Development of rationally attenuated live vaccines for effective control of infectious bronchitis

The overall aim of this project is to attenuate the pathogenicity of infectious bronchitis virus (IBV) of poultry in a non-reversible way, whilst maintaining immunogenicity for both vaccination of chickens and for in ovo application. Control of infectious diseases and a reduction in the use of therapeutic antibiotics are two major challenges faced by the UK poultry industry. The avian coronavirus, IBV, is a highly contagious poultry pathogen prevalent in all types of poultry flocks worldwide. IBV is the causal agent of infectious bronchitis (IB) and continues to be responsible for economic loss, welfare problems in chickens and a potential risk to food security. IBV preferentially causes respiratory disease, but can also infect other organs such as the kidneys (resulting in kidney disease) or the reproductive tract (resulting in loss of egg production and/or egg quality). IBV has been reported to be responsible for more economic loss to the UK poultry industry than any other infectious disease. Although live attenuated vaccines and inactivated vaccines are universally used in the control of IBV, the protection gained by use of vaccination can be lost either due to vaccine breakdown or the introduction of a new IBV serotype that is not related to the vaccine used, posing a risk to the poultry industry. It is important that new and safer vaccines are developed for the control of IBV. This proposal seeks to develop an infectious clone system for the generation of rationally attenuated IBV vaccines, identifying two spatially distant regions of the genome that can be modified for attenuation. The project is divided into four main objectives:- 1) To produce an IBV reverse genetics system based on the pathogenic M41 strain of IBV. 2) To remove the M41 accessory non-structural genes to identify whether they play a role in pathogenicity. 3) To study the role of the M41 essential (replicase) non-structural protein genes in pathogenicity. 4) To investigate the attenuation of IBV for in ovo vaccination. This highly innovative project will be carried out by the coronavirus research group at the Institute for Animal Health, Compton which has the necessary IBV reverse genetics technology and the animal facilities to test rIBVs in chickens. The submission is in direct response to research requirements identified and agreed by the Poultry Research Committee at their meeting on the 17th November 2008. Expected benefits to the food chain: Relaxation of IBV vaccination strategies or the breakdown of vaccination, due to new IBV strains, would have a profound and devastating affect on the UK poultry industry in terms of bird welfare and production costs, with associated risks to food security. This work will pave the way for new rationally modified and safer vaccines, as they will be less likely to revert. A further expected benefit from the development of safer vaccines, is a reduction in the amount of antibiotics used to counteract secondary bacterial infections associated with IB.

The overall aim of this project is to attenuate the pathogenicity of infectious bronchitis virus (IBV) of poultry in a non-reversible way, whilst maintaining immunogenicity for both vaccination of chickens and for in ovo application. Control of infectious diseases and a reduction in the use of therapeutic antibiotics are two major challenges faced by the UK poultry industry. The avian coronavirus, IBV, is a highly contagious poultry pathogen prevalent in all types of poultry flocks worldwide. IBV is the causal agent of infectious bronchitis (IB) and continues to be responsible for economic loss, welfare problems in chickens and a potential risk to food security. IBV preferentially causes respiratory disease, but can also infect other organs such as the kidneys (resulting in kidney disease) or the reproductive tract (resulting in loss of egg production and/or egg quality). IBV has been reported to be responsible for more economic loss to the UK poultry industry than any other infectious disease. Although live attenuated vaccines and inactivated vaccines are universally used in the control of IBV, the protection gained by use of vaccination can be lost either due to vaccine breakdown or the introduction of a new IBV serotype that is not related to the vaccine used, posing a risk to the poultry industry. It is important that new and safer vaccines are developed for the control of IBV. This proposal seeks to develop an infectious clone system for the generation of rationally attenuated IBV vaccines, identifying two spatially distant regions of the genome that can be modified for attenuation.

Exploitation of the project outcomes: The submission is in direct response to research requirements identified and agreed by the Poultry Research Committee at their meeting on the 17th November 2008. The aims of the project also fulfil the Defra requirements for coronaviruses in poultry under 'Alternative pharmaceutical control of endemic animal diseases (Requirements 36-38)'. The IAH coronavirus group is the only research group in the UK that has the IBV reverse genetics system capable of modifying the IBV genome. At present there is only one other group in the world also using an IBV reverse genetics system. The work described in the proposal will benefit the poultry industry, not only from the development of safer vaccines but from benefits in terms of livestock husbandry, welfare and environmental impacts. The continuous use of IB vaccines to protect this important food source is responsible for keeping the impact of IBV on British poultry to a minimum. In the 2005 Defra report, IB was estimated to have affected 22.5 million chickens at a total cost of £23.6M (including £12.6M involving loss of egg production). Relaxation of vaccination strategies, or the breakdown of strategies by loss of protection due to new IBV strains, would have a profound and devastating affect on the UK poultry industry, in terms of welfare and economic cost. A major goal of the poultry industry is the development of an IBV vaccine that can be used for in ovo vaccination. The overall aim of the proposal is to identify suitable regions of the IBV genome that can be modified to attenuate a virulent IBV so that it may be developed as a basic vaccinial strain against different serotypes of IBV. It is unlikely that there will be direct commercialisation of the attenuated virus to be produced at the end of this project as it is at the developmental stage. The project will produce scientific information to underpin the development of a new generation of rationally attenuated IBV vaccines that are safer, have the potential to be modified for wider use against different serotypes and the possibility to be used for in ovo vaccination. This project is not directed towards the production of a formulation designed for an individual product. Subject to IP protection, results will be published in peer-reviewed scientific journals and presented at scientific meetings. The commercial partner, Pfizer Animal Health, is one of the few remaining major animal pharmaceutical companies. They produce a number of animal health vaccines and also support other work into basic and applied virology, with a direct interest in the development of vaccines against poultry diseases including IBV. They are therefore perfect partners to exploit outcomes from this work; for example, to investigate the development of rationally attenuated IBV vaccines that may be used in ovo. The support of an industrial partner will provide a bridge whereby promising vaccine candidates can be taken forward for commercial development. The information gained will be unique and of great value as to how IBV can be rationally attenuated and have a wider application than the development of a single product. Our previous work of spike swapping has demonstrated how IBV can be manipulated to afford protection over a wider range of IBV serotypes. I can foresee no problems why the attenuated virus from this project could not be manipulated in the same way.