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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.

项目概要/摘要伤寒是全球主要的健康问题，在一些发展中国家持续爆发。伤寒的病原体是革兰氏阴性菌伤寒沙门氏菌。已经是最近发现伤寒沙门氏菌产生一种不寻常的毒素，称为伤寒毒素。本研究计划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。在具体目标 1 中，我们将对 Ty21a 疫苗株进行基因改造，使其表达无活性的伤寒毒素，在具体目标 2 中，我们将生成表达毒素受体结合亚基的 Ty21a，但不包含其两个酶亚基。具体来说目标 3，我们将调查 PltB 变体以确定其特定的聚糖结合偏好，以便指定对 PltB 序列进行调整，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产生的 Ty21a 疫苗预计会更有效，甚至可能具有潜力用于人类的应用。