MICA: Developmental Clinical Studies-a novel vaccine candidate MVA-NS for use in a prime boost schedule in HCV infection.

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

Abstract

Hepatitis C virus currently infects 180 million people world-wide and 0.5-1% 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 will prevent infection or that is given to patients during combination therapy so that more patients will get rid of the virus.
To date we have developed a vaccine that very successfully stimulates the immune system of healthy people against the HCV virus. This vaccine is made from a part of the common cold virus-an 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.
We have tried to increase the immune response further, by giving a second different but related adenoviral vaccine to the volunteers. However, we were unable to achieve this as antibodies to the first injection developed after vaccination and so prevented the second one from working (cross-reactive antibodies). We now wish to develop a vaccine vector (MVA) that is quite different from adenoviral vectors so that the problem of the cross reactivity will not occur. We wish to test this in a small number of healthy and HCV infected patients. In doing so, we believe we will successfully boost the immune response further, and so significantly increase the chances of preventing or curing HCV infection.

Technical Summary

The global burden of hepatitis C virus (HCV) infection is immense with 180 million people infected world-wide leading to liver fibrosis, cirrhosis, liver failure and hepatocellular cancer. There is currently no vaccine for either the prevention or the treatment of HCV, and the best available current treatments are expensive, unpleasant and frequently ineffective. HCV infection is particularly susceptible to a T-cell vaccination strategy since it has been clearly shown by our group and others that spontaneous viral clearance occurs following primary infection in 20% of individuals and is crucially dependent on the induction of a robust and durable CD4 and CD8+ T-cell response. This forms the scientific rationale for our overarching aim-the development of a prophylactic and therapeutic T-cell vaccine for HCV.

Since pre-existing anti-vector immunity may limit vaccine efficacy we have conducted a phase-I clinical trial in healthy human subjects using human (AdHu6) and simian (AdCh3) adenoviral vectors found at low sero-prevalence in human populations, in a heterologous prime/boost regimen. These encode the HCV non-structural proteins with a genetically inactivated polymerase gene (NS). We show that both vectors are safe and highly immunogenic following a single priming injection. In preclinical primate studies using identical vectors, heterologous boosting increased peak responses and long-term immunity. However, in humans it appears that although HCV specific T-cell responses increase following boosting, the magnitude of this response is significantly reduced compared to that observed during vaccine priming. This is due to the induction of cross-reactive immunity between the two vectors. In contrast, it has recently been shown that Modified Vaccinia Ankara (MVA) encoding the malaria antigen ME-TRAP very successfully boosts T-cell responses primed with a simian Adenovirus vector, inducing the highest level of CD4+ and CD8+ T-cell responses ever observed using a vectored vaccine and affording protection from malaria infection.

For these reasons we now wish to develop an MVA construct encoding NS. This will be combined with AdCh3NS in a heterologous prime/boost vaccination regimen and used to assess the safety and immunogenicity of this strategy in healthy and HCV infected patients. We believe that the development of an MVA-NS vector and Phase I testing of the Adeno/MVA regimen will allow a comparison of the two most promising vectored vaccine approaches to date and so enable a comprehensive and rational approach toward development of an effective vaccine for HCV prevention and cure.

Publications

10 25 50
 
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
 
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 Industry partnership-Okairos 
Organisation Okairos
Country Greece 
Sector Private 
PI Contribution Our phase I vaccine studies are investigator led (staff/immunology assays/analysis and trials are all managed by my team)
Collaborator Contribution Provided vectored vaccines, trial management staff and knowledge.
Impact Publications
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 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 Health Organisation website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact I was asked by the WHO to do the webpages for HCV vaccine development.

NA
Year(s) Of Engagement Activity 2010
 
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