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Overpowering helminth-mediated immune-modulation is a route towards vaccine development against these major animal pathogens

Final Report Summary - HELIVAC (Overpowering helminth-mediated immune-modulation is a route towards vaccine development against these major animal pathogens)

The current use of chemical products to control parasitic worms on farms is not sustainable because of the continual emergence of drug-resistant parasites. Also, the presence of chemical residues in food has heightened consumer concerns about how food is produced and what they are eating. Vaccines, on the other hand, can have a major impact on livestock production, including on animal health and welfare. They are the most appropriate way forward because they are safe, leave no chemical residues in food, are environmentally friendly, and are acceptable to farmers and consumers. Novel parasitic vaccines will enable the future control of farm animal parasitic pathogens to drive sustainable agriculture and food production. However, despite the huge successes we have made in vaccine development against viruses and bacteria over the past 200 years, there are presently few commercialized vaccines for any animal or human helminth pathogen. Thus, the development of novel vaccines depends a deep understanding of the parasite-host relationship.

Fasciola hepatica (liver fluke) is the causative agent of fasciolosis, a major global disease of livestock, particularly sheep and cattle. The global prevalence of this multi-cellular worm parasite is due to its remarkable ability to infect and migrate within amny different mammalian hosts. In their hosts, the parasites feed on its tissue to support its rapid growth and development. Within two months of infection, parasites grow from <0.1 mm to >2 cm and their feeding activity causes extensively hemorrhaging and tissue pathology in the liver of the host. Infected livestock, therefore, thrive very poorly, produce less milk (dairy) or meat (beef), and, in the case of sheep, heavy infections can cause sudden death. Another, aspect of this parasite’s success is its ability effectively disarm and control various facets of its host’s immune system ensuring its own longevity (up to 20 years) and production of many off-spring (in the form of eggs). By understanding how the parasite achieves all these aspects of infection we can develop new means of intervention via vaccination and ‘turn the table on the parasite’.

Using modern technologies, we determined the genomic make-up of F. hepatica and coupled this with detailed information of how genes are expressed (transcriptomics) and synthesized as proteins (proteomics) by the parasite as it infects, grows and develops within its host. We particularly focused on molecules that the parasite releases or secretes (secretome) into host tissues to breakdown the tissue to allow it migrate via its tunneling activity and to feed on the breakdown products to build their own molecules. We found that the parasite has expanded and duplicated many genes that produce secreted molecules that allow it to manufacture an abundance of these pivotal molecules; these include protease enzymes that digest tissue, inhibitors that can block host enzyme function, anti-oxidants that neutralize attack by immune cells and small molecular immunomodulators that thwart the behavior of immune cells.

Genes for several critical parasite molecules (cathepsin Ls, cathepsin Bs and cystatins) were removed from the parasites and inserted into surrogate cells (bacteria and yeast) for the production of the gene products in high quantities. These were then purified and used as vaccines to induce immune responses in sheep that could neutralise the parasite upon infection. We showed that we can induce potent immune responses that are boosted following infection; in some cases, we observed that these vaccine-induced responses provided significant benefits against disease. Parasites in vaccinated animals were less able to produce progeny (eggs) and vaccinated animals were shown to thrive better. Studies to develop ‘cocktail’ vaccines with improved performance were undertaken and indicated that experimental vaccines can be manufactured that would provide protective effects against infection. These vaccines could be of great future benefit to stakeholder, particularly farmers.