In silico analysis of predicted differential MHC binding and CD8+ T-cell immune escape of SARS-CoV-2 B.1.1.529 variant mutant epitopes

  1. Pablo Riesgo-Ferreiro
  2. Ranganath Gudimella
  3. Thomas Bukur
  4. Patrick Sorn
  5. Thomas Rösler
  6. Barbara Schrörs
  7. Martin Löwer

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Abstract

Introduction

The B.1.1.529 (Omicron) SARS-CoV-2 variant has raised global concerns due to its high number of mutations and its rapid spread. It is of major importance to understand the impact of this variant on the acquired and induced immunity. Several preliminary studies have reported the impact of antibody binding and to this date, there are few studies on Omicron’s CD8 + T-cell immune escape.

Methods

We first assessed the impact of Omicron and B.1.617.2 (Delta) variant mutations on the SARS-CoV-2 spike epitopes submitted to the Immune Epitope Database (IEDB) with positive out-come on MHC ligand or T-cell assays (n=411). From those epitopes modified by a mutation, we found the corresponding homologous epitopes in Omicron and Delta. We then ran the netMHCpan computational MHC binding prediction on the pairs of IEDB epitopes and matching homologous epitopes over top 5 MHC I alleles on some selected populations. Lastly, we applied a Fisher test to find mutations enriched for homologous epitopes with decreased predicted binding affinity.

Results

We found 31 and 78 IEDB epitopes modified by Delta and Omicron mutations, respectively. The IEDB spike protein epitopes redundantly cover the protein sequence. The WT pMHC with a strong predicted binding tend to have homologous mutated pMHC with decreased binding. A similar trend is observed in Delta over all HLA genes, while in Omicron only for HLA-B and HLA-C. Finally, we obtained one and seven mutations enriched for homologous mutated pMHC with decreased MHC binding affinity in Delta and Omicron, respectively. Three of the Omicron mutations, VYY143-145del, K417N and Y505H, are replacing an aromatic or large amino acid, which are reported to be enriched in immunogenic epitopes. K417N is common with Beta variants, while Y505H and VYY143-145del are novel Omicron mutations.

Conclusion

In summary, pMHC with Delta and Omicron mutations show decreased MHC binding affinity, which results in a trend specific to SARS-CoV-2 variants. Such epitopes may decrease overall presentation on different HLA alleles suggesting evasion from CD8+ T-cell responses in specific HLA alleles. However, our results show B.1.1.529 (Omicron) will not totally evade the immune system through a CD8 + immune escape mechanism. Yet, we identified mutations in B.1.1.529 (Omicron) introducing amino acids associated with increased immunogenicity.

Availability

All the code and results from this study are available at https://github.com/TRON-bioinformatics/omicron-analysis .

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  1. ScreenIT

    SciScore for 10.1101/2022.01.31.478157: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    We downloaded the Pfam domains from the Ensembl annotations at ftp://ftp.ensem-blgenomes.org/pub/viruses/json/sars_cov_2/sars_cov_2.json.
    Pfam
    suggested: (Pfam, RRID:SCR_004726)
    We obtained the homologous epitopes by performing a global alignment using BioPython [18] with parameters mode=‘global’, match=2, mismatch=-2, open_gap_score=-3 and extend_gap_score=-1.
    BioPython
    suggested: (Biopython, RRID:SCR_007173)
    MHC binding is performed with the tool netMHCpan 4.1 [16] with the following parameters ‘netMHCpan -p (fasta) -a (hla_allele) -s’ for every epitope of 8, 9, 10 and 11 amino acids using NeoFox [20] API.
    netMHCpan
    suggested: (NetMHCpan Server, RRID:SCR_018182)
    Finally, we test each mutation for the enrichment of mutated pMHC with decreased binding with the Fisher’s exact test as implemented in Scipy [22] and the contingency table indicated below (Table 2).
    Scipy
    suggested: (SciPy, RRID:SCR_008058)

    Results from OddPub: Thank you for sharing your code and data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  2. Version published to 10.1101/2022.01.31.478157 on bioRxiv