Development of a New Tularemia Vaccine

描述(由申请人提供)： 图拉热症是一种人畜共患病，由高度毒力的兼性细胞内细菌Francisella tularsis引起。由于这种细菌的毒力和易于气雾剂传播，它已被归类为A类生物恐怖分子。一种含有图拉氏丝虫活疫苗株(活疫苗株)的减毒图拉热活疫苗目前可供人类作为研究新药(IND)使用。这种注射方法对于快速、大规模的疫苗接种来说是次优的，而且产品存在反应性问题。因此，需要一种改进的图拉热症疫苗。本研究的目的是利用土拉氏原虫的Tul4、FOPA、Cpn60(热休克蛋白)和FT23KDAP(23 kDa蛋白)四种蛋白作为疫苗组分，通过鼻腔和经皮免疫途径与复制缺陷型腺病毒联合免疫，研制出一种有效且易于接种的图拉热疫苗。这些非侵入性的疫苗投放方式无疑将提高疫苗接种计划的合规性。在本项目中，将构建编码Tul4、FOPA、Cpn60和FT23KDAP的腺病毒和质粒表达载体。为了获得最佳的疫苗接种方案，将在小鼠模型中研究不同的腺病毒和质粒载体的组合以及不同序列的鼻腔、经皮和肌肉注射方式的免疫方案。 该项目的具体目标是： 具体目标#1：研制一种复制缺陷的、腺病毒载体的抗图拉氏丝虫疫苗。 具体目的#2：对腺病毒载体疫苗通过鼻腔、经皮和肌肉注射联合给药和土拉夫酵母皮内注射诱导的全身和粘膜免疫进行比较。 由于以前没有研究表明用腺病毒或质粒载体进行基因免疫可以诱导对图拉氏肺吸虫的保护性免疫，因此该项目具有探索性和发展性。

DESCRIPTION (provided by applicant): Tularemia is a zoonotic disease caused by the highly virulent, facultative intracellular bacterium Francisella tularensis. Because of the virulence of this bacterium and its ease of aerosol transmission, it has been classified as a Category A bioterrorism agent. A live, attenuated tularemia vaccine containing F. tularensis LVS (live vaccine strain) is currently available for human use as an investigational new drug (IND). It is given by scarification; this delivery method is sub-optimal for rapid, mass vaccination and the product has reactogenicity issues. Therefore, an improved vaccine against tularemia is needed. The objective of this research is to develop an effective and easily administrated tularemia vaccine using four protein antigens: Tul4, FopA, Cpn60 (heat shock protein), and FT23KDAP (the 23 kDa protein) from F. tularensis as vaccine components, delivered with replication-defective adenovirus by the intranasal and transcutaneous immunization routes. These non-invasive vaccine delivery methods will undoubtedly enhance the compliance of a vaccination program. In this project, adenovirus and plasmid expression vectors encoding Tul4, FopA, Cpn60, and FT23KDAP will be constructed. In order to obtain an optimal vaccination protocol, immunization regimens with different combinations of adenovirus and plasmid vectors and with different sequences of intranasal, transcutaneous, and intramuscular delivery modes will be studied in a mouse model. The specific aims of this project are: Specific Aim #1: To develop a replication-defective, adenovirus-vectored vaccine against F. tularensis. Specific Aim #2: To compare the systemic and mucosal immunity elicited by the adenovirus-vectored vaccine delivered by combinations of intranasal, transcutaneous, and intramuscular administrations with that elicited by F. tularensis LVS through intradermal injection. Since no previous research has shown that genetic immunization with adenovirus or plasmid vectors could elicit protective immunity to F. tularensis, the proposed project is exploratory and developmental in nature.