Improving existing vaccine platforms to minimise the economic impact of emerging Bluetongue virus (BTV) serotypes

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

Bluetongue is a major infectious disease of livestock (sheep and cattle mainly) caused by a virus known as Bluetongue virus (BTV). BTV is transmitted from infected to uninfected animals by the biting midges. Historically, bluetongue has been described almost exclusively in temperate and tropical areas of the world where the warm temperatures favoured both the spread of the susceptible insect vector population and also the viral replication cycle within the vector. However, in the last decade BTV has spread extensively in Southern Europe and, unexpectedly, also in Northern Europe (including the United Kingdom) reaching well beyond its known geographical upper limits and causing serious problems to both animal health and the economy. Interestingly there are worldwide 24 different 'types' (known as 'serotypes') of BTV. Basically, these different serotypes possess slightly different proteins that form the outside shell of the viral particle. In essence bluetongue can be considered a single disease caused by 24 different viruses! This is because if an animal is vaccinated against serotype 1 of BTV for example(BTV-1), it will then be protected only against infection by BTV-1 but not against the other 23 BTV serotypes. Since 1998 there have been 13 BTV incursions into Europe of 9 different serotypes. The development of safe and effective inactivated vaccines has had an enormous beneficial impact in preventing and limiting the BTV epidemic. However, any significant incursion of a new serotype forces the selection of the relevant new virus for vaccine production. Because BTV is transmitted by an insect vector it has a seasonal pattern. Most bluetongue outbreaks will have a limited diffusion in the first vector season after introduction, but will spread considerably and cause extensive damage in the following year. Thus, the timeline of vaccine production can be absolutely critical to halting the spread of a newly introduced serotype. At present it takes approximately 1 to 6 months for a vaccine manufacturer to acquire a new BTV strain from the field and a further 14-20 months to develop, test and produce a new vaccine. Rapid production of vaccines will assure containment of bluetongue. For example, it has been estimated that the control of the BTV-8 outbreak in the UK saved the UK economy £ 485M and 10,000 jobs. That successful vaccination campaign saved the UK from its second BTV-8 'season'. However, the previous year there was no BTV-8 vaccine ready to halt the devastating outbreak of the disease in its second year in several Central European countries. The overarching objectives of this proposal are to: (i) reduce the time needed to bring to market an appropriate vaccine for a newly introduced BTV serotype; (ii) collect the data necessary to determine (and optimize) the criteria of strain selection used in BTV vaccine preparations; (iii) engineer viruses that elicit an immune response able to protect against multiple BTV serotypes. By using new genetic engineering techniques, we will develop and characterize BTV 'synthetic' viruses that can function as 'off-the-shelf' strains for vaccine development. This system has the potential to reduce the time required by manufacturers to obtain a new strain from the field. We will study how these synthetic viruses function in tissue culture and their ability to induce a protective immunity in vaccinated sheep. In addition we will determine which portions of the BTV vaccines induce an immune response in the vaccinated animal and we will attempt to engineer viruses that can be used as vaccines to protect the animals against multiple seroptypes. The completion of this proposal offers the possibility to develop the tools to avoid in the future most of the economical damages induced by newly introduced BTV serotypes.

Technical Summary

Bluetongue is a major infectious disease of ruminants caused by an arbovirus (Bluetongue virus, BTV) that is transmitted from infected to uninfected hosts by Culicoides. Worldwide there are 24 BTV serotypes. Since 1998 there have been 13 BTV incursions into Europe of 11 separate strains belonging to 9 different serotypes. The development of safe and effective inactivated vaccines has had an enormous beneficial impact in preventing and limiting the BTV epidemic. However, because there is only partial or no cross-protection between different BTV serotypes, any significant incursion of a new serotype forces the selection of the relevant new strain for vaccine production. Thus, the timeline of vaccine production and selection of the 'correct' BTV strain can be absolutely critical to halting the spread of a newly introduced serotype. Because BTV is transmitted by an insect vector it has a seasonal pattern. Most bluetongue outbreaks will have a limited diffusion in the first vector season after introduction, but will spread considerably and cause extensive damage in the following year. The recent development of a reverse genetic system allows now to genetically manipulate BTV and offers a window of opportunity to improve the existing vaccine platform. The overall objectives of this proposal are to (i) develop and characterize both in vitro and in vivo BTV 'synthetic' reassortants that can function as 'off-the-shelf' strains for vaccine development; (ii) understand the basis for variations in immunogenicity between BTV vaccines that will help to establish criteria for the selection of BTV strains used by vaccine manufacturers and (iii) determine whether it is possible to engineer virus reassortants capable of inducing a cross-protective immunity between different BTV serotypes. The completion of this proposal will offer the possibility to improve an existing vaccine platform in order to avoid most of the economical damages induced by an emerging BTV serotype.

