Award details

An effective vaccination programme for the eradication of foot-and-mouth disease from India

Reference	BB/L004828/1
Principal Investigator / Supervisor	Dr Donald King
Co-Investigators / Co-Supervisors	Professor Daniel Haydon, Professor Satya Parida, Professor David Paton, Professor Richard Reeve, Dr Tobias Tuthill
Institution	The Pirbright Institute
Department	Livestock Viral Diseases
Funding type	Research
Value (£)	673,500
Status	Completed
Type	Research Grant
Start date	17/11/2014
End date	16/02/2018
Duration	39 months

Abstract

A reverse genetics approach will be used to establish the relative immunodominance of established and putative capsid surface epitopes of serotype A viruses which exhibit the highest antigenic diversity of FMDV in Europe and Asia. Preliminary data obtained from modelling the correlation between capsid variability and serological cross-reactivity for 56 serotype A viruses and 7 virus-specific antisera will inform the design of capsid protein substitutions and mutations. Incorporation of additional sequence and serological data from India will focus the model on the current situation there. The impact of the changes made on seroreactivity will build up a more detailed understanding of the antigenic relationships between residues across the virus surface and provide the basis for an improved antigenic prediction model and more effective vaccine strain selection. Work with influenza and human immunodeficiency viruses has led to the hypothesis that even antigenically variable viruses possess conserved, antibody eliciting epitopes, but that they are weakly immunogenic. Such cross-reactive mAbs have already been developed for FMDV and we will focus on characterising the binding sites of those that target the external virus surface, and on investigating their protective capabilities. We will establish tests for FMDV antibodies and genomes in individual and bulk milk samples and investigate their application to detection and characterisation of virus circulation within vaccinated populations. Pilot field studies in India will investigate the use of these techniques and the efficacy of vaccination.

Summary

Foot-and-mouth disease (FMD) is a global social and economic burden. Worldwide, ~3 billion doses of vaccine are used. The Indian Government plans to use ~800 million doses of trivalent vaccine annually and the UK has a policy encompassing emergency vaccination in case of FMD outbreaks. However, vaccination is constrained by lack of or incomplete inter and intra serotype cross-protection and by cost and vaccine production capacity. Our scientific aims address (1) the problems of narrow-spectrum antigenic protection elicited by FMD vaccines and (2) the need to monitor the effectiveness of vaccination programmes and to target vaccine use. Our objectives are to develop new approaches to (a) improve predictions of the need for and value of new vaccine strains; (b) produce more broadly cross-reactive vaccines; (c) monitor viral circulation in vaccinated areas, and (d) evaluate vaccine performance in the field and target vaccine use. This will be delivered by bringing together FMD research and control expertise in India and the UK. The Project Directorate on FMD (PDFMD) is responsible for surveillance, diagnosis and epidemiology of FMD in India and Indian Immunologicals (IIL) is the largest Indian FMD vaccine producer. The Pirbright Institute (PIR) is a leading centre for FMD research and diagnosis and collaborates extensively with the University of Glasgow (UoG) to benefit from expertise in quantitative epidemiology and antigenic modelling, and with the Istituto Zooprofilattico Sperimentale in Brescia (IZSLER) who have renowned monoclonal antibody (mAb) collections. 1. Overcoming the problems of narrow-spectrum antigenic protection elicited by FMD vaccines. The antigenic determinants of FMDV that elicit protective antibodies are on the virus surface. We hypothesise that as with other antigenically variable viruses, the dominant epitopes here act as decoys, subverting the immune response from recognition of conserved features. We will generate a model to understand the dominance of antigenic sites, and infer antigenic relationships between viruses for vaccine strain selection. Secondly, we will use cross-reactive mAbs to help identify conserved epitopes for incorporation into new, more broadly protective vaccines. PDFMD will undertake serological and sequencing studies of their extensive virus collections with help from UoG for data modelling. IZSLER will provide existing mAbs augmented by new ones prepared and selected with automated hybridoma screening technology at IIL. PIR will provide reverse genetics to test epitope findings and will quantify antibody-virus cross-protection. 2. Monitoring the effectiveness of the vaccination programme and evaluating targeted vaccine use. We will develop systems to accurately measure virus circulation in the field and identify the impact that vaccination is having on this. Systems for detecting antibodies and for detecting and characterising viral RNA in milk using type/strain-specific assays will be established along with methodologies to infer the extent of continuing virus circulation from the genetic diversity that is revealed from sequencing these viruses. Longitudinal field studies and sample collections will be targeted to areas at different stages of FMD control. These unbiased approaches will be combined with existing and new field data to inform future models to identify the spatial and temporal distribution of specific serotypes of FMDV in the country. This work will be carried out by PDFMD with technical support from PIR and UoG.

