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

Dolton, Garry; Rius, Cristina; Hasan, Samiul; 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, A.K.

doi:10.1101/2021.06.21.21259010

Cited by 12 publications

(6 citation statements)

References 68 publications

(82 reference statements)

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“…Neither A02_YLQ-specific TCR line was activated by the mutant S:P272L epitope YLQPRTFLL ( Extended data Fig. 10 ), confirming the data from Dolton et al This mutation was speculated to play a role in a second Europe COVID-19 wave in summer-autumn of 2020 45 . However, none of the currently abundant SARS-CoV-2 variants bear this or any other variant of the A02_YLQ epitope at large frequency.…”

Section: Resultssupporting

confidence: 83%

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8+ T cells

et al. 2022

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Although mRNA vaccine efficacy against severe COVID-19 remains high, variant emergence has prompted booster immunizations. However, repeated antigen exposure effects on SARS-CoV-2 memory T cells are poorly understood. Here, we utilize MHC-multimers with scRNAseq to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two, or three antigen exposures, including vaccination, primary, and breakthrough infection. Exposure order determined the distribution between spike- and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7-CD45RA+ effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell receptor sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory.

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Section: Resultssupporting

confidence: 83%

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8+ T cells

et al. 2022

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“…Neither A02_YLQ-specific TCR line was activated by the mutant S:P272L epitope YLQPRTFLL (Extended data, Fig. 19), confirming the data from Dolton et al This mutation was speculated to play a role in a second Europe COVID-19 wave in summer-autumn of 2020 48 . However, none of the currently abundant SARS-CoV-2 variants bear this or any other variant of the A02_YLQ epitope at large frequency.…”

Section: Tcr Motifs Recognize Most Mutated Epitopes In Sars-cov-2 Variantssupporting

confidence: 83%

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8 T cells

Minervina

Pogorelyy

Kirk

et al. 2021

Preprint

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SARS-CoV-2 mRNA vaccines, including Pfizer/Biontech BNT162b2, were shown to be effective for COVID-19 prevention, eliciting both robust antibody responses in naive individuals and boosting pre-existing antibody levels in SARS-CoV-2-recovered individuals. However, the magnitude, repertoire, and phenotype of epitope-specific T cell responses to this vaccine, and the effect of vaccination on pre-existing T cell memory in SARS-CoV-2 convalescent patients, are still poorly understood. Thus, in this study we compared epitope-specific T cells elicited after natural SARS-CoV-2 infection, and vaccination of both naive and recovered individuals. We collected peripheral blood mononuclear cells before and after BNT162b2 vaccination and used pools of 18 DNA-barcoded MHC-class I multimers, combined with scRNAseq and scTCRseq, to characterize T cell responses to several immunodominant epitopes, including a spike-derived epitope cross-reactive to common cold coronaviruses. Comparing responses after infection or vaccination, we found that T cells responding to spike-derived epitopes show similar magnitudes of response, memory phenotypes, TCR repertoire diversity, and αβTCR sequence motifs, demonstrating the potency of this vaccination platform. Importantly, in COVID-19-recovered individuals receiving the vaccine, pre-existing spike-specific memory cells showed both clonal expansion and a phenotypic shift towards more differentiated CCR7-CD45RA+ effector cells. In-depth analysis of T cell receptor repertoires demonstrates that both vaccination and infection elicit largely identical repertoires as measured by dominant TCR motifs and receptor breadth, indicating that BNT162b2 vaccination largely recapitulates T cell generation by infection for all critical parameters. Thus, BNT162b2 vaccination elicits potent spike-specific T cell responses in naive individuals and also triggers the recall T cell response in previously infected individuals, further boosting spike-specific responses but altering their differentiation state. Overall, our study demonstrates the potential of mRNA vaccines to induce, maintain, and shape T cell memory through vaccination and revaccination.

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“…As with antibody recognition, mutations within epitopes can also lead to escape from the cellular arm of the adaptive immune response, whereby T cells fail to recognize infected cells, for instance due to the mutant epitope failing to be processed and presented effectively, or due to loss of recognition of the MHC-peptide complex by the T cells receptor (TCR) [ 91 , 249–252 ]. Studies to date suggest the majority of T cells induced by vaccination or infection retain their ability to recognize epitopes within Omicron and other variants [ 253 , 254 ].…”

Section: How ‘Specific’ Is Sars-cov-2-specific Immunitymentioning

confidence: 99%

The past, current and future epidemiological dynamic of SARS-CoV-2

Balloux

Tan

Swadling

et al. 2022

Oxford Open Immunology

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SARS-CoV-2, the agent of the COVID-19 pandemic, emerged in late 2019 in China, and rapidly spread throughout the world to reach all continents. As the virus expanded in its novel human host, viral lineages diversified through the accumulation of around two mutations a month on average. Different viral lineages have replaced each other since the start of the pandemic, with the most successful Alpha, Delta and Omicron Variants of Concern (VoCs) sequentially sweeping through the world to reach high global prevalence. Neither Alpha nor Delta was characterised by strong immune escape, with their success coming mainly from their higher transmissibility. Omicron is far more prone to immune evasion and spread primarily due to its increased ability to (re-)infect hosts with prior immunity. As host immunity reaches high levels globally through vaccination and prior infection, the epidemic is expected to transition from a pandemic regime to an endemic one where seasonality and waning host immunisation are anticipated to become the primary forces shaping future SARS-CoV-2 lineage dynamics. In this review, we consider a body of evidence on the origins, host tropism, epidemiology, genomic and immunogenetic evolution of SARS-CoV-2 including an assessment of other coronaviruses infecting humans. Considering what is known so far, we conclude by delineating scenarios for the future dynamic of SARS-CoV-2, ranging from the good—circulation of a fifth endemic ‘common cold’ coronavirus of potentially low virulence, the bad—a situation roughly comparable to seasonal flu, and the ugly—extensive diversification into serotypes with long-term high-level endemicity. Lay Summary SARS-CoV-2, the agent of the COVID-19 pandemic, emerged in late 2019 and spread globally causing the COVID-19 pandemic. When SARS-CoV-2 jumped into humans, it had essentially no genetic diversity, but as the viral population expanded, it diversified into myriad genetically distinct lineages through the acumulation of approximately two mutations a month. The vast majority of those lineages are now extinct. The most successful lineages so far were the Alpha, Delta and Omicron variants which all reached global prevalence and replaced each other in the process. Alpha and Delta emerged in late 2020 and spread at a time when immunisation of the human population was still low and reached global prevalence primarily by being more transmissible. Omicron started expanding in late 2021, at a time when a large proportion of the human population had already been vaccinated and/or exposed to SARS-CoV-2. Omicron was so successful mainly due to its ability to (re-)infect hosts with prior immunity. In this review, we provide an overview of the evolution of SARS-CoV-2 and put it in context of what is known about other coronaviruses infecting humans. We conclude by delineating plausible scenarios for the ‘endemic’ future of SARS-CoV-2.

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

Cited by 12 publications

References 68 publications

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8+ T cells

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8+ T cells

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8 T cells

The past, current and future epidemiological dynamic of SARS-CoV-2

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