Work Package Livestock production, health and welfare
Introduction
Controlling endemic diseases of livestock in Scotland has major economic, environmental and animal health and welfare benefits for the nation. Vaccination against disease is recognised as being one of the most cost-effective and successful disease control strategies that can be implemented in both human and animal health. In selecting the livestock diseases to target for vaccine development in this work, we have taken into account the views of key stakeholders and have sought opinion directly from farmers and producers on disease prioritisation in Scottish livestock. Scottish Government policy priority areas have also informed this work, specifically through the key priority areas identified in the Scottish Rural Development Programme (SRDP) 2014-2020. The outcomes of the research performed here will align directly with key policy documents such as Scottish Government’s Animal Health and Welfare Strategy, Good Food Nation and Ambition 2030.
Aim of Research
The aim of this RD is to develop safe, highly effective, optimised, novel vaccines for the control of the most production- and welfare-limiting endemic diseases of Scottish livestock. The key drivers for this research are:
- Prevention is better than cure. Anthelmintics (chemotherapeutics for the control of intestinal worms) and antibiotics are used to treat diseases but can leave environmental residues, adversely affect operator and food safety and are not sustainable due to increasing resistance;
- Vaccines offer a cost-effective, sustainable alternative to overcome these limitations and to provide increased productivity and efficiency in livestock production with economic, food security and environmental benefits, including reductions in greenhouse gas emissions.
Progress
Good progress was made in a number of areas to develop vaccines against important endemic diseases of livestock: Based on information about how the vaccine works, we delivered a simplified vaccine against the “brown stomach worm” of sheep in a number of different formulations to try to standardise the immune responses of lambs and to give more consistent vaccine effects. One of these formulations gave consistently high levels of antibody and more uniform vaccine efficacy than the other formulations, providing important information as we move towards commercialisation of the vaccine. Vaccine trials were also performed to test if a by-product of the manufacture of Barbervax could protect calves against Ostertagia, which is a parasitic worm living in the abomasum (true stomach) of cattle. The tests showed that, although a strong immune response was raised after vaccination, there was no protection against Ostertagia challenge in the calves and that the work that is being done on synthetic vaccines for this species will be more valuable. Delivery of a prototype novel mastitis vaccine through an intra-mammary route led to short-term protection against the disease but longer term protection will still require some further development work with this vaccine. The components of the prototype sheep scab vaccine were all produced, for the first time, in a single system - a step which will be highly important to the successful commercialisation of this vaccine. In this year, work on vaccine delivery systems was also progressed, with the generation of vaccine delivery particles and matrices from agricultural by-products and also through the use of animal viruses (“vectors”) to deliver vaccines against diseases of livestock. These vectors were successfully used in experiments to induce vaccine antibody responses against a range of viral, bacterial and parasitic pathogens of cattle and sheep.
As in many areas of the Strategic Research Programme, some of the studies planned on Novel Vaccines in Year 5 were impacted by the restrictions on travel and working imposed due to the COVID-19 pandemic. Nevertheless, progress was made in a number of areas: Using a complex vaccine against the “brown stomach worm” of sheep, in field experiments, showed that the vaccine demonstrated some level of protection in ewes around the time of lambing but that additional parasite species should be targeted for maximum impact in this setting. One of the highlights in Year 5 was, therefore, the discovery of components for incorporation into such a vaccine which may protect sheep against multiple species of parasitic worm. A selection of regions in the brown stomach worm vaccine proteins have also been identified for further vaccine simplification and enhancement. These regions were selected using two independent computer-based techniques to identify which parts of the vaccine components are actually targeted by sheep antibodies. The results will allow us to further reduce the complexity of this vaccine. Vaccine trials to test a new prototype vaccine against parasitic worms which live in the abomasum (true stomach) of cattle also showed promising results and further work in this area will continue in Yr6. The prototype sheep scab vaccine was also assessed for long term storage of it’s components in different formats and best practise for long-term storage and preparation of the vaccine was established. In year 5, the use of animal viruses (“vectors”) to deliver vaccines against diseases of livestock was further progressed; key developments included enhancing the production efficiency of the vector system to produce more vaccine but also to incorporate further vaccine components to give protection against a range of livestock diseases. These updated methods will be used in future studies to produce vaccine for protection trials.
