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

剖析宿主对旨在控制绵羊 teladorsagoosis 的重组疫苗反应的变化

• 批准号: BB/M011968/1
• 负责人: Jacqueline Matthews
• 金额: $ 39.44万
• 依托单位: Moredun Research Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM011968%2F1
• 关键词: Dissecting; variation; host; responsiveness; recombinant

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.

在全球范围内实现粮食安全要求通过最有效地利用投入来提供可持续、安全和可靠的优质粮食供应。传染病在很大程度上影响畜牧业生产的效率，寄生虫是这一领域的主要罪魁祸首。事实上，在英国，蠕虫感染是影响绵羊的最昂贵的地方性疾病，而圆锥线虫是这个国家存在的主要蠕虫。据估计，英国养羊业每年感染蛔虫的成本约为8000万GB。驱虫剂(称为驱虫剂)在世界各地用于控制绵羊的蠕虫感染已有40多年的历史，但对这三种传统药物的抗药性是常见的。令人担忧的是，已经有报道称，对这两种新型驱虫剂中的一种产生了抗药性，尽管这种产品在两年前才推出。从历史上看，很多资源和研究都是针对绵羊的选择性繁殖来抵抗蠕虫，但这项工作的成果很少在英国的农场得到实际应用。培育绵羊以抵抗蠕虫的一个明显的替代方法是通过接种疫苗来诱导绵羊对感染的抵抗力，以特定地刺激对蠕虫攻击的免疫保护。这将产生否定蠕虫对绵羊生长和生产力的影响的效果，更重要的是，将减少蠕虫通过环境传播。与驱虫药控制方法相比，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，而且在绵羊的一生中可能需要较少的给药。最近，这个研究小组在发现一种有效的重组(亚单位)疫苗以控制圆锥虫方面取得了非凡的成功。这种疫苗(称为“CircVax”)由8种重组(合成)蛋白组成，可诱导羔羊对蠕虫攻击产生显著的免疫水平，尽管免疫水平各不相同。这种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(S)，并检查这是否受动物年龄的影响。全面了解接种疫苗和随后的蠕虫挑战过程中个体反应的变化，对于进一步优化疫苗(例如，在佐剂选择中)作为羊群综合蠕虫控制的工具是至关重要的。从这个项目中获得的知识将有助于确定疫苗在非常年轻的羔羊身上的效果是否可以改善，以及在年龄较大的动物身上的反应是否可以进一步优化。这些参数中的每一个都可以通过使用更合适的佐剂或给药系统来解决。此外，如果结果表明幼年羔羊的免疫系统天生无法控制弓形虫，则可以利用所获得的信息在整体、综合控制策略中部署疫苗，以解决将蠕虫中的耐药性选择压力降至最低的问题。总之，这些成果将为开发一种具有商业意义的疫苗提供重要步骤，供农民使用，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。

项目成果

The rational simplification of a recombinant cocktail vaccine to control the parasitic nematode Teladorsagia circumcincta

• DOI: 10.1016/j.ijpara.2018.10.006
• 发表时间: 2019-03-01
• 期刊: INTERNATIONAL JOURNAL FOR PARASITOLOGY
• 影响因子: 4
• 作者: Nisbet, Alasdair J.;McNeilly, Tom N.;Matthews, Jacqueline B.
• 通讯作者: Matthews, Jacqueline B.

Vaccine-induced time- and age-dependent mucosal immunity to gastrointestinal parasite infection.

• DOI: 10.1038/s41541-022-00501-0
• 发表时间: 2022-07-07
• 期刊: NPJ vaccines
• 影响因子: 9.2

A curated multivariate approach to study efficacy and optimisation of a prototype vaccine against teladorsagiasis in sheep.

• DOI: 10.1007/s11259-023-10208-9
• 发表时间: 2024-02
• 期刊: VETERINARY RESEARCH COMMUNICATIONS
• 影响因子: 2.2
• 作者: Palarea-Albaladejo, Javier;McNeilly, Tom N.;Nisbet, Alasdair J.
• 通讯作者: Nisbet, Alasdair J.

The right time and place: time- and age-dependent vaccine-enhanced mucosal immunity to parasite infection

正确的时间和地点：时间和年龄依赖性疫苗增强对寄生虫感染的粘膜免疫力

• DOI: 10.1101/2021.04.28.441781
• 发表时间: 2021
• 作者: Liu W