Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases

Tarke, Alison; Sidney, John; Kidd, Conner K.; Dan, Jennifer M.; Ramirez, Sydney I.; Yu, Esther Dawen; Mateus, José; Antunes, Ricardo da Silva; Moore, Erin; Rubiro, Paul; Methot, Nils; Phillips, Elizabeth; Mallal, S.; Rawlings, Stephen A.; Greenbaum, Jason A.; Peters, Bjoern; Smith, Davey M; Crotty, Shane; Weiskopf, Daniela; Grifoni, Alba; Sette, Alessandro

doi:10.1101/2020.12.08.416750

Cited by 96 publications

(174 citation statements)

References 54 publications

(112 reference statements)

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“…In this regard, a particular attention was allocated in our study to the B*07:02-restricted N105 epitope SPRWYFYYL. This epitope is of high interest as its immunodominance was experimentally demonstrated in many independent studies (Ferretti et al, 2020;Kared et al, 2021;Saini et al, 2021;Schulien et al, 2021;Sekine et al, 2020;Tarke et al, 2021). Precisely, we found a rare mutation consisting of PàS at P2 of this epitope (SPRWYFYYL à SSRWYFYYL).…”

Section: Discussionsupporting

confidence: 64%

“…A comprehensive map of epitopes recognized by CD4+ and CD8+ T cell responses across the entire SARS-CoV-2 viral proteome was also recently reported (Tarke et al, 2020). Notably, the structural proteins Spike (S), Nucleocapsid (N) and Membrane (M) were shown to be rich sources of immunodominant HLAassociated epitopes, accounting for a large proportion of the total CD4+ and CD8+ T cell response in the context of a broad set of HLA alleles (Tarke et al, 2021). To date (May 2021), ~700 HLA class I-restricted SARS-CoV-2-derived epitopes have been experimentally validated (https://www.mckayspcb.com/SARS2TcellEpitopes/) (Quadeer et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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The mutational landscape of SARS-CoV-2 variants diversifies T cell targets in an HLA supertype-dependent manner

Hamelin

Fournelle

Grenier

et al. 2021

Preprint

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The rapid, global dispersion of SARS-CoV-2 since its initial identification in December 2019 has led to the emergence of a diverse range of variants. The initial concerns regarding the virus were quickly compounded with concerns relating to the impact of its mutated forms on viral infectivity, pathogenicity and immunogenicity. To address the latter, we seek to understand how the mutational landscape of SARS-CoV-2 has shaped HLA-restricted T cell immunity at the population level during the first year of the pandemic, before mass vaccination. We analyzed a total of 330,246 high quality SARS-CoV-2 genome assemblies sampled across 143 countries and all major continents. Strikingly, we found that specific mutational patterns in SARS-CoV-2 diversify T cell epitopes in an HLA supertype-dependent manner. In fact, we observed that proline residues are preferentially removed from the proteome of prevalent mutants, leading to a predicted global loss of SARS-CoV-2 T cell epitopes in individuals expressing HLA-B alleles of the B7 supertype family. In addition, we show that this predicted global loss of epitopes is largely driven by a dominant C-to-U mutation type at the RNA level. These results indicate that B7 supertype-associated epitopes, including the most immunodominant ones, were more likely to escape CD8+ T cell immunosurveillance during the first year of the pandemic. Together, our study lays the foundation to help understand how SARS-CoV-2 mutants shape the repertoire of T cell targets and T cell immunity across human populations. The proposed theoretical framework has implications in viral evolution, disease severity, vaccine resistance and herd immunity.

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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

The mutational landscape of SARS-CoV-2 variants diversifies T cell targets in an HLA supertype-dependent manner

Hamelin

Fournelle

Grenier

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The peptides used in our immunoassay predominantly stimulate CD4 + T cell responses, and cover all major immunodominant regions of the virus, including those in the spike, membrane and nucleocapsid proteins, as recently defined (26). TH1-type responses to these immunogenic regions were detected in the vast majority of convalescent SARS-CoV-2 infected and/or vaccinated individuals, in keeping with prior findings (26,27), although convalescent asymptomatic donors and a minority of naïve individuals demonstrate low-level reactivity. Prior studies have revealed the functionality and magnitude of adaptive immune responses to SARS-CoV-2 were significantly lower in mild cases of COVID-19 in comparison to severe (5), potentially the result of lower viral loads (27,28).…”

