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  1. Article ; Online: The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity

    Geng Liu / Wojciech Barczak / Lian Ni Lee / Amit Shrestha / Nicholas M. Provine / Gulsah Albayrak / Hong Zhu / Claire Hutchings / Paul Klenerman / Nicholas B. La Thangue

    Communications Biology, Vol 6, Iss 1, Pp 1-

    2023  Volume 14

    Abstract: The clinical HDAC inhibitor zabadinostat increases MHC class I and II expression in dendritic cells, activates T and B cells, and enhances adaptive immune responses to COVID-19 spike protein in mice. ...

    Abstract The clinical HDAC inhibitor zabadinostat increases MHC class I and II expression in dendritic cells, activates T and B cells, and enhances adaptive immune responses to COVID-19 spike protein in mice.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: The Design and Development of a Multi-HBV Antigen Encoded in Chimpanzee Adenoviral and Modified Vaccinia Ankara Viral Vectors; A Novel Therapeutic Vaccine Strategy against HBV

    Senthil K. Chinnakannan / Tamsin N. Cargill / Timothy A. Donnison / M. Azim Ansari / Sarah Sebastian / Lian Ni Lee / Claire Hutchings / Paul Klenerman / Mala K. Maini / Tom Evans / Eleanor Barnes

    Vaccines, Vol 8, Iss 184, p

    2020  Volume 184

    Abstract: Chronic hepatitis B virus (HBV) infection affects 257 million people globally. Current therapies suppress HBV but viral rebound occurs on cessation of therapy; novel therapeutic strategies are urgently required. To develop a therapeutic HBV vaccine that ... ...

    Abstract Chronic hepatitis B virus (HBV) infection affects 257 million people globally. Current therapies suppress HBV but viral rebound occurs on cessation of therapy; novel therapeutic strategies are urgently required. To develop a therapeutic HBV vaccine that can induce high magnitude T cells to all major HBV antigens, we have developed a novel HBV vaccine using chimpanzee adenovirus (ChAd) and modified vaccinia Ankara (MVA) viral vectors encoding multiple HBV antigens. ChAd vaccine alone generated very high magnitude HBV specific T cell responses to all HBV major antigens. The inclusion of a shark Invariant (SIi) chain genetic adjuvant significantly enhanced the magnitude of T-cells against HBV antigens. Compared to ChAd alone vaccination, ChAd-prime followed by MVA-boost vaccination further enhanced the magnitude and breadth of the vaccine induced T cell response. Intra-cellular cytokine staining study showed that HBV specific CD8+ and CD4+ T cells were polyfunctional, producing combinations of IFNγ, TNF-α, and IL-2. In summary, we have generated genetically adjuvanted ChAd and MVA vectored HBV vaccines with the potential to induce high-magnitude T cell responses through a prime-boost therapeutic vaccination approach. These pre-clinical studies pave the way for new studies of HBV therapeutic vaccination in humans with chronic hepatitis B infection.
    Keywords Hepatitis B virus (HBV) ; therapeutic HBV vaccine ; T cell vaccine ; chimpanzee adenovirus ; ChAd ; ChAdOx1 ; Medicine ; R
    Subject code 570 ; 610
    Language English
    Publishing date 2020-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Single-cell transcriptome analysis of CD8+ T-cell memory inflation [version 1; peer review

    Andrew J. Highton / Madeleine E. Zinser / Lian Ni Lee / Claire L. Hutchings / Catherine De Lara / Chansavath Phetsouphanh / Chris B. Willberg / Claire L. Gordon / Paul Klenerman / Emanuele Marchi

    Wellcome Open Research, Vol

    2 approved]

    2019  Volume 4

    Abstract: Background: Persistent viruses such as murine cytomegalovirus (MCMV) and adenovirus-based vaccines induce strong, sustained CD8+ T-cell responses, described as memory “inflation”. These retain functionality, home to peripheral organs and are associated ... ...

    Abstract Background: Persistent viruses such as murine cytomegalovirus (MCMV) and adenovirus-based vaccines induce strong, sustained CD8+ T-cell responses, described as memory “inflation”. These retain functionality, home to peripheral organs and are associated with a distinct transcriptional program. Methods: To further define the nature of the transcriptional mechanisms underpinning memory inflation at different sites we used single-cell RNA sequencing of tetramer-sorted cells from MCMV-infected mice, analyzing transcriptional networks in virus-specific populations in the spleen and gut intra-epithelial lymphocytes (IEL). Results: We provide a transcriptional map of T-cell memory and define a module of gene expression, which distinguishes memory inflation in spleen from resident memory T-cells (TRM) in the gut. Conclusions: These data indicate that CD8+ T-cell memory in the gut epithelium induced by persistent viruses and vaccines has a distinct quality from both conventional memory and “inflationary” memory which may be relevant to protection against mucosal infections.
    Keywords Medicine ; R ; Science ; Q
    Subject code 612
    Language English
    Publishing date 2019-05-01T00:00:00Z
    Publisher Wellcome
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Induction and Maintenance of CX3CR1-Intermediate Peripheral Memory CD8+ T Cells by Persistent Viruses and Vaccines

