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

Lead Research Organisation: Moredun Research Institute
Department Name: Vaccines and Diagnostics

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Blanco C (2015) Total mixed ration pellets for light fattening lambs: effects on animal health. in Animal : an international journal of animal bioscience

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Entrican G (2020) The Veterinary Immunological Toolbox: Past, Present, and Future. in Frontiers in immunology

 
Title The route to identification of immunological correlates of protection in ruminants 
Description Production of a research video via University of Edinburgh website showcasing this BBSRC IPA project and explaining the purpose of the project to a non-specialised audience 
Type Of Art Film/Video/Animation 
Year Produced 2013 
Impact Used by our industrial partner on the project to demonstrate value of the project 
URL http://www.nutshell-videos.ed.ac.uk/elizabeth-glass-ruminant-immunology/
 
Title The route to identification of immunological correlates of protection in ruminants 
Description Production of a research video via University of Edinburgh website showcasing this BBSRC IPA project and explaining the purpose of the project to a non-specialised audience 
Type Of Art Film/Video/Animation 
Year Produced 2013 
Impact Used by our industrial partner on the project to demonstrate value of the project 
URL http://www.nutshell-videos.ed.ac.uk/gary-entrican-ruminant-immunology/
 
Description We have discovered that white cells called monocytes in the blood of sheep and cattle that are responsible for stimulating immune responses are more complex than originally thought. These cells exist as different subsets and can be identified by the molecules they express on their surface and the way they respond to stimuli derived from bacteria. These findings have been published in a scientific paper in 2015 (see publications). We have also developed methods for identifying subsets of other white cells called lymphocytes in the blood of cattle and sheep that important for fighting infection, especially bacteria. These results are currently being written up for publication. This project was funded in collaboration with an Industrial Partner with whom we have licenced a new immunological reagent (a monoclonal antibody) that can detect a molecule produced by immune cells (including monocytes) in response to bacterial infections. Collectively, these results will influence they way that we develop and evaluate new vaccines for diseases of cattle and sheep.
Exploitation Route Potential applications to vaccine design and as biomarkers for disease The knowedge can be used to investigate how to improve cattle vaccines, the techniques used to characterise the cells will be made available to the research community through publication and transfer to our Industrial Partner on the project
Sectors Agriculture, Food and Drink,Manufacturing, including Industrial Biotechology

URL https://www.youtube.com/watch?v=Pc99AbL_pgo
 
Description The findings have been used to investigate immune responses in sheep and cattle, particularly to a bacterial disease that affects animal welfare and livestock productivity. The results have been presented at several international scientific conferences, scientific papers and through transfer of tools and technologies to research groups in the UK and Europe and to industry. This is already having impact as several national and international research groups have been able to make use of our findings and tools through collaboration resulting in refereed publications: see publication list. Ultimately we expect this to inform on new disease control strategies for ruminant livestock diseases, including the development of deployable vaccines.
First Year Of Impact 2012
Sector Agriculture, Food and Drink,Manufacturing, including Industrial Biotechology
Impact Types Policy & public services

 
Description Contribution to BBSRC Veterinary Vaccinology Strategy
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
URL http://www.bbsrc.ac.uk/documents/1506-veterinary-vaccinology-strategy/
 
Description Contribution to UK Vaccine Network
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL https://interact.innovateuk.org/competition-display-page/-/asset_publisher/RqEt2AKmEBhi/content/new-...
 
Description Membership of the STAR-IDAZ International Research Consortium Scientific Committee
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description Steering Group of the BBSRC UK Veterinary Vaccinology Research Network
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
URL http://www.bbsrc.ac.uk/funding/opportunities/2013/uk-veterinary-vaccinology-research-network.aspx
 
Description The route to identification of immunological correlates of protection in ruminants
Geographic Reach National 
Policy Influence Type Participation in a national consultation
URL http://www.parliament.uk/business/publications/research/briefing-papers/POST-PN-433
 
Title Datasheet on the applications of a monoclonal antibody to detect ovine CXCL8 
Description The applications of the monoclonal antibody for detecting ovine CXCL8 (see patents section) were reported in a datasheet available on the website of the marketing company (see hyperlink below). 
Type Of Material Antibody 
Year Produced 2017 
Provided To Others? Yes  
Impact The datasheet supports research applications of the monoclonal antibody. 
URL https://www.bio-rad-antibodies.com/static/datasheets/mca60/sheep-ovine-il-8-antibody-2c9-mca6013ga.p...
 
