Group Head / PI and Supervisor
Respiratory disease in young calves is a major animal welfare problem, affecting approximately 1.9 million calves in the UK each year, at a cost of £54 million. Bovine respiratory syncytial virus (BRSV) is the most important primary viral cause of respiratory disease in young calves and the development of a safe and effective vaccine against this pathogen would enhance the sustainability of livestock farming and improve calf welfare. BRSV is structurally and antigenically related to human (H)RSV, which is the single most important cause of bronchiolitis and pneumonia in infants, and the viruses share many epidemiological and pathological features. The high degree of similarity between HRSV and BRSV indicates that comparative studies of the immunobiology of these viruses will yield important insights that should benefit both man and cattle. Furthermore, BRSV has provided an ideal model to study the function of bovine class I MHC molecules, virus-specific bovine T cells and to investigate antigen-delivery systems for induction of specific types of immune response. This work underpins studies on many of the major livestock pathogens that are currently of greatest strategic importance for The Pirbright Institute.
The development of safe and effective RSV vaccines has been hampered by the need to induce protective immunity within the first month of life, at a time when maternal antibodies can pose a major obstacle to successful vaccination; and the observation that vaccination can exacerbate RSV disease. Because vaccine-augmented disease is associated with inactivated virus, it has been proposed that a live, attenuated virus administered intranasally would make a safer and more effective vaccine. The lack of disease potentiation following natural RSV infection is a critical safety advantage of the live vaccine strategy and the mucosal route of vaccination would directly stimulate local immunity, prime CD8+ T cells, which are important in virus clearance, and overcome the immunosuppressive effects of maternally-derived antibodies. Recent advances in the molecular biology of negative-sense RNA viruses have provided a means to manipulate the genome of BRSV and opened the way for producing genetically stable, attenuated BRSV vaccine candidates. The main focus of current research is to analyse of the molecular determinants of virulence of BRSV in order to identify suitable attenuated virus vaccine candidates; to characterise BRSV-specific CD8+ T cells in order to determine if qualitative or quantitative differences in their priming influences the outcome of infection; to investigate ways in which the immune response to RSV can be manipulated in order to induce protective immunity whilst avoiding potentially damaging immune responses; to identify immune inductor and effector sites in the upper airways of cattle; and to analyse the influence of the site of antigen expression on induction of mucosal immunity.
A second area of the group’s research is the development of a safe and effective African swine fever (ASF) vaccine. ASF is a highly contagious fatal acute haemorrhagic viral disease of pigs which causes major economic losses. ASFV is currently endemic in many sub-Saharan African countries and in Madagascar and Sardinia. There is no vaccine available and disease control relies on implementing movement restrictions and slaughter policies which are difficult to achieve in countries lacking a good infrastructure. To date, the use of empirical methods have failed to produce an effective vaccine, partly due to the complexity of the virus, the acute fatal nature of the disease and a poor understanding of the what types of immune response protect against infection. Recent studies have highlighted an important role for CD8+ T cells in immunity induced by a naturally occurring, avirulent isolate of ASFV. Current studies are focusing on characterizing the role of various CD8+ T cell subsets in protection; identifying the ASFV proteins recognized by these cells; and the development of a vaccine that induces strong CD8+ T-cell responses. In addition, we are investigating the nature of the porcine innate immune response to ASFV infection and it’s interaction with the adaptive response, using virulent and mutant ASFV in collaboration with Dr. Linda Dixon, at The Pirbright Institute.