We are focused on studies of the immune response to viral infections in cattle. In addition, we have provided advice and expertise on the design of infectious disease challenge models for a wide range of pathogens in cattle, pigs and African buffalo. Currently, the group’s efforts are focused on understanding the immune response to foot-and–mouth disease virus in cattle to develop novel vaccines.
We have recently conducted a large systematic study to quantify FMD virus (FMDV) transmission and our findings that cattle are infectious for less than 50 hours challenge previous assumptions on incubation and latent periods. In conjunction with work to quantify the degree of protection afforded by vaccines, this will improve the accuracy of disease spread models that were a highly controversial source of policy and culling advice during the UK 2001 epidemic. Our conclusions will impact greatly on how the UK deals with future outbreaks.
We have localised persisting virus in FMDV carriers to follicular dendritic cells within lymph node germinal centres. From studies of FMDV infection in calves, we showed antibody responses to capsid surface sites are T cell-independent, whereas those directed against nonstructural proteins are T cell-dependent. Furthermore, CD4(+) T-cell-independent antibody plays a major role in the resolution of disease. These results have shaped the course of our FMDV vaccinology programme to optimise the design of vaccine antigens.
Our substantial FMD vaccine development efforts focus on delivery of whole viral capsids by a variety of approaches and routes. Collaborating with Prof. David Stuart’s structural biology group in Oxford and Prof. Ian Jones at Reading, we have developed an in vitro system to make empty capsids stabilised by targeted mutagenesis to survive heat and pH changes. These have potential as vaccines with safer production, better shelf life, and greater potency.
In the last four years 6 PhD students have been supervised to successful completion of their projects and all students have published in good quality peer reviewed journals, given presentations at international meetings.
- Develop novel foot-and-mouth disease vaccines
- Understand the immune response to foot-and-mouth disease in cattle, especially interrogation of the complexity of the protective antibody response in collaboration with Dr. John Hammond.
- Understand the mechanisms of persistence of foot-and-mouth disease virus in African buffalo.
- Develop preclinical sampling methods to identify foot-and-mouth disease virus infection animals prior to the onset of transmission.
Novel FMD vaccines
We have developed a system to express virus like particles (VLP) for foot-and-mouth disease virus (FMDV) in insect cells. This is the only technology currently available with the potential to be a commercially viable alternative to conventional killed vaccines. The utility of these VLP can be further enhanced by improving their thermostability and pH sensitivity.
Our novel technology is patented and VLP are undergoing technical and economical assessment by our commercial partner. We intend now to focus on developments specifically for endemically infected countries by enhancing the duration of immunity and increasing the breadth of protection against different virus strains. We will develop methods to enhance long-term T-dependent antibody responses and combine data from several high throughput techniques to identify cross-strain specific epitopes that will then be made more prominent in VLP. The validation of our methods will be a FMD vaccine with improved immunogenic properties.
The persistence of FMDV in populations
Pathogens replicate within hosts, transmit between individuals, and spread among host populations; consequently, selection may operate and trade-offs occur at different levels. For pathogens with rapid host-to-host transmission, life history theory predicts long-term persistence to be limited by two central constraints. First, efficient transmission may depend on high pathogen concentrations within the host, which come at the expense of short infectious periods as hosts rapidly succumb to illness or achieve protective immunity (transmission – virulence trade-off. Second, while rapidly transmitting pathogens initially spread quickly through the host population, their epidemics tend to exhibit violent fluctuations, exposing them to greater risk of extinction in the medium term (invasion – persistence trade-off. We will investigate how one of the most contagious animal pathogens known to man, foot-and-mouth disease virus, overcomes these challenges and persists in isolated populations of its reservoir host, the African buffalo. Extremely contagious pathogens that cause acute disease are among the most important global public and animal health concerns, because of their high burden of morbidity and mortality, their violent outbreaks, and as potential threats to biosecurity. Understanding the conditions and mechanisms that allow continued circulation of such pathogens is therefore of obvious interest.
Foot-and-mouth-disease virus (FMDV) can infect over 70 ungulate species, including domestic livestock and numerous wildlife species. Foot-and-mouth disease (FMD) inflicts severe economic losses in endemic countries and is arguably the most important trade-restricting livestock disease in the world. Extreme contagiousness is one of the most striking eatures of FMDV biology - R0 has been estimated at 20 in buffalo. Following acute infection, most buffalo become carriers; and it has been assumed that transmission from carriers is responsible for ensuring FMDV persistence in buffalo populations. However, most attempts at demonstrating transmission between carrier and susceptible buffalo or cattle under experimental conditions have been unsuccessful. Our recent attempts to affect transmission from carrier buffalo, challenged simultaneously with 3 FMDV serotypes support the apparent inefficiency of transmission by carrier buffalo under experimental conditions. Based on recent immunologic and genetic research, we propose ecological and evolutionary mechanisms that may contribute to FMDV persistence in buffalo populations.
Current vaccines against FMD are based on a live but inactivated virus and have serious drawbacks. They have to be produced in expensive facilities with extremely high levels of containment and are unstable needing to be refrigerated during storage and transport.
We have developed a new method uses the outer shell of the virus — the ‘capsid’ — without any of the genetic material that enables it to cause an infection.
The new ‘synthetic’ capsid is more stable than existing vaccines and, because it does not use the live virus, is safer and cheaper to produce, and easier to transport and store. Importantly, because the new vaccine does not include all the proteins of a live virus, it should be possible to distinguish between vaccinated and infected animals, enabling farmers to continue to export cattle globally.
An affordable vaccine that does not require a cold storage chain will help to control FMD in Asia and Africa where it is currently endemic. Not only does the disease place a huge economic burden on low-income countries, but it also increases the threat of reintroducing the disease in other countries. An initial vaccine efficacy trial has been successful and a commercial version should be available within six to eight years.