Description Provision of recombinant ovine and bovine cytokines for development of a cytokine multiplex assay as a welfare indicator in sheep 
Organisation Scotland's Rural College
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of recombinant ovine IL-1b, IL-4, IL-6, IL-10, TNF-a, IFN-g and bovine IL-10
Collaborator Contribution Development of the assay under the AWIN FP7 Project
Impact Assay still under development
Start Year 2013
 
Description Provision of recombinant ovine cytokines as ELISA standards 
Organisation University of Leon
Department Institute of Livestock Mountain
Country Spain 
Sector Academic/University 
PI Contribution Provision of recombinant ovine cytokines for measurement of immune responses in relation to diet in sheep
Collaborator Contribution Conducted the dietary experiments in sheep
Impact Multidisciplinary (animal welfare, animal production, biochemistry, immunology). Resulted in a collaborative publication with full reference to the project. Blanco et al, Animal, doi:10.1017/S1751731114002249
Start Year 2013
 
Description The route to identification of immunological correlates of protection in ruminants 
Organisation University of Massachusetts
Country United States 
Sector Academic/University 
PI Contribution International collaboration with USDA-funded project
Collaborator Contribution Provision of monoclonal antibodies and recombinant cytokines for comparative testing
Impact Evaluation of monoclonal antibodies to ruminant cytokines, presented as a talk at the Veterinary Immunology Toolkit Workshop, 10th IVIS Congress, Milan, August 2013
Start Year 2012
 
Title A new licence agreement for commercialisation of a monoclonal antibody to ruminant GM-CSF 
Description A new licence agreement for commercialisation of an existing monoclonal antibody to bovine and ovine GM-CSF 
IP Reference  
Protection Protection not required
Year Protection Granted 2012
Licensed Yes
Impact Transfer of the parent hybridoma cell line to our Industrial Partner Bio-Rad AbD Serotec and creation of a new commercial product
 
Title Licence agreement to allow commercialisation of a recombinant cytokine 
Description Licence agreement for commercialisation of ruminant cytokines (principally bovine IL-10) with our Industrial Partner, Bio-Rad AbD Serotec 
IP Reference  
Protection Protection not required
Year Protection Granted 2012
Licensed Yes
Impact None to date
 
Description BBSRC Veterinary Vaccinology Network Stand at the Cheltenham Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Representation of Veterinary Vaccinology Research to the general public. The stand included literature and hands-on activities where participants could 'design' a vaccine and answer questions on their views on vaccination, including GMOs.
Year(s) Of Engagement Activity 2016
URL http://www.vetvaccnet.ac.uk/news/2016/06/animal-and-human-vaccines-exhibit-times-cheltenham-science-...
 
Description Challenges in the prevention and control of livestock disease in a changing climate 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Laboratory presentation to The Princess Royal on immunology, explaining the purpose of the work conducted at Moredun, inlcuding the outputs of this particular project.

The visit was reported in national newspapers and on the BBSRC website, resulted in interest and requests from peers on the outcomes of the project.
Year(s) Of Engagement Activity 2014
URL http://www.bbsrc.ac.uk/news/health/2014/140224-n-princess-royal-safeguard-livestock.aspx
 
Description Immunology Congress, Medellin 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker at 11th Congress of the Latin American Association of Immunology. The talk prompted debate and resulted in an invitation to attend a committee meeting of the Latin American Veterinary Immunologists
Year(s) Of Engagement Activity 2015
 
Description Presentation to School teachers on Immunology in the new Scottish Curriculum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Gave a talk to Biology School Teachers on basic immunology and how immune correlates can be used for vaccines. Stimulated many questions on the elements of immunology embedded in the new Curriculum for Excellence.

Requests for visits to the laboratory by teachers and pupils, requests for teaching aids relating to immunology.
Year(s) Of Engagement Activity 2012,2013,2014
 
Description Public Education Event at Edinburgh International Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Edinburgh International Science Festival public event. Practical demonstration and hands-on activity for schoolchildren to learn immunology techniques and the importance of vaccination to prevent infectious diseases.
Year(s) Of Engagement Activity 2017
 
Description Research in a nutshell: Ruminant Immunology 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Short video produced in conjunction with University of Edinburgh to describe the project in 60 seconds. Available from the Moredun website via the following hyperlink:

http://www.moredun.org.uk/staff/professor-gary-entrican




A video describing collaborative research project characterising the immune systems of cattle and sheep. The aim is to generate knowledge for the development of new vaccines for farmed livestock. Video

no actual impacts realised to date
Year(s) Of Engagement Activity 2013
URL http://www.moredun.org.uk/staff/professor-gary-entrican
 
Description Roadshow event for farmers and vets 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Presented a talk on the importance of immune correlates for vaccine design and prevention of infectious abortion in sheep, Rhosmaen, Wales, 29 November 2012. Took questions and answers from the audience that stimulated further discussion during networking afterwards.