Section: Discussionmentioning

confidence: 99%

Whole blood-based measurement of SARS-CoV-2-specific T cell responses reveals asymptomatic infection and vaccine efficacy in healthy subjects and patients with solid organ cancers

Scurr

Zelek

Lippiatt³

et al. 2021

Preprint

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Accurate assessment of SARS-CoV-2 immunity in the population is critical to evaluating vaccine efficacy and devising public health policies. Whilst the exact nature of effective immunity remains incompletely defined, SARS-CoV-2-specific T cell responses are a critical feature of the immune response that will likely form a key correlate of protection against COVID-19. Here, we developed and optimised a high-throughput whole blood-based assay to determine the T cell response associated with prior SARS-CoV-2 infection and/or vaccination amongst 156 healthy donors and 67 cancer patients. Following overnight in vitro stimulation with SARS-CoV-2-specific peptides, blood plasma samples were harvested and analysed for Th1-type effector cytokines (IFN-γ and IL-2). Amongst healthy donors, highly significant differential IFN-γ+/IL-2+ SARS-CoV-2-specific T cell responses were seen amongst vaccinated or previously infected COVID-19-positive individuals in comparison to unknown/naïve individuals (P < 0.0001). IL-2 production from T cells in response to SARS-CoV-2 derived antigens was a highly predictive diagnostic assay (P < 0.0001; 96.0% sensitivity, 93.9% specificity); measurement of IFN-γ+ SARS-CoV-2 specific T cell responses was equally effective at identifying asymptomatic (antibody and T cell positive) participants. A single dose of COVID-19 vaccine induced IFN-γ and/or IL-2 SARS-CoV-2-specific T cell responses in 28/29 (96.6%) of healthy donors, reducing significantly to 27/56 (48.2%) when measured in cancer patients (P = 0.0003). Overall, this cost-effective standardisable test ensures accurate and comparable assessments of SARS-CoV-2-specific T cell responses amenable to widespread population immunity testing.

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“…The copyright holder for this preprint (which this version posted April 26, 2021. ; https://doi.org/10.1101/2021.04.23.441209 doi: bioRxiv preprint cells 38 , could be associated with the escape from the T-cell immunity. Furthermore, recent evidence suggests that this region contains an additional epitope for antibody binding 39 .…”

Section: Insertions In the S Protein Produce Putative Antibody Escape Variantsmentioning

confidence: 99%

Insertions in SARS-CoV-2 genome caused by template switch and duplications give rise to new variants that merit monitoring

Garushyants

Rogozin

Koonin

2021

Preprint

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The appearance of multiple new SARS-CoV-2 variants during the winter of 2020-2021 is a matter of grave concern. Some of these new variants, such as B.1.351 and B.1.1.17, manifest higher infectivity and virulence than the earlier SARS-CoV-2 variants, with potential dramatic effects on the course of the COVID-19 pandemic. So far, analysis of new SARS-CoV-2 variants focused primarily on point nucleotide substitutions and short deletions that are readily identifiable by comparison to consensus genome sequences. In contrast, insertions have largely escaped the attention of researchers although the furin site insert in the spike protein is thought to be a determinant of SARS-CoV-2 virulence and other inserts might have contributed to coronavirus pathogenicity as well. Here, we investigate insertions in SARS-CoV-2 genomes and identify 141 unique inserts of different lengths. We present evidence that these inserts reflect actual virus variance rather than sequencing errors. Two principal mechanisms appear to account for the inserts in the SARS-CoV-2 genomes, polymerase slippage and template switch that might be associated with the synthesis of subgenomic RNAs. We show that inserts in the Spike glycoprotein can affect its antigenic properties and thus have to be monitored. At least, two inserts in the N-terminal domain of the Spike (ins246DSWG and ins15ATLRI) that were first detected in January 2021 are predicted to lead to escape from neutralizing antibodies whereas other inserts might result in escape from T-cell immunity.

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Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases

Cited by 96 publications

References 54 publications

The mutational landscape of SARS-CoV-2 variants diversifies T cell targets in an HLA supertype-dependent manner

The mutational landscape of SARS-CoV-2 variants diversifies T cell targets in an HLA supertype-dependent manner

Whole blood-based measurement of SARS-CoV-2-specific T cell responses reveals asymptomatic infection and vaccine efficacy in healthy subjects and patients with solid organ cancers

Insertions in SARS-CoV-2 genome caused by template switch and duplications give rise to new variants that merit monitoring

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