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

在全球实现粮食安全要求通过最有效地利用投入，提供可持续、安全和有保障的优质粮食供应。传染病严重影响畜牧业生产效率，寄生蛔虫是这一竞技场的主要罪魁祸首。事实上，蠕虫感染是影响英国绵羊的最昂贵的地方病，Teladorsagia circumcincta是该国的主要蠕虫。据估计，英国养羊业每年因蛔虫感染造成的损失约为8000万英镑。 驱虫剂（称为驱虫剂）已被用于控制世界各地的绵羊蠕虫感染超过四十年，但对三种传统药物的耐药性很常见。令人担忧的是，T。据报道，两种新的驱虫剂中的一种对包皮环切虫产生了抗药性，尽管这种产品两年前才上市。从历史上看，许多资源和研究都是针对绵羊的抗蠕虫选择性育种，但这项工作的成果很少，在英国的农场中得到实际应用。一个明显的替代方法来饲养绵羊抵抗蠕虫是诱导抵抗感染的绵羊接种疫苗，特别是刺激免疫保护蠕虫的挑战。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的传播。与驱虫控制方法相比，疫苗也具有优势，因为它们与肉类中的化学残留物无关，对环境没有影响，并且在羊的一生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）疫苗来控制T。包皮环切术该疫苗（称为“CircVax”）包含8种重组（合成）蛋白，并在羔羊中诱导显著的（尽管可变的）针对蠕虫攻击的免疫水平。该疫苗开发的下一步是了解绵羊对疫苗反应性变化所涉及的潜在局部免疫机制，并检查这是否受动物年龄的影响。在接种疫苗和随后的蠕虫挑战过程中，个体反应的变化的这种全面的理解是必不可少的，以优化疫苗进一步（例如，在佐剂选择）作为一种工具，在羊群中的综合蠕虫控制。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轻的羔羊中得到改善，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轻的羔羊的免疫系统固有地不能控制T。对于circumcincta，可以在整体综合控制策略中部署疫苗时利用所获得的信息，该策略解决了蠕虫抗药性的选择压力最小化。总之，这些产出将为开发供农民使用的商业相关疫苗提供重要步骤，以减轻这种重要的绵羊寄生虫感染的影响，因此，完全属于BBSRC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.