The route to identification of the immunological correlates of protection in ruminants

Effective vaccines are the most efficient way of preventing the transmission and spread of infectious diseases. This applies to diseases of both humans and animals. However there are still many diseases for which no effective vaccines exist. This may be because no vaccines have yet been tested, because vaccines that have been tested do not protect, or because vaccines that have been tested present a hazard in themselves (benefit versus risk). In the past, vaccines were developed empirically. In contrast, strategic approaches to the development of safe and effective vaccines relies on an understanding of how the immune system is activated and regulated so that optimum protection is achieved (benefit) with minimum adverse effects (risk). Investigation of the immune system reveals the correlates of protection that should be mimicked by a good vaccine. Since the correlates of protection are not the same for every infection, vaccines against different diseases need to stimulate different components of the immune system. The capability to identify immunological correlates of protection in farmed ruminants such as cattle and sheep is relatively poor compared to small laboratory animals such as mice that are commonly used as models of human disease. This is largely due to a relative paucity of immunological techniques in ruminants. The most effective way of understanding immune responses to infection is to study the natural host. Cattle and sheep offer an excellent opportunity to do this, and are hosts for economically important diseases, but the lack of knowledge of their immune systems is a major block to strategic vaccine development. Furthermore, these animals may represent better models for developing solutions to human diseases than mice. In this project we aim to develop new techniques to investigate the activation and regulation of the immune systems of cattle and sheep. These techniques will be applied to studies on cells activated under different conditions. This work will facilitate the identification of immunological correlates of protection to many different diseases of cattle and sheep and will also inform on the best ways to deliver new vaccines to maximise their effects. Ultimately this will lead to more strategic approaches to the management and control of infectious diseases of farmed ruminants. This will benefit the agricultural sector and the general public through improved animal welfare, animal production and food security. Furthermore, the work will be done in conjunction with an Industrial Partner, ensuring that the techniques and reagents developed in the project will be made widely available to the research community.

Defining correlates of protection and understanding how they can be elicited are integral components of strategic vaccine design. The route to defining these immunological correlates is dependent on the appropriate reagents to study immune responses that then allow the investigation of cell-cell interactions. In this project we aim to characterise myeloid and T cell subsets in cattle and sheep to generate an understanding of immune of cell-surface molecules, intracellular transcription factors and cytokines that have been ascribed to phenotypically-distinct macrophage, dendritic cell (DC) and T cell subsets in other species. The cloned and expressed molecules will be used to screen existing commercially-available monoclonal antibodies (Mab) for species cross-reactivity. Such studies will confirm the specificity of any such Mab that are identified and hence they can be used with confidence for studies in cattle and sheep. Where we fail to find Mab we will produce Mab to the targets of interest. In this project we aim to develop new techniques to enable the investigation of the activation and regulation of the immune systems of cattle and sheep. These techniques will be applied herein to studies on cells activated under different conditions. This work will facilitate the identification of immunological correlates of protection to many different diseases of cattle and sheep and will also inform on the best ways to deliver new vaccines to maximise their effects. Ultimately this will lead to more strategic approaches to the management and control of infectious diseases of farmed ruminants. This will benefit the agricultural sector and the general public through improved animal welfare, animal production and food security. Furthermore, the work will be done in conjunction with an Industrial Partner, ensuring that the techniques developed in the project will be made widely available to the research community.

This project aims to generate new knowledge on immune activation and immune regulation in two farmed ruminant species (cattle and sheep) that are of significant importance to the UK agricultural sector and economy. In the process, will identify and produce reagents that will enable the definition of immunological correlates of protection and facilitate the design of effective control strategies for economically important diseases in ruminants. There will be several beneficiaries of this research. Potential stakeholders include research scientists, academic and government research organisations, farmers, veterinary disease diagnostic agencies and industry (companies with an interest in animal health products and veterinary immunology products). We aim to investigate the induction of innate and adaptive immune responses and the interactions between these two arms of the immune system in ruminants. The knowledge we generate will open up pathways to impact through strategic vaccine design. Ultimately the general public will benefit through improved animal welfare, animal production and food safety. We will engage and communicate with the various stakeholders to maximise the global impact of the proposed research. The Industrial Partner, AbD Serotec, will provide expertise in product development and marketing, enhancing outreach and impact of this project to the veterinary research community. Staff working on the project will gain scientific skills and will be given training that meets their personal and professional development needs. We anticipate that these skills and training will be transferable. Research training will include a broad range of molecular and cellular immunology techniques (as appropriate depending on the existing skills base). Transferable professional skills will include presentation and writing for communication with academic and non-academic audiences, time-management and project-management. All staff will be actively encouraged to attend training courses. Knowledge exchange and outreach are important activities for communication and promotion of scientific outputs to a variety of audiences. For the scientific community this will involve presentations at conferences, peer-reviewed publications and commercialisation of reagents through AbD Serotec. We will promote the outputs of this project through the Veterinary Immunology Committee (VIC) Toolkit Workshops which are an important part of the International Veterinary Immunology Symposia. Prof Entrican, Prof Glass and Dr Hope all have positions on either VIC Committee or VIC Toolkit Committee. There is open communication with the US-VIRN Toolkit project which will avoid duplication of effort and hence accelerate progress. Communication with non-academic based and non-research stakeholders will include public engagement through presentations at science events, farming shows, talks to school teachers and pupils and liaising with government policy makers, potential commercial partners and distributors. All of the investigators have contacts and experience in these areas, providing an opportunity to promote the importance of this project in providing capacity for the design and implementation of rational approaches for controlling animal disease to a wider audience. This includes the Knowledge Scotland website. Our approach fits with the BBSRC Science in Society remit.