Improved vaccine manufacture to control foot-and-mouth disease: Production of recombinant vaccines by design

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One of our biggest challenges will be to meet a growing demand for food especially in the developing world. Animal diseases have a significant impact on the productivity of the livestock industry and safeguarding animal welfare will be a major part of maximising food production. Foot-and-mouth disease (FMD) is endemic in many regions of the world and affects huge numbers of animals, both wild animals and livestock (e.g. cattle, sheep, goats, pigs) and is greatly feared due to the enormous economic losses associated with outbreaks. Thus improved control of FMD could sustainably improve the performance of livestock industries and have enormous economic and social value worldwide especially in developing regions where livestock are seen as a means to raise millions from poverty. In FMD-free regions, such as UK, the costs of FMD primarily result from the need to maintain a disease free status. However, FMD-free countries can face enormous losses as the result of periodic incursions and the estimated cost of the 2001 UK outbreak was £8-10Bn. Future incursions into the UK will undoubtedly occur with the potential to inflict substantial economic losses. Vaccination remains the most effective approach for controlling viral diseases and an estimated 2.35 billion doses of FMD vaccine are administered annually. Currently vaccination-led eradication campaigns are ongoing in India, South-East Asia and South America. Two major constraints on FMD vaccination are (i) production capacity and (ii) the need to produce new vaccines from field isolates. Production capacity: FMD vaccines are chemically-inactivated virus preparations produced in cell-culture and the highly contagious nature of FMD requires they are produced in expensive, high-containment facilities. Thus measure that improve vaccine yield from existing production facilities could have an enormous impact by increasing the amount of vaccine available globally for FMD control.New vaccines: FMD is caused by FMD virus (FMDV). A major problem for FMD control is the existence of seven FMDV serotypes, each formed by multiple and constantly evolving virus subtypes. Importantly, vaccination against one serotype does not protect against the others. Further, it is essential that within a serotype the vaccine offers protection against the circulating outbreak strain. This necessitates the periodic need to produce new vaccines, especially against emerging strains for which the current vaccines are a poor match. Vaccine production uses established cell lines (such as BHK cells) that are not normally targeted by FMDV. Thus, the production of new vaccines is critically dependent upon adaptation of a field virus for growth in cell-culture which can prove time consuming or impossible for some field viruses. Thus the challenge is to produce sufficient quantities of vaccine for FMD control We have shown that cell-culture adaptation of FMDV and improved cell-culture growth are achieved by specific mutations at either of two distinct sites in the viral capsid. It is our hypothesis that recombinant FMDV with such mutations will have in-built, improved cell-culture growth and can be used to overcome the delays in producing new vaccines from field viruses and, through improved cell-culture growth, increase vaccine yield from the existing manufacturing capacity. Here we will use reverse genetics to genetically engineer FMDV to include mutations in the viral capsid that result in improved virus growth and develop these viruses a vaccines. We will focus on four of the most prevalent serotypes and include viruses that are known to currently give a poor vaccine yield and have proven difficult to grow in cell-culture. Our ambition is to develop marketable products that could have enormous value by reducing the prevalence of FMD worldwide and the likelihood of further outbreaks of FMD in the UK and Europe.