Immunity safety and protection of an Adenovirus-Prime:MVA-Boost vaccine against Mycobacterium avium subspecies paratuberculosis infection in calves

鸟分枝杆菌副结核亚种（MAP）是在许多动物中引起称为约翰氏病（JD）的肠道慢性炎症的细菌。JD对牛、绵羊和山羊的管理具有重要的经济意义，因为它会导致产奶量的损失，并且在疾病发展到晚期时需要提前扑杀;估计每年的成本为15亿美元。在美国和1300万英镑。在英国目前控制JD传播的措施已被证明是不够的，目前英国一半以上的牛群受到感染，包括美国在内的其他一些发达国家几乎所有牛群都受到感染。MAP在感染的后期会大量排泄，但即使使用目前的疫苗也会排泄。这导致MAP扩散到野生动物水库，并污染河流和湖泊等环境水库。MAP由受感染的奶牛分泌到牛奶中，并在巴氏灭菌后存在于超市牛奶中。在人类中，MAP感染和克罗恩病之间的联系越来越令人信服，在高达一半的正常人肠道样品和几乎所有的克罗恩病样品中已经检测到MAP。目前，市售的全细胞疫苗不能提供对JD的完全保护。它们可以缓解临床症状，但不能显著减少感染动物的数量或阻止MAP排泄到乳汁和粪便中。通过允许诱导亚临床感染，这些疫苗可能隐藏MAP感染的问题，因此是适得其反的。因此，迫切需要开发更好的疫苗来治疗这种疾病，并了解MAP影响动物免疫系统导致JD的方式。该项目将研究一种新型疫苗，该疫苗已被证明在小鼠中有效。它使用两种不会在动物或环境中生长的病毒来提供称为HAV的MAP抗原的鸡尾酒。尽管小鼠的疫苗接种试验并不总是成功地转移到其他动物种属，但初步实验的结果表明，我们建议使用的初免-加强疫苗接种方法在一定程度上有利于预防其他分枝杆菌感染。我们将研究HAV疫苗预防实验性MAP感染小牛的能力，并详细测量牛的免疫系统，目的是了解这种新型疫苗如何起作用。这项工作将提高我们对分枝杆菌疾病过程的认识，因此也可能有利于其他相关研究，例如结核病疫苗。如果这项研究确实表明新疫苗可能具有保护作用，那么它可能是改善对这种日益蔓延的疾病控制的第一步。

Mycobacterium avium subspecies paratuberculosis (MAP) is the bacterium that causes a chronic inflammation of the gut known as Johne's disease (JD) in many animals. JD is of significant economic importance to the management of cattle, sheep and goats due to loss in milk production and the need for premature culling when the disease becomes advanced; the cost has been estimated to be $1.5billion pa. in the USA and £13million pa. in the UK. Current measures to control the spread of JD have been shown to be inadequate and at present more than half of cattle herds in the UK are infected and nearly all herds in some other developed countries, including the USA. MAP is excreted in very large amounts in later stages of infection but can also be excreted even when current vaccines are used. This has led to the spread of MAP into wildlife reservoirs and contamination of environmental reservoirs such as rivers and lakes. MAP is excreted by infected dairy cattle in their milk and is present in supermarket milk as it survives pasteurization. There is an increasingly convincing link between MAP infection and Crohn's disease in humans, MAP has been detected in up to half of normal human intestinal samples and nearly all of Crohn's Disease samples. Currently, commercially available whole cell vaccines do not provide complete protection against JD. They may relieve clinical symptoms but do not significantly reduce the number of animals that are infected or stop excretion of MAP into milk and faeces. By allowing the induction of sub-clinical infection, these vaccines may hide the problem of MAP infection and consequently be counterproductive. Therefore, there is an urgent need to develop a better vaccine to treat this disease and to understand the way that MAP affects the animal's immune system to cause JD. This project will study a new type of vaccine that has been shown to work in mice. It uses two viruses that will not grow in animals or the environment, to deliver a cocktail of MAP antigens called HAV. Although vaccination trials in mice do not always transfer successfully to other animal species, results from preliminary experiments have shown that the prime-boost vaccination method we are proposing to use has been beneficial in conferring a degree of protection against other mycobacterial infections. We will look at the ability of the HAV vaccine to prevent an experimental infection of calves with MAP and measure in detail the cattle's immune system with the aim of understanding how this new type of vaccine might be working. This work will improve our knowledge of mycobacterial disease processes and could therefore also benefit other related research such as vaccines for tuberculosis for example. If the study does show that the new vaccine may be protective it could be a first step in improving the control of this increasingly spreading disease.