Impact Summary

Summary - this project will contribute to major priorities of disease control and scientific research. Improved FMD control is a top animal health, food security and national and international socioeconomic priority. Meanwhile, developing broadly protective vaccines against highly mutable pathogens is a major, unfulfilled research goal in biological sciences. This and approaches to measure the burden of unrecognised infection through detection and characterisation of virus in milk have applicability beyond FMD. Details - Better tools to control foot-and-mouth disease (FMD) are needed. FMD remains endemic in developing countries that do not control borders and animal movements, nor vaccinate systematically on a large scale. It is often the biggest constraint to trade in livestock and their products, limiting access to markets and stunting livestock sector investment. FMD may be reintroduced, costing billions of pounds (e.g. UK, 2001; Japan, 2010; Korea 2011). A progressive FMD control strategy has been designated a global public good, benefiting rich and poor countries[1]. At the launch of this initiative, the PI of this proposal gave the plenary talk on research needs[2]. Antigenic diversity is a feature of several highly significant pathogens affecting man and livestock. This flexibility helps them avoid elimination by adaptive arms of the immune response including antibodies. Influenza and FMDV are prominent examples where vaccination is of great importance. The need to adapt vaccines to emerging threats contributes to the resource intensive requirement to monitor for emergence of new variants and for the spread of known variants into new regions. Vaccination is key to FMD contingency plans for the UK and those for control and eventual eradication in India. It is predicated by growing aversion to large-scale slaughtering to control disease spread, something doubly unacceptable in India where cattle are sacred. Better vaccines and their use will assist the global FMD control strategy; e.g. Africa has great diversity of FMDV but few tailored vaccine strains, making vaccine strain selection a priority. Better prediction of vaccine efficacy will help decide whether and where to apply emergency vaccination in the face of new FMD incursions. More broadly protective vaccines would greatly simplify vaccine development, production and delivery. Huge sums are invested in vaccine production and implementation of vaccination. Little is often dedicated to monitoring vaccination programmes. This can result in failure to correct and identify problems that would have saved resources (e.g. better targeting of vaccination) and/or improved programme effectiveness (e.g. use of inappropriate vaccine strains). Monitoring is also essential to demonstrate the success of vaccination to trading partners. Therefore the research in this proposal will have impact at a number of levels. 1. Improvements in the way that vaccine strains are selected leading to more optimal vaccines, developing new vaccine strains in a timely fashion when needed and contributing to informed decisions on when and where to vaccinate. 2. Improvements in the way that vaccination programmes are monitored so that failure to control virus circulation can be detected and quantified, improved strategies implemented and trading partners reassured. 3. A better scientific understanding of how mutable viruses avoid elimination by host antibody responses. 4. Candidate epitopes that can be evaluated as a basis for development of vaccines to better protect against a wider diversity of FMD serotypes and strains. 5. Improved capability of scientists in UK and India to conduct research, diagnosis and surveillance and to advise policy makers on optimal disease control strategies. [1]:http://www.fao.org/docrep/015/an390e/an390e.pdf [2]: http://www.ars.usda.gov/GFRA/files/Paton%20Research%20Paraguay%20240609.pdf

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Animal Health, Immunology, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	Farmed Animal Disease and Health (FADH) [2013]
Funding Scheme	X – not Funded via a specific Funding Scheme

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