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.

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.

Publications

10 25 50

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Pybus OG (2009) Genetic history of hepatitis C virus in East Asia. in Journal of virology

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Klenerman P (2009) What are the prospects for controlling hepatitis C? in PLoS medicine

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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

 
Description MRC senior fellowship
Amount £1,300,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2013 
End 03/2018
 
Description NDM studentship
Amount £42,870 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2007 
End 10/2010
 
Description NDM studentship award; T cell immunity to HCV gt3a infection
Amount £47,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2010 
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 Public
Country United Kingdom
Start 04/2010 
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 Public
Country United Kingdom
Start 04/2007 
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 09/2010 
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 05/2011 
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 Italy 
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 Italy 
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 Oxford Curiosity Carnival, 29th September 2017 (part of 'European Researchers' Night) 
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, discussions
Year(s) Of Engagement Activity 2017
 
Description Public lecture series 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Primary Audience Participants in your research and patient groups
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
 
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
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