Development of a New Tularemia Vaccine

描述（由申请人提供）： 土拉菌病是一种人畜共患疾病，由剧毒、兼性细胞内细菌土拉弗朗西斯菌引起。由于这种细菌的毒力和其易于气溶胶传播，它已被列为A类生物恐怖主义制剂。一种含有F.土拉热LVS（活疫苗株）目前可作为研究性新药（IND）供人类使用。通过划痕接种;这种接种方法对于快速、大规模接种而言是次优的，并且该产品存在反应原性问题。因此，需要针对兔热病的改进的疫苗。本研究的目的是利用土拉菌的Tul 4、FopA、Cpn 60（热休克蛋白）和FT 23 KDAP（23 kDa蛋白）四种蛋白抗原，研制一种有效且易于接种的兔拉菌疫苗。土拉热菌作为疫苗组分，通过鼻内和经皮免疫途径用复制缺陷型腺病毒递送。这些非侵入性疫苗输送方法无疑将提高疫苗接种计划的依从性。本研究将构建Tul 4、FopA、Cpn 60和FT 23 KDAP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具有腺病毒和质粒载体的不同组合以及具有鼻内、经皮和肌内递送模式的不同序列的免疫方案。 该项目的具体目标是： 具体目标#1：开发针对F.土拉热。 具体目标#2：比较鼻内、经皮和肌内联合给药的腺病毒载体疫苗与F.土拉热LVS皮内注射。 由于以往的研究均未证实腺病毒或质粒载体的基因免疫能诱导对F. tularensis，拟议的项目是探索性和发展性的。

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.