Planned Impact

The current proposal is within the scheme of the Industrial Partnership Award and aims to join the efforts of a basic virology laboratory with a vaccine manufacturer (Merial) in order to control more efficiently newly introduced BTV serotypes. The proposal falls into the BBSRC Key Strategic Priority of Food Security and in particular in maintaining animal health. Global demand for food is increasing drammatically and infectious diseases of livestock are a threat to animal health and the global economy. Who will benefit from this research? If successful, this project will have a major impact on (i) animal health and welfare; (ii) food security; (iii) vaccine manufacturing and (iv) the UK and EU economies as a whole. The beneficiaries of this research will therefore include: (i) farmers; (ii) veterinarians; (iii) government policy-makers concerned with disease control and food security at the local, national and international level; (iv) vaccine manufacturing companies and (v) the general public more widely. Why and how will this research be beneficial? Because BTV is transmitted by an insect vector it has a seasonal pattern. Most bluetongue outbreaks will have a limited diffusion in the first vector season after introduction, but will spread considerably and cause extensive damage in the following year. Thus, the timeline of vaccine production can be absolutely critical to halting the spread of a newly introduced serotype. For example, in the Netherlands the direct net costs for the BTV epidemic in 2006 were estimated to be 32 million Euros and were mainly due to control measures. However in 2007 these costs increased to 170 million Euros mostly due to production losses (Velthuis AGJ et al, Preventive Veterinary Medicine 2009). In 2007 BTV-8 spread for the first time to the UK where it caused limited damage but fortunately in 2008 the epidemic was avoided, as a vaccination campaign could take place because by this time a BTV-8 vaccine was available. The control of the UK outbreak of bluetongue was estimated to have saved the UK economy £485M and 10,000 jobs (http://framework.rcuk.ac.uk/prodeco/pcase.htm). Thus, delays in vaccine production or selection of the 'wrong' BTV strain by vaccine manufacturers would not only decrease substantially the margins of the vaccine industry but also, and more importantly, expose the farming industry and the economy of whole countries to substantial losses. The current application is centred on improving the vaccine platform that is already in the market, consequently this project has an almost immediate impact. What will be done to ensure that this research will benefit stakeholders? This research project will be conducted in collaboration with Merial, a major vaccine manufacturer. Merial produces its BTV vaccine in its facilities in the UK and it has distributed more than 80 million doses of the vaccine in 14 European countries. In the short-term, this collaboration will ensure that the information generated in this research project is rapidly communicated to industry where it can be quickly put to use, thus having an almost immediate impact on vaccine production. Merial has extensive links with national and European policy-makers and veterinary professionals thus ensuring that these beneficiaries will be made aware of developments and improvements in the production of BTV vaccines. These beneficiaries will in turn communicate directly with farmers and other veterinarians regarding the availability and distribution of new vaccines. We will obviously publish our data in specialised journals but we will also make a specific effort to write commentaries and reviews in journals that reach the veterinary profession and farming community. Our research will also be presented at National and International scientific meetings.

Publications

10 25 50
 
Description Overall, this vaccine platform can significantly reduce the time taken from the identification of new BTV strains to the development and production of new vaccines, since the viral genomes of these viruses can be entirely synthesized in vitro. In addition, these vaccines can be brought quickly into the market because they alter the approach, but not the final product, of existing commercial products.
Exploitation Route Patent application
Sectors Agriculture, Food and Drink

 
Description Patent for novel BTV vaccine platform has been granted in Austrialia and New Zealand. 2019 Update: Through a research agreement between the Palmarini Laboratory and Merial a jointly owned patent "Reassortant BTV and AHSV Vaccines" has been prosecuted in multiple territories, under the following publication numbers: 1. AU2013274191 2. CA2876196 3. CN104582724 4. EP2861248 5. IL236148 6. KR20150036057 A 7. US2013337010 AA 8. WO13188673 A2 To date, this patent has been granted in the European Union, South Africa, Australia and New Zealand. In late 2016, the University concluded an Exclusive Licence Agreement with Merial to exploit the technology.
First Year Of Impact 2016
Sector Agriculture, Food and Drink
 
Title Vaccine platform 
Description We have developed a novel vaccine platform for the production of inactivated synthetic viruses which facilitates vaccine production against current and newly emerging BTV serotypes. Importantly, the ability for these vaccines to be scaled to an industrial scale has been proven. Our vaccine platform is based on the design and rescue of viruses containing the VP2 (or VP2 and VP5) of distinct BTV serotypes with a viral "backbone" already adapted to tissue culture conditions and vaccine production. We validated this approach by selecting two reassortants, B1BTV-8VP2/VP5 and B1BTV-8VP2, which have been prepared in an industrial setting and proved to protect sheep as effectively as current commercial inactivated vaccines based upon wild-type strains of BTV-8. 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? Yes  
Impact We are coinventors in a patent application covering the synthetic vaccine platform described in this study (U.S. Patent and Trademark Office, U.S. patent 20130337010 A1). 
 
