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

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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 todirect 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.