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. 2022 Apr 27:13:891524.
doi: 10.3389/fimmu.2022.891524. eCollection 2022.

In Silico Analysis Predicts a Limited Impact of SARS-CoV-2 Variants on CD8 T Cell Recognition

Olga I Isaeva  1   2   3 , Steven L C Ketelaars  1 , Pia Kvistborg  1
Affiliations

In Silico Analysis Predicts a Limited Impact of SARS-CoV-2 Variants on CD8 T Cell Recognition

Olga I Isaeva et al. Front Immunol. .

Abstract

Since the start of the COVID-19 pandemic, mutations have led to the emergence of new SARS-CoV-2 variants, and some of these have become prominent or dominant variants of concern. This natural course of development can have an impact on how protective the previously naturally or vaccine induced immunity is. Therefore, it is crucial to understand whether and how variant specific mutations influence host immunity. To address this, we have investigated how mutations in the recent SARS-CoV-2 variants of interest and concern influence epitope sequence similarity, predicted binding affinity to HLA, and immunogenicity of previously reported SARS-CoV-2 CD8 T cell epitopes. Our data suggests that the vast majority of SARS-CoV-2 CD8 T cell recognized epitopes are not altered by variant specific mutations. Interestingly, for the CD8 T cell epitopes that are altered due to variant specific mutations, our analyses show there is a high degree of sequence similarity between mutated and reference SARS-CoV-2 CD8 T cell epitopes. However, mutated epitopes, primarily derived from the spike protein, in SARS-CoV-2 variants Delta, AY.4.2 and Mu display reduced predicted binding affinity to their restriction element. These findings indicate that the recent SARS-CoV-2 variants of interest and concern have limited ability to escape memory CD8 T cell responses raised by vaccination or prior infection with SARS-CoV-2 early in the pandemic. The overall low impact of the mutations on CD8 T cell cross-recognition is in accordance with the notion that mutations in SARS-CoV-2 are primarily the result of receptor binding affinity and antibody selection pressures exerted on the spike protein, unrelated to T cell immunity.