One of the highlights of work in this year was the progress in the use of animal viruses (“vectors”) to deliver vaccines against livestock diseases; key developments included the demonstration of strong immune responses against vaccines designed in this way following both initial and “booster” vaccinations. The vaccines being developed here encompass tick-borne and reproductive diseases of sheep and cattle respiratory diseases. This work may lead to the production of new vaccines against the virus which causes louping ill (in sheep), for example, for which our stakeholders have expressed great interest.
Other work on novel delivery methods included the use of new technologies to deliver vaccines on the surface of microscopic “nanoparticles” and this work also showed that the components of a prototype sheep scab vaccine could be delivered to animals in this way and induce strong immune reactions. Work on the prototype sheep scab vaccine also demonstrated the ability to produce a diagnostic blood test which could discriminate between animals which were vaccinated and animals which were infected. This tool is a key component in the development of the vaccine if it is to be used in conjunction with effective diagnosis. Further progress was also made with a vaccine to protect sheep against one of the major bacterial causes of mastitis, where it was demonstrated that the vaccine effect demonstrated in Yr3 was repeatable and gave some protection against two of the three major bacteria which cause mastitis. Work to demonstrate the effectiveness of a simplified prototype vaccine against the “brown stomach worm” of sheep, in field experiments, showed that the vaccine demonstrated low levels of protection in this setting so ewes in the second year of the experiment (Y4) were vaccinated with a more complex version of the vaccine while work continued to develop a vaccine which would protect sheep against multiple species of parasitic worm. Vaccine trials to test a new prototype vaccine against parasitic worms which live in the abomasum (true stomach) of cattle showed promising results and further work in this area will continue in Yr5.
A clear highlight of this work in Year 3 was the authorisation for the sale of the Barbervax vaccine (which was developed by our scientists to control barber’s pole worm in the intestinal tract of sheep) under a Special Treatment Certificate in the UK. A different prototype simplified vaccine against another nematode, the “brown stomach worm” which lives in the abomasum of sheep was produced in large quantities to test it’s ability to prevent pregnant ewes contaminating the pasture with nematode eggs around the time of lambing. The vaccine was delivered safely with no adverse reactions. Vaccine trials to test a new prototype vaccine against the nematodes which live in the abomasum of cattle and a refined version of another vaccine for the parasite, liver fluke, only provided low levels of protection, suggesting further optimisation will be needed. Progress was also made with a vaccine to protect sheep against one of the major bacterial causes of mastitis, where it was demonstrated that the vaccine effect was relatively short-lived, warranting further investigation into the specificity and duration of the response. For the prototype vaccine which was designed against sheep scab mites a trial was successfully completed to compare the vaccine produced in plants with the same vaccine made in our standard systems. Growth conditions in the lab for Chlamydia abortus, the major cause of abortion in sheep, were further optimised and a novel vaccine was formulated in different adjuvants; two of these vaccine formulations gave high levels of protection against abortion and could be correlated with the type of immune response the vaccines generated. The use of animal viruses (“vectors”) to deliver vaccines against diseases of livestock was further progressed; key developments included the doubling of vaccine production by modifying the vector and demonstrating good immune responses against vaccines designed in this way. Ultimately this may lead initially to the production of a new vaccine against the virus which causes louping ill (in sheep) for which our stakeholders have expressed great interest.. Vaccines for other diseases could also exploit the same vectors.
The prototype simplified vaccine against nematodes which live in the abomasum of sheep was successfully tested in 6 month old lambs and gave acceptable levels of protection and the liver fluke vaccine which was based on extracts of the flukes also reduced the numbers of parasites in vaccinated sheep by approximately 50%. For the prototype vaccines which were designed against sheep scab mites and cattle gut nematodes, sufficient quantities of synthetic antigens were prepared in plants and bacteria (respectively) for future vaccine trials and appropriate methods for testing the effectiveness of the vaccines were also designed. Encouraging progress was also made with a vaccine to protect sheep against one of the major bacterial causes of mastitis, with full protection of all immunised sheep in a preliminary trial. Growth conditions in the lab for C. abortus were further optimised and the novel vaccine was formulated in different adjuvants to optimise protection. Immune responses to these differently formulated vaccines were analysed and will be used in Yr3 to determine how they relate to protection. Two further types of animal viruses were adapted to optimise their expression of antigens from a range of pathogens to help in their commercial production potential and effectiveness. A key example of this is our efforts to produce a novel louping ill vaccine for which there is a current market opportunity. One of our vaccines, against nematodes which live in the abomasum of sheep, was reformulated in a novel slow-release formulation to test for enhanced duration of immunity.
