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Evaluation of mucosal vaccination with live, attenuated mutant bovine respiratory syncytial viruses - OD0904

Respiratory infections of livestock are a major animal welfare problem and pose a considerable financial burden to UK agriculture. It is estimated that up to 1.9 million cattle are affected by respiratory disease each year, at a cost to the cattle industry £54 million per annum. Furthermore, approximately 160,000 calves, which have a potential market value of £99 million, die annually as a result of pneumonia and related illnesses. Outbreaks of respiratory disease in calves can be associated with a single pathogen or may be multifactorial. Irrespective of the aetiology, treatment invariably involves the use of antibiotics, which increase the likelihood of the emergence of antibiotic-resistant organisms, posing a risk to human health.

Bovine respiratory syncytial virus (BRSV) is the single most important viral cause of lower respiratory tract disease in young calves. However, BRSV infection may be accompanied by infection with other viral, bacterial or mycoplasma pathogens. For example, Mycoplasma bovis infection also causes calf respiratory disease, mastitis and arthritis and it has been estimated that M. bovis may be responsible for up to a third of all pneumonia-related deaths in Europe. Guidelines for the treatment of mycoplasma infections are based on aggressive and long-term antimicrobial therapy, but in most cases treatment appears to be ineffective. Recent evidence suggests that European strains of M. bovis are becoming resistant to antibiotics that are traditionally used to treat mycoplasma infections. Vaccination provides a sustainable method of disease control and the successful implementation of effective vaccines will reduce the reliance on antimicrobial compounds. However, the development of effective vaccines to control calf pneumonia has had only limited success.

Since the peak incidence of BRSV disease in calves is at 1 to 7 months of age, BRSV vaccines needs to be given shortly after birth. However, the immunosuppressive effects of maternally-derived serum antibodies and the finding that immunity following natural infection is incomplete, pose a challenge to successful BRSV vaccination. There are a number of problems associated with current BRSV vaccines. Thus, some vaccines have manufacturing problems, others are poorly effective, especially in young calves with maternal antibodies and repeated doses are required. Furthermore, one inactivated BRSV vaccine has been withdrawn following incidents of high morbidity and mortality in vaccinated animals. This observation is reminiscent of that seen in babies vaccinated with formalin-inactivated human (H)RSV and indicates that the immune response can contribute to the pathogenesis of disease. Because of the problems associated with inactivated vaccines, it has been proposed that a live, attenuated virus vaccine administered intranasally would mimic natural infection without causing disease. The lack of disease potentiation following natural RSV infection is a critical safety advantage of the live vaccine strategy. The mucosal route of vaccination has the advantage of directly stimulating local immunity and of reducing the immunosuppressive effects of maternally derived antibodies. Furthermore, mucosal vaccination with a live, attenuated BRSV vaccine is more likely to induce rapid and sustained immunity following a single dose of vaccine than parenterally administered inactivated vaccines. In field trials to evaluate the ability of two experimental vaccines to protect calves against respiratory disease, mortality rates in calves infected with BRSV and M. bovis were greater than those associated with BRSV or M. bovis alone. Nevertheless, vaccination with an inactivated exprimental BRSV vaccine significantly reduced the number of pneumonia-associated deaths as well as the number of calves that were treated for respiratory disease. These findings demonstrate that even in mixed infections of BRSV and M. bovis, vaccination against BRSV alone can significantly reduce the incidence of respiratory disease.

The development of live, attenuated HRSV vaccines using conventional methods such as extensive passage in vitro or chemical mutagenesis has shown that such viruses are either too attenuated and do not induce a protective immune response or are unstable and revert to virulence in human volunteers. It is therefore likely that this will also be true for BRSV and in fact we have demonstrated that the virulence of a tissue-culture-adapted strain of BRSV can be increased by passage in the bovine respiratory tract. Recent advances in the molecular biology of negative-sense RNA viruses have provided a means to manipulate the genome of RS viruses. The deletion of genes, gene rearrangements, the introduction of a combination of point mutations and/or the introduction of genes encoding foreign proteins are more likely to lead to the development of stably attenuated viruses than those derived by conventional methods. In previous DEFRA-commissioned projects (OD1611 & OD1612), we have investigated the effects of various mutations on the pathogenesis and immunogenic potential of BRSV in young calves. These studies have identified a number of attenuating mutations and have demonstrated that a single mucosal vaccination with a live, attenuated rBRSV can induce a rapid protective immune response. However, it is not clear which of these attenuated mutant viruses would make the most effective vaccine. In this project we propose to compare the magnitude and duration of local and systemic cellular and humoral immune responses induced by candidate mutant BRSV viruses following mucosal vaccination of calves.
The main aim of this project is to increase our understanding of the role of various viral genes in the development of acquired immunity to BRSV. This knowledge will lead to the development of a safe and effective live, attenuated BRSV vaccine. Since the aetiology of enzootic calf pneumonia is frequently complex, the role of BRSV in severe Mycoplasma bovis infections will also be investigated.
The principal scientific objectives are to:
1. Determine the effects of mucosal vaccination with live, attenuated mutant BRSV on the magnitude and duration of BRSV-specific CD4+ and CD8+ T-cell memory
2. Determine the effects of mucosal vaccination with live, attenuated mutant BRSV on the magnitude and duration of BRSV-specific antibodies in serum and nasal secretions
3. Determine the duration of protective immunity induced by mucosal vaccination with live, attenuated mutant BRSV
4. Investigate the interaction of Mycoplasma bovis with bovine airway epithelial cells and macrophages
Project Documents
• EVID4 - Final project report : 20120716 OD0904 EVID4 Final Report   (428k)
Time-Scale and Cost
From: 2007

To: 2010

Cost: £800,211
Contractor / Funded Organisations
Institute for Animal Health (BBSRC)
Animal Diseases              
Animal Health              
Bovine Immunology              
Plants and Animals              
Vaccine Development              
Fields of Study
Animal Health