Dr Paul Barnett
	Tel:	+44 (0)1483 231 153
	E-mail:	paul.barnett@bbsrc.ac.uk
	Address:	Institute For Animal Health, Pirbright Laboratory Pirbright, Surrey GU24 0NF
	Website:	www.iah.ac.uk/research/fmd_vac/fmd_vac.shtml

Principal areas of research
Higher potency Foot-and-Mouth Disease vaccines and novel FMD vaccination regimes.

Biography
Dr Paul V Barnett began his career in 1976 as a laboratory technician with the Wellcome Foundation Ltd, Foot-and-Mouth Disease Vaccine Laboratory and progressed to a Scientific Officer grade, gaining much experience in the different areas of foot-and-mouth disease (FMD) production. This included tissue culture production, vaccine formulation, production of reference reagents, including monoclonal antibodies, and immunoassay development and application. Some of his early research work was closely orientated toward a better understanding of the antigenic structure of FMDV. At the latter stages of his employment with Wellcome he worked on Human Rhinovirus as a model for peptide vaccine research and its application. Following his subsequent move to the International Vaccine Bank (IVB) at the Institute for Animal Health, Pirbright in 1991, the composition of these rhinovirus studies were essential to his award of a Doctorate in 1994 for a thesis entitled 'Antigenic Definition of an Important Linear Epitope of Human Rhinovirus Serotype 2' through the University of Hertfordshire.

In 1997, he was appointed Head of the International FMD Vaccine Bank and currently leads a research group engaged in studies relating to high potency emergency or novel FMD vaccines. In the last decade this group have shown the rapidity by which protection is conferred by ‘emergency’ foot-and-mouth disease vaccines in the three main target species. As an authority on foot-and-mouth disease vaccines, with around 100 scientific publications he has advised OIE, FAO and the European Union. He has also sat on various working groups examining proposals and guidelines on foot-and-mouth disease vaccine testing, and has regularly contributed to the OIE manual of standards for diagnostic tests and vaccines since 1996.

Research
Foot-and-mouth disease virus (FMDV) occurs as multiple serotypes causing a highly contagious disease in cloven-hoofed animals including pigs, sheep and cattle. In cattle, vesicular lesions on the tongue and feet can cause weight loss, and udder lesions decreasing milk production. FMD is a notifiable disease of animals and it is strictly forbidden to import farm animals, meat and milk products from countries experiencing FMD outbreaks. Financial losses can be significant. There are direct losses due to deaths in young animals, loss of milk, loss of meat and a decrease in productive performance. The costs associated with eradication or control can also be high and, in addition, there are indirect losses due to the imposition of trade restrictions and reduced tourism. For these reasons, FMD is one of the most economically important diseases of livestock worldwide.

FMDV can also cause sub-clinical persistent infections in ruminants which can occur following clinical or sub-clinical disease in both vaccinated and non-vaccinated ruminants. Persistently infected animals are defined as carriers if live viruses can still be isolated from the oropharynx beyond 28 days after initial infection. Cattle, for example, have been shown to maintain carrier status for up to 3.5 years. Persistently infected animals may be considered a potential risk for FMD transmission. The difficulty in identifying vaccinated animals that subsequently become persistently infected may delay the return to FMD-free status with deleterious economic consequences for the livestock industry of that country in terms of reduced international livestock movement and trade.

During and following the 2001 UK epidemic there has been growing demand, both from the public and scientific communities, for vaccination to be more readily considered as an alternative to large-scale pre-emptive culling. The foremost recommendation of the Royal Society Inquiry following the 2001 outbreak was that priority should be given to the development of improved FMD vaccines. The World Animal Health Organisation (Office International des Epizooties (OIE)) has amended its Animal Health Code shortening the time frame to regain FMD-free status from twelve to six months after the completion of vaccination, provided that thorough serological surveillance is undertaken to support the absence of circulating virus. Similarly, the EU recently adopted a revised FMD directive (2003/85/EC), which promotes a more flexible approach to different control measures and makes detailed provision for the use of a vaccinate-to-live policy. However, if current vaccines are to be used as the preferred control measure we must broaden our understanding, and improve, on their effectiveness.           This firmly places greater emphasis on the need to scrutinize FMD vaccines further, particularly with regard to those used in an emergency situation, and to gain a greater understanding of their effectiveness and the practicalities of how, when and where they can be usefully implemented.

