Immunity in the face of diversity and the development of novel potent HCV vaccines

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

Abstract

The aim of this research is to develop new vaccines against hepatitis C virus (HCV) infection. Importantly, our new vaccines will be effective against different strains of the virus. This is urgently needed as the global burden of HCV infection is immense with 180 million people infected world wide. Within the United Kingdom (UK) 300,000 people are infected. This may lead to liver scarring that progresses to cirrhosis, liver failure and liver cancer. HCV is now the most common reason for liver transplantation in the UK. There is currently no vaccine for either the prevention or the treatment of HCV, and the best available drug treatments are expensive, fraught with side effects, prolonged and frequently ineffective. New drug therapies are on the horizon, but these are only effective against some strains, may be associated with viral resistance, and do not protect against re-infection.

Over centuries, HCV has evolved so that there are now 7 different major viral strains (genotypes) located in particular regions of the world. However, even within a single person, HCV exists as a swarm of closely related but different viruses. Within the UK the two major strains are genotype-1 and genotype-3. The equal prevalence of two genotypes within a country is a unique and special feature of the HCV epidemic in the UK. However, some parts of the virus are the same between strains -these are known as conserved regions. These regions may be the "Achilles heel" of the virus, since a vaccine that effectively targets conserved regions may protect against multiple strains.

So far, we have developed a vaccine that we believe will protect against genotype-1 infection. The vaccine works by stimulating the immune system to make very high number of T cells that attack multiple parts of the virus. We know that T cells are important, since our earlier work showed that these cells are crucial in clearing HCV naturally after infection. Our vaccine is also able to stimulate immune responses in people that are already infected -although responses are weaker in this situation. In this way we hope to use the vaccine to both prevent and eradicate established infection.

Now we plan to improve our T cell vaccine so that it works against different strains -and especially against both genotypes 1 and 3 in the UK. We will design the vaccine so that the T cells generated by the vaccine target regions that are conserved between viral regions. Once we have developed this, we can test and use the new vaccine in the UK where both genotypes-1 and -3 circulate. We also want to understand why some people respond better than others to vaccination. In addition, whilst we know a lot about the immune system and how it clears genotype-1 virus, we know very little about it clears genotype-3 virus. Understanding these things will allow us to develop new strategies to improve vaccines against HCV. The lessons that we learn in designing a T cell vaccine that is effective against multiple viral strains may also prove useful in combating other variable viruses like HIV and HBV.

The research is being carried out by Dr. Ellie Barnes (Oxford University). She is collaborating closely with Okairos, a biotechnology company based in Italy, and several investigators from around the world. These collaborations draw together experts in the biology of T cells, vaccinology, and viral sequence analysis and uses new technologies to characterise T cells in great detail. We plan to use blood samples that we have collected from people who have been vaccinated with our vaccines to understand why some people respond better than others. We will design new vaccines against the conserved regions of multiple HCV strains using a database of thousands of HCV sequences that has been developed over the last decade. In this way we will develop a T cell vaccine against HCV that can be used throughout the world and prevent one of the major causes of liver disease.

Technical Summary

The long term goal is to develop effective T cell vaccines to tackle hepatitis C virus (HCV) diversity. HCV exists globally as seven major genotypes, multiple subtypes and swarms of variants within each host. Within the UK genotype-1 and subtype-3a are equally prevalent - a unique feature of the epidemic.

To date I have, in collaboration, developed a highly immunogenic HCV T cell vaccine in healthy volunteers. This consists of simian and human adenoviral (Ad) vectors derived from rare serotypes, in addition to Modified Vaccinia Ankara (MVA) vectors, used in heterologous prime/boost regimens. Both vectors encode the entire non-structural (NS) genotype-1b HCV proteins (1995 amino-acids) Significant immunogenicity is also induced in HCV infected patients, though the mean magnitude of the response is lower.

My aims are to identify the determinants of the relative immune non-responsiveness in HCV infected patients. This will be achieved through the detailed characterisation of innate RNA signatures and adaptive T cell immunity, at baseline and in response to vaccination, in association with viral sequence analysis. This will give insight into the mechanism of T cell non-responsiveness that is the hallmark of many persistent viral infections. I will assess the immune correlates of viral clearance in HCV subtype-3a infection through the assessment of T and B cell immunity in natural infection. This will aid the rational design of effective UK HCV vaccines. Finally I will design a prophylactic vaccine for "broad" HCV coverage based on conserved peptide fragments. This will be delivered through the generation of a global relative prevalence HCV subtype dataset, and the "virtual" design of novel immunogens through computer algorithms that interrogate the dataset. Vaccines encoding the novel immunogens will be assessed in pre-clinical models.

Delivering these aims will facilitate the rational development of novel HCV vaccines within the UK and globally.

Planned Impact

Beneficiaries of the proposed research;
The ultimate aim is to develop a prophylactic and therapeutic HCV vaccine that is effective against multiple viral genotypes. This is highly relevant to the UK population that are infected with both subtype-3a and genotype-1, but potential beneficiaries include people globally at risk of HCV (health care workers, intravenous drug users, renal dialysis patients, those living in high HCV prevalence countries, people with HIV, and partners and children of people with HCV) and people with HCV. Major objectives are to understand why people with HCV infection have an attenuated response to potent T cell vaccines, and to develop an effective strategy to tackle viral variability. Achieving these objectives, may protect people from other persistent viruses (HIV and HBV), other variable pathogens (e.g. Dengue), and other diseases where T cells are attenuated in the face of prolonged antigen exposure-such as cancer.

