Defining protective immunity in hepatitis C virus infection, using novel ultra-sensitive techniques
Lead Research Organisation:
University of Oxford
Department Name: Unknown
Abstract
Hepatitis C virus is a pandemic infection. Following infection with HCV the majority of individuals develop persistent infection associated with progressive liver disease and ultimately liver cirrhosis. The minority spontaneously eradicate the virus. The reasons as to why individuals have completely different clinical outcomes are currently unclear.
The best therapy to date for HCV infection is interferon- given in combination with ribavirin over 6-12 months. This therapy is effective in 45% of patients with genotype-1 HCV infection, but in 75% of genotype-3 infection. In the UK the majority of individuals are infected with therapy resistant genotype-1 HCV infection. The reasons for the dramatically different response rates between viral genoptypes is not known.
I plan to assess the role of the immune response, and in particular the T-lymphocyte response, in determining the resolution of HCV infection. I will assess this both in the context of spontaneous resolution and in the context of therapy. A better understanding of the factors which influence viral control is crucially important in directing future effective therapeutic and vaccination strategies.
The best therapy to date for HCV infection is interferon- given in combination with ribavirin over 6-12 months. This therapy is effective in 45% of patients with genotype-1 HCV infection, but in 75% of genotype-3 infection. In the UK the majority of individuals are infected with therapy resistant genotype-1 HCV infection. The reasons for the dramatically different response rates between viral genoptypes is not known.
I plan to assess the role of the immune response, and in particular the T-lymphocyte response, in determining the resolution of HCV infection. I will assess this both in the context of spontaneous resolution and in the context of therapy. A better understanding of the factors which influence viral control is crucially important in directing future effective therapeutic and vaccination strategies.
Technical Summary
Aims and relevance: Hepatitis C virus (HCV) infects 170 million people and is a significant cause of patient mortality and morbidity. My aim is to define those aspects of cellular immunity associated with viral control. This is essential for the development of future therapeutic strategies.
Scientific objectives and plan: My objectives are to study this in two distinct situations: (1) spontaneous control of virus following primary infection; (2) control of virus during drug therapy.
Following primary infection, 15% of individuals spontaneously control virus, whilst 85% develop persistent infection. Once persistent infection is established T-cell responses are clearly attenuated. However, previous work has shown that the quality of the T-cell response as well as the magnitude of the response is likely to play an important role in determining outcome. I plan to determine the qualitative aspects of the T-cell response in individuals with distinct clinical outcomes and to track the evolution of these responses and the virus during the primary phase of infection. I have established a collaboration with Dr. Paolo Fabris (Italy) who is providing sequential samples from patients with primary HCV infection.
My second objective is to study the cellular immune responses associated with viral control during combination therapy (pegylated-interferon- and ribavirin), having previously demonstrated that these drugs have immunomodulatory activity, in vitro and in vivo. During combination therapy, a sustained virological response is achieved in only 45% of genotype-1 patients treated for 12 months, but in 75% of genotype-3 patients treated for 6 months. Despite this fascinating observation, the host cellular response to genotype-3 infection is currently completely unknown. Since the viral sequences of these genotypes are very different they will present distinct T-cell epitopes. Thus, one explanation is that there is a different T-cell response to genotype-3 infection, which is preferentially enhanced by combination therapy. I plan to examine this hypothesis.
Design and collaborations: This will involve the use of techniques that I am proficient in (ELISpot matrix of genotype specific peptides to define HCV epitopes, panels of HLA class-I and HLA class-II tetramers, the technique of magnetic selection to identify rare populations of HCV specific T-cells, phenotypic analysis, cytokine secretion and cytotoxicity assays). Additionally I will develop techniques that are new to me. To do this I have set up the following collaborations; E. Holmes (Oxford) and Peter Simmonds (Edinburgh) -the analysis of viral evolution, V. Cerundolo (IMM, Oxford)-T-cell priming, A. Sewell (Oxford)-TCR affinity binding.
Scientific objectives and plan: My objectives are to study this in two distinct situations: (1) spontaneous control of virus following primary infection; (2) control of virus during drug therapy.
Following primary infection, 15% of individuals spontaneously control virus, whilst 85% develop persistent infection. Once persistent infection is established T-cell responses are clearly attenuated. However, previous work has shown that the quality of the T-cell response as well as the magnitude of the response is likely to play an important role in determining outcome. I plan to determine the qualitative aspects of the T-cell response in individuals with distinct clinical outcomes and to track the evolution of these responses and the virus during the primary phase of infection. I have established a collaboration with Dr. Paolo Fabris (Italy) who is providing sequential samples from patients with primary HCV infection.
My second objective is to study the cellular immune responses associated with viral control during combination therapy (pegylated-interferon- and ribavirin), having previously demonstrated that these drugs have immunomodulatory activity, in vitro and in vivo. During combination therapy, a sustained virological response is achieved in only 45% of genotype-1 patients treated for 12 months, but in 75% of genotype-3 patients treated for 6 months. Despite this fascinating observation, the host cellular response to genotype-3 infection is currently completely unknown. Since the viral sequences of these genotypes are very different they will present distinct T-cell epitopes. Thus, one explanation is that there is a different T-cell response to genotype-3 infection, which is preferentially enhanced by combination therapy. I plan to examine this hypothesis.
Design and collaborations: This will involve the use of techniques that I am proficient in (ELISpot matrix of genotype specific peptides to define HCV epitopes, panels of HLA class-I and HLA class-II tetramers, the technique of magnetic selection to identify rare populations of HCV specific T-cells, phenotypic analysis, cytokine secretion and cytotoxicity assays). Additionally I will develop techniques that are new to me. To do this I have set up the following collaborations; E. Holmes (Oxford) and Peter Simmonds (Edinburgh) -the analysis of viral evolution, V. Cerundolo (IMM, Oxford)-T-cell priming, A. Sewell (Oxford)-TCR affinity binding.
People |
ORCID iD |
Eleanor Barnes (Principal Investigator / Fellow) |
Publications