Much of the research from the group has been in examining the efficacy of emergency vaccines under different challenge conditions, including more recent studies to determine the rate at which immunity is conferred against a severe direct contact challenge. However, a number of key areas still need to be addressed on the high potency FMD vaccines that would be implemented in an emergency situation, and the recent change of strategy in relying on the commercial sector to both store and formulated such vaccines give further reason for national authorities to ensure that these vaccines perform as effectively as that indicated by the vaccines held previously in the International FMD Vaccine Bank. These key areas include duration of protective immunity and the capacity of these vaccines to dampen down virus excretion and prevent transmission of infection

Recent studies have shown the importance of antigen payload in preventing transmission of infection to vaccinated protected sheep by the aerosol route. Furthermore, using a more severe direct contact challenge of vaccinated cattle with infected cattle has also supported the finding that payload plays some part in reducing the level of virus transmission. However, whilst preventing transmission of infection is desirable, in part, to successfully controlling disease incursion, the reality is that full prevention is not likely to be the outcome and therefore a further element of importance  is onward transmission of any residual sub-clinical infection  to other animals particularly those of similar vaccination status. In part, this is being addressed through a recently funded BBSRC project in which one of its objectives is to obtain quantitative data on shedding and transmission of FMDV following challenge of fully susceptible and vaccinated cattle to determine how soon after vaccination that transmission is effectively blocked, and to quantify the mean and variance of infectiousness of partially protected animals. We propose to extend the data generated by using exactly the same experimental protocol but examining transmission from vaccinates to further vaccinates of similar immune status. An accumulation of the results would add greater statistical interpretation and provide a better picture not only on the vaccines initial ability to prevent transmission but its capacity to influence whether ongoing infection is possible through other vaccinated animals. These results will provide accurate parameter estimates for mathematical models to design FMDV vaccination programmes. Thus having a major impact by improving models and a providing better understanding on what could be expected from vaccine implementation.

Novel vaccine approaches are also an area being explored by the group. Currently we are targeting an optimized FMD DNA vaccination regime, with or without protein antigen boost, in cattle, which has previously been shown to induce stronger immune responses involving cellular, humoral and innate parameters that not only confer protection against homologous virus challenge in target animals but also are capable of preventing a persistent infection.
DNA vaccines have certain advantages, not least the ease of manipulating the DNA plasmid, which provides both the ability to generate an appropriately matching vaccine strain, avoiding difficulties in adapting a suitable conventional vaccine strain to large-scale culture, and one with appropriate markers to assist in the surveillance that would subsequently be required after vaccine-induced control. The ability of DNA vaccination regimes to substantially enhance so many immune parameters provides a unique opportunity to study the importance of each of these in the context of protection and local virus inhibition. DNA vaccines would also be expected to induce long lasting memory responses and if, as anticipated, they prevent persistence, comparison to conventional vaccine responses should highlight the key immune parameters. This is of paramount importance in the design of new generation vaccines and improvement of those currently available, with the potential for protecting and improving  the economics of European and World agricultural sectors.

The Royal Society’s inquiry into Infectious Diseases of Livestock concluded that emergency FMD vaccination should be seen as a major tool for controlling FMD and should therefore be considered as a first rather than last resort. However, it also acknowledged the need to improve current vaccines and encourage the generation of epidemiological data that can inform and dictate vaccination strategies. My group aims at addressing these issues through investigation of various aspects of FMDV emergency vaccination in the hope that it will lead to a better understanding of the current vaccines capabilities which overall will lead to improved vaccines and vaccine strategies, greater logistical efficiency through performance monitoring and the generation of transmission dynamics data that is necessary for mathematical modellers to predict the impact of control through vaccination.

Key publications

Further studies on the early protective responses of pigs following immunisation with high potency foot-and-mouth disease vaccine. Barnett, P. V,  S. J. Cox, N. Aggarwal, H. Gerber and K.C. McCullough 2002: Vaccine: 20:25-26: 3197-3208

Stratified and cryogenically stored (SACS) vaccines, a new concept in emergency foot-and-mouth disease vaccine formulation and storage. P.V. Barnett and  R.J. Statham. 2002: Vaccine: 20: 16: 2060-2064

A review of emergency foot-and-mouth disease (FMD) vaccines. P.V. Barnett and H. Carabin 2002: Vaccine: 20: 11-12: 1505-1514

Aspects of emergency vaccination against foot-and-mouth disease. P. Barnett, A.J.M. Garland, R.P. Kitching, C.G. Schermbrucker. Comparative Immunology, Microbiology & Infectious Diseases 25 (2002) 345-364.

Foot-and-mouth disease vaccine potency testing: Determination and statistical validation of a model using a serological approach. Paul V Barnett, Robert J Statham, Wilna Vosloo and Daniel T. Haydon. Vaccine 2003: 21: 3240-3248 

Evidence that high potency foot-and-mouth disease vaccine inhibits local virus replication and prevents the 'carrier' state in sheep. P. V. Barnett, P. Keel , S. Reid , R. M. Armstrong , R. J. Statham , C. Voyce , N. Aggarwal and S. J. Cox . Vaccine 2004 22, Nos 9-10, pp. 1221-1232

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