Typhoid Vaccines Targeting Both Salmonella Typhi and Its Secreted Virulence Factor

针对伤寒沙门氏菌及其分泌的毒力因子的伤寒疫苗

基本信息

批准号：
10160775
负责人：
Jeongmin Song
金额：
$ 39.25万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-08 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160775
关键词：
Adjuvant Adult Affect Africa Africa South of the Sahara Agreement Amino Acids Animals Antibiotic Therapy Antigens Area Asia Attenuated Bacteria Binding Catalysis Cell surface Cells Cessation of life Child Clinical Research Developing Countries Development Disease Disease Outbreaks Dose Engineering Failure Gastroenteritis Genes Genetic Engineering Goals Gram-Negative Bacteria Human Immune Immune response Immunization Immunize Individual Infection Knowledge Laboratory Animals Life Malawi Mediating Multi-Drug Resistance Mus Mutate Neurologic Patients Pilot Projects Play Polysaccharides Prevalence Reporting Research Role SWI1 Salmonella Salmonella typhi Southeastern Asia Specific qualifier value Surveys Symptoms System Testing To specify Toxic effect Toxin Toxoids Tropism Ty21a typhoid vaccine Typhoid Fever Typhoid Vaccine Vaccinated Vaccination Vaccines Vacuole Variant Virulence Factors World Health Organization age group attenuation base clinical development design global health holotoxins immunoreactivity in vivo islet neutralizing antibody novel preference prevent programs promoter receptor binding resistant strain vaccine candidate

项目摘要

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.

项目摘要 /摘要伤寒是全球主要的健康问题，在一些发展中国家中发生了持续的爆发。伤寒的真正药物是革兰氏阴性细菌，沙门氏菌鼠伤寒。最近已经发现鼠伤寒链球菌会产生一种不寻常的毒素，称为伤寒毒素。该研究计划的目标是为了产生靶向细菌及其分泌病毒因子伤寒毒素的伤寒疫苗，并设计和指定这些疫苗的右内辅助系统。在特定目标1中，我们将从遗传上设计Ty21a疫苗菌株，使其表达不活跃的伤寒毒素，在特定的目标2中我们将生成Ty21a，表达毒素的接收器结合亚基，而无需其两个酶促亚基。具体 AIM 3，我们将调查PLTB变体以定义其特定的聚糖结合偏好，以指定对PLTB序列进行调整，旨在最大化目标年龄组的免疫反应性。修改后作为这项研究的一部分，产生的TY21a疫苗有望更有效，甚至可能具有潜力人类用途的应用。