Barnes E
(2010)
Failure to detect xenotropic murine leukemia virus-related virus in blood of individuals at high risk of blood-borne viral infections.
in The Journal of infectious diseases

Barnes E
(2009)
Cellular immune responses during high-dose interferon-alpha induction therapy for hepatitis C virus infection.
in The Journal of infectious diseases

Barnes E
(2011)
Vaccines in clinical trials: infectious disease.
in Expert review of vaccines

Barnes E
(2008)
Monocyte derived dendritic cells retain their functional capacity in patients following infection with hepatitis C virus.
in Journal of viral hepatitis

Billerbeck E
(2010)
Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties.
in Proceedings of the National Academy of Sciences of the United States of America

Colloca S
(2012)
Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species.
in Science translational medicine

Culver EL
(2012)
A rare cause of an ileocaecal mass and lymphadenopathy.
in Gut

Di Iulio J
(2011)
Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance.
in Hepatology (Baltimore, Md.)

Fabris P
(2008)
Acute hepatitis C: clinical aspects, diagnosis, and outcome of acute HCV infection.
in Current pharmaceutical design

Fleming VM
(2010)
Virological footprint of CD4+ T-cell responses during chronic hepatitis C virus infection.
in The Journal of general virology
Description | MRC senior fellowship |
Amount | £1,300,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2013 |
End | 03/2018 |
Description | NDM studentship |
Amount | £42,870 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2007 |
End | 10/2010 |
Description | NDM studentship award; T cell immunity to HCV gt3a infection |
Amount | £47,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2010 |
End | 10/2014 |
Description | NIHR Oxford Biomedical Research Centre-FSF funding |
Amount | £94,199 (GBP) |
Organisation | Oxford University Hospitals NHS Foundation Trust |
Department | NIHR Oxford Biomedical Research Centre |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2010 |
End | 04/2011 |
Description | NIHR Oxford Biomedical Research Centre-cohorts |
Amount | £400,000 (GBP) |
Organisation | Oxford University Hospitals NHS Foundation Trust |
Department | NIHR Oxford Biomedical Research Centre |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2007 |
End | 04/2017 |
Description | Wellcome Trust Biomedical Sciences Training Fellowship; Biological role of IFN-lambda-3 |
Amount | £208,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2010 |
End | 09/2014 |
Description | Wellcome Trust Clinical Training Fellowship; Natural History and Pathogenesis of Systemic IgG4 Disease |
Amount | £270,000 (GBP) |
Funding ID | 095160 |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2011 |
End | 05/2014 |
Title | A state of the art Cellma HCV database to establish a HCV patient cohort |
Description | This is state of the art database that we instigated in 2009 to collect clinical information on HCV patients for a longitudinal cohort study of HCV. This will inform not only natural history, but also identify markers of HCV progression and aid recruittment of studies of experimental medicine. |
Type Of Material | Improvements to research infrastructure |
Provided To Others? | No |
Impact | No impacts yet, though this tool has been very recently conceived |
Title | MVA vectored HCV vaccine |
Description | MVA vector that contains the entire non-structural regions of the HCV polyprotein. |
Type Of Material | Technology assay or reagent |
Year Produced | 2013 |
Provided To Others? | Yes |
Impact | phase II efficacy study underway |
Description | Biopharmaceutical company-Okairos |
Organisation | Okairos |
Country | Greece |
Sector | Private |
PI Contribution | We have embarked on a HCV vaccine research program in healthy volunteers and HCV infected patients. We have designed three phase I clinical studies, are recruiting and caring for the patients, and are performing the immunology assays and data analysis. |
Collaborator Contribution | Okairos have made the adenoviral vaccine vectors required for our phase I clinical studies and have helped in project management |
Impact | Plenary session presentation at American liver meeting 2009. An MRC experimental medicine award to assess the same vaccine in HCV infected patients in an academic led study. |
Start Year | 2007 |
Description | Centre for Clinical Immunology and Biomedical Statistics, Perth, Australia |
Organisation | Murdoch University |
Department | Centre for Clinical Immunology and Biomedical Statistics |
Country | Australia |
