared against the ancestral Wuhan strain. Colored regions and numbers refer to amino acid locations of predicted epitope alterations, with red indicating changes seen in Omicron, blue for Delta, and yellow for epitopes affected in all 16 variants. Protein characteristics were generated using UniProt’s Feature Viewer (38).

Figure 5

Nucleocapsid epitopes lost (regions colored red) and gained (in blue) in Delta (top) and Omicron (bottom) variants when compared against the ancestral Wuhan strain. Protein characteristics were generated using UniProt’s Feature Viewer.

Figure 6

Spike epitopes gained in nine Omicron and five Delta variants, when compared against the original Wuhan strain. Figures were generated using BioRender (RRID: SCR_018361).

Figure 7

Nucleocapsid (N) and membrane (M) epitopes gained in nine Omicron (colored red) and five Delta (blue) variants when compared against the original Wuhan strain. Figures were generated using BioRender (RRID: SCR_018361).

Figure 8

Heatmap of estimated ΔG (kcal/mol) values predicted for ligands docked with target SARS-CoV-2 epitopes with crystalized HLA-B*15:01 structures (n = 7) by FoldX.