Typhoid Vaccines Targeting Both Salmonella Typhi and Its Secreted Virulence Factor

项目摘要/摘要 伤寒是一个重大的全球卫生问题，在一些发展中国家持续发生疫情。 伤寒的病原体是革兰氏阴性杆菌伤寒沙门氏菌。它是最近发生的 发现伤寒沙门氏菌产生一种不寻常的毒素，即伤寒毒素。这项研究计划的目标是 是生产针对该细菌及其分泌的毒性因子伤寒毒素的伤寒疫苗， 并设计和指定这些疫苗的权利-内在-佐剂系统。在具体目标1中，我们将 对Ty21a疫苗株进行基因改造，使其表达灭活伤寒毒素，并针对特定目标2 将产生表达毒素受体结合亚基的Ty21a，而不表达其两个酶亚基。具体而言 目的3，我们将调查PltB变异体以确定其特定的糖链结合偏好，以便明确 调整PltB序列，旨在最大限度地提高目标年龄组的免疫反应性。修改后的 作为这项研究的一部分，生产的Ty21a疫苗预计会更有效，甚至可能有潜力 用于人类的应用程序。

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.