Scientists have developed a new methodology to produce a vaccine for foot-and-mouth disease virus (FMDV). Because the vaccine is all synthetic, made up of tiny protein shells designed to trigger optimum immune response, it doesn't rely on growing live infectious virus and is therefore much safer to produce.
Furthermore, these empty shells have been engineered to be more stable; making the vaccine much easier to store and reducing the need for a cold chain. This is important research because it represents a big step forward in the global campaign to control FMDV in countries where the disease is endemic, and could significantly reduce the threat to countries currently free of the disease. Crucially, this new approach to making and stabilising vaccine could also impact on how viruses from the same family are fought, including polio.
This collaborative research was led by Professor David Stuart, Life Science Director at Diamond Light Source and MRC Professor of Structural Biology at the Department of Medicine University of Oxford and Dr Bryan Charleston, Head of Livestock Viral Diseases Programme at The Pirbright Institute.
Dr Bryan Charleston, whose team at The Pirbright Institute has developed a detailed understanding of the immune response to FMDV in cattle and is leading the vaccination trials work, says, "The FMDV epidemic in the UK in 2001 was disastrous and cost the economy billions of pounds in control measures and compensation. As a result of the outbreak the Royal Society recommended new approaches should be developed to control the virus should it happen again.
"This important work has been a direct result of the additional funding that was provided as a result of the 2001 outbreak to research this highly contagious disease. Using our detailed knowledge of the immune responses to FMDV in cattle we were able to define the characteristics that needed to be incorporated into the new vaccine platform to induce protection."
Professor David Stuart, explains, "What we have achieved here is close to the holy grail of foot-and-mouth vaccines. Unlike the traditional vaccines, there is no chance that the empty shell vaccine could revert to an infectious form. This work will have a broad and enduring impact on vaccine development, and the technology should be transferable to other viruses from the same family, such as poliovirus and hand foot and mouth disease, a human virus which is currently endemic in South-East Asia,"
Key results were published in the journal PLOS Pathogens on Wednesday 27 March 2013. The work is principally funded by the Department for Environment, Food and Rural Affairs, UK (Defra) and the Wellcome Trust.
Clinical trials of the synthetic shell based vaccine on cattle carried out by Dr Charleston and his team have shown it is as effective as current vaccines. Whilst a commercial product is still several years away the team hopes that the technology can be transferred as quickly as possible to make it available to a global market.
Professor Stuart says; "Instead of using infectious virus as the basis for the vaccine, which is the main traditional method of vaccine development, the team using a methodology developed by Professor Ian Jones from the University of Reading synthetically created empty protein shells to imitate the protein coat that forms the strong outer layer of the virus. By using Diamond's visualisation capabilities and the expertise of Oxford University in structural analysis and computer simulation, we were able to visualise something a billion times smaller than a pinhead and further enhance the design atom by atom of the empty shells. Through information gained at Diamond, we also verified that these have essentially the same structure as the native virus to ensure an appropriate immune response."
Fine adjustments have been made to the empty shell to improve stability to produce a vaccine that is inherently more stable than live virus based products. This makes transporting and storing the vaccine much easier, as the pre-clinical trials have shown it to be stable at temperatures up to 56°C for at least two hours. The disease is endemic in central Africa and some parts of the Middle East and Asia (ref. World map), so this is a major advantage over the traditional vaccine, which has to be produced and stored in a chilled and stable environment.
Dr Charleston adds, "The ability to produce a vaccine outside of high containment and that does not require a cold storage chain should greatly increase production capacity and reduce costs. Globally there is an undersupply of the vaccine due to the high cost of production and this new development could solve this problem and significantly control foot-and-mouth disease worldwide.
"Furthermore, the complete absence of some viral proteins from this new vaccine will also allow companion diagnostic tests to be further refined to demonstrate the absence of infection in vaccinated animals with greater confidence."
Professor Stuart, concludes, "Foot-and-mouth disease is one of the most economically important diseases in livestock worldwide. With approximately 3 to 4 billion doses of vaccine administered every year, you can start appreciating the pertinence of our work. What we achieved is down to the continued support of our many funding agencies, the individual and collective perseverance of the entire collaboration and access to 21st century scientific tools to push the boundaries of scientific research."
Nigel Gibbens, the UK's Chief Veterinary Officer comments on the work, "This vaccine is a major breakthrough that has the potential to be an invaluable new weapon in the fight to eradicate foot-and-mouth disease. There are many more years of work and research to be done to get this vaccine ready for use, but this is undoubtedly an exciting leap forward. Once available, vaccines of this type would have clear advantages over current technology as a possible option to help control the disease should we ever have another FMD outbreak.
"This vaccine has been developed using some truly groundbreaking techniques which are a credit to the quality of British scientists working in the field of animal health."
