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Article ; Online: Identification of a spike-specific CD8+ T cell epitope following vaccination against the Middle East respiratory syndrome coronavirus in humans.

Harrer, Caroline E / Mayer, Leonie / Fathi, Anahita / Lassen, Susan / Ly, My L / Zinser, Madeleine E / Wolf, Timo / Becker, Stephan / Sutter, Gerd / Dahlke, Christine / Addo, Marylyn M

The Journal of infectious diseases

2024

Abstract: Licensed vaccines against the Middle East respiratory syndrome coronavirus (MERS-CoV), an emerging pathogen of concern, are lacking. The Modified Vaccinia virus Ankara vector-based vaccine MVA-MERS-S, expressing the MERS-CoV-spike glycoprotein (MERS-S), ... ...

Abstract	Licensed vaccines against the Middle East respiratory syndrome coronavirus (MERS-CoV), an emerging pathogen of concern, are lacking. The Modified Vaccinia virus Ankara vector-based vaccine MVA-MERS-S, expressing the MERS-CoV-spike glycoprotein (MERS-S), is one of three candidate vaccines in clinical development and elicits robust humoral and cellular immunity. Here, we identified for the first time a MERS-S-specific CD8+ T-cell epitope in an HLA-A03:01/HLA-B35:01-positive vaccinee using a screening assay, intracellular cytokine staining, and in silico epitope prediction. As evidence from MERS-CoV infection suggests a protective role of long-lasting CD8+ T-cell responses, the identification of epitopes will facilitate longitudinal analyses of vaccine-induced T-cell immunity.
Language	English
Publishing date	2024-01-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiad612
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Article: Single-cell transcriptome analysis of CD8

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

Wellcome open research

2019 Volume 4, Page(s) 78

Abstract: ... ...

Abstract	Background
Language	English
Publishing date	2019-05-09
Publishing country	England
Document type	Journal Article
ISSN	2398-502X
ISSN	2398-502X
DOI	10.12688/wellcomeopenres.15115.1
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Article: Persistence of MERS-CoV-spike-specific B cells and antibodies after late third immunization with the MVA-MERS-S vaccine

Cell reports medicine. 2022 July 19, v. 3, no. 7

2022

Abstract: The Middle East respiratory syndrome (MERS) is a respiratory disease caused by MERS coronavirus (MERS-CoV). In follow up to a phase 1 trial, we perform a longitudinal analysis of immune responses following immunization with the modified vaccinia virus ... ...

Institution	MVA-MERS-S Study Group
Abstract	The Middle East respiratory syndrome (MERS) is a respiratory disease caused by MERS coronavirus (MERS-CoV). In follow up to a phase 1 trial, we perform a longitudinal analysis of immune responses following immunization with the modified vaccinia virus Ankara (MVA)-based vaccine MVA-MERS-S encoding the MERS-CoV-spike protein. Three homologous immunizations were administered on days 0 and 28 with a late booster vaccination at 12 ± 4 months. Antibody isotypes, subclasses, and neutralization capacity as well as T and B cell responses were monitored over a period of 3 years using standard and bead-based enzyme-linked immunosorbent assay (ELISA), 50% plaque-reduction neutralization test (PRNT50), enzyme-linked immunospot (ELISpot), and flow cytometry. The late booster immunization significantly increases the frequency and persistence of spike-specific B cells, binding immunoglobulin G1 (IgG1) and neutralizing antibodies but not T cell responses. Our data highlight the potential of a late boost to enhance long-term antibody and B cell immunity against MERS-CoV. Our findings on the MVA-MERS-S vaccine may be of relevance for coronavirus 2019 (COVID-19) vaccination strategies.
Keywords	B-lymphocytes ; COVID-19 infection ; Orthocoronavirinae ; T-lymphocytes ; Vaccinia virus ; enzyme-linked immunosorbent assay ; flow cytometry ; immunoglobulin G ; longitudinal studies ; medicine ; neutralization ; neutralization tests ; respiratory tract diseases ; secondary immunization ; vaccination ; vaccines
Language	English
Dates of publication	2022-0719
Publishing place	Elsevier Inc.
Document type	Article
ISSN	2666-3791
DOI	10.1016/j.xcrm.2022.100685
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Human MAIT cells show metabolic quiescence with rapid glucose-dependent upregulation of granzyme B upon stimulation.