Sector | Academic/University |
PI Contribution | We performed detailed sequence analysis in a cohort of HCV genotype-3 infected patients, performed data analysis and manuscript preparation. |
Collaborator Contribution | This group performed HLA and sequence analysis on HCV samples to identify immune selective pressures in HCV infection. |
Impact | 19670417 19263475 |
Start Year | 2007 |
Description | Evolutionary analysis of HCV genotype-6 infection in Asia |
Organisation | University of Oxford |
Department | Department of Zoology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Genetic sequencing, sample collection and data analysis |
Collaborator Contribution | The provision of expertise in phylogentic analysis |
Impact | 18971279 |
Start Year | 2008 |
Description | industry partner collaboration-Okairos |
Organisation | Okairos |
Country | Greece |
Sector | Private |
PI Contribution | We have embarked on a HCV vaccine research program in healthy volunteers and HCV infected patients. We have designed three phase I clinical studies, are recruiting and caring for the patients, and are performing the immunology assays and data analysis. |
Collaborator Contribution | production and supply of HCV adenoviral and MVA viral vectored vaccines |
Impact | This collaboration is essential to meet the aims of the project |
Start Year | 2008 |
Title | An adenoviral vectored vaccine for HCV infection |
Description | We have assessed a novel HCV vaccine in healthy volunteers we have shown to be safe and highly immunogenic. |
Type | Therapeutic Intervention - Vaccines |
Current Stage Of Development | Refinement. Clinical |
Year Development Stage Completed | 2009 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Further funding (MRC experimental medicine award) to assess the same vaccine in HCV infected patients has been obtained |
URL | https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-006127-32 |
Title | MVA vaccine |
Description | HCV MVA viral vectored vaccine, in phase-I clinical studies, funded by Okairos and the MRC DCS award in collaboration. |
Type | Therapeutic Intervention - Vaccines |
Current Stage Of Development | Initial development |
Year Development Stage Completed | 2011 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Ni yet |
URL | https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-018260-10 |
Description | Didcot All Saints Primary School Workshop, 23rd June 2017 'Hand cleanliness, viruses and treatment' - in association with University Hospital Southampton |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Questions and discussions |
Year(s) Of Engagement Activity | 2017 |
Description | Dissemination of information about Oxford HCV vaccine programme |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | We wrote an article (in press) that is distributed to both health professionals and patients about the HCV Oxford vaccine programme, Publication-in press |
Year(s) Of Engagement Activity | 2009 |
Description | International Liver Congress, EASL 2017 (Barcelona) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Registry grant presentation" Thursday 14 April 2016 from 12:00 to 13:30. |
Year(s) Of Engagement Activity | 2016 |
Description | News letter-viral hepatitis |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | This study was presented in a newsletter on viral hepatitis that is sent to healthcare professionals in Europe. N/A |
Year(s) Of Engagement Activity | 2009 |
Description | Public lecture series |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | As Above Further dissemination to the public resulted with an invitations to write for public news letters |
Year(s) Of Engagement Activity | 2009 |
Description | Public lecture series to HCV infected patients |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | 50 patients and interested health care professionals attended. Initial talk has turned into a 6 monthly rolling programme. |
Year(s) Of Engagement Activity | 2009,2010,2011,2012,2013,2014 |
Description | World Hepatitis Day, 18th July 2017 (The John Radcliffe Hospital) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Questions and discussion |
Year(s) Of Engagement Activity | 2017 |
Description | public lecture Oxford |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | 40 patients and interested health care workers attended a public lecture (held every 6 months) which sparked questions, discussions and resulted in us recruiting lay people to our research group. Resulted in patient recruitment to our study. |
Year(s) Of Engagement Activity | 2010,2011 |