SARS-CoV-2 breakthrough infection in vaccinees induces virus-specific nasal-resident CD8+ and CD4+ T cells of broad specificity

Lim, Joey Ming Er; Tan, Anthony T.; Bert, Nina Le; Hang, Shou Kit; Low, Jenny; Bertoletti, Antonio

doi:10.1084/jem.20220780

Cited by 90 publications

(83 citation statements)

References 38 publications

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“…We did, however, detect SARS-CoV-2-specific T RM cells in the nasal mucosa of infected mice, as well as Mtb-specific T cells in the nasal mucosa of M. tuberculosis infected macaques. Moreover, it was also recently shown that virus-specific T cells can be detected in the nasal secretions of previously vaccinated humans who acquire breakthrough SARS-CoV-2 infections ( 55 ). Therefore, it is not clear why primary intranasal SARS-CoV-2 infection fails to induce a primary effector spike-specific T cell response in the nasal mucosa in rhesus macaques.…”

Section: Discussionmentioning

confidence: 99%

IL-10 suppresses T cell expansion while promoting tissue-resident memory cell formation during SARS-CoV-2 infection in rhesus macaques

Nelson¹,

Foreman²,

Kauffman³

et al. 2022

Preprint

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The pro- and anti-inflammatory pathways that determine the balance of inflammation and viral control during SARS-CoV-2 infection are not well understood. Here we examine the roles of IFNγ and IL-10 in regulating inflammation, immune cell responses and viral replication during SARS-CoV-2 infection of rhesus macaques. IFNγ blockade tended to decrease lung inflammation based on 18FDG-PET/CT imaging but had no major impact on innate lymphocytes, neutralizing antibodies, or antigen-specific T cells. In contrast, IL-10 blockade transiently increased lung inflammation and enhanced accumulation of virus-specific T cells in the lower airways. However, IL-10 blockade also inhibited the differentiation of virus-specific T cells into airway CD69+CD103+ TRM cells. While virus-specific T cells were undetectable in the nasal mucosa of all groups, IL-10 blockade similarly reduced the frequency of total TRM cells in the nasal mucosa. Neither cytokine blockade substantially affected viral load and infection ultimately resolved. Thus, in the macaque model of mild COVID-19, the pro- and anti-inflammatory effects of IFNγ and IL-10 have no major role in control of viral replication. However, IL-10 has a key role in suppressing the accumulation of SARS-CoV-2-specific T cells in the lower airways, while also promoting TRM at respiratory mucosal surfaces.

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Section: Discussionmentioning

confidence: 99%

IL-10 suppresses T cell expansion while promoting tissue-resident memory cell formation during SARS-CoV-2 infection in rhesus macaques

Nelson¹,

Foreman²,

Kauffman³

et al. 2022

Preprint

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“…The large degree of overlap between expanded and scAIM-TCRseq-con rmed clonotypes indicates that comparison of serial blood TRB repertoires may be a suitable surrogate for resource-intensive AIM-or peptide-HLA oligomer-scTCRseq to assign TRB sequences as vaccine antigenspeci c. AIM-scTCRseq data from this report substantially augment databases 50 used to match to estimate T cell responses to vaccines, as reported for adenovirus-based SARS-CoV-2 products 51,52 . While limited data suggest that intramuscular mRNA vaccination alone can result in nasal S-speci c CD8 + T cells 11 , more research is required to assess the contribution of a priming or breakthrough infection 12 for the emplacement of SARS-Cov2-speci c T RM in the nose. Here we show that vaccine-expanded clonotypes in circulation are detectable in the nose in persons with hybrid immunity.…”

Section: Discussionmentioning

confidence: 99%

“…Data suggest that in most persons, the recognition of multiple T cell epitopes 5,6 largely preserves T-cell responses despite VOC evolution 7 , although T cell escape has been observed in a minority of persons 8 . Animal models suggest that T cells found in the airway protect against respiratory coronavirus challenge 9,10 , and recent functional data in humans document tissue-resident memory S-speci c T cells after SARS-CoV-2 mRNA vaccination 11 or breakthrough infection 12 . These data motivated detailed studies of T cells in hybrid immunity.…”

Section: Mainmentioning

confidence: 99%

“…SARS-CoV-2 infection increases the abundance of memory virus-speci c T cells [12][13][14][15] . In each person, a diverse repertoire of heterodimeric TCRs recognize SARS-CoV-2 by binding complexes of antigen-derived peptides presented by polymorphic major histocompatibility complex proteins, encoded in humans by human leukocyte antigen (HLA) genes 16 .…”

Section: Mainmentioning

confidence: 99%

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CD8+ T cell clonotypes from prior SARS-CoV-2 infection predominate during the cellular immune response to mRNA vaccination