Zinser, Madeleine E / Highton, Andrew J / Kurioka, Ayako / Kronsteiner, Barbara / Hagel, Joachim / Leng, Tianqi / Marchi, Emanuele / Phetsouphanh, Chansavath / Willberg, Chris B / Dunachie, Susanna J / Klenerman, Paul

Immunology and cell biology

2018 Volume 96, Issue 6, Page(s) 666–674

Abstract: Mucosal-associated invariant T (MAIT) cells are a well-characterized innate-like T cell population abundant in the human liver, peripheral tissues and blood. MAIT cells serve in the first line of defense against infections, through engagement of their T ... ...

Abstract	Mucosal-associated invariant T (MAIT) cells are a well-characterized innate-like T cell population abundant in the human liver, peripheral tissues and blood. MAIT cells serve in the first line of defense against infections, through engagement of their T cell receptor, which recognizes microbial metabolites presented on MR1, and through cytokine-mediated triggering. Typically, they show a quiescent memory phenotype but can undergo rapid upregulation of effector functions including cytolysis upon stimulation. T cells profoundly change their cellular metabolism during their maturation and activation. We sought to determine how MAIT cell metabolism may facilitate both the long-term memory phase in tissue and the transition to rapid effector function. Here, we show, by flow cytometric metabolism assays and extracellular flux analysis that, despite an effector-memory profile, human MAIT cells are metabolically quiescent in a resting state comparable to naïve and central memory T cells. Upon stimulation, they rapidly increase uptake of glucose and show a concomitant upregulation of the effector molecules notably granzyme B, which is impaired by inhibition of glycolysis with 2-deoxyglucose. These findings suggest that MAIT cells share some metabolic characteristics of both resting and effector T cell subsets, with a rapid transition upon triggering. Metabolic programming of this cell type may be of interest in understanding and modulating their function in infectious diseases and cancer.
MeSH term(s)	Glucose/metabolism ; Granzymes/metabolism ; Humans ; Lymphocyte Activation/immunology ; Mucosal-Associated Invariant T Cells/immunology ; Mucosal-Associated Invariant T Cells/metabolism ; Up-Regulation
Chemical Substances	GZMB protein, human (EC 3.4.21.-) ; Granzymes (EC 3.4.21.-) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2018-03-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1111/imcb.12020
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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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Article ; Online: Safety and immunogenicity of a modified vaccinia virus Ankara vector vaccine candidate for Middle East respiratory syndrome: an open-label, phase 1 trial.

Koch, Till / Dahlke, Christine / Fathi, Anahita / Kupke, Alexandra / Krähling, Verena / Okba, Nisreen M A / Halwe, Sandro / Rohde, Cornelius / Eickmann, Markus / Volz, Asisa / Hesterkamp, Thomas / Jambrecina, Alen / Borregaard, Saskia / Ly, My L / Zinser, Madeleine E / Bartels, Etienne / Poetsch, Joseph S H / Neumann, Reza / Fux, Robert /

Schmiedel, Stefan / Lohse, Ansgar W / Haagmans, Bart L / Sutter, Gerd / Becker, Stephan / Addo, Marylyn M

The Lancet. Infectious diseases

2020 Volume 20, Issue 7, Page(s) 827–838

Abstract: Background: The Middle East respiratory syndrome coronavirus (MERS-CoV) causes a respiratory disease with a case fatality rate of up to 35%. Given its potential to cause a public health emergency and the absence of efficacious drugs or vaccines, MERS is ...

