Development and Evaluation of a Dual-Antigen Nasal Brucella Vaccine

描述（由申请人提供）：摘要：兼性细胞内布鲁氏菌属在动物和人类中引起布鲁氏菌病，并已被归类为NIAID类别B优先病原体。布鲁氏菌通过呼吸道、皮肤和消化道感染人体。目前尚无布鲁氏菌疫苗可供人类使用。因此，需要对人类无感染性但有效刺激广泛保护性免疫应答的新型疫苗。一种能同时诱导全身和粘膜免疫的鼻用疫苗将是理想的。纯化的光滑布鲁氏菌脂多糖（LPS）在不同的动物模型中诱导对强毒布鲁氏菌感染的保护作用。布鲁氏菌LPS的毒性也比E.已被用作疫苗佐剂以促进诱导HIV抗原特异性细胞介导的免疫应答。此外，布鲁氏菌Cu/Zn超氧化物歧化酶（SOD）是一种保护性抗原，当与IL-2结合时，在布鲁氏菌疫苗中过表达或在DNA或RNA疫苗中表达时，可诱导显著的保护作用。我们假设，含有LPS和Cu/Zn SOD的双抗原布鲁氏菌疫苗，当与适当的佐剂鼻内给药时，将诱导显着水平的LPS和Cu/Zn SOD特异性Th 1和细胞介导的免疫力，以保护免受强毒布鲁氏菌感染。该提案的总体目标是1）通过结合B开发双抗原布鲁氏菌疫苗。Melitensis LPS和Cu/Zn SOD（LPS-SOD），和2）在良好建立的小鼠模型中评价当鼻内给予适当的佐剂时诱导的免疫应答。本项目有望产生一种新的鼻用布鲁氏菌疫苗候选物原型，并为开发有效的人用鼻用布鲁氏菌疫苗奠定良好的科学基础。公共卫生相关性：布鲁氏菌属物种在人类和动物中引起使人衰弱的布鲁氏菌病，并已被列为可能用于生物恐怖主义的病原体。然而，目前还没有布鲁氏菌疫苗可供人类使用。本研究旨在通过结合两种保护性布鲁氏菌抗原来开发和分析一种新型的鼻用布鲁氏菌疫苗原型。

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.