Emergence of immune escape at dominant SARS-CoV-2 killer T cell epitope

Dolton, Garry; Rius, Cristina; Hasan, Md. Faruk; Wall, Aaron; Szomolay, Barbara; Behiry, Enas M.; Whalley, Thomas; Southgate, Joel; Fuller, Anna; Morin, Théo; Topley, Katie; Tan, Li Rong; Goulder, Philip; Spiller, Owen B.; Rizkallah, P.J.; Jones, Lucy C.; Connor, Thomas R.; Sewell, Andrew K.

doi:10.1016/j.cell.2022.07.002

Cited by 68 publications

(76 citation statements)

References 80 publications

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“…Interestingly, 9.2% of the Delta strains display a P1640L mutation in the immunodominant HLA‐A*01:01/ORF1ab 1637–1646 epitope. Furthermore, previous studies have shown that a P272L mutation of the highly prevalent HLA‐A*02:01/S 269–277 epitope is associated with reduced recognition by CD8 + T cells 38 . However, our sequence analysis revealed that this mutation was found in < 1% of current and past VOC sequences and thus this mutation is not included in Table 1.…”

Section: Resultsmentioning

confidence: 74%

“…Furthermore, previous studies have shown that a P272L mutation of the highly prevalent HLA‐A*02:01/S 269–277 epitope is associated with reduced recognition by CD8 + T cells. 38 However, our sequence analysis revealed that this mutation was found in < 1% of current and past VOC sequences and thus this mutation is not included in Table 1 . These data indicate that the SARS‐CoV‐2 CD8 + T cell epitopes are highly conserved in VOC.…”

Section: Resultsmentioning

confidence: 95%

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Parallel detection of SARS‐CoV‐2 epitopes reveals dynamic immunodominance profiles of CD8⁺ T memory cells in convalescent COVID‐19 donors

et al. 2022

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Objectives High‐magnitude CD8 + T cell responses are associated with mild COVID‐19 disease; however, the underlying characteristics that define CD8 + T cell‐mediated protection are not well understood. The antigenic breadth and the immunodominance hierarchies of epitope‐specific CD8 + T cells remain largely unexplored and are essential for the development of next‐generation broad‐protective vaccines. This study identified a broad spectrum of conserved SARS‐CoV‐2 CD8 + T cell epitopes and defined their respective immunodominance and phenotypic profiles following SARS‐CoV‐2 infection. Methods CD8 + T cells from 51 convalescent COVID‐19 donors were analysed for their ability to recognise 133 predicted and previously described SARS‐CoV‐2‐derived peptides restricted by 11 common HLA class I allotypes using heterotetramer combinatorial coding, which combined with phenotypic markers allowed in‐depth ex vivo profiling of CD8 + T cell responses at quantitative and phenotypic levels. Results A comprehensive panel of 49 mostly conserved SARS‐CoV‐2‐specific CD8 + T cell epitopes, including five newly identified low‐magnitude epitopes, was established. We confirmed the immunodominance of HLA‐A*01:01/ORF1ab 1637–1646 and B*07:02/N 105–113 and identified B*35:01/N 325–333 as a third epitope with immunodominant features. The magnitude of subdominant epitope responses, including A*03:01/N 361–369 and A*02:01/S 269–277 , depended on the donors' HLA‐I context. All epitopes expressed prevalent memory phenotypes, with the highest memory frequencies in severe COVID‐19 donors. Conclusion SARS‐CoV‐2 infection induces a predominant CD8 + T memory response directed against a broad spectrum of conserved SARS‐CoV‐2 epitopes, which likely contributes to long‐term protection against severe disease. The observed immunodominance hierarchy emphasises the importance of T cell epitopes derived from nonspike proteins to the overall protective and cross‐reactive immune response, which could aid future vaccine strategies.

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Section: Resultsmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 95%

Parallel detection of SARS‐CoV‐2 epitopes reveals dynamic immunodominance profiles of CD8⁺ T memory cells in convalescent COVID‐19 donors

et al. 2022

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“…As of July 2022, Omicron was composed of 5 main sublineages, BA.1, BA.2, BA.3, BA.4 and BA.5 1,2 , harboring numerous mutations compared to the ancestral wuhan strain 1,2 . The BA.1 strain has 34 mutations in its spike, associated with antibody escape [3][4][5][6][7][8][9][10][11][12][13][14] , CD8 T cell evasion 15 and modified tropism [16][17][18] . BA.2 harbors 30 mutations, 21 of which are not present in BA.1 2 .…”

Section: Introductionmentioning

confidence: 99%

Longitudinal analysis of serum neutralization of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 in patients receiving monoclonal antibodies

