14-ATC2 - Vaccination based control of fasciolosis in farmed ruminants (TSB App # 45264-298219)

F. hepatica is the cause of fasciolosis, an economically important parasitic disease of cattle and sheep which is the cause of chronic liver infection in an estimated 700 million animals worldwide. Infection results in an estimated annual global loss of US$2000 million through livestock mortality, reductions in productivity and condemnation of animal products that should go into the human food chain. Costs of this infection to UK industry is estimated to be around £14M/annum in beef cows, £13.5M/annum in dairy cattle and £3.1M/annum in sheep, although these are most certainly conservative and relate to
direct losses only. The proposed project is a pre-industrial research project that will enable us to validate a collection of important components of F. hepatica that could be combined into sub-unit vaccine formulations for protecting ruminants against infection with this pathogen. Infection by F. hepatica is acquired by the ingestion of water or vegetation that is contaminated by parasitic metacercariae which excyst to produce newly excysted juveniles (NEJs) , these migrate across the intestine and peritoneal cavity to the liver and develop into sexually mature hermaphrodite adults. The adults release eggs into the bile ducts, which are transported to the intestine and are released into the environment via faeces. These parasites cause reduced milk yields, poor fertility and high perinatal loses, and chronic weight loss in cattle. Acute disease will cause sudden death from haemorrhage and liver damage in sheep. Control of fluke infection is heavily reliant on a limited number of anthelmintic compounds, which due to their widespread and often indiscriminate use has led to problems associated with drug resistance. There are also emerging concerns regarding the use of these drugs in food production animals, with recent legislation banning the use of four major classes of these drugs in dairy animals where milk is destined for the food chain. The most viable alternative to drug treatment would be vaccination against Fasciolosis. Currently no vaccine preparation is commercially available to control F. hepatica. The delay in bringing a commercial vaccine to market is a result of the complex lifecycle of the parasite, its large genome and complex biology, and the strategies it employs to evade host immunity. F. hepatica is well known to alter the host immune responses thereby deflecting attacks aimed at it which could damage and eventually kill the parasite. These strategies employ a number of molecules termed immunomodulators. Furthermore, the naturally occurring immune responses against this parasite often provide limited protection to the host. We now know that full protection will be offered by the two distinct arms of the immune system the antibody and the cellular arms. This project aims to characterise i) both the antibody and cellular immune response to this organism in animals that show variation in levels of fluke burdens and ii) a novel set of recently identified Immunomodulator proteins, produced by F. hepatica that are likely to suppress the host immune response. Aim i) will be conducted by a selection method exploiting the ability of antibodies against F. hepatica to bind to small proteins (peptides) - we will then test the reaction of infected animals to these peptides to determine their usefulness. Aim ii) will use a novel set of immunomodulators generated in the applicants lab that will be tested for their ability to subvert normal host immune functions. Upon completion this 18 month study will evaluate potential vaccine candidates that have the greatest potential for formulation into subunit vaccine preparations that will show efficacy in either preventing infection or reducing worm burden. Our project will benefit from incorporating a range of proteins/peptides into the final vaccine formulation, presenting antigens that stimulate an optimal Th1/Th2 response as well as overcoming parasite immunosuppression.

F. hepatica is the cause of fasciolosis, an economically important parasitic disease of cattle and sheep which is the cause of chronic liver infection in an estimated 700 million animals worldwide. Infection results in an estimated annual global loss of US$2000 million through livestock mortality, reductions in productivity and condemnation of animal products that should go into the human food chain. Costs of this infection to UK industry is estimated to be around £14M/annum in beef cows, £13.5M/annum in dairy cattle and £3.1M/annum in sheep, although these are most certainly conservative and relate to
direct losses only. The proposed project is a pre-industrial research project that will enable us to validate a collection of important components of F. hepatica that could be combined into sub-unit vaccine formulations for protecting ruminants against infection with this pathogen. These parasites cause reduced milk yields, poor fertility and high perinatal loses, and chronic weight loss in cattle. Control of fluke infection is heavily reliant on a limited number of anthelmintic compounds, which due to their widespread and often indiscriminate use has led to problems associated with drug resistance. The most viable alternative to drug treatment would be vaccination against Fasciolosis. Currently no vaccine preparation is commercially available to control F. hepatica. Upon completion this 18 month study will evaluate potential vaccine candidates that have the greatest potential for formulation into subunit vaccine preparations that will show efficacy in either preventing infection or reducing worm burden. Our project will benefit from incorporating a range of proteins/peptides into the final vaccine formulation, presenting antigens that stimulate an optimal Th1/Th2 response as well as overcoming parasite immunosuppression.

Endemic and chronic bacterial diseases are a major health and welfare issue for animals and undermine the continued
production of a global food supply in a sustainable fashion. In our project, we aim to address one of the most insidious
parasitic diseases within the UK and temperate climates of the globe - Fasciolosis. Our research programme has
immediate and long term beneficial impacts in the areas of livestock production, the veterinary pharmaceutical industry,
consumer perception, scientific community, and the environment. The 'Pathways to Impact' of this proposal describes how
end-users and other stakeholders will be engaged. Livestock producers face increasing pressure to provide a more
sustainable product at a fixed price for growing markets. The consumer, environment, and pharmaceutical industry are also
all affected by this. To realistically meet this demand, stakeholders must improve disease control with an alternative to
chemotherapy, i.e. vaccination. Key is securing successful disease control is a novel approach to vaccine candidate
selection which our project will deliver. Our novel approach to this problem will have immediate impacts on the
pharmaceutical industry and a longer term impact on livestock stakeholders.
Development of effective vaccines and a consequent reduction in use of anthelmintics concerns both livestock
stakeholders and the veterinary pharmaceutical industry. The current ineffective control of fasciolosis leads to wasted
resources, animal welfare issues and disease outbreaks and spread. We will develop both a novel approach to vaccine
candidate selection but also a novel portfolio of vaccine candidates for a sub-unit vaccine against one of the most
devastating parasitic infections thereby improving producers' chances of using vaccination strategies to reduce the
incidence of disease. The pharmaceutical industry will be able to develop solutions based on our results, leading to novel
vaccine formulations that are applicable both in the UK and Globally. Reductions in rates of clinical disease will mean a decrease in the use of anthelmintics, positively impacting upon the consumer and environment. Furthermore, the
generation of data and outputs from this project will make a meaningful contribution of the knowledge-based economy of
the UK in coming years through the generation of revenue via IP.
Impacting upon environmental wellbeing will parallel the consumer perception of the farming industry. Our research
programme will result in a more sustainable and environmentally friendly farm incorporating less waste through reduced
disease burden and increased production. These will cause subsequent reductions in the total carbon footprint of farming
and UK economy, key priorities going forward for UK PLC. Publicising this will positively influence consumer perception as
improvements in animal welfare and environmental awareness with regard to origin of food products are foremost in the
consumer mind. Improvements and benefits at this level will improve consumer confidence, growing the home and
international UK beef market but also increasing demand for translation of UK practice to foreign markets.
Our research programme offers a plethora of benefits to the scientific community. It can act as a training ground for
collaborating scientists at it embodies a diverse yet fully integrated range of disciplines. Our data sets to be made public
include large transcriptomics data, via NCBI, immunological data sets via publication, and a collection of valuable
resources including RNA/cDNA libraries and recombinant proteins. Once published these, resources permitting, can be
made available upon request. Our published data will represent novel integrated data sets validated in target species with
significant translatable outcomes. Thereby, allowing veterinary and human scientists to build upon our observations in
fields including immunology; infection biology and vaccine development