    Claire Louse Gordon / Lian Ni Lee / Leo Swadling / Claire Hutchings / Madeleine Zinser / Andrew John Highton / Stefania Capone / Antonella Folgori / Eleanor Barnes / Paul Klenerman

    Cell Reports, Vol 23, Iss 3, Pp 768-

    2018  Volume 782

    Abstract: Summary: The induction and maintenance of T cell memory is critical to the success of vaccines. A recently described subset of memory CD8+ T cells defined by intermediate expression of the chemokine receptor CX3CR1 was shown to have self-renewal, ... ...

    Abstract Summary: The induction and maintenance of T cell memory is critical to the success of vaccines. A recently described subset of memory CD8+ T cells defined by intermediate expression of the chemokine receptor CX3CR1 was shown to have self-renewal, proliferative, and tissue-surveillance properties relevant to vaccine-induced memory. We tracked these cells when memory is sustained at high levels: memory inflation induced by cytomegalovirus (CMV) and adenovirus-vectored vaccines. In mice, both CMV and vaccine-induced inflationary T cells showed sustained high levels of CX3R1int cells exhibiting an effector-memory phenotype, characteristic of inflationary pools, in early memory. In humans, CX3CR1int CD8+ T cells were strongly induced following adenovirus-vectored vaccination for hepatitis C virus (HCV) (ChAd3-NSmut) and during natural CMV infection and were associated with a memory phenotype similar to that in mice. These data indicate that CX3CR1int cells form an important component of the memory pool in response to persistent viruses and vaccines in both mice and humans. : Gordon et al. demonstrate that CX3CR1int peripheral memory T cells are a substantial component of memory inflation induced by persistent CMVs and adenoviral vaccination. They are characterized by sustained proliferation and an effector-memory phenotype linked to these expanded CD8+ T cell memory responses. Core phenotypic features are shared by humans and mice. Keywords: cytomegalovirus, T cells, memory, adenovirus, vaccination, CX3CR1, memory inflation, mouse, human
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2018-04-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Immunization of mice with a recombinant adenovirus vaccine inhibits the early growth of Mycobacterium tuberculosis after infection.

    Edward O Ronan / Lian Ni Lee / Peter C L Beverley / Elma Z Tchilian

    PLoS ONE, Vol 4, Iss 12, p e

    2009  Volume 8235

    Abstract: In pulmonary Mycobacterium tuberculosis (Mtb) infection, immune responses are delayed compared to other respiratory infections, so that antigen-specific cells are not detected in the lungs earlier than day 14. Even after parenteral immunization with ... ...

    Abstract In pulmonary Mycobacterium tuberculosis (Mtb) infection, immune responses are delayed compared to other respiratory infections, so that antigen-specific cells are not detected in the lungs earlier than day 14. Even after parenteral immunization with Bacille Calmette Guerin (BCG) or a subunit vaccine, the immune response after Mtb challenge is only slightly accelerated and the kinetics of pulmonary Mtb growth do not differ between naïve and immunized animals up to day 14.Mice were immunized intranasally with a recombinant adenovirus expressing mycobacterial antigen 85A (Ad85A), challenged by aerosol with Mtb and the kinetics of Mtb growth in the lungs measured. Intranasal immunization with Ad85A inhibits Mtb growth in the early phase of infection, up to day 8. Protection is sustained for at least 7 months and correlates with the presence of antigen-specific activated effector CD8 T cells in the lungs. Antigen 85A-specific T cells respond to antigen presenting cells from the lungs of mice immunized with Ad85A 23 weeks previously, demonstrating the persistence of antigen in the lungs.Intranasal immunization with Ad85A can inhibit early growth of Mtb because it establishes a lung antigen depot and maintains an activated lung-resident lymphocyte population. We propose that an optimal immunization strategy for tuberculosis should aim to induce both lung and systemic immunity, targeting the early and late phases of Mtb growth.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2009-12-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

    Anna L. McNaughton / Robert S. Paton / Matthew Edmans / Jonathan Youngs / Judith Wellens / Prabhjeet Phalora / Alex Fyfe / Sandra Belij-Rammerstorfer / Jai S. Bolton / Jonathan Ball / George W. Carnell / Wanwisa Dejnirattisai / Christina Dold / David W. Eyre / Philip Hopkins / Alison Howarth / Kreepa Kooblall / Hannah Klim / Susannah Leaver /
    Lian Ni Lee / César López-Camacho / Sheila F. Lumley / Derek C. Macallan / Alexander J. Mentzer / Nicholas M. Provine / Jeremy Ratcliff / Jose Slon-Compos / Donal Skelly / Lucas Stolle / Piyada Supasa / Nigel Temperton / Chris Walker / Beibei Wang / Duncan Wyncoll / Oxford Protective T Cell Immunology for COVID-19 (OPTIC) consortium / Scottish National Blood Transfusion Service (SNBTS) consortium / Peter Simmonds / Teresa Lambe / John Kenneth Baillie / Malcolm G. Semple / Peter J.M. Openshaw / International Severe Acute Respiratory and emerging Infection Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) investigators / Uri Obolski / Marc Turner / Miles Carroll / Juthathip Mongkolsapaya / Gavin Screaton / Stephen H. Kennedy / Lisa Jarvis / Eleanor Barnes