Bruel

Stéfic

Nguyen

et al. 2022

Preprint

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The emergence of novel Omicron lineages, such as BA.5, may impact the therapeutic efficacy of anti-SARS-CoV-2 neutralizing monoclonal antibodies (mAbs). Here, we evaluated the neutralization and ADCC activity of 6 therapeutic mAbs against Delta, BA.2, BA.4 and BA.5 isolates. The Omicron sub-variants escaped most of the antibodies but remained sensitive to Bebtelovimab and Cilgavimab. Consistent with their shared spike sequence, BA.4 and BA.5 displayed identical neutralization profiles. Sotrovimab was the most efficient at eliciting ADCC. We also analyzed 121 sera from 40 immunocompromised individuals up to 6 months after infusion of 1200 mg of Ronapreve (Imdevimab + Casirivimab), and 300 or 600 mg of Evusheld (Cilgavimab + Tixagevimab). Sera from Ronapreve-treated individuals did not neutralize Omicron subvariants. Evusheld-treated individuals neutralized BA.2 and BA.5, but titers were reduced by 41- and 130-fold, respectively, compared to Delta. A longitudinal evaluation of sera from Evusheld-treated patients revealed a slow decay of mAb levels and neutralization. The decline was more rapid against BA.5. Our data shed light on the antiviral activities of therapeutic mAbs and the duration of effectiveness of Evusheld pre-exposure prophylaxis.

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“…As Dolton et al recently highlighted, 'broad brush' approaches have failed to uncover evidence of T cell escape following key variant mutations [10,32]. Indeed, during the early stages of Omicron's rise to global dominance, the overwhelming consensus argued that Omicron does not significantly impair T cell responses [7,10,[44][45][46][47][48][49].…”

Section: Discussionmentioning

confidence: 99%

“…Sampling under some form of evolutionary pressure may suggest that the virus is taking a path to escape cellular immunity. Indeed, as optimal ACE2 affinity and cell entry are approached, wider forms of escape are likely to be evaluated by the virus [32]. A first step toward addressing this fundamental question and estimating the impact of emergent mutations on T cell responses, is to evaluate the impact of each theoretical single point mutation in a CD8+ T cell epitope on its immunogenicity.…”

Section: Inference Of Sars-cov-2 T Cell Escape Potential By In Silico...mentioning

confidence: 99%

A systems approach evaluating the impact of SARS-CoV-2 variant of concern mutations on CD8+ T cell responses

Buckley

Lee

Antanaviciute

et al. 2022

Preprint

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T cell recognition of SARS-CoV-2 antigens after vaccination and/or natural infection has played a central role in resolving SARS-CoV-2 infections and generating adaptive immune memory. However, the clinical impact of SARS-CoV-2-specific T cell responses is variable and the mechanisms underlying T cell interaction with target antigens are not fully understood. This is especially true given the virus’ rapid evolution, which leads to new variants with immune escape capacity. In this study, we used the Omicron variant as a model organism and took a systems approach to evaluate the impact of mutations on CD8+ T cell immunogenicity. We computed an ‘immunogenicity potential’ score for each SARS-CoV-2 peptide antigen from the ancestral strain and Omicron, capturing both antigen presentation and T cell recognition probabilities. By comparing ancestral vs. Omicron immunogenicity scores, we reveal a divergent and heterogeneous landscape of impact for CD8+ T cell recognition of mutated targets in Omicron variants. While T cell recognition of Omicron peptides is broadly preserved, we observed mutated peptides with deteriorated immunogenicity that may assist breakthrough infection in some individuals. We then combined our scoring scheme with anin-silicomutagenesis, to characterise the position- and residue-specific theoretical mutational impact on immunogenicity. While we predict many escape trajectories from the theoretical landscape of substitutions, our study suggests that Omicron mutations in T cell epitopes did not develop under cell-mediated pressure. Our study provides a generalisable platform for fostering a deeper understanding of existing and novel variant impact on antigen-specific vaccine- and/or infection-induced T cell immunity.

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Emergence of immune escape at dominant SARS-CoV-2 killer T cell epitope

Cited by 68 publications

References 80 publications

Parallel detection of SARS‐CoV‐2 epitopes reveals dynamic immunodominance profiles of CD8⁺ T memory cells in convalescent COVID‐19 donors

Parallel detection of SARS‐CoV‐2 epitopes reveals dynamic immunodominance profiles of CD8⁺ T memory cells in convalescent COVID‐19 donors

Longitudinal analysis of serum neutralization of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 in patients receiving monoclonal antibodies

A systems approach evaluating the impact of SARS-CoV-2 variant of concern mutations on CD8+ T cell responses

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Emergence of immune escape at dominant SARS-CoV-2 killer T cell epitope

Cited by 68 publications

References 80 publications

Parallel detection of SARS‐CoV‐2 epitopes reveals dynamic immunodominance profiles of CD8+ T memory cells in convalescent COVID‐19 donors

Parallel detection of SARS‐CoV‐2 epitopes reveals dynamic immunodominance profiles of CD8+ T memory cells in convalescent COVID‐19 donors

Longitudinal analysis of serum neutralization of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 in patients receiving monoclonal antibodies

A systems approach evaluating the impact of SARS-CoV-2 variant of concern mutations on CD8+ T cell responses

Contact Info

Product

Resources

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Parallel detection of SARS‐CoV‐2 epitopes reveals dynamic immunodominance profiles of CD8⁺ T memory cells in convalescent COVID‐19 donors

Parallel detection of SARS‐CoV‐2 epitopes reveals dynamic immunodominance profiles of CD8⁺ T memory cells in convalescent COVID‐19 donors