Mucosal Vaccines for Brucellosis

 描述（由申请方提供）：高传染性革兰氏阴性布鲁氏菌仍然是全球健康威胁，并导致布鲁氏菌病。在人类中，B。梅利滕西斯群岛 被认为是大多数感染的原因，并且它通过摄入未经巴氏消毒的乳制品或受感染的动物产品的气溶胶而自然传播，导致鼻口咽组织感染。虽然感染主要发生在粘膜暴露后，但它可引起全身性疾病，表现为流感样症状。尽管积极的抗生素治疗，它仍然可以导致反复出现的后遗症，明显的波状热和关节炎。布鲁氏菌在宿主体内的存活与其逃避细胞内识别的能力有关，因此，允许它们在各种组织中隔离。可以概括布鲁氏菌感染的疫苗应该被证明在预防感染方面是有效的。因此，我们假设，一种疫苗，模仿天然粘膜B。羊种布氏杆菌感染，并且能够通过产生TNF-α和IFN-γ刺激细胞介导的免疫力，将对粘膜和全身布鲁氏菌攻击具有保护作用。为了实现这种方法，我们最近开发了一种疫苗原型，可以在大多数情况下提供完全的保护，而在脾脏或肺部没有检测到布鲁氏菌。鉴于该疫苗的效力，我们建议使用两种动物模型来测试我们的假设，以确定该疫苗对野生型B的效力。melitensis挑战。特定目标1的研究将建立一种粘膜（口腔、鼻腔或口腔+鼻腔）免疫策略，用于对B提供保护。羊种和异源布鲁氏菌种。特异性目标2的研究将在山羊（B的天然宿主）中建立类似的粘膜免疫策略。Melitensis，用于提供保护， B。人工流产特定目标3中的研究将评估该疫苗的生物安全性，以保证未来的临床试验。因此，这些研究将表明，我们的口服/鼻用疫苗可以在两种不同的实验动物模型中预防布氏杆菌的挑战。

 DESCRIPTION (provided by applicant): The highly infectious Gram-negative Brucella remains a global health threat and is responsible for the disease, brucellosis. In humans, B. melitensis is believed to be responsible for most infections, and it is naturally transmitted via ingestion of unpasteurized dairy products or aerosols of infected animal products resulting in infection of naso-oropharyngeal tissues. Although infection primarily occurs following a mucosal exposure, it can cause a systemic disease manifested by its flu-like symptoms. Despite aggressive antibiotic treatment, it can still result in a recurring sequelae evident as undulant fever and arthritis. Brucellae survival within the host is linked to its ability to evade intracellular recognition, thu, allowing them to sequester in various tissues. Vaccines that can recapitulate aspects of Brucella infection should prove effective in protecting against infection. Hence, we hypothesize that a vaccine that mimics aspects of natural mucosal B. melitensis infections and capable of stimulating cell-mediated immunity via the production of TNF-a and IFN-g will be protective against mucosal and systemic Brucella challenges. To enable this approach, we have recently developed a vaccine prototype that can confers complete protection in most cases with no detectable brucellae in spleens or lungs. Given the potency of this vaccine, we propose to test our hypothesis using two animal models to determine the efficacy of this vaccine against wild-type B. melitensis challenges. Studies in Specific Aim 1 will establish a mucosal (oral, nasal, or oral + nasal) immunization strategy for conferring protection to B. melitensis and to heterologous Brucella species. Studies in Specific Aim 2 will establish similar mucosal immunization strategy in goats, a natural host for B. melitensis, for conferring protection against B. melitensis-induced abortion. Studies in Specific Aim 3 will evaluate the biosafety of this vaccine to warrant future clinical testing. Thus, these studies will show that our oral/nasal vaccine can protect against Brucella challenges in two different experimental animal models.