Keywords: CD8 T cell epitopes; CD8 T cells; SARS-CoV-2; SARS-CoV-2 variants; bioinformatics & computational biology.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Overview of the investigated SARS-CoV-2 CD8 T cell reactive epitopes. (A) Phylogenetic tree where isolates originating from variants of concern (VOCs) Alpha, Beta, Gamma, Delta and Omicron are highlighted, as well as variants of interest (VOIs) Lambda and Mu. AY.4.2 is a subvariant of Delta and overlaps with the Delta branch. The length of the branches reflects the time of emergence. Visualization generated using the Nextstrain platform (22). (B) Depiction of the project workflow. Created with Biorender. (C) Stacked bar graph indicating the percentages of CD8 T cell recognized epitopes per variant that are conserved or harbor the indicated types of mutations. (D) Numbers of CD8 T cell recognized epitopes per variant that harbor the indicated types of mutations.
Figure 2
Figure 2
Sequence similarity and predicted binding affinity of mutated CD8 T cell recognized epitopes. (A) Sequence similarity scores between the reference SARS-CoV-2 CD8 T cell recognized epitopes and the altered epitopes. Sequence similarity of epitopes in red is set to zero as a result of one or more deletions/insertions in the epitope sequence (Alpha, n = 3; Delta, n = 2; AY.4.2, n = 2; Omicron, n = 13) or due to the ORF8 Q27* stop codon mutation (Alpha, n = 6). (B) Box plot indicating the predicted immunogenicity of the reference SARS-CoV-2 CD8 T cell recognized epitopes and the altered epitopes according to the IEDB T cell class I pMHC immunogenicity prediction tool. (C) Fractions of total altered CD8 T cell recognized epitopes where the predicted binding affinity of the epitope to the corresponding HLA restriction element was increased (≤0.5-fold change in IC50), remained neutral (0.5< fold change in IC50 <2) or was decreased (≥2-fold change in IC50) as a result of the mutation. Epitopes were considered eliminated as a result of the ORF8 Q27* stop codon mutation (Alpha variant). (D) Box plot indicating the predicted binding affinity IC50 (nM) of the reference and altered CD8 T cell recognized epitope to the corresponding HLA restriction element. Box plots indicate the median (line), 25th and 75th percentile (box), min and max (whiskers), and all data points (single circles). Statistical significance was tested with a two-tailed Wilcoxon matched-pairs signed rank test. Variation in numbers of epitopes in the analyses are due to inclusion of epitopes binding one or more HLA restriction elements. *P < 0.05, **P < 0.01, ***P < 0.001. n indicates the number of epitopes analyzed per group.
Figure 3
Figure 3
Sequence similarity and predicted binding affinity of mutated CD8 T cell recognized epitopes derived from the spike protein. (A) Numbers of spike protein-derived CD8 T cell recognized epitopes per variant that harbor the indicated categories of mutations. (B) Sequence similarity scores between the spike protein-derived reference SARS-CoV-2 CD8 T cell recognized epitopes and the matched variant epitopes. Sequence similarity of epitopes in red is set to zero as a result of one or more deletions/insertions in the epitope sequence (Alpha, n = 3; Delta, n = 2; AY.4.2, n = 2; Omicron, n = 12) (C) Box plot indicating the predicted immunogenicity of the spike protein-derived reference SARS-CoV-2 CD8 T cell recognized epitopes and the altered epitopes according to the IEDB T cell class I pMHC immunogenicity prediction tool. (D) Fractions of total altered spike protein-derived CD8 T cell recognized epitopes where the predicted binding affinity of the epitope to the corresponding HLA restriction element was increased (≤0.5-fold change in IC50), remained neutral (0.5< fold change in IC50 <2) or was decreased (≥2-fold change in IC50) as a result of the mutation. (E) Box plot indicating the predicted binding affinity IC50 (nM) of the reference and altered spike protein-derived CD8 T cell recognized epitope to the corresponding HLA restriction element. Box plots indicate the median (line), 25th and 75th percentile (box), min and max (whiskers), and all data points (single circles). Statistical significance was tested with a two-tailed Wilcoxon matched-pairs signed rank test. Variation in numbers of epitopes in the analyses are due to inclusion of epitopes binding one or more HLA restriction elements. AA, amino acid; DEL, deletion; INS, insertion. *P < 0.05, **P < 0.01, ***P < 0.001. n indicates the number of epitopes analyzed per group.
Figure 4
Figure 4
Sequence similarity and predicted binding affinity of spike- versus non-spike-derived mutated CD8 T cell recognized epitopes. (A) Box plot comparing the sequence similarity of the altered spike and non-spike protein-derived CD8 T cell recognized epitopes, to the reference epitopes. Sequence similarity of indicated epitopes is set to zero as a result of one or more deletions/insertions in the epitope sequence (Alpha, n = 6/3; Delta, n = 0/2; AY.4.2, n = 0/2; Omicron, n = 1/12). (B) Fraction of spike versus non-spike protein-derived epitopes where the sequence similarity of the epitope to the reference epitope dropped below 85% as a result of the mutation. (C) Box plot comparing the log2 fold change in predicting binding affinity of spike and non-spike protein-derived CD8 T cell recognized epitopes to the corresponding HLA restriction element, as a result of the mutation. (D) Fraction of spike versus non-spike protein-derived CD8 T cell recognized epitopes where the predicted binding affinity of the epitope to the corresponding HLA restriction element was decreased (≥2-fold change in IC50) as a result of the mutation. (E) Fractions of unique spike protein-derived CD8 T cell recognized epitopes overlapping with a mutation located in the N-terminal domain (NTD), receptor-binding domain (RBD), receptor-binding motif (RBM) or a mutation located outside of these domains. (F) SARS-CoV-2 spike trimer in the open conformation with one erect RBD. Colors represent unique altered CD8 T cell recognized epitopes overlapping with the indicated domains. Image produced with ChimeraX using PDB accession: 6ZGG. Box plots indicate the median (line), 25th and 75th percentile (box), min and max (whiskers), and all data points (single circles). Statistical significance was tested with a two-tailed Mann–Whitney U test (A, C) or with a two-tailed Wilcoxon matched-pairs signed rank test (B, D). Variation in numbers of epitopes in the analyses are due to inclusion of epitopes binding one or more HLA restriction elements. *P < 0.05. n indicates the number of epitopes analyzed per group.
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