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H2020

Paragone Report Summary

Project ID: 635408
Funded under: H2020-EU.3.2.

Periodic Reporting for period 1 - Paragone (PARAGONE: vaccines for animal parasites)

Reporting period: 2015-04-01 to 2016-09-30

Summary of the context and overall objectives of the project

The problem being addressed is parasitic infections of domestic livestock. These prevalent infectious agents have a major impact on ruminant and poultry production worldwide. They also have a detrimental effect on animal health/welfare. Currently, control relies almost exclusively on anti-parasitic drugs, but this is no longer sustainable due to increasing drug resistance. There are also concerns regarding chemical residues in food products and the environment. Vaccines prevent rather than cure infection and provide longer protection, with no associated residue issues. Vaccine development against multicellular parasites has been a major challenge in veterinary medicine. The lack of vaccines is indicative of difficulties associated with generating effective immunity against these complex organisms. In PARAGONE, the partners are developing at least two new parasite vaccines towards commercial translation. The target parasites have been selected carefully according to their economic impact and the existence of promising prototypes. The partners are utilizing innovative and unique antigen formulations to develop these prototypes further on the pathway to uptake.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Work performed in this period has progressed on all prototype vaccines. The prototypes are at various stages of development. For vaccines being developed against the bovine gastrointestinal worms, Ostertagia ostertagi and Cooperia oncophora, immunological and animal studies have demonstrated the importance of the antigen’s conformation for the efficacy of the vaccine. Results indicate that protection associated with the protein is linked to its conformation. Clear differences could be observed between the immune responses against protective and non-protective antigens. Biochemical experiments will inform how changes at the molecular level of the antigen can induce better responses in vaccinates. Adaptation is being undertaken in the next reporting period. Concurrent studies are testing the ability of the Cooperia vaccine to protect against different types of Cooperia species in cattle and sheep. These trials are ongoing with initial results in cattle looking promising.
Work on the second prototype (a vaccine designed to control the ovine stomach worm, Teladorsagia circumcincta) are aiming to simplify production processes for a 8-protein sub-unit vaccine, shown previously to induce significant protection against infection in sheep. Here, the aim is to simplify the vaccine production process by co-expressing the eight constituent antigens in fewer systems. The studies are progressing well, with each protein co-expressed with at least one other vaccine component. Also for this vaccine, novel delivery systems are being tested to see if more durable immune responses can be stimulated and reduce variability previously observed in protection. These studies have been successful, with novel formulations prepared for upcoming trials. For this prototype, the partners are also investigating mechanisms of immune responsiveness to the vaccine. A trial was completed in two sheep breeds, previously shown to have different levels of resistance to gut worm infections in general. In these studies, the 'resistant' sheep breed was confirmed to be relatively resistant to T. circumcincta. In the more 'susceptible' breed, vaccination with the prototype was shown to have a significant negative effect on worm development: the immunological analyses are ongoing. The partners are also studying DNA sequences that encode the vaccine antigens in worms from different regions. This is being done to assess the impact that antigen sequence variation might have on the vaccine's effectiveness in different populations. Thus far, in three isolates, low sequence diversity was observed in 7 of the 8 vaccine proteins.
Studies are being undertaken on the prototype for liver fluke (Fasciola hepatica). Previously, fluke recombinant antigens have afforded protection in ruminants, but with a high degree of variation observed between trials and between animals. Here, partners are testing the lead candidate antigens as cocktails to examine if protection can be improved by combining these antigens. The first set of trials are complete and immunological analyses are ongoing. Thus far, significant protection was observed was in sheep using a cocktail of several antigens. Concurrent work is being undertaken to understand mechanisms of variation in immune responsiveness. Studies examined modulatory properties of carbohydrates on the worm surface. Results indicate that ability of antibodies to bind antigens is lower for some types of antibody than others and that some antibody types were lower in trials where protection was not observed. A large-scale RNA analysis in sheep was undertaken. This revealed pathways significantly changed in response to infection; these may play a role in immune evasion. A trial was conducted to study responses during early infection in sheep to examine how the parasite can ‘switch off’ a protective response. These studies provide important insights into the host/parasite relationship and inform vaccine formulation strategies to overcome variation in responsiveness. DNA sequences of vaccine antigens were studied in worms from different regions to assess the impact that this might have on vaccine effectiveness across populations; low diversity was reported in 3/4 candidates.
Early development work is being performed on a prototype vaccine for the mite, Psoroptes ovis. Recombinant proteins that comprise a vaccine previously shown to have promise in protecting against the effect of the mite in sheep are being used in a trial to test its effect in cattle. The trial is ongoing.
New delivery systems are being developed for poultry vaccines. This work focuses on a vaccine candidate for poultry red mite. This has been formulated in 3 systems to compare level of immune response induced; i. antigen combined with standard adjuvant; ii) a DNA vaccine and iii) antigen expressed in a delivery system based on a unicellular parasite. The trial is complete and the immunological analysis ongoing.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

PARAGONE is looking for sustainable solutions to worm control in the form of vaccines against some of the most common livestock parasites in which drug resistance is rife. Progress beyond state-of-the-art includes:
1. simplification of a complex prototype
2. testing combinations of proteins identified previously to improve effectiveness of the vaccines and aligning studies with those examining variation in responsiveness and sequence variation in antigen genes
3. developing novel systems to deliver the most promising vaccine candidates and testing these in trials to compare levels of immune response/protection induced
4. testing previous single-pathogen target vaccines for effects on other parasite species to make the prototypes more commercially attractive
5. addressing previously intractable issues in vaccine development by exploiting state-of-the-art technologies and developing pipelines for complex data outputs

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