Minipigs as animal model for infant TB and vaccine efficacy

描述（由申请人提供）：四个月前，2013年2月，报告了婴儿中最大的结核病（TB）疫苗有效性试验之一的结果。试验测试了M.卡介苗（BCG）初免-MVA 85 A加强免疫，保护婴儿免受结核病的侵害。从这一试验中吸取的教训之一是，迫切需要一种不同的方法来测试疫苗对婴儿和儿童结核病的有效性。今天，有几种动物模型来测试结核病疫苗的效力，但没有动物模型来解决婴儿结核病，更没有动物模型来测试婴儿的疫苗和诊断。鉴于这种情况，在本申请中，我们提出开发一种动物模型，以研究使用成年和仔猪小型猪的婴儿TB和TB疫苗效力测试。我们的长期目标是开发一种由感染结核病的成年小型猪和接种疫苗的仔猪形成的高负荷环境，这将允许研究婴儿结核病和结核病疫苗的效力、结核病的生物标志物和结核病传播。然而，为了实现我们的长期目标，我们首先需要证明小型猪（成年猪和仔猪）通过产气途径感染结核分枝杆菌时会发生结核病。此外，我们还需要证明新生仔猪接种卡介苗后产生的抗结核免疫力与婴儿相似。我们还需要解决是否有潜在的生物标志物在尿液和血清中的结核病仔猪，可用于诊断婴儿结核病。如果成功，这些研究中提出的小型猪动物环境将有助于理解婴儿结核病及其诊断，并改善用于儿童结核病预防的疫苗选择。本文提出的研究结果将使用我们实验室目前常规的综合细菌学、免疫学和病理学方法进行记录。科罗拉多州立大学的分枝杆菌研究实验室配备了最先进的BSL-III研究设施， 这些研究。为了这些研究的目的，我们在位于科罗拉多州立大学和ARS-USDA的猪免疫学、结核病感染动物模型、疫苗效力测试和结核病生物标志物领域组建了一个经验丰富的研究人员团队。

DESCRIPTION (provided by applicant): Four months ago, in February of 2013 the results from one of the largest tuberculosis (TB) vaccine efficacy trial in infants were reported. The trai tested the capacity of M. bovis Bacille Calmette Guerin (BCG) prime -MVA85A boosting to protect infants against TB. One of the lessons learnt from this trail was that there is an urgent need for a different approach to test vaccine efficacy against infant and childhood TB. Today, there are several animal models to test TB vaccine efficacy but there are no animal models to address infant TB, less so animal models to test vaccines and diagnostics for infants. In view of this scenario, in this application we propose to develop an animal model to study infant TB and TB vaccine efficacy testing using adult and piglet minipigs. Our long term goal is to develop a high burden setting formed by adult minipigs affected with TB and vaccinated piglets that will allow to study infant TB and TB vaccine efficacy, biomarker of TB disease and TB transmission. However, to achieve our long term goal, we first need to demonstrate that minipigs (adult and piglets) develop TB disease when infected by aerogenic route with Mycobacterium tuberculosis. Further, we need to demonstrate that vaccination of neonatal piglets with BCG results in the development of similar immunity against TB as that seen in infants. We will also need to address whether there are potential biomarkers in urine and sera of TB diseased piglets that could be used to diagnose infant TB. If successful, the minipig animal setting proposed in these studies will facilitate the understanding of infant TB and its diagnosis, as well as improve the choice of vaccines to be used in childhood TB prevention. The outcomes of the studies proposed here will be documented using comprehensive bacteriologic, immunologic, pathologic approaches now routine in our laboratory. The Mycobacteria Research Laboratories at Colorado State University are uniquely equipped with state-of-the-art BSL-III research facilities to develop these studies. For the purposes of these studies we have assembled a team of highly experienced researchers in the fields of swine immunology, animal models of TB infection, vaccine efficacy testing and biomarkers of TB disease located at Colorado State University and the ARS-USDA.