The research has focussed on two major aspects of vaccine development: designing prototype vaccines and optimising delivery systems for these vaccines to make them work to their full capacity. To address the first of these aspects, teams identified genetic information from parasitic worms (nematodes) which live in the stomach (abomasum) of sheep and cattle to allow them to produce synthetic versions of the worm proteins for use in future vaccination/protection experiments. We typically use bacteria to produce these synthetic proteins in the laboratory, but one of our teams has started to use plants as a way of producing the synthetic proteins and has produced the proteins required for a prototype sheep scab vaccine in this system. Staying with parasites, scientists in this RD made extracts of liver flukes and analysed the contents of these extracts to produce a prototype vaccine for testing in subsequent years of the programme. Our groups working on vaccines against bacterial diseases optimised the growth conditions for Chlamydia abortus (which causes enzootic abortion in sheep) and extracted components from it to produce a vaccine. They tested the ability of various doses of this vaccine to protect sheep against abortion and showed that, even at a very low dose, the vaccine was effective. Importantly, they were also able to demonstrate that the vaccine could stimulate strong immune responses which can be used in future work to predict the effectiveness of vaccines. The second aspect of the work in this RD addresses vaccine delivery: Here the proteins from the pathogens (viruses, bacteria or parasites) which stimulate the protective immune responses can be delivered by injecting them with a compound which provokes the immune system (an adjuvant) or as part of a modified virus. Our scientists delivered anti-parasite vaccines in different adjuvants to try to stimulate long-lasting effects in sheep and our teams of virologists also created modified versions of a viral vaccine which allows the virus from the vaccine to be grown in large scale and to carry antigens from other infectious agents.
Future Activities
Several of the successful outcomes and outputs from RD 2.2.5 will be represented in projects in the new Strategic Research Programme. Vaccine delivery methods, including the particle-based approaches will be refined using novel laboratory-based experimental systems in the project MRI-A2-1 and will be put into practice in MRI-A2-8. The viral-vector-vaccine approach developed in RD 2.2.5 will be employed in MRI-A2-7, MRI-A2-8 and in MRI-A2-9 to control multiple pathogens of livestock including tick-borne diseases. Vaccine development against several parasitic nematode species in sheep will continue in MRI-A2-6, which will also feature the refinement of vaccines for use against parasitic helminths in cattle. Novel gene-editing methods will be used to further vaccine development against reproductive diseases of cattle in MRI-A2-7.
Selected Outputs
Immunity to Haemonchus contortus and Vaccine Development.
A recombinant subunit vaccine for the control of ovine psoroptic mange (sheep scab).
Global food security via efficient livestock production: targeting poor animal husbandry.
Enhancing the toolbox to study IL-17A in cattle and sheep.
Mind the gaps in research on the control of gastrointestinal nematodes of farmed ruminants and pigs
Estimating genetic and phenotypic parameters of cellular immune-associated traits in dairy cows.
Gene silencing by RNA interference in the ectoparasitic mite, Psoroptes ovis.
Draft Genome Assembly of the Sheep Scab Mite, Psoroptes ovis.
Presentations at the International Veterinary Vaccinology meeting: Vaccines projects at Moredun Research Institute
Immunological Homeostasis at the Ovine Placenta May Reflect the Degree of Maternal Fetal Interaction
The Potential for Vaccines Against Scour Worms of Small Ruminants
Senescence in Immunity Against Helminth Parasites Predicts Adult Mortality in a Wild Mammal
https://www.frontiersin.org/articles/10.3389/fvets.2020.00036/full
The potential for vaccines against scour worms of small ruminants
Attempts to induce tolerance to Trichostrongylus colubriformis infection in sheep
Defining immune correlates during latent and active chlamydial infection in sheep
Moredun’s Centenary Science Stories Volume 1: Enzootic Abortion of Ewes
Prevention and control of ovine abortion: Test don’t guess
Vaccine-induced time- and age-dependent mucosal immunity to gastrointestinal parasite infection
Moredun’s Centenary Science Stories – Volume 3
Moredun’s Centenary Science Stories – Volume 4
Research Deliverable Lead
Dr Alasdair Nisbet
Research Deliverable Staff
Dr Colin McInnes
Dr Keith Ballingall
Dr Stewart Burgess
Dr Christina Cousens
Professor Gary Entrican
Dr Bill Golde
Dr David Griffiths
Dr David Longbottom
Dr Andrew Love
Professor Jacqui Matthews
Dr Tom McNeilly
Dr Alasdair Nisbet
Dr George Russell