Feedback forms indicated that farmers and vets had gained new knowledge and would be very likely to attend future roadshow events.
Year(s) Of Engagement Activity 2012
 
Description STAR-IDAZ International Research Consortium 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact The International Research Consortium of STAR-IDAZ was launched in Nairobi on 30 January 2017. The purpose was to bring together scientific experts and policy makers involved in infectious diseases of animals and zoonoses to discuss global co-ordinated approaches to research.
Year(s) Of Engagement Activity 2017
URL http://www.star-idaz.net/?page_id=72
 
Description STAR-IDAZ International Research Consortium Scientific Committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact The Scientific Committee of the International Research Consortium of STAR-IDAZ met in Copenhagen, Denmark on 15 June 2017. The purpose was to bring together scientific experts and policy makers involved in research into infectious diseases of animals and zoonoses to discuss global co-ordinated approaches to research. The Working Groups were identified to begin gap analyses into priority diseases and priority areas, including veterinary vaccinology which relates to this project.
Year(s) Of Engagement Activity 2017
URL http://www.star-idaz.net/
 
Description STAR-IDAZ International Research Consortium Scientific Committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact The Scientific Committee of the International Research Consortium of STAR-IDAZ met in Tel Aviv, Israel on 19 February 2018. The purpose was to bring together scientific experts and policy makers involved in research into infectious diseases of animals and zoonoses to discuss global co-ordinated approaches to research. Road maps were constructed to assist in the gap analyses into priority diseases and priority areas, including veterinary vaccinology which relates to this project. A report on STAR-IDAZ IRC has been published on the Discontools website (see link below).
Year(s) Of Engagement Activity 2018
URL http://www.discontools.eu/
 
Description The Route to Identification of the Immunological Correlates of Protection in Ruminants 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Stimulated discussions with our Industrial Partner and peers on targets for development of ruminant immunological tools.

The Industrial Partner has used the material to promote the applications of veterinary immunological reagents
Year(s) Of Engagement Activity 2013
URL http://www.abdserotec.com/ruminant-immunological-correlates.html
 
Description Vaccine Presentation at SVS Conference, Newquay 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Presentation entitled: 'Sheep vaccines: their benefits, how they work, the different types and their limitations' with a focus on immunology with a themed session on vaccination of sheep. This was followed by a panel discussion with all speakers and a debate. The audience feedback indicated an improved awareness of vaccine design and understanding of how vaccines work and reasons why they might fail. This was done with the support of the BBSRC UK Veterinary Vaccinology Network.
Year(s) Of Engagement Activity 2016
URL http://www.sheepvetsoc.org.uk/event/archive/2016-09
 
Description Vet Summit (Berlin) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Presented a talk and co-chaired a workshop on the applications of immunology to veterinary diagnostics
Year(s) Of Engagement Activity 2015
URL http://www.informa-ls.com/event/vetsummit
 
Description Veterinary Congress (Perugia) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker at the 69th Congress of the Societa Italiana delle Scienze Veterinarie, Perugia, Italy. Presentation and discussion on strategies and networks for international communication in veterinary immunology. Plans made to support an EU COST Action by IUIS Veterinary Immunology Committee.
Year(s) Of Engagement Activity 2015
 
Description Veterinary Immune Toolbox Meeting, Pirbright 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact A workshop was held at The Pirbright Institute to discuss national and international efforts to develop the Veterinary Immune Toolbox, which relates directly to the objectives of this project. A presentation was delivered by Gary Entrican on the history of global Veterinary Immune Reagent Development initiatives and a report was written which can be found at the hyperlink below.
Year(s) Of Engagement Activity 2017
URL http://www.vetvaccnet.ac.uk/publications/veterinary-immunology-toolbox-meeting-uk-veterinary-vaccino...
 
Description Veterinary Immune Toolbox Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact A Workshop on the Veterinary Immune Toolbox was held at the Veterinary Vaccinology Annual Conference in Stirling on 17 January 2018. The objective was to identify gaps in capability and make plans to develop web-based resources on immune reagent availability and function. A report on the conference can be found at the hyperlink below.
Year(s) Of Engagement Activity 2018
URL http://www.vetvaccnet.ac.uk/news/2018/01/uk-veterinary-vaccinology-network-conference-2018-report