Ford¹,

Mayer-Blackwell²,

Jing³

et al. 2022

Preprint

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Almost three years into the SARS-CoV-2 pandemic, hybrid immunity is highly prevalent worldwide and more protective than vaccination or prior infection alone. Given emerging resistance of variant strains to neutralizing antibodies (nAb), it is likely that T cells contribute to this protection. To understand how sequential SARS-CoV-2 infection and mRNA-vectored SARS-CoV-2 spike (S) vaccines affect T cell clonotype-level expansion kinetics, we identified and cross-referenced TCR sequences from thousands of S-reactive single cells against deeply sequenced peripheral blood TCR repertoires longitudinally collected from persons during COVID-19 convalescence through booster vaccination. Successive vaccinations recalled memory T cells and elicited antigen-specific T cell clonotypes not detected after infection. Vaccine-related recruitment of novel clonotypes and the expansion of S-specific clones were most strongly observed for CD8+ T cells. Severe COVID-19 illness was associated with a more diverse CD4+ T cell response to SARS-CoV-2 both prior to and after mRNA vaccination, suggesting imprinting of CD4+ T cells by severe infection. TCR sequence similarity search algorithms revealed myriad public TCR clusters correlating with human leukocyte antigen (HLA) alleles. Selected TCRs from distinct clusters functionally recognized S in the predicted HLA context, with fine viral peptide requirements differing between TCRs. Most subjects tested had S-specific T cells in the nasal mucosa after a 3rd mRNA vaccine dose. The blood and nasal T cell responses to vaccination revealed by clonal tracking were more heterogeneous than nAb boosts. Analysis of bulk and single cell TCR sequences reveals T cell kinetics and diversity at the clonotype level, without requiring prior knowledge of T cell epitopes or HLA restriction, providing a roadmap for rapid assessment of T cell responses to emerging pathogens.

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“…A goal of vaccination is to induce the type of immune response that most closely approximates natural immune protection against infection, while eliminating risks of disease. For COVID-19, despite some controversy 56 , human vaccinees to parenteral SARS-CoV-2 do not appear to induce robust airway-resident antigen-specific T cells, unlike those who experienced natural infections 57,58 . This highlights the potential of next-generation COVID-19 vaccines to improve mucosal and systemic immune responses through modulation of T cells.…”

Section: Discussionmentioning

confidence: 99%

Mucosal vaccination for SARS-CoV-2 elicits superior systemic T central memory function and cross-neutralizing antibodies against variants of concern

O'Neill

Kala

Wah

et al. 2022

Preprint

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COVID-19 vaccines used in humans are highly effective in limiting disease and death caused by the SARS-CoV-2 virus, yet improved vaccines that provide greater protection at mucosal surfaces, which could reduce break-through infections and subsequent transmission, are still needed. Here we show that intranasal (I.N.) vaccination with the receptor binding domain of Spike antigen of SARS-CoV-2 (S-RBD) in combination with the mucosal adjuvant mastoparan-7 improved systemic T cell responses compared to an equivalent dose of antigen delivered by the sub-cutaneous (S.C.) route, adjuvanted by either M7 or the gold-standard adjuvant, alum. T cell phenotypes induced by I.N. vaccine administration included enhanced polyfunctionality (combined IFN and TNF expression) and greater numbers of T central memory (TCM) cells. These phenotypes were T cell-intrinsic and could be recalled in the lungs and/or brachial LNs upon antigen challenge after adoptive T cell transfer to naive recipients. Furthermore, mucosal vaccination induced antibody responses that were similarly effective in neutralizing the binding of the parental strain of S-RBD to its ACE2 receptor, but showed greater cross-neutralizing capacity against multiple variants of concern (VOC), compared to S.C. vaccination. These results highlight the role of nasal vaccine administration in imprinting an immune profile associated with long-term T cell retention and diversified neutralizing antibody responses, which could be applied to improve vaccines for COVID-19 and other infectious diseases.

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SARS-CoV-2 breakthrough infection in vaccinees induces virus-specific nasal-resident CD8+ and CD4+ T cells of broad specificity

Cited by 90 publications

References 38 publications

IL-10 suppresses T cell expansion while promoting tissue-resident memory cell formation during SARS-CoV-2 infection in rhesus macaques

IL-10 suppresses T cell expansion while promoting tissue-resident memory cell formation during SARS-CoV-2 infection in rhesus macaques

CD8+ T cell clonotypes from prior SARS-CoV-2 infection predominate during the cellular immune response to mRNA vaccination

Mucosal vaccination for SARS-CoV-2 elicits superior systemic T central memory function and cross-neutralizing antibodies against variants of concern

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