Development and Evaluation of a Dual-Antigen Nasal Brucella Vaccine

描述(申请人提供)：摘要：兼性胞内布鲁氏菌可引起动物和人类的布鲁氏菌病，已被归类为NIAID B类优先病原体。布鲁氏菌通过呼吸道、皮肤和消化道感染人体。目前还没有可供人类使用的布鲁氏菌疫苗。因此，需要对人类不具传染性但能有效刺激广泛保护性免疫反应的新型疫苗。一种既能诱导全身免疫又能诱导粘膜免疫的鼻腔疫苗将是理想的。纯化的光滑布氏杆菌脂多糖在不同动物模型中诱导对布氏杆菌强毒力感染的保护作用。布鲁氏菌的毒性也比大肠杆菌的低得多，并已被用作疫苗佐剂，以促进诱导HIV抗原特异性细胞免疫反应。此外，布鲁氏菌铜锌超氧化物歧化酶(SOD)是一种保护性抗原，当与IL-2结合、在布鲁氏菌疫苗中过表达或在DNA或RNA疫苗中表达时，可诱导对布鲁氏菌病的显著保护。我们推测，同时含有内毒素和铜/锌超氧化物歧化酶的双抗原布鲁氏菌疫苗，在鼻腔注射适当佐剂(S)时，将诱导显著水平的针对内毒素和铜/锌超氧化物歧化酶的Th1和细胞免疫，以对抗布鲁氏菌的强毒感染。这项建议的总体目标是：1)通过将羊布鲁氏菌的内毒素和铜锌超氧化物歧化酶结合起来，研制出一种双抗原布鲁氏菌疫苗(内毒素-超氧化物歧化酶)；2)在已建立的小鼠模型上，评估鼻腔注射适当佐剂时所诱导的免疫应答。该项目有望产生一种新颖的鼻用布鲁氏菌疫苗候选原型，并为开发有效的人用鼻用布鲁氏菌疫苗奠定坚实的科学基础。与公共卫生相关：布鲁氏菌会在人和动物中引起衰弱的布鲁氏菌病，并已被列为可能用于生物恐怖主义的病原体。然而，目前还没有可供人类使用的布鲁氏菌疫苗。本研究旨在通过两种布氏杆菌保护性抗原的结合，开发和分析一种新型的鼻腔布氏杆菌疫苗原型。

DESCRIPTION (provided by applicant): Abstract: Facultative intracellular Brucella species cause brucellosis in animals and humans and have been classified as NIAID category B priority pathogens. Brucella infects the body via the respiratory tract, the skin, and the digestive tract. There is no Brucella vaccine available for human use. Thus, novel vaccines that are non-infectious to humans but effective in stimulating a broad protective immune response are needed. A nasal vaccine that induces both systemic and mucosal immunities would be ideal. Purified smooth Brucella lipopolysaccharide (LPS) induces protection against virulent Brucella infections in different animal models. Brucella LPS is also much less toxic than that from E. coli and has been used as a vaccine adjuvant to facilitate the induction of HIV antigen specific cell-mediated immune response. Additionally, Brucella Cu/Zn Superoxide Dismutase (SOD) is a protective antigen that induces significant protection against brucellosis when combined with IL-2, overexpressed in a Brucella vaccine, or expressed in DNA or RNA vaccines. We hypothesize that a dual-antigen Brucella vaccine containing both LPS and Cu/Zn SOD, when dosed intranasally with appropriate adjuvant(s), will induce significant levels of LPS- and Cu/Zn SOD-specific Th1 and cell mediated immunity to protect against virulent Brucella infection. The overall goal of this proposal is 1) to develop a dual antigen Brucella vaccine by conjugating B. melitensis LPS and Cu/Zn SOD (LPS-SOD) and 2) to evaluate the immune responses induced when nasally dosed with appropriate adjuvants in a well-established mouse model. This project is expected to generate a novel prototype nasal Brucella vaccine candidate and lay a sound scientific foundation for the development of an efficacious nasal Brucella vaccine for human use. PUBLIC HEALTH RELEVANCE: Brucella species cause debilitating brucellosis in humans and animals and have been listed as pathogens potentially used for bioterrorism. However, there is no Brucella vaccine available for human use. This proposal aims to develop and analyze a novel prototype nasal Brucella vaccine by conjugating two protective Brucella antigens.