A novel strategy for the therapeutic vaccination of hepatitis C Virus using adenoviral vectors

Lead Research Organisation: University of Oxford
Department Name: Clinical Medicine

Abstract

Hepatitis C virus currently infects 180 million people world-wide and 1% of the population in the United Kingdom. The majority of people that become infected do not clear the virus from the body and approximately 20% of people will develop severe liver scarring (cirrhosis) and may require liver transplantation. One of the main reasons why people do not get rid of hepatitis C is that the immune system does not see and attack the virus.
The current best treatment is called combination therapy. This treatment has many side effects, involves weakly injections and has to be given for a year in many patients. At the end of this treatment less than half of patients get rid of the virus. Our aim is to develop a vaccine that is given to patients before or during combination therapy so that more patients will get rid of the virus. To do this we have developed a vaccine that we hope will stimulate the immune system of patients.
This vaccine is made from a part of the common cold virus-called adenovirus-and we have put a part of the hepatitis C virus into the cold virus. The adenovirus acts like a carrier to deliver the part of the hepatitis C virus and hopefully turn on the immune system. Importantly, the cold virus and the part of the hepatitis C virus have been altered to that they cannot replicate and themselves cause an infection. However, many people have previously been infected with the cold virus and because of this their immune system may try to attack our vaccine. To get around this problem we are going to use two unusual types of carrier cold vaccines that will not have infected people before. One of these is a cold virus that usually infects only chimpanzees. We are going to test these vaccines in 2007-2008 in people without hepatitis C. In this project we want to give these vaccines to patients with hepatitis C to see if we can turn on the immune system to attack the virus.

Technical Summary

Introduction/aims: Hepatitis C virus (HCV) infection is a world-wide epidemic. HCV genotype-1 is the commonest genotype in the UK and is resistant to therapy with current gold-standard treatment, pegylated-interferon and ribavirin, in the majority of patients. This treatment is prolonged, expensive and unpleasant. HCV protease and polymerase inhibitors are in development, however early viral resistance and side-effects appear problematic. In patients who spontaneously eradicate virus, effective cellular immunity plays a crucial role, whereas in persistent infection HCV specific T-cell responses are weak. Our aim is to develop a safe, effective, therapeutic T-cell vaccine for HCV that will prime or boost antiviral T-cell responses. These may contribute to control of viremia. We hypothesise that this strategy may be more effective in the setting of a reduced viral load and anticipate that in the future this would be given before or in conjunction with HCV antivirals to improve sustained virological response rates.

Methodology/outcomes: In this proof of concept study our primary outcomes will be safety, tolerability and immunogenicity using adenoviral vectors in HCV infected patients with high and low viral loads. Effect on HCV viral load will be a secondary end-point. Adenoviral vectors are highly immunogenic but immunogenicity against the vectors is an issue. To circumvent this problem, we will use a human adenoviral vector rarely encountered (Ad6) and a simian adenoviral vector (AdCh3) in a heterologous prime/boost regimen. The immunogen will be the non-structural HCV proteins NS3-NS5b, genetically mutated to inactivate the HCV polymerase, encoding multiple CD4+ and CD8+ T-cell epitopes. We are currently testing this regimen in healthy volunteers.

Experimental design/techniques: Vaccination will comprise 2 priming injections 4 weeks apart followed by a boost 8 weeks later. We will perform a sequential dose escalation study in 2 groups of patients (i) low viral load patients: These will be 12 weeks into combination therapy and have a 2 log decline in HCV load, or undetectable HCV-RNA and (ii) high viral load patients: these will have untreated chronic infection. State of the art immunological techniques will assess the quantity and quality of HCV specific T-cell responses before and after vaccination. These include IFN-? ELISpot, HLA class-I and class-II tetramer technology, and multiparametric assessment of cytokine secretion.

Application/Exploitation: These aims will be achieved together with an industrial partner (Okairos). If proof of concept is demonstrated we will be in an excellent position to take this technology into clinical trials of efficacy.

Publications

10 25 50
 
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 NDM studentship
Amount £208,037 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 10/2013
 
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 
 
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 Jenner Institute 
Organisation University of Oxford
Department Jenner Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution HCV vaccine development
Collaborator Contribution Expertise in vaccine development
Impact Publication and sharing of expertise
Start Year 2010
 
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
 
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