New hope for safer, more stable foot and mouth disease vaccine
28 March 2013
This collaborative research, involving researchers at the Pirbright Institute and the Universities of Oxford and Reading, was made possible by the ability to visualise the foot and mouth disease (FMD) virus on an atomic scale at the Diamond Light Synchrotron.
Extensive studies will be required before a new vaccine can be registered for veterinary use but, if successful, it is estimated that it could be available within six to eight years.
Current vaccines for FMD are based on the live but inactivated FMD virus. They have to be manufactured in expensive facilities with extremely high levels of containment to minimise the risk of the virus escaping into the environment and causing disease. They are also very unstable and have to be refrigerated during manufacture, transport and storage.
Another drawback to the use of current vaccines is the inability to tell the difference between vaccinated and infected animals, which has important implications for policy makers when deciding how best to deal with an outbreak.
The new method uses just the outer shell of the virus, known as the capsid, without any of the genetic material that enables the virus to cause an infection. The capsids can be produced in insect cells - which is potentially much cheaper than current methods - and because it doesn't involve the live virus, the process does not require the high levels of containment that current vaccines demand.
Importantly, because the capsids do not include all of the proteins from the virus, there is an opportunity to develop companion diagnostic tests that will be able to demonstrate the absence of infection in vaccinated animals with greater confidence.
The team used the high-intensity pinpoint beams of light generated by the Diamond Light Synchrotron to visualise the FMD virus on an atomic scale. This enabled them to engineer the empty capsids atom by atom to improve their stability while keeping their structure as close to the original virus as possible.
Professor David Stuart, Science Director at Diamond Light Source and MRC Professor of Structural Biology in the Department of Medicine at the University of Oxford, explains: "Instead of using infectious virus as the basis for the vaccine, which is the main traditional method of vaccine development, the team 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."
A preclinical study of the technology involving four animals reveals that cows vaccinated with the empty virus capsids were protected from infection with the normal FMD virus for up to nine months. The study, which was published today in the journal 'PLOS Pathogens', also reports stability of the re-engineered capsids at temperatures of up to 56°C for at least two hours, a property that will make transporting and storing the eventual vaccine much easier.
Dr Bryan Charleston, Head of Livestock Viral Diseases Programme at the Pirbright Institute, explained: "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."
Although outbreaks of foot and mouth disease are rare in the UK and Europe, the disease is endemic in parts of Asia and Africa where it is a daily burden on the farming industry. In addition to the economic burden the virus places on already struggling farming communities, there remains the constant threat of reintroduction of the virus into countries that are currently free of the disease. Approximately three to four million doses of the current vaccine are administered each year in an attempt to control the disease.
Richard Seabrook, Head of Business Development at the Wellcome Trust (which has supported the research through a Translation Award), 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 low-income countries. This vaccine still has some way to go before it will be available to farmers, but these early results are very encouraging."
Nigel Gibbens, the UK's Chief Veterinary Officer, commented on the discovery: "This vaccine is a major breakthrough that has the potential to be an invaluable new weapon in the fight to eradicate FMD. 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."
The new approach to making and stabilising the empty capsids could also be applied to other viruses from the same family, including polio.
Dr Charleston concludes: "We hope that a broad range of research groups working on vaccine development for viruses related to FMD 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 Diamond Light Source, the UK's national synchrotron facility, which receives funding from the Science and Technology Facilities Council (STFC) and the Wellcome Trust, along with the Universities of Oxford and Reading.
Image caption: Structure of the foot-and-mouth disease virus. Credit: David Stuart, University of Oxford, Wellcome Images.
Porta C et al. Rational engineering of recombinant picornavirus capsids to produce safe, protective vaccine antigen. PLOS Pathogens 2013 (epub ahead of print).