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

在全球范围内实现粮食安全需要通过最有效地利用投入物来提供可持续、安全和可靠的优质粮食供应。传染病严重影响牲畜生产效率，而寄生蛔虫是其中的罪魁祸首。事实上，蠕虫感染是影响英国绵羊的最昂贵的地方病，环切角绦虫是这个国家主要的蠕虫。据估计，英国绵羊业每年因蛔虫感染而损失约8000万英镑。驱虫剂（被称为驱虫药）已经在世界各地使用了40多年来控制绵羊的蠕虫感染，但是对这三种传统药物的耐药性很常见。令人担忧的是，两种新型驱虫剂中的一种已经被报道对环虫有抗药性，尽管这种产品两年前才推出。从历史上看，很多资源和研究都是针对绵羊的抗虫性的选择性育种，但这项工作的成果很少能在英国的农场上得到实际应用。一种明显的替代方法是通过给绵羊接种疫苗，以特异性地刺激对蠕虫攻击的免疫保护，从而诱导绵羊对感染的抗性。这将消除蠕虫对绵羊生长和生产力的影响，重要的是，将减少蠕虫通过环境传播。与驱虫剂控制方法相比，疫苗还具有优势，因为它们与肉类中的化学残留物无关，对环境没有影响，并且在绵羊的整个生命周期中可能需要较少的施用。最近，这个研究小组在发现一种有效的重组（亚单位）疫苗控制环切t方面取得了非凡的成功。这种疫苗（称为“CircVax”）包含8种重组（合成）蛋白，可诱导羔羊对蠕虫攻击产生显著（尽管是可变的）免疫力。该疫苗开发的下一步是了解绵羊对疫苗反应性变化的潜在局部免疫机制，并检查这是否受到动物年龄的影响。在接种疫苗和随后的蠕虫攻击期间，对个体反应变化的全面了解对于进一步优化疫苗（例如，在佐剂选择中）作为羊群蠕虫综合控制工具至关重要。在这个项目中获得的知识将有助于确定疫苗的效果是否可以在非常年幼的羔羊中得到改善，以及是否可以进一步优化老年动物的反应。这些参数中的每一个都可以通过使用更合适的佐剂或递送系统来解决。此外，如果结果表明非常年幼的羔羊的免疫系统固有的无法控制环切弓形虫，则衍生的信息可以用于在一个整体的、综合的控制策略中部署疫苗，以解决蛔虫耐药性的选择压力最小化问题。总而言之，这些产出将为开发与商业相关的疫苗提供重要步骤，供农民使用，以减轻绵羊这一重要寄生虫感染的影响，因此完全属于英国畜牧科学委员会动物健康研究俱乐部的优先事项。

Delivering food security globally requires that a sustainable, safe and secure supply of quality food be provided by making the most efficient use of inputs. Infectious diseases substantially affect the efficiency of livestock production and parasitic roundworms are major culprits in this arena. Indeed, worm infections are the most costly endemic disease affecting sheep in the UK, with Teladorsagia circumcincta being the dominant worm present in this country. Estimated costs of roundworm infections to the UK sheep industry run at around £80 million per annum. Dewormers (known as anthelmintics) have been used for over four decades to control worm infections in sheep throughout the world, but resistance to the three traditional drug classes is common. Worryingly, T. circumcincta resistance has already been reported against one of the two new classes of dewormer, even although this product was only launched two years ago. Historically, much resource and research has been directed at selective breeding of sheep for resistance to worms, but there have been few outputs from this work that have made it to practical application on farms in the UK. An obvious alternative approach to breeding sheep for resistance to worms is to induce resistance to infection in sheep by vaccinating them to specifically stimulate immune protection against worm challenge. This will have the effect of negating the impact of the worms on sheep growth and productivity and importantly, will reduce worm transmission via the environment. Vaccines also hold the advantage over anthelmintic methods of control in that they are not associated with chemical residues in meat, have no environmental impact and are likely to require fewer administration applications over the lifetime of the sheep. Recently, this research group have had singular success in the discovery of an effective recombinant (sub-unit) vaccine for control of T. circumcincta. This vaccine (known as 'CircVax') comprises 8 recombinant (synthetic) proteins and induces significant, albeit variable, levels of immunity against worm challenge in lambs. The next step in development of this vaccine is to understand the underlying local immune mechanism(s) involved in this variation in sheep responsiveness to the vaccine and to examine if this is affected by the age of the animal. Such a comprehensive understanding of variation in individual responses during vaccination and subsequent worm challenge is essential to optimize the vaccine further (for example, in adjuvant selection) as a tool for integrated worm control in sheep flocks. The knowledge gained in this project will help determine if the effect of the vaccine can be improved in very young lambs and if responses in older animals can be optimised further. Each of these parameters could be addressed by using more appropriate adjuvants or delivery systems. In addition, if the results point to an inherent inability of the immune system of the very young lamb to control T. circumcincta, the derived information can be exploited in the deployment of the vaccine in a holistic, integrated control strategy that addresses the minimization of selection pressure for drug resistance in the worm. In summary, the outputs will provide significant steps to developing a commercially relevant vaccine for use by farmers to mitigate the effects of this important parasitic infection of sheep and, as such, fall squarely within the priorities of the BBSRC Animal Health Research Club.