Abstract	Background: The Middle East respiratory syndrome coronavirus (MERS-CoV) causes a respiratory disease with a case fatality rate of up to 35%. Given its potential to cause a public health emergency and the absence of efficacious drugs or vaccines, MERS is one of the WHO priority diseases warranting urgent research and development of countermeasures. We aimed to assess safety and tolerability of an anti-MERS-CoV modified vaccinia virus Ankara (MVA)-based vaccine candidate that expresses the MERS-CoV spike glycoprotein, MVA-MERS-S, in healthy adults. Methods: This open-label, phase 1 trial was done at the University Medical Center Hamburg-Eppendorf (Hamburg, Germany). Participants were healthy men and women aged 18-55 years with no clinically significant health problems as determined during medical history and physical examination, a body-mass index of 18·5-30·0 kg/m Interpretation: Vaccination with MVA-MERS-S had a favourable safety profile without serious or severe adverse events. Homologous prime-boost immunisation induced humoral and cell-mediated responses against MERS-CoV. A dose-effect relationship was demonstrated for reactogenicity, but not for vaccine-induced immune responses. The data presented here support further clinical testing of MVA-MERS-S in larger cohorts to advance MERS vaccine development. Funding: German Center for Infection Research.
MeSH term(s)	Adult ; Antibodies, Viral/blood ; Coronavirus Infections/genetics ; Coronavirus Infections/immunology ; Coronavirus Infections/prevention & control ; Dose-Response Relationship, Immunologic ; Enzyme-Linked Immunosorbent Assay ; Female ; Genetic Vectors ; Germany ; Humans ; Immunization, Secondary ; Immunogenicity, Vaccine ; Male ; Middle Aged ; Middle East Respiratory Syndrome Coronavirus/immunology ; Neutralization Tests ; Vaccines, DNA ; Vaccinia virus/genetics ; Viral Vaccines/immunology ; Young Adult
Chemical Substances	Antibodies, Viral ; MVA vaccine ; Vaccines, DNA ; Viral Vaccines
Keywords	covid19
Language	English
Publishing date	2020-04-21
Publishing country	United States
Document type	Clinical Trial ; Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2061641-7
ISSN	1474-4457 ; 1473-3099
ISSN (online)	1474-4457
ISSN	1473-3099
DOI	10.1016/S1473-3099(20)30248-6
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Article ; Online: Chronic pancreatitis in patients with liver cirrhosis negatively affects graft survival after liver transplantation.

Wehmeyer, Malte H / Dammermann, Werner / Seiz, Oliver / Zinser, Madeleine E / Galante, Antonio / Lohse, Ansgar W / Sterneck, Martina / Nashan, Björn / Herden, Uta / Lüth, Stefan

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.

2017 Volume 17, Issue 6, Page(s) 898–904

Abstract: Background: Limited data exists concerning the coincidence of chronic pancreatitis (CP) and liver cirrhosis with respect to the patient outcome after liver transplantation (LT). The aim of the study was to identify risk factors for graft loss after ... ...

Abstract	Background: Limited data exists concerning the coincidence of chronic pancreatitis (CP) and liver cirrhosis with respect to the patient outcome after liver transplantation (LT). The aim of the study was to identify risk factors for graft loss after liver transplantation and to evaluate the impact of CP on graft survival. Methods: We analyzed the data of 421 cirrhotic patients who underwent evaluation for primary liver transplantation from January 2007 to January 2014. Diagnosis of CP based on morphologic findings which were graded according to the Cambridge and Manchester classification. (Graft) survival after LT was analyzed by Cox regression analysis. Recipient- and donor-related risk factors for graft loss were evaluated using univariate and multivariate analysis. Results: 40/421 cirrhotic patients suffered from CP (9.5%). 250/421 (59.4%) patients underwent LT between January 2007 and January 2014. In total, 89 patients died or were in need of a re-transplantation during follow-up until August 2017. Patients with CP (N = 26) were at increased risk for graft loss after LT (hazard ratio = 2.183; 95% confidence interval = 1.232-3.868). CP (P = 0.001), a MELD score ≥24 (P = 0.021), absence of esophageal or gastrical varices (P = 0.018), the age of the donor (P = 0.008) and infections after transplantation (P = 0.030) were independent risk factors for organ loss after transplantation in the multivariate Cox regression analysis. Conclusion: Patients with chronic pancreatitis are at increased risk for graft loss after LT. A high MELD score, the absence of esophageal or gastrical varices, an advanced donor age and post-transplant infections negatively affect graft survival, too.
MeSH term(s)	Aged ; Case-Control Studies ; Female ; Graft Survival/physiology ; Humans ; Liver Cirrhosis/therapy ; Liver Transplantation ; Male ; Middle Aged ; Multivariate Analysis ; Pancreatitis, Chronic/complications ; Proportional Hazards Models ; Retrospective Studies
Language	English
Publishing date	2017-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2056680-3
ISSN	1424-3911 ; 1424-3903
ISSN (online)	1424-3911
ISSN	1424-3903
DOI	10.1016/j.pan.2017.09.006
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Article ; Online: Detectable Vesicular Stomatitis Virus (VSV)-Specific Humoral and Cellular Immune Responses Following VSV-Ebola Virus Vaccination in Humans.

The Journal of infectious diseases

2018 Volume 219, Issue 4, Page(s) 556–561

Abstract: In response to the Ebola virus (EBOV) crisis of 2013-2016, a recombinant vesicular stomatitis virus (VSV)-based EBOV vaccine was clinically tested (NCT02283099). A single-dose regimen of VSV-EBOV revealed a safe and immunogenic profile and demonstrated ... ...

