Mucosal Vaccines for Brucellosis

布鲁氏菌病粘膜疫苗

• 批准号: 9079710
• 负责人: David W Pascual
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-20 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9079710
• 关键词: Adopted; Aerosols; Affect; Affinity; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Arthritis; Attenuated Live Virus Vaccine; Attenuated Vaccines; Benign; Brucella; Brucella Vaccine; Brucella abortus; Brucella melitensis; Brucellosis; Cellular Immunity; Cholera; Chronic; Clinical; Communicable Diseases; DNA; Dairy Products; Development; Disease; Elements; Endocarditis; Experimental Animal Model; Future; Goals; Goat; Headache; Human; Immune response; Immunity; Immunization; Incidence; Induced Abortion; Infection; Ingestion; Interferon Type II; Interleukin-12; Intestines; Joints; LacZ Genes; Learning; Licensing; Life; Link; Liver; Livestock; Lung; M cell; Malaise; Meat; Milk; Mucous Membrane; Mus; Neurologic; Nose; Oral; Oropharyngeal; Outcome; Population; Production; Regimen; Research; Route; Safety; Shigella Infections; Site; Socioeconomic Status; Spleen; Study models; Subunit Vaccines; Symptoms; Systemic disease; T-Lymphocyte; TNF gene; Testing; Tissues; Tuberculosis; Tularemia; Typhoid Fever; Vaccination; Vaccines; Work; attenuation; economic impact; efficacy testing; flu; global health; human disease; human morbidity; immunogenicity; improved; mucosal vaccination; mucosal vaccine; mutant; neglect; nitric oxide reductase; novel; pathogen; prototype; public health relevance; research clinical testing; response; unpasteurized; vaccination strategy; vaccine development; vaccine efficacy; vaccine evaluation

 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.

 描述（由申请人提供）：高度传染性的革兰氏阴性布鲁氏菌仍然对全球健康构成威胁，并导致布鲁氏菌病。在人类中，B. melitensis 是 据信，这是大多数感染的原因，它是通过摄入未经高温消毒的乳制品或受感染动物产品的气溶胶自然传播的，导致鼻口咽组织感染。虽然感染主要发生在粘膜暴露后，但它可以引起全身性疾病，表现为流感样症状。尽管采取积极的抗生素治疗，但仍可能导致反复出现的后遗症，如波状热和关节炎。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，从而使它们能够隔离在各种组织中。能够重现布鲁氏菌感染各个方面的疫苗应该能有效预防感染。因此，我们假设一种模拟天然粘膜羊种布鲁氏菌感染并能够通过产生 TNF-a 和 IFN-g 刺激细胞介导的免疫的疫苗将能够针对粘膜和全身布鲁氏菌挑战提供保护。为了实现这种方法，我们最近开发了一种疫苗原型，在大多数情况下可以提供完全保护，并且脾或肺中没有检测到布鲁氏菌。鉴于这种疫苗的效力，我们建议使用两种动物模型来检验我们的假设，以确定这种疫苗针对野生型羊种伯克霍尔德氏菌挑战的功效。具体目标 1 的研究将建立粘膜（口腔、鼻腔或口腔 + 鼻腔）免疫策略，为羊种布鲁氏菌和异源布鲁氏菌物种提供保护。具体目标 2 中的研究将在山羊（B. melitensis 的天然宿主）中建立类似的粘膜免疫策略，以提供针对 B. melitensis 引起的流产。具体目标 3 的研究将评估该疫苗的生物安全性，以保证未来的临床测试。因此，这些研究将表明我们的口服/鼻疫苗可以在两种不同的实验动物模型中预防布鲁氏菌挑战。