    JCI Insight, Vol 7, Iss

    2022  Volume 13

    Abstract: The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal outcomes ... ...

    Abstract The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal outcomes with coronavirus disease 2019 (COVID-19) is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to an intensive care unit (ICU) with fatal COVID-19 outcomes, but not in individuals with nonfatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to an ICU with fatal and nonfatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an “original antigenic sin” type response.
    Keywords Immunology ; Infectious disease ; Medicine ; R
    Subject code 570
    Language English
    Publishing date 2022-07-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Adenoviral Vector Vaccination Induces a Conserved Program of CD8+ T Cell Memory Differentiation in Mouse and Man

    Beatrice Bolinger / Stuart Sims / Leo Swadling / Geraldine O’Hara / Catherine de Lara / Dilair Baban / Natasha Saghal / Lian Ni Lee / Emanuele Marchi / Mark Davis / Evan Newell / Stefania Capone / Antonella Folgori / Ellie Barnes / Paul Klenerman

    Cell Reports, Vol 13, Iss 8, Pp 1578-

    2015  Volume 1588

    Abstract: Following exposure to vaccines, antigen-specific CD8+ T cell responses develop as long-term memory pools. Vaccine strategies based on adenoviral vectors, e.g., those developed for HCV, are able to induce and sustain substantial CD8+ T cell populations. ... ...

    Abstract Following exposure to vaccines, antigen-specific CD8+ T cell responses develop as long-term memory pools. Vaccine strategies based on adenoviral vectors, e.g., those developed for HCV, are able to induce and sustain substantial CD8+ T cell populations. How such populations evolve following vaccination remains to be defined at a transcriptional level. We addressed the transcriptional regulation of divergent CD8+ T cell memory pools induced by an adenovector encoding a model antigen (beta-galactosidase). We observe transcriptional profiles that mimic those following infection with persistent pathogens, murine and human cytomegalovirus (CMV). Key transcriptional hallmarks include upregulation of homing receptors and anti-apoptotic pathways, driven by conserved networks of transcription factors, including T-bet. In humans, an adenovirus vaccine induced similar CMV-like phenotypes and transcription factor regulation. These data clarify the core features of CD8+ T cell memory following vaccination with adenovectors and indicate a conserved pathway for memory development shared with persistent herpesviruses.
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2015-11-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Simultaneous immunization against tuberculosis.

    Elma Z Tchilian / Edward O Ronan / Catherine de Lara / Lian Ni Lee / Kees L M C Franken / Martin H Vordermeier / Tom H M Ottenhoff / Peter C L Beverley

    PLoS ONE, Vol 6, Iss 11, p e

    2011  Volume 27477

    Abstract: BCG, the only licensed vaccine against tuberculosis, provides some protection against disseminated disease in infants but has little effect on prevention of adult pulmonary disease. Newer parenteral immunization prime boost regimes may provide improved ... ...

    Abstract BCG, the only licensed vaccine against tuberculosis, provides some protection against disseminated disease in infants but has little effect on prevention of adult pulmonary disease. Newer parenteral immunization prime boost regimes may provide improved protection in experimental animal models but are unproven in man so that there remains a need for new and improved immunization strategies.Mice were immunized parenterally, intranasally or simultaneously by both routes with BCG or recombinant mycobacterial antigens plus appropriate adjuvants. They were challenged with Mycobacterium tuberculosis (Mtb) and the kinetics of Mtb growth in the lungs measured. We show that simultaneous immunization (SIM) of mice by the intranasal and parenteral routes is highly effective in increasing protection over parenteral BCG administration alone. Intranasal immunization induces local pulmonary immunity capable of inhibiting the growth of Mtb in the early phase (the first week) of infection, while parenteral immunization has a later effect on Mtb growth. Importantly, these two effects are additive and do not depend on priming and boosting the immune response. The best SIM regimes reduce lung Mtb load by up to 2 logs more than BCG given by either route alone.These data establish SIM as a novel and highly effective immunization strategy for Mtb that could be carried out at a single clinic visit. The efficacy of SIM does not depend on priming and boosting an immune response, but SIM is complementary to prime boost strategies and might be combined with them.
    Keywords Medicine ; R ; Science ; Q
    Subject code 630
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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