Abstract	In response to the Ebola virus (EBOV) crisis of 2013-2016, a recombinant vesicular stomatitis virus (VSV)-based EBOV vaccine was clinically tested (NCT02283099). A single-dose regimen of VSV-EBOV revealed a safe and immunogenic profile and demonstrated clinical efficacy. While EBOV-specific immune responses to this candidate vaccine have previously been investigated, limited human data on immunity to the VSV vector are available. Within the scope of a phase 1 study, we performed a comprehensive longitudinal analysis of adaptive immune responses to internal VSV proteins following VSV-EBOV immunization. While no preexisting immunity to the vector was observed, more than one-third of subjects developed VSV-specific cytotoxic T-lymphocyte responses and antibodies.
MeSH term(s)	Adult ; Antibody Formation ; Ebola Vaccines/administration & dosage ; Ebola Vaccines/immunology ; Humans ; Immunity, Cellular ; Longitudinal Studies ; Vaccines, Synthetic/administration & dosage ; Vaccines, Synthetic/immunology ; Vesiculovirus/immunology
Chemical Substances	Ebola Vaccines ; Vaccines, Synthetic
Language	English
Publishing date	2018-11-19
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiy565
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Article ; Online: Dose-dependent T-cell Dynamics and Cytokine Cascade Following rVSV-ZEBOV Immunization.

EBioMedicine

2017 Volume 19, Page(s) 107–118

Abstract: Background: The recent West African Ebola epidemic led to accelerated efforts to test Ebola vaccine candidates. As part of the World Health Organisation-led VSV Ebola Consortium (VEBCON), we performed a phase I clinical trial investigating rVSV-ZEBOV (a ...

Abstract	Background: The recent West African Ebola epidemic led to accelerated efforts to test Ebola vaccine candidates. As part of the World Health Organisation-led VSV Ebola Consortium (VEBCON), we performed a phase I clinical trial investigating rVSV-ZEBOV (a recombinant vesicular stomatitis virus-vectored Ebola vaccine), which has recently demonstrated protection from Ebola virus disease (EVD) in phase III clinical trials and is currently in advanced stages of licensing. So far, correlates of immune protection are incompletely understood and the role of cell-mediated immune responses has not been comprehensively investigated to date. Methods: We recruited 30 healthy subjects aged 18-55 into an open-label, dose-escalation phase I trial testing three doses of rVSV-ZEBOV (3×10 Findings: Immunization with rVSV-ZEBOV was well tolerated without serious vaccine-related adverse events. Ebola virus-specific neutralizing antibodies were induced in nearly all individuals. Additionally, vaccinees, particularly within the highest dose cohort, generated Ebola glycoprotein (GP)-specific T cells and initiated a cascade of signaling molecules following stimulation of peripheral blood mononuclear cells with Ebola GP peptides. Interpretation: In addition to a benign safety and robust humoral immunogenicity profile, subjects immunized with 2×10
MeSH term(s)	Adult ; Antibodies, Bacterial/blood ; Antibodies, Neutralizing/blood ; Antibodies, Viral/blood ; B-Lymphocytes/immunology ; Cytokines/immunology ; Ebola Vaccines/administration & dosage ; Ebola Vaccines/adverse effects ; Ebolavirus/immunology ; Female ; Glycoproteins/genetics ; Glycoproteins/immunology ; Hemorrhagic Fever, Ebola/prevention & control ; Humans ; Immunization ; Male ; Middle Aged ; Peptides/genetics ; Peptides/immunology ; T-Lymphocytes/immunology ; Vesicular stomatitis Indiana virus/genetics ; Viral Proteins/genetics ; Viral Proteins/immunology ; Young Adult
Chemical Substances	Antibodies, Bacterial ; Antibodies, Neutralizing ; Antibodies, Viral ; Cytokines ; Ebola Vaccines ; Glycoproteins ; Peptides ; Viral Proteins
Language	English
Publishing date	2017-04-05
Publishing country	Netherlands
Document type	Clinical Trial, Phase I ; Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2017.03.045
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Article: Safety and immunogenicity of a modified vaccinia virus Ankara vector vaccine candidate for Middle East respiratory syndrome: an open-label, phase 1 trial

Schmiedel, Stefan / Lohse, Ansgar W / Haagmans, Bart L / Sutter, Gerd / Becker, Stephan / Addo, Marylyn M

Lancet Infect Dis

Abstract: BACKGROUND: The Middle East respiratory syndrome coronavirus (MERS-CoV) causes a respiratory disease with a case fatality rate of up to 35%. Given its potential to cause a public health emergency and the absence of efficacious drugs or vaccines, MERS is ... ...

