Dissecting variation in host responsiveness to a recombinant vaccine designed to control teladorsagiosis in sheep

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The overall objective is to understand and overcome variation in host immune responsiveness to a promising Teladorsagia circumcincta sub-unit vaccine prototype, CircVax.

Here, the applicants will analyse parasitological outputs from vaccinated, then challenged, lambs and assess temporal parameters in vaccine responsiveness using recent technological advances in transcriptomics (RNAseq, nextSeq 500 Sequencing) and ovine genomic and immunological tools (http://www.sheephapmap.org/news/OARv2p0.php, http://www.immunologicaltoolbox.co.uk). Using multivariate (general linear mixed models) and network analyses (BioLayoutExpress 3D, Qiagen's Ingenuity Pathway Analysis) to assess relationships between immune gene expression and phenotypic characteristics, and between parasitological outcomes and immune variables and, importantly, how these are affected by lamb age, the project will generate a deep understanding of how sheep respond optimally to CircVax vaccination.

The resultant data will be exploited to develop an understanding of how the vaccine induces immunity against worm challenge and to identify what pathways are different in animals that are not protected by the vaccine. This knowledge, in turn, will be used to optimise the vaccine's effect in the field through optimal delivery(for exmaple, via adjuvant selection) and/or strategic use (for example, in integrated control programmes exploiting the vaccine with minimal use of effective anthelmintics in sheep of different ages).

It is estimated that the direct global cost of parasitic worms of livestock is ~£1,200M per annum. There are approximately 101 M sheep and 12 M goats in the EU, with the UK having the largest sheep industry in Europe. In the UK, the brown stomach worm, Teladorsagia circumcincta, is the major contributor to parasitic gastroenteritis, estimated to cost the UK sheep industry >£80M each year. Helminths such as T. circumcincta impact hugely on the welfare and productivity of sheep. They do this by affecting growth rate, fertility, meat quality, and wool/milk production and, in heavy infections, by causing clinical disease. The research in this project will impact upon the effect of these worms by furthering development of a much-needed alternative control option; an anti-nematode vaccine known as CircVax.

Chemotherapeutic approaches have been the cornerstone of sheep nematode control for decades; however, resistance to the traditional three broad-spectrum anthelmintic classes is common in T. circumcincta, with resistance already reported to a member of a new class of anthelmintic, monepantel, which was only launched 2 years ago. For these reasons, alternative control methods are sought for sustainable control in the long term. Control by vaccination is the most obvious alternative, with the added value that vaccines have no environmental impact, do not leave chemical residues in food and are likely to require fewer applications over an animal's lifetime. Over the last 8 years, the applicants have developed, designed and tested a recombinant sub-unit T. circumcincta vaccine. Immunisation with this vaccine had a significant effect on worm burden and egg excretion in parasite-challenged lambs >6 months-old. Here, the applicants aim to develop this prototype vaccine further by investigating variation in sheep responsiveness to the vaccine; particularly how immunological unresponsiveness may be overcome in very young lambs. A comprehensive understanding of such responses during vaccination and subsequent parasite challenge is essential to develop this vaccine as a tool for integrated control that will be taken up on UK sheep farms and beyond. The aims are to establish what elements of the local response correlate best with efficacy amongst vaccinates and how variability in vaccine efficacy is affected by lamb age. This knowledge will determine whether or not vaccine efficacy can be improved in young lambs and whether variability in responsiveness in older animals can be addressed by exploiting appropriate adjuvants or delivery systems. Moreover, if the results point to an inherent, and insurmountable, inability to control T. circumcincta in the very young, the information will be used to deploy the vaccine in older animals as part of an integrated strategy to minimise selection pressure for anthelmintic resistance, in particular aiming to preserve use of the Class IV and V anthelmintics.

The outputs of this project will provide significant steps to developing a commercially-relevant subunit nematode vaccine (the 1st of its kind) for use by farmers to mitigate the effects of this important parasite. In so doing, the outcomes address a priority of the Animal Health Research Club ('Understanding variation in vaccine responsiveness and immune-competence at different developmental stages and its impact on disease outcomes'). Industrial stakeholders will benefit through generation of revenue from vaccine sales, as well as from availability of an option that will help prolong efficacy of the remaining effective anthelmintics. In addition, human health policymakers can exploit the data if defined strategies for delivery against ruminant gastrointestinal nematodes can be shown to improve efficacy. This is because there are many similarities (such as host niche, distribution pattern, primary candidate antigens) between the T. circumcincta vaccine and the subunit vaccine currently under development for control of human hookworm.