Typhoid Vaccines Targeting Both Salmonella Typhi and Its Secreted Virulence Factor

项目总结/摘要 伤寒是一个主要的全球健康问题，在一些发展中国家正在发生疫情。 伤寒的病原体是革兰氏阴性细菌伤寒沙门氏菌。最近已经 发现S.伤寒产生一种不寻常的毒素，称为伤寒毒素。这个研究项目的目标 是生产针对细菌及其分泌的毒力因子伤寒毒素的伤寒疫苗， 并设计和指定这些疫苗的正确内在佐剂系统。具体目标1： 对Ty21a疫苗株进行基因工程改造，使其表达非活性伤寒毒素，在特定目标2中， 将产生表达毒素的受体结合亚基而没有其两个酶亚基的Ty21a。在特定 目的3，我们将调查PltB变体以定义它们的特异性聚糖结合偏好，以便指定PltB变体的结构。 调整PltB序列，旨在最大化目标年龄组的免疫反应性。修改后的 作为本研究的一部分，Ty21a疫苗预计将更有效，甚至可能具有潜力。 应用于人类。

PROJECT SUMMARY / ABSTRACT Typhoid fever is a major global health concern, with ongoing occurring outbreaks in some developing countries. The causative agent of typhoid fever is the gram-negative bacterium, Salmonella Typhi. It has been recently discovered that S. Typhi produces an unusual toxin known as typhoid toxin. The goal of this research program is to generate typhoid fever vaccines targeting both the bacterium and its secreted virulence factor typhoid toxin, and to design and specify the right-intrinsic-adjuvant system of those vaccines. In Specific Aim 1 we will genetically engineer the Ty21a vaccine strain to make it express inactive typhoid toxin, and in Specific Aim 2 we will generate Ty21a expressing the toxin’s receptor binding subunit without its two enzymatic subunits. In Specific Aim 3, we will survey PltB variants to define their specific glycan binding preference, in order to specify the adjustment on the PltB sequence, aimed at maximizing immunoreactivities of targeted age groups. The modified Ty21a vaccines generated as part of this study are expected to be more effective and may even have potential applications for uses in humans.