Abstract	BACKGROUND: The Middle East respiratory syndrome coronavirus (MERS-CoV) causes a respiratory disease with a case fatality rate of up to 35%. Given its potential to cause a public health emergency and the absence of efficacious drugs or vaccines, MERS is one of the WHO priority diseases warranting urgent research and development of countermeasures. We aimed to assess safety and tolerability of an anti-MERS-CoV modified vaccinia virus Ankara (MVA)-based vaccine candidate that expresses the MERS-CoV spike glycoprotein, MVA-MERS-S, in healthy adults. METHODS: This open-label, phase 1 trial was done at the University Medical Center Hamburg-Eppendorf (Hamburg, Germany). Participants were healthy men and women aged 18-55 years with no clinically significant health problems as determined during medical history and physical examination, a body-mass index of 18·5-30·0 kg/m2 and weight of more than 50 kg at screening, and a negative pregnancy test for women. A key exclusion criterion was a previous MVA vaccination. For the prime immunisation, participants received doses of 1â×â107 plaque-forming unit (PFU; low-dose group) or 1â×â108 PFU (high-dose group) MVA-MERS-S intramuscularly. A second identical dose was administered intramuscularly as a booster immunisation 28 days after first injection. As a control group for immunogenicity analyses, blood samples were drawn at identical study timepoints from six healthy adults, who did not receive any injections. The primary objectives of the study were safety and tolerability of the two dosage levels and reactogenicity after administration. Immunogenicity was assessed as a secondary endpoint by ELISA and neutralisation tests. T-cell immunity was evaluated by interferon-Î³-linked enzyme-linked immune absorbent spot assay. All participants who were vaccinated at least once were included in the safety analysis. Immunogenicity was analysed in the participants who completed 6 months of follow-up. This trial is registered with ClinicalTrials.gov, NCT03615911, and EudraCT, 2014-003195-23 FINDINGS: From Dec 17, 2017, to June 5, 2018, 26 participants (14 in the low-dose group and 12 in the high-dose group) were enrolled and received the first dose of the vaccine according to their group allocation. Of these, 23 participants (12 in the low-dose group and 11 in the high-dose group) received a second dose of MVA-MERS-S according to their group allocation after a 28-day interval and completed follow-up. Homologous prime-boost immunisation with MVA-MERS-S revealed a benign safety profile with only transient mild-to-moderate reactogenicity. Participants had no severe or serious adverse events. 67 vaccine-related adverse events were reported in ten (71%) of 14 participants in the low-dose group, and 111 were reported in ten (83%) of 12 participants in the high-dose group. Solicited local reactions were the most common adverse events: pain was observed in 17 (65%; seven in the low-dose group vs ten in the high-dose group) participants, swelling in ten (38%; two vs eight) participants, and induration in ten (38%; one vs nine) participants. Headaches (observed in seven participants in the low-dose group vs nine in the high-dose group) and fatigue or malaise (ten vs seven participants) were the most common solicited systemic adverse events. All adverse events resolved swiftly (within 1-3 days) and without sequelae. Following booster immunisation, nine (75%) of 12 participants in the low-dose group and 11 (100%) participants in the high-dose group showed seroconversion using a MERS-CoV S1 ELISA at any timepoint during the study. Binding antibody titres correlated with MERS-CoV-specific neutralising antibodies (Spearman's correlation r=0·86 [95% CI 0·6960-0·9427], p=0·0001). MERS-CoV spike-specific T-cell responses were detected in ten (83%) of 12 immunised participants in the low-dose group and ten (91%) of 11 immunised participants in the high-dose group. INTERPRETATION: Vaccination with MVA-MERS-S had a favourable safety profile without serious or severe adverse events. Homologous prime-boost immunisation induced humoral and cell-mediated responses against MERS-CoV. A dose-effect relationship was demonstrated for reactogenicity, but not for vaccine-induced immune responses. The data presented here support further clinical testing of MVA-MERS-S in larger cohorts to advance MERS vaccine development. FUNDING: German Center for Infection Research.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #708118
Database	COVID19

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