The immunological basis of protection obtained by prime-boost immunisation against bovine tuberculosis

牛结核病初免-加强免疫获得保护的免疫学基础

• 批准号: BB/K010018/1
• 负责人: Ivan Morrison
• 金额: $ 92.29万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK010018%2F1
• 关键词: immunological; basis; protection; obtained; prime

The causal agents of bovine (bTB) and human tuberculosis (hTB), Mycobacterium bovis and M. tuberculosis respectively, are closely related organisms that result in similar diseases. M. bovis can also cause disease when transmitted to humans, and this led in the 1950s to the introduction of national eradication programmes based on testing of cattle herds to remove infected cattle. Although initially successful in reducing herd incidence, the disease has re-emerged as a major problem in the UK over the last 25 years. This has led to consideration of vaccination as an additional control option. A laboratory attenuated strain of M. bovis (BCG) has been used extensively since the early 20th century to vaccinate against hTB. However the vaccine shows variable efficacy, particularly against disease in adults. BCG vaccination of cattle can reduce the incidence and severity of pathology, but only prevents establishment of infection in a proportion of vaccinates. Therefore, its use has been considered incompatible with current bTB control programmes. An improved vaccine is therefore required for both hTB and bTB. Recent studies in humans and cattle have demonstrated that BCG vaccination boosted by virally vectored subunit vaccines expressing mycobacterial antigens results in enhanced protection compared to BCG alone. For example, combination of BCG and a recombinant adenovirus (rAd) expressing the 85A antigen reduced the number of cattle that presented with visible lesions after M. bovis challenge, compared to animals vaccinated with BCG only. This project aims to identify those features of the immune response induced by boosting with 85A that are associated with the enhanced immunity.Although it is well established that immunity against M. bovis is mediated by cellular immune responses, primarily involving the CD4 subset of T cells, the precise properties of the protective CD4 T cells that determine immunity are poorly understood. The demonstration that immunity induced by BCG can be enhanced by boosting with the 85A antigen clearly shows that responses to this antigen contribute to immunity. The project will therefore focus on analysing immune responses to 85A in cattle immunised with BCG followed by 85A and subsequently challenged with virulent M. bovis. CD4 T cells utilise a large library of antigen-specific receptors to recognise short fragments of foreign microbial proteins presented on the surface of infected cells. The project will utilise newly developed methods for analysing the sequences of these receptors to track the responding 85A-specific CD4 T lymphocyte populations following immunisation and challenge. This methodology will be used in conjunction with biological assays that measure the frequency, fine specificity and functional potency of the 85A-specific response to address the following questions:- To what extent is the frequency of CD4 T cells reactive with 85A increased following boost immunisation with 85A? - Does boost immunisation with 85A alter the fine specificity of the responding CD4 -lymphocytes response and/or the repertoire of their antigen-specific receptors?- Does boosting with 85A enhance the functional potency of the specific CD4 T cells compared to BCG immunisation only? - Are particular components of the 85A-specific CD4 T cell response more effective than others at recognising and responding to M. bovis-infected cells?- Which components of the of the 85A-specific CD4 T cell population respond most rapidly following challenge of immunised animals with M. bovis? The results of these studies will identify properties of the specific CD4 T cell response that are associated with immunity and thus provide measurable parameters that will be useful for assessing the immune responses to other candidate vaccines. Although primarily of relevance to vaccine development for tuberculosis in cattle, the outputs of the project will also inform studies of TB vaccine development for other species.

牛结核病（bTB）和人结核病（hTB）的病原体牛分枝杆菌（Mycobacterium bovis）和M.结核病是导致类似疾病的密切相关的生物体。M.牛传染给人也会引起疾病，因此在1950年代实行了国家根除方案，对牛群进行检测，清除受感染的牛。虽然最初成功地降低了牛群发病率，但在过去的25年里，这种疾病再次成为英国的一个主要问题。这导致考虑将接种疫苗作为一种额外的控制选择。实验室分离的M.自世纪早期以来，牛（BCG）已被广泛用于接种抗hTB的疫苗。然而，疫苗显示出不同的效力，特别是针对成人疾病。牛的BCG疫苗接种可以降低病理的发生率和严重程度，但只能防止一部分接种者建立感染。因此，它的使用被认为与目前的bTB控制方案不相容。因此，hTB和bTB都需要改进的疫苗。最近在人类和牛中的研究已经证明，与单独的BCG相比，由表达分枝杆菌抗原的病毒载体亚单位疫苗加强的BCG疫苗接种导致增强的保护。例如，BCG和表达85 A抗原的重组腺病毒（rAd）的组合减少了M.牛攻毒，与仅接种BCG的动物相比。本项目的目的是确定与增强的免疫力相关的85 A加强诱导的免疫应答的那些特征。牛的免疫是由细胞免疫应答介导的，主要涉及T细胞的CD 4亚群，但对决定免疫力的保护性CD 4 T细胞的精确特性知之甚少。BCG诱导的免疫可通过用85 A抗原加强而增强的证明清楚地表明，对该抗原的应答有助于免疫。因此，该项目将重点分析牛对85 A的免疫应答，这些牛先用BCG免疫，然后用85 A免疫，然后用强毒M攻毒。牛CD 4 T细胞利用抗原特异性受体的大型文库来识别感染细胞表面上呈递的外源微生物蛋白的短片段。该项目将利用新开发的方法来分析这些受体的序列，以跟踪免疫和激发后的85 A特异性CD 4 T淋巴细胞群。该方法将与测量85 A特异性应答的频率、精细特异性和功能效力的生物测定结合使用，以解决以下问题：-在用85 A加强免疫后，与85 A反应的CD 4 T细胞的频率增加到何种程度？- 用85 A加强免疫是否改变了应答性CD 4淋巴细胞应答的精细特异性和/或其抗原特异性受体的库？与仅BCG免疫相比，用85 A加强是否增强了特异性CD 4 T细胞的功能效力？- 85 A特异性CD 4 T细胞应答的特定组分在识别和应答M.牛感染的细胞85 A特异性CD 4 T细胞群的哪些组分在用M.牛？这些研究的结果将确定与免疫相关的特异性CD 4 T细胞应答的特性，从而提供可测量的参数，这些参数将用于评估对其他候选疫苗的免疫应答。虽然该项目的产出主要与牛结核病疫苗开发有关，但也将为其他物种结核病疫苗开发研究提供信息。

项目成果

Protection associated with a TB vaccine is linked to increased frequency of Ag85A-specific CD4(+) T cells but no increase in avidity for Ag85A.

• DOI: 10.1016/j.vaccine.2016.07.055
• 发表时间: 2016-08-31
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Metcalfe HJ;Steinbach S;Jones GJ;Connelley T;Morrison WI;Vordermeier M;Villarreal-Ramos B
• 通讯作者: Villarreal-Ramos B

Genomic analysis offers insights into the evolution of the bovine TRA/TRD locus.

• DOI: 10.1186/1471-2164-15-994
• 发表时间: 2014-11-19
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Connelley TK;Degnan K;Longhi CW;Morrison WI
• 通讯作者: Morrison WI