The generation of the first effective T cell vaccine would drive the commercial and academic sectors that manufacture viral vectors (IDT Germany, CBF, Oxford UK), and who are striving to develop T cell vaccines against a range of pathogens (e.g. RDT-malaria; Okairos-HCV, HIV, malaria and RSV). A successful HCV vaccine would also significantly impact upon public health policy decisions both nationally and globally.
Societal impacts; The work could be enormously beneficial to health and quality of life globally. HCV currently infects 180 million people worldwide and 4 million people are newly infected annually. Within the UK 0.4% of the population are infected, whilst in other countries the prevalence increases to 10-30% (Egypt and parts of Asia). Many of the people susceptible to HCV exist within vulnerable sectors of society and developing countries, where treatment with current therapies is not an option.

HIV infected people in particular would benefit from an effective HCV vaccine. By the end of 2010, there were 2.3 million HIV+ people in Europe, of whom over half were co-infected with HCV (WHO data 2011). HCV infection in HIV+ people is associated with an increased risk of developing chronic HCV infection and rapidly progressive liver fibrosis, and is the commonest cause of death in HIV+ people on HAART. Furthermore, there are currently epidemic outbreaks of acute HCV infection in multiple major European cities in men who have sex with men highlighting the failure of preventative measures aimed at changing behaviour.

New protease inhibitors for HCV represent a major breakthrough in the field, increasing viral clearance rates to 70% for genotype-1. However, these will be ineffective in the 50% of the UK population with genotype-3 infection, and will inevitably be associated with the development of drug resistance. New oral agents currently in development should be available in the future to treat other viral genotypes-but the costs will be prohibitive for the majority. As an analogy, we have had effective treatments with HAART for HIV for over a decade, and yet millions of people around the world have no access to these drugs.

Enhancing economic prosperity;
T cell vaccine technologies are highly competitive at an international level within the UK. The development of the first effective T cell vaccine would place the UK at the forefront of the field. This would increase UK economic prosperity through the commercialisation and exploitation of novel vaccines, and would increase innovative research capacity within academic organisations that seek to develop T cells strategies to combat disease.

Direct economic savings can also be anticipated since the cost of protease inhibitors is £18,000-£32,000/treatment course. Treatment of only 1% of those currently infected within the UK with these therapies will cost the UK £75 million.

Realistic time-scales for the benefits to be realised are 5-10 years.
 
Description MRC DTP Supplementary Funding
Amount £16,000 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start  
 
Description MRC project grant in rat hepacivirus
Amount £1,481,955 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2017 
End 09/2020
 
Description Oxford NIHR principle fellow award
Amount £45,000 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Public
Country United Kingdom
Start 02/2015 
End 02/2018
 
Description PEACHI
Amount £3,500,000 (GBP)
Funding ID 305632 
Organisation European Union 
Sector Public
Country European Union (EU)
Start 08/2013 
End 10/2017
 
Description University of Oxford Confidence in Concept Scheme - Round 6
Amount £50,000 (GBP)
Funding ID MC_PC_17174 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2018 
End 02/2020
 
Description Collaboration with Heidi Drummer 
Organisation Burnet Institute
Country Australia 
Sector Learned Society 
PI Contribution Collaboration with Heidi Drummer' research team, Melbourne, Australia; Developing a combined B cell (Heidi), T cell (me) vaccine.
Collaborator Contribution Collaboration with Heidi Drummer' research team, Melbourne, Australia; Developing a combined B cell (Heidi), T cell (me) vaccine.
Impact Successful grant application by Heidi to support the collaboration
Start Year 2017
 
Description Industry partnership-Okairos 
Organisation Okairos
Country Italy 
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 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
 
Title T cell vaccine for HCV 
Description Generation of a new HCV vaccines 
IP Reference GB1605099.9 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact Not yet
 
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 BSCGT Public Engagement Event - Vaccines & Infectious Disease (hosted stall) 
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 This all-day event included a series of seminars and a 2hr exhibitor event at which STOP-HCV Consortium hosted a stall. ~100-200 delegates registered for the event, and the target audience was primarily secondary school children and the general public. There was a high level of interest in the stall, from both school children and the general public, and the feedback received will inform plans for future events.
Year(s) Of Engagement Activity 2015
 
Description Barnes, E & Hudson, E. STOP-HCV - Stratified Medicine to Optimise Treatment for Hepatitis C Virus Infection. Impact, Volume 2017, Number 6, August 2017, pp. 81-83(3) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact STOP-HCV published an article with Science Impact Ltd showcasing the work of the consortium. The article appeared in the August edition of the magazine (the focus of which is 'Effective and cost-effective solutions')
Year(s) Of Engagement Activity 2017
URL http://www.ingentaconnect.com/content/sil/impact/2017/00002017/00000006/art00029
 
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 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 event (hosted stall) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Stall sparked interest/further questions surounding virology and personalised medicine

Increased awareness for STOP-HCV project - new followers on twitter
Year(s) Of Engagement Activity 2014
 
Description Public event (hosted stall) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact Stall sparked questions and answers surrounding virology and personalised medicine

Positive feedback from attendees at the stall resulted in an invitation to host the stall at another public event (Oxford Open Doors)
Year(s) Of Engagement Activity 2014
URL http://www.ndm.ox.ac.uk/cheltenham-science-festival-2014-2
 
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 STOP-HCV Podcast 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Podcast with STOP-HCV researchers describing their work within the consortium. Published on the STOP-HCV website.
Year(s) Of Engagement Activity 2017
URL http://www.stop-hcv.ox.ac.uk/stop-hcv-podcasts
 
Description Spotlight on CRN hepatitis C research - interview for website 
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 Interview for NIHR CRN spotlight on hepatitis C research - published on CRN website
Year(s) Of Engagement Activity 2014
URL https://www.crn.nihr.ac.uk/hepatology/about-hepatology-research/spotlight-on-hepatitis/researcher/
 
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