Collaborative UK research released this week by a group consisting of members of the University of Oxford, University of Reading, The Pirbright Institute and Diamond Light Source detailing a new vaccination approach towards foot-and-mouth disease has garnered wide spread, high profile praise for its ingenuity, therapeutic prospects and cost- effectiveness. Nigel Gibbens, Chief Veterinary officer of the UK, stated “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”.
Caused by the exceedingly infectious and multi-strain FMDV (foot-and-mouth disease virus), foot-and-mouth disease is characterised by fever and blistering of the mouth and feet. It is primarily contracted by cloven-hoof animals (whose hooves split into two toes) including species of agriculturally utilised pig, sheep and cow. Hence, a potential vaccination scheme from this newly-developed vaccine would be aimed at immunising livestock; the disease is rarely contracted by humans. By affecting livestock, FMDV not only has a serious environmental impact, but also considerable economic impact when it strikes. Such impacts were more than evident in the 2001 UK outbreak, estimated to have led to the destruction of some 6 million infected animals with a coupled £8 billion dent to the national economy, according to the World Organisation for Animal Health. Thankfully such events are few and far between in Britain -the only other recorded occurrences being in 1967 and 2007-, however the actions of FMDV are much less sporadic globally with the virus endemic and even more economically inconveniencing to many other nations, especially those of central Africa. All of these facts make what the UK group has achieved even more significant; this new FMDV vaccination has the potential to be safer, more transport and storage durable as well as more financially viable than any current vaccination on the market.
The work was led by Professor David Stuart (Diamond Light Source Life Sciences Director and MRC Professor of Structural Biology in the Department of Medicine, University of Oxford) and Dr Bryan Charleston (Head of the Life Stock Viral Diseases Programme, The Pirbright Institute) and based on ideas pioneered by Professor Ian Jones of the University of Reading. In doing so the collaboration has utilised state of the art technology and computer simulation to successfully design, implement and synthetically produce (via cell culture) an artificially modified version of FMDV’s capsid (the outer mosaic of proteins which “tessellate” together to form the three dimensional, often geometrically intricate, outer boundary or “shell” of a single virus particle). These alterations (which constitute amino acid changes) enable FMDV’s capsid to assemble correctly and stably from its constituent proteins but without its naturally enclosed payload, an RNA (a close relation to DNA) genome. It is this genome which is normally utilised by the virus to replicate within infected host cells (e.g. tongue cells) via exploitation of the host’s cellular machinery or organelles. This empty capsid assembly represents a major breakthrough as without the RNA genome FMDV’s capsid is no longer pathogenic (disease causing) but still features the key antigens (pathogen proteins or other biomolecules which produce an immune response in infected organisms) to which affected animal immune-systems can raise antibodies (immune response proteins which stick to their associated antigens, helping to target the pathogen for destruction by white blood cells) and thus gain immunity. Consequently, a purified solution of modified FMDV capsids represents an entirely safe vaccine (no “live” virus used at any point in its production); a fact being demonstrated in Dr Charleston’s current clinical trials of the vaccine in cattle.
As previously eluded to, the success of this research is in part due to the use of cutting edge methods; one of the most important of which was X-ray crystallography. This technique fires X-rays at a sample (in this case the viral capsids or “shells”) off which the X-rays then diffract; the subsequent diffraction pattern is interpreted by a computer which then renders an atomic-resolution image of the sample. An impressive feat indeed, considering that the capsid is “a billion times smaller than a pinhead” as Professor Stuart puts it. This visualisation, the X-rays for which were provided by Oxfordshire’s very own Diamond light synchrotron (electron-accelerator), generated X-rays some 100 billion times as bright as those used in hospitals, allowed the team to verify that their new synthetic viral shell was identical enough in structure to that of authentic FMDV to trigger the desired immune response.
The collaboration’s modifications to FMDV’s capsid also improved its stability, meaning the vaccine can be readily transported and withstand temperatures up to 56oC for at least two hours, a significant improvement over more traditional vaccines which require constant cold storage. Dr Charleston says this “should greatly increase the production capacity and reduce costs [of manufacture]. Globally there is an undersupply of the [traditional] vaccine due to the high cost of production and this new development could solve this problem significantly”. If all of these benefits weren’t enough the team hopes that the FMDV model of empty capsid production at commercially viable levels will change how viruses of the same family are also combatted (e.g. the polio virus). Whilst it may still be a few years until the vaccine is available to farmers, the advancement of this methodology of empty capsid production is undeniably a triumph for both British research and the global war against viral disease.