A reverse vaccinology approach to a bTB vaccine

bTB 疫苗的逆向疫苗学方法

• 批准号: BB/N004698/1
• 负责人: Ian Jones
• 金额: $ 183.03万
• 依托单位: University of Reading
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN004698%2F1
• 关键词: reverse; vaccinology; approach; bTB; vaccine

Bovine tuberculosis, bTB, is the result of the infection of cattle by the bacterium Mycobacterium bovis. The bacterium is distributed widely in nature as it also infects many other wildlife species and as a result of this, wildlife infection acts as a reservoir for the bacterium which periodically get across into domestic cattle. The consequence of this is twofold. First, cattle that are bTB positive must be culled with a knock-on effect on the farmer and his ability to maintain a herd. Second, bTB is a threat for human infection, primarily via the consumption of contaminated milk. Today bTB infection of individuals is extremely rare, but the threat remains and for these reasons bTB infection is unwelcome and needs to be controlled or, preferably, eradicated. Since a historical review in the mid-1990s, the badger has been identified as one of the major routes of transmission of bTB to domestic cattle and this, in turn, has led to attempts to break this transmission route via badger culling. These have met with only limited success and immense public concern leaving the physical breaking of the transmission route mostly unaltered. An alternative approach is to accept that bTB circulates widely in the environment but to prevent cattle infection by previous vaccination. At the present time however an effective vaccine for bTB in cattle is not available and new methods to develop such a vaccine are urgently needed. It is generally accepted that vaccines function by generating an antibody response in the target animal which prevents the bacterium from establishing the initial infection. These antibodies, which are a normal product of the immune system of all mammals, generally bind to the outside of the bacterium and so prevent it from binding to cattle cells, usually the epithelial cells of the lung. It follows that the protective components of bTB, that is, the components that will generate the antibody response that is protective, are to be found on the outside of the bacterium surface. Bacteria have many components on their surface and any, or perhaps a combination of many, of these components, proteins encoded by the bacterium genome, could be essential for the development of effective immunity. However exactly which are required is currently unknown. In this research, we propose to produce all of the surface components of bTB and to test them in batches for their ability to induce an effective immune response. We propose to do this work in cattle so that the response measured to our test vaccines is typical of what will be found if an eventual vaccine is used in typical herds. Our work breaks down into three related components. Firstly, we will identify all of those proteins from the M. bovis bacterium that are to be found on the surface of the organism and produce each of them in a safe and efficient manner. Our initial calculations suggest that several hundred such proteins may be required in order to find the few that are necessary for effective immunity. Secondly, we will use our surface proteins as test vaccines in cattle and to make this process efficient we will carry out this work with mixes of proteins so that the least number of cattle has to be used. Following the immunizations we will take blood samples from the cattle and test them for the ability to prevent M. bovis infection. Finally, we will examine the mechanism of protection and how the individual components so we have identified work together to provide the cattle with an effective barrier of immunity. Our approach is exhaustive but it has the potential to draw a line under the vaccine discovery program for bTB and to identify the best mix of candidates for eventual effective vaccine production.

BTB牛结核病是牛菌细菌感染牛的结果。该细菌在自然界中分布广泛，因为它也感染了许多其他野生动植物物种，因此，野生动植物感染可作为细菌的储层，这些储层会定期进入家养牛。结果的结果是双重的。首先，BTB阳性的牛必须对农民及其维持牛群的能力产生连锁反应。其次，BTB主要是通过消费受污染的牛奶的威胁。如今，BTB感染个体极为罕见，但是威胁仍然存在，因此，由于这些原因，BTB感染是不受欢迎的，需要控制或最好被根除。自1990年代中期的历史审查以来，该badge被确定为BTB向家养牛的主要传播途径之一，这又导致试图通过badge扣来破坏这一传输路线。这些仅取得了有限的成功和巨大的公众关注，使传输路线的身体破坏大多是没有改变的。另一种方法是接受BTB在环境中广泛循环，但要通过先前的疫苗接种来防止牛感染。目前，目前尚无牛BTB的有效疫苗，迫切需要开发这种疫苗的新方法。人们普遍认为，疫苗通过在靶向动物中产生抗体反应来阻止细菌建立初始感染来发挥作用。这些抗体是所有哺乳动物的免疫系统的正常产物，通常结合到细菌的外部，因此阻止其与牛细胞（通常是肺上皮细胞）结合。因此，可以在细菌表面的外部找到BTB的保护性成分，即将产生保护性的抗体反应的成分。细菌在其表面上有许多成分，这些成分，或可能是许多由细菌基因组编码的蛋白质组成的组成部分，对于有效免疫的发展至关重要。但是，确切的确切需要目前未知。在这项研究中，我们建议生产BTB的所有表面成分，并分批测试它们，以诱导有效的免疫反应。我们建议在牛做这项工作，以便对我们的测试疫苗的反应是典型的，即如果在典型群中使用最终疫苗，将会发现什么。我们的工作分解为三个相关组成部分。首先，我们将从牛乳杆菌细菌中鉴定出所有这些蛋白质，这些蛋白质在生物体的表面上可以找到，并以安全有效的方式生产它们。我们的最初计算表明，可能需要数百种此类蛋白质才能找到有效免疫所必需的少数蛋白质。其次，我们将使用表面蛋白作为牛的测试疫苗，并使该过程有效，我们将使用蛋白质混合进行这项工作，以便必须使用最少的牛。接到免疫接种后，我们将从牛中采集血液样本，并测试它们是否能够预防牛乳杆菌感染。最后，我们将研究保护的机制以及单个组件的方式，因此我们已经确定了为牛提供有效的免疫障碍的工作。我们的方法是详尽的，但它有可能在BTB的疫苗发现计划下划定一条线，并确定最终有效疫苗生产的候选者的最佳组合。

项目成果

SARS-CoV-2 Virus-like Particles Produced by a Single Recombinant Baculovirus Generate Anti-S Antibody and Protect against Variant Challenge.

• DOI: 10.3390/v14050914
• 发表时间: 2022-04-27
• 期刊: Viruses

Towards Reverse Vaccinology for Bovine TB: High Throughput Expression of Full Length Recombinant Mycobacterium bovis Proteins.

• DOI: 10.3389/fmolb.2022.889667
• 发表时间: 2022
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5

Affordable mobile microfluidic diagnostics: minimum requirements for smartphones and digital imaging for colorimetric and fluorometric anti-dengue and anti-SARS-CoV-2 antibody detection.

• DOI: 10.12688/wellcomeopenres.16628.1
• 发表时间: 2021
• 期刊: Wellcome open research