Description Merial Animal Health 
Organisation Sanofi
Department Merial Plc
Country Global 
Sector Private 
PI Contribution Collaborative project on improving existing vaccine platforms with the aim of rapidly responding to the emergence and outbreaks of Bluetongue virus.
Collaborator Contribution Collaborative project on improving existing vaccine platforms with the aim of rapidly responding to the emergence and outbreaks of Bluetongue virus.
Impact Patent Agreement Publication
Start Year 2010
 
Title "Reassortant BTV and AHSV Vaccines" 
Description In late 2016, the University of Glasgow concluded an Exclusive Licence Agreement with Merial to exploit the technology. 
IP Reference AU2013274191 
Protection Patent granted
Year Protection Granted 2016
Licensed Yes
Impact N/A
 
Title Reassortant BTV and AHSV vaccines 
Description This patent application has been published (WO 2013/188673) and encompasses Bluetongue virus (BTV) and African Horse Sickness virus (AHSV) vaccines or compositions and methods of producing recombinant reassortant BTV and AHSV vectors and methods of vaccination against BTV and AHSV. Patent has been granted in the European Union, South Africa, Australia and New Zealand. 
IP Reference WO2013188673 
Protection Patent application published
Year Protection Granted 2013
Licensed Commercial In Confidence
Impact Manuscript
 
Description CVR Website Updated April 2015 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact In March 2015, we embarked on a project to update our website to include up to date information about our staff, research groups and current projects. During the later half of 2014, we filmed 'talking head' interviews of our Principal Investigators to be included on their research group pages, proving interactive and engaging content for our web pages and a valuable source of information for other researchers, stakeholders, target audiences and prospective employees.



We have received very positive feedback about the developments including both internally from CVR staff but also from other research centres within the University of Glasgow who have subsequently requested advice on how we have delivered the project.

We this is a positive step, which demonstrates that we are taking the lead in promoting the CVR as a World-class centre of science research.

New interactive and up to date content, also means that visitors to our pages, spend longer looking at content and therefore, this provides a better opportunity to share information.
Year(s) Of Engagement Activity 2015
URL http://www.cvr.ac.uk
 
Description Cafe Scientifique April 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact CVR scientists David Bhella and Gillian Slack gave a Cafe Scientifique in the Victorian bar of the Tron theatre. The subject was emerging viruses and the Ebola virus. David gave an overview of the causes of viral emergence and Gillian gave a personal account of her experiences working in Sierra Leone to help to bring the current Ebola outbreak under control. The talk was followed by a lively discussion covering such diverse topics as MMR, complementary medicines, endogenous retroviruses and the cultural impact of outbreaks such as Ebola and SARS.



None at present but it is anticipated that we would make plans for further future related activity or get involved in another Cafe Scientifique event with new presenters and cover different topics.
Year(s) Of Engagement Activity 2015
URL https://www.facebook.com/centreforvirusresearch
 
Description Massimo Palmarini - BBC World Service Oct 2014 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Director of the CVR, Professor Massimo Palmarini was interviewed by the BBC about his team's research on Bluetongue virus and the development of a new vaccine platform. The interview was aired on the BBC Science in Action Programme.

This interview helped to raise the profile of the publication of a CVR research paper about a new, fast track vaccine platform for Bluetongue Virus in the Journal of Virology in October 2014. We were also subsequently contacted by the BBC and asked to contribute to further interviews for a BBC Radio Scotland programme about the history of plague where our researchers were asked to explain how the study of virology has changed and developed over time.
Year(s) Of Engagement Activity 2014
URL https://www.facebook.com/centreforvirusresearch
 
Description TWIV 188 - Podcast June 2012 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Vincent Racaniello visited the CVR in 2012 to interview some of our researchers about their work in Hepatitis C virusand jaagsiekte sheep retrovirus.

The TWIV podcast is incredibly popular with followers throughout the World. This allowed us to share information about the CVR and our research to a large, digital audience.

Vincent Racaniello has since returned to work with the CVR on further podcasts. The podcast also sparked online comments and questions.
Year(s) Of Engagement Activity 2012
URL https://www.facebook.com/centreforvirusresearch