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

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.

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.

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.