Abstract
We identify amino acid variants within dominant SARS-CoV-2 T-cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T-cells assessed by IFN-γ and cytotoxic killing assays. These data demonstrate the potential for T-cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T-cell as well as humoral immunity.Funding: This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute of Health Research (NIHR) Oxford Biomedical Research Centre and by UK Research and Innovation (UKRI)/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data was undertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute. TIdS is supported by a Wellcome Trust Intermediate Clinical Fellowship (110058/Z/15/Z). MDP is funded by the NIHR Sheffield Biomedical Research Centre (BRC – IS-BRC-1215-20017). JCK is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centre and CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR, or MRC.Conflict of Interest: The authors declare no competing interests.Ethical Approval: Cryopreserved PBMCs were used from SARS-CoV-2 recovered donors recruited into the Sepsis Immunomics study with ethical approval from the South Central - Oxford C Research Ethics Committee in England (Ref 13/SC/0149).
Highlights
Evolution of SARS-CoV-2 can lead to evasion from adaptive immunity generated following infection and vaccination
Amino acid variants within experimentally proven SARS-CoV-2 T cell epitopes To explore the potential for viral evasion from SARS-CoV-2-specific T cell responses, we conducted a proofof-concept study, focusing initially on identifying common amino acid mutations within experimentally proven T cell epitopes and testing the functional implications in selected immunodominant epitopes
We found that several variants resulted in complete loss of responsiveness to the T cell lines evaluated: the Q213K variant in the A*01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215 (Ferretti et al, 2020; Kared et al, 2021; Peng et al, 2020; Schulien et al, 2021); the P13L, P13S, and P13T variants in the B*27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17 (Nelde et al, 2021; Peng et al, 2020); and T362I and P365S variants in the A*03:01/A*11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369 (Ferretti et al, 2020; Gangaev et al, 2020; Kared et al, 2021; Peng et al, 2020) (Figures 1A–1C)
Summary
Evolution of SARS-CoV-2 can lead to evasion from adaptive immunity generated following infection and vaccination. T cells specific to conserved proteins play a significant protective role in respiratory viral infections such as influenza, in broad heterosubtypic immunity (Hayward et al, 2015). Escape from antigen-specific CD8+ T cells has been studied extensively in HIV-1 infection, where rapid intra-host evolution renders T cell responses ineffective within weeks of acute infection (Goonetilleke et al, 2009). These escape variants play an important role in the dynamics of chronic viral infections, the opportunities for T cell escape in acute respiratory viral infections are fewer and consequences are different. Long-term adaptation of influenza A/H3N2 has been demonstrated, with the loss of one CTL epitope every 3 years since its emergence in 1968 (Woolthuis et al, 2016)
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