Identifying epitopes that induce antibody mediated protection against foot-and-mouth disease using reverse genetics

Foot-and-mouth disease virus (FMDV) is the causative agent of a highly contagious and economically devastating disease of cloven hoofed domestic and wild animals. FMD is the single most important constraint to international trade in live animals and animal products. The disease is generally controlled by restriction of animal movement and slaughter of infected and in-contact animals which is very costly and unpopular with the public. The recent outbreaks in the United Kingdom in 2001, have significantly increased public awareness of this disease and now there is heightened interest in a strategy that encompasses a 'vaccinate to-live-policy' to complement stamping out as a means of controlling FMD outbreaks. Vaccinated animals produce antibodies which are believed to be important in providing protection against FMD. However, it is not well understood how such antibodies provide protection nor which parts of the virus are most important to be recognised for protection to be optimal. There are many variants of the FMD virus and multiple vaccine strains are needed to protect against all of these. Current methods to select the most appropriate vaccine are not well standardised or reliable because of dependence on antisera raised in animals that do not react to vaccination in a consistent manner. This project will use genetic engineering to construct a series of closely related FMD viruses in which individual features on the surface of the virus shell will have been slightly altered so as to affect antibody recognition. By looking at how well each of these viruses is recognised by antibodies from immune animals and by seeing how well each virus is able to induce a FMD protective immune response, we shall build up a picture of the contribution of each feature to antibody mediated protection. A better understanding of which viral structures are needed to induce a protective immune response will enable us to make accurate and much more rapid predictions of which vaccines have the necessary configurations to offer protection against a new strain of FMDV. This will be of enormous benefit when faced with the decision of whether and where to apply emergency vaccination in the face of a new FMD incursion, since the effectiveness of any vaccination programme is heavily dependent on the speed of its implementation. This knowledge will also be of fundamental value in efforts to develop broader spectrum FMD vaccines that would dramatically improve the prospects for global FMD control and eradication.

FMDV causes a highly contagious and economically devastating disease of domestic animals and is generally controlled by vaccination in endemic countries and restriction of animal movement and slaughter of infected and in-contact animals in FMD-free countries. The recent 2001 outbreaks in the United Kingdom have significantly increased public awareness of this disease and now there is heightened interest in a 'vaccinate to-live-policy'. Current FMD vaccines are serotype specific and may fail to protect fully against subtypes. Vaccines therefore have to be selected, currently based on serological match between vaccine strain and field isolate. The mechanism for FMD vaccine induced protection is not clear with respect to both the viral determinants of protection and the role of different immune responses. Antibody mediated protection is believed to be an important component as there is a strong correlation between antibody titre and protection. Various neutralising epitopes have been identified on the surface of the FMD virus using murine MAb escape mutants. In addition there is evidence for the existence of other non-neutralising epitopes that are believed to play a significant role. The relative importance of different epitopes has not been ascertained. This project will help to define viral determinants of antibody mediated protection which will help in the development of sequence-based vaccine selection methods and novel broadly cross-reactive vaccines. Using reverse genetics approach a recombinant virus will be generated that is identical to its parent except that the major antigenic sites will be mutated until no serological cross-reaction between the mutant and its parent. Once it has been shown that the mutant virus does not elicit antibodies able to protect against a parental virus infection, the contribution of the different epitopes to serological recognition and in vivo protection will be established by reconstituting each epitope one at a time.