Improving the quality of FMD vaccines by understanding the correlation of vaccine-induced protection with humoral and cellular immune responses

Foot-and-mouth disease (FMD) is a highly contagious disease of cloven-hoofed domestic and wild animals with a global distribution. It remains widespread in developing countries including those of sub-Saharan Africa and South Asia, where it seriously affects livestock productivity through weight loss, decrease in milk yield and loss of draught power. This damage is greatly exacerbated by the cost of control measures and the restrictions imposed on the trade of animals and their products within and from FMD-infected areas reducing output and investment in agriculture. FMD can be controlled by restricting animal movements, by slaughtering affected animals and by vaccination; the latter being used continuously in countries where the disease is common and as an emergency measure if disease is newly introduced. FMD virus (FMDV) is in the genus Aphthovirus and the family Picornaviridae. It exists as 7 immunologically distinct types (serotypes) with little or no cross-protection between them. New variant viruses emerge periodically and may be poorly controlled by immunity to existing subtypes of the same serotype. Consequently, vaccine strain requirements differ according to the types and subtypes of virus prevailing in or threatening different regions and vaccines have to be selected with care. To inform this selection process requires collection of circulating viruses and determination of their match to existing vaccine strains, followed where necessary by development of new vaccine strains. Vaccination using killed virus grown in large cell cultures is critical to FMD control in developing countries where the weakness of veterinary services and lack of animal movement controls preclude reliance on other measures. However, current vaccines provide only short-lived protection (~6 months) that is serotype-specific and sometimes strain-specific. Each batch of the vaccine also needs to be tested in animals with live FMDV challenge to ensure quality and potency. This requires costly high containment facilities that may be unavailable or pose a risk of virus escape. These challenges to vaccine-mediated FMD control programmes have led to the virtual abandonment of attempts to establish FMD surveillance and control programmes in many parts of the developing world and to a lack of vaccine strains tailored for some regions. This project seeks to overcome the above-mentioned constraints to developing effective vaccine-based control strategies in developing countries. This will be achieved by three complementary initiatives. Firstly, vaccine strains will be selected that are appropriate for Eastern Africa, and associated to this work, the methodology for selecting vaccine strains will be simplified, bringing benefits to other regions as well. Secondly, novel adjuvants that have been identified for use in human vaccine formulations and that could enhance the potency and duration of vaccine-induced protection will be evaluated for FMD control. Thirdly, new methodology will be developed and validated to enable batch testing of FMD vaccines based on analysis of the immune responses of vaccinated animals, without a requirement to challenge these animals with virulent live virus. The combination of the use of novel adjuvants to increase the potency and duration of protection, better vaccine matching to induce more targeted coverage of circulating strains, and the increased use of in vitro assays to reduce the costs of vaccine testing could provide a significant breakthrough in the cost-effectiveness of vaccine use and hence FMD control in sub-Saharan Africa and South Asia.

Foot-and-mouth disease virus (FMDV) causes a contagious and devastating disease of domestic animals (FMD) and vaccination is of paramount importance for its control in developing countries. However, vaccine-mediated protection is short-lived, making vaccination policies hard to afford. Current FMD vaccines are serotype specific and may fail to protect fully against subtypes. Consequently, vaccine strains have to be selected, based on cumbersome and difficult to standardise serological matching methods. Batch testing of vaccine efficacy is essential to guarantee the quality of vaccines but current potency tests require costly and risky challenges of vaccinated animals with virulent live virus. In order to improve vaccine selection, the project will target East Africa, where there is a diversity of circulating viruses and lack of tailored vaccine strains. This deficit will be overcome by serological characterisation of field isolates and vaccine strains. The genes encoding the virion proteins of these viruses will be sequenced to determine genetic determinants of their antigenic phenotypes and to develop a sequence-based vaccine selection method to replace the current serological approaches. This will have world-wide application to vaccine strain selection and to design of more broadly cross-reactive vaccines. To avoid reliance on live virus animal challenges in vaccine testing, the project will develop a mathematical model for predicting protection from the immune responses of vaccinated animals, combining serological data with novel measures of cell-mediated immunity. This technology will be transferred to African and Asian partners. It is hypothesised that the efficacy and duration of immunity of FMD vaccines can be improved by strengthening both the Th1 and Th2 responses and that this should be possible by introduction of novel TLR agonists that will be analysed for this use, thereby making FMD vaccines more affordable in developing countries.

Foot-and-mouth disease is an important cause of loss of productivity and due to its rapid spread is considered to be the single most important constraint to international trade in animals and animal products. It is very difficult for small-scale livestock producers to take unilateral actions to protect against the effects of FMD, since the virus spreads readily from their neighbours and prevents them from marketing their products abroad. This in turn leads to a reduction in inward investment to improve productivity and output. Furthermore, since the seriousness of the losses incurred during FMD outbreaks is directly related to the productivity of the animals, it makes it difficult for livestock keepers to move beyond subsistence agriculture. Better FMD vaccines are the key to improved FMD control in developing countries. They can be used by individual farmers to protect their animals from direct losses, and form the basis for national/regional control schemes to reduce and eventually curtail virus circulation. There is a growing body of opinion that access to international markets for certain animal products such as deboned beef need not be dependent on achieving national control of FMD. Instead, FMD-free compartments could be established from which these commodities could be safely exported, providing that there are adequate quarantine facilities and crucially that appropriate and efficacious vaccines are available. This project has specifically targeted a number of practical measures that would make a significant impact on the availability of appropriate vaccines and thereby encourage the development of new vaccine-based FMD control programmes to help developing countries. In parts of East Africa, there are regions where profitability of livestock production could be significantly improved if FMD control were better. Therefore, the project has targeted the selection of new vaccine strains that would be tailored to the needs of this region. These local benefits could be realised within or shortly after the life of the project, as there are regional (as well as distant) vaccine manufacturers in Botswana and Kenya that could rapidly introduce these new vaccine strains. The project also addresses the wider need to develop simplified vaccine selection techniques that could be applied, also in the short term, to improve availability of suitable vaccine strains. The project also looks to introduce vaccines with greater potency and duration of protection, developments that would significantly improve the cost-benefit of vaccine-based control schemes in developing countries. Since the approach is based on novel adjuvants and retains the existing procedure for manufacturing vaccine antigens, it is envisaged that these developments could lead to new registered products in a relatively short timescale - perhaps 3-5 years after completion of the project. Finally, long experience of vaccine-based FMD control in South America made clear that without proper batch testing, it was impossible to guarantee the quality of vaccines on the market and without this, confidence in vaccine-based control was soon under-mined. The project therefore provides a novel approach to improving vaccine efficacy testing that could also be introduced shortly after the end of the project's life. Although targeted at problems for the developing world for FMD control, some of the outputs of this project would also be expected to contribute to FMD control in the developed world, where experience with the massive culling of animals required to control FMD in UK in 2001 has led to a desire to place greater emphasis on vaccination as a means of FMD control.