Minipigs as animal model for infant TB and vaccine efficacy

描述（由申请人提供）：四个月前，即2013年2月，报告了最大的婴儿结核病（TB）疫苗疗效试验之一的结果。该试验测试了牛分枝杆菌（BCG） prime -MVA85A增强剂保护婴儿免受结核病的能力。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效力。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问题，更没有动物模型来测试婴儿疫苗和诊断方法。鉴于这种情况，在本申请中，我们建议建立一种动物模型来研究婴儿结核病和结核病疫苗的效力测试，使用成年和仔猪迷你猪。我们的长期目标是建立一个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担环境，以便研究婴儿结核病和结核病疫苗的功效、结核病和结核病传播的生物标志物。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）在通过气源途径感染结核分枝杆菌后会发生结核病。此外，我们需要证明新生仔猪接种卡介苗可产生与婴儿相似的结核病免疫。我们还需要解决结核病患病仔猪的尿液和血清中是否存在可用于诊断婴儿结核病的潜在生物标志物。如果成功，这些研究中提出的迷你猪动物环境将有助于了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的选择。本文提出的研究结果将采用我们实验室常规的综合细菌学、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

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.