Mucosal Vaccines for Brucellosis

 描述(申请人提供)：高度传染性的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，羊巴氏杆菌是 据信是大多数感染的罪魁祸首，它通过摄入未经巴氏灭菌的乳制品或受感染动物产品的气雾剂而自然传播，导致鼻咽部组织感染。虽然感染主要发生在粘膜接触之后，但它可能会导致系统性疾病，表现为流感样症状。尽管积极的抗生素治疗，它仍然可能导致复发的后遗症，明显的波浪热和关节炎。清华说，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，使它们能够隔离在各种组织中。可以概括布鲁氏菌感染方面的疫苗应该被证明在预防感染方面是有效的。因此，我们推测，一种模拟自然黏膜感染的疫苗，并能够通过产生肿瘤坏死因子-a和干扰素-g来刺激细胞免疫，将对粘膜和系统性布鲁氏菌的挑战具有保护作用。为了实现这一方法，我们最近开发了一种疫苗原型，它可以在大多数情况下提供完全保护，而不会在脾或肺中检测到布鲁氏菌。鉴于这种疫苗的效力，我们建议使用两个动物模型来验证我们的假设，以确定该疫苗对野生型羊瘟杆菌挑战的效力。具体目标1的研究将建立一种黏膜(口腔、鼻腔或口腔+鼻腔)免疫策略，以保护羊毛虫和异源布鲁氏菌物种。在特定目标2中的研究将在山羊身上建立类似的粘膜免疫策略，山羊是山羊的自然宿主，以提供对 羊肚菌人工流产。具体目标3的研究将评估这种疫苗的生物安全性，以保证未来的临床测试。因此，这些研究将表明，我们的口服/鼻腔疫苗可以在两个不同的实验动物模型中预防布鲁氏菌的挑战。

 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.