Development of the vaccine was supported by a Translation Award from the Wellcome Trust. Richard Seabrook, Head of Business Development at the Wellcome Trust, said: "Most people in the UK will remember the foot-and-mouth outbreaks of the 1960s and early 2000s, but FMD is a daily scourge for millions living in countries where the disease is endemic. An affordable vaccine is urgently needed to alleviate the huge economic burden that the disease places on the farming industry, particularly in the developing world. This vaccine still has some way to go before it will be available to farmers but these early results are very encouraging."
Dr Charleston concludes, "We hope that a broad range of research groups working on vaccine development for viruses related to foot-and-mouth disease will be interested in taking our discovery forward to help tackle other major global disease challenges."
The research was carried out by a UK partnership between The Pirbright Institute, which receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and grant funding to research FMDV, and Diamond Light Source, the UK's national synchrotron facility, which receives funding from Science and Technology Facilities Council (STFC) and Wellcome Trust, along with the Universities of Oxford and Reading. As well as vaccine development, The Pirbright Institute, is a centre of excellence for foot-and-mouth diagnostics and is home to the World Reference Laboratory for FMDV virus.
Notes to editors
Reference 'Rational Engineering of Recombinant Picornavirus Capsids to Produce Safe, Protective Vaccine Antigen' Claudine Porta et al. PLOS Pathogens March 2013 http://dx.plos.org/10.1371/journal.ppat.1003255.
For more information and interview requests please see external contacts below.
About the collaboration
The structural work was carried out by Prof Dave Stuart and his team at Oxford University using Diamond Light Source and developed structure-based methods for the prediction of stabilising mutations tailored to each serotype. Incorporation of the mutations into the empty shells, validation of the predicted improved stability and showing they stimulate protective immunity is performed by Dr Bryan Charleston at Pirbright Institute and Prof. Ian Jones at Reading University and their teams. The stable mutated empty shells are analysed by the Oxford team to demonstrate they remain as authentic copies of the original viruses. Together the three groups have developed a system for the production of empty protein shells at commercially viable amounts.
The UK led the world with the first dedicated synchrotron light source which was used to solve the structure of the virus back in 1989. Since then experimental and computational technology has advanced dramatically and capabilities, including those on offer at Diamond, have allowed us to design and evaluate drugs, vaccines and diseases at unprecedented levels of details thus pushing the boundaries of scientific research.
About The Pirbright Institute
The Pirbright Institute is a world leading centre of excellence in research and surveillance of virus diseases of farm animals and viruses that spread from animals to humans. Based in the UK and receiving strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC), the Institute works to enhance capability to contain, control and eliminate these economically and medically important diseases through highly innovative fundamental and applied bioscience.
With an annual income of over £25 million from grants and commercial activity, and a total of £76.9 million strategic investment from BBSRC during 2011-12, the Institute contributes to global food security and health, improving quality of life for animals and people. For more information see www.pirbright.ac.uk.
The Jenner Institute is a partnership between the University of Oxford and the Pirbright Institute and focuses both on diseases of humans and livestock and tests new vaccine approaches in parallel in different species. A major theme is translational research involving the rapid early-stage development and assessment of new vaccines in clinical trials. http://www.jenner.ac.uk
About Diamond Light Source
Diamond Light Source is funded by the UK Government through the Science and Technology Facilities Council (STFC), and by the Wellcome Trust.
Diamond generates extremely intense pin-point beams of synchrotron light. Diamond's X-rays are around 100 billion times brighter than a standard hospital X-ray machine.
Diamond Light Source is used by over 3,000 academic and industrial researchers across a wide range of disciplines, including structural biology, health and medicine, solid-state physics, materials & magnetism, nanoscience, electronics, earth & environmental sciences, chemistry, cultural heritage, energy and engineering. For more information about Diamond visit www.diamond.ac.uk
About Reading University Biological Sciences Department
The School of Biological Sciences is a research intensive institution, which prides itself on the excellence and relevance of its degree courses. The School was formed in 2005 from the former Schools of Animal and Microbial Sciences, Applied Statistics and Plant Sciences. This has resulted in the formation of a School with a formidable range of expertise, and this unique combination makes Reading a very attractive place to work and study. www.reading.ac.uk/biologicalsciences/about
About Oxford University STRUBI
The Division of Structural Biology (STRUBI) is part of the Nuffield Department of Clinical Medicine (NDM) at the University of Oxford, which hosts one of the largest groupings of Biomedical Researchers in the University Sector. STRUBI is also part of the Wellcome Trust Centre for Human Genetics. The Division includes the Oxford Protein Production Facility (OPPF) and the Oxford Particle Imaging Centre (OPIC). www.strubi.ox.ac.uk/strubi/index
About the Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk
BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.
Funded by Government, and with an annual budget of around £500M (2012-2013), we support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.