A Novel Vaccine to Prevent Urinary Tract Infections

预防尿路感染的新型疫苗

基本信息

批准号：
8713666
负责人：
Drew Catron
金额：
$ 29.4万
依托单位：
SYNTIRON, LLC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-10 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8713666
关键词：
Accident and Emergency department Accounting Address Adjuvant Affect Animal Testing Animals Antibiotics Antigen-Presenting Cells Antigens Bacteria Bacterial Infections Biochemical Bladder Cell surface Chelating Agents Chitosan Clinical Data Development Disease Drug Formulations Engineering Ensure Environment Epithelium Escherichia coli Escherichia coli Vaccines Feces Female Future Goals Growth Health Care Costs Hospitalization Human Immune response Immunity Immunization Immunoglobulin A Immunoglobulin G Industry Infection Infectious Disease Immunology Invaded Iron Kidney Licensing Lipid Bilayers Lipoproteins Lymphoid Tissue Measures Mediating Medical Membrane Membrane Proteins Microbiology Monitor Morbidity - disease rate Mucosal Immune Responses Mucosal Immunity Multi-Drug Resistance Mus Mutation Nanotechnology Nutrient Organ Pathogenesis Patients Phase Population Probability Process Production Protein Subunits Proteins Recurrence Research Resistance Scientific Advances and Accomplishments Secretory Immunoglobulin A Serum Subunit Vaccines Surface System Technology Tissues United States Urinary tract Urinary tract infection Urine Vaccine Antigen Vaccine Design Vaccine Production Vaccines Variant Visit Woman Work base clinically relevant cost design economic impact evidence base experience immunogenic improved innovation innovative technologies manufacturing process manufacturing scale-up mouse model nano nanoparticle novel novel vaccines particle pathogen pathogenic Escherichia coli phase 1 study prevent protective efficacy protein expression public health relevance receptor resistant strain response standard of care success vaccine candidate vaccine delivery vaccine development vaccine efficacy vaccinology

项目摘要

DESCRIPTION (provided by applicant): Urinary tract infections (UTIs) caused by extraintestinal pathogenic E. coli (ExPEC) account for nearly 1.3 million emergency room visits and 245,000 hospitalizations per year for women in the U.S. alone. Approximately half of all women will experience a symptomatic UTI in their lifetime, and 25% will experience a recurrence within 6 to 12 months. While several attempts have been made to design a vaccine to address this important medical need, no vaccines are currently available. The goal of this proposal is to develop a broad- spectrum, multivalent subunit vaccine based on bacterial iron receptor proteins (IRPs). Iron is an essential nutrient for bacteria, and IRPs make excellent vaccine targets because they are highly conserved and are induced during infection in response to the low availability of iron in the host. Our innovative vaccine production strategy for bacteri mimics iron restriction through use of an iron chelator to enrich the content of these proteins on the surface of the cell, whereupon they can be purified through a proprietary platform process to create a subunit vaccine. Protective immunity to a pathogen such as ExPEC likely requires an optimal immune response at mucosal surfaces. Bacterial IRPs are attractive targets but present a significant challenge for vaccine development due to their insolubility and the low efficiency with which these antigens can be delivered across the mucosal epithelium to the underlying lymphoid tissue. The current proposal will address these issues by combining a novel IRP antigen composition with several innovative CpG delivery systems in order to maximize mucosal immune responses to ExPEC and provide protection against UTI. In Aim 1, IRPs will be purified from a selected, broadly-expressing ExPEC strain and incorporated into nanolipoprotein particles or derivatives of chitosan nanoparticles. Mice will be immunized with these nanoparticle formulations to screen for production of antigen-specific secretory IgA, thereby determining which types of nanoparticles stimulate a robust mucosal immune response to IRPs. Aim 2 will proceed to evaluate the protective efficacy of promising vaccine candidates in a clinically relevant mouse model of UTI. Successful completion of the work outlined in this proposal will provide proof of concept for a novel UTI vaccine based on iron receptors packaged in a nanoparticle delivery vehicle, advance our understanding of mucosal immunity, and provide an evidence- based rationale for the development of outer membrane protein subunit vaccines against bacterial pathogens that invade through a mucosal port of entry.

描述（由申请人提供）：尿路感染（UTI）是由肠外致病性大肠杆菌（EXPEC）造成的，仅美国妇女每年为近130万次急诊室就诊和245,000次住院。大约一半的女性将在其一生中经历有症状的UTI，而25％的女性将在6到12个月内复发。虽然已经尝试了几次设计疫苗来满足这一重要的医疗需求，但目前尚无疫苗。该提案的目的是基于细菌铁受体蛋白（IRP）开发广泛的多价亚基疫苗。铁是细菌的必不可少的营养素，而IRP是出色的疫苗靶标，因为它们是高度保守的，并且在宿主中铁的低可用性响应期间被诱导。我们通过使用铁螯合剂将这些蛋白质的含量丰富在细胞表面上的含量来模仿细菌的创新疫苗生产策略，因此可以通过专有的平台过程纯化它们以创建亚基疫苗。对病原体（例如EXPEC）的保护性免疫可能需要在粘膜表面具有最佳的免疫反应。细菌IRP是有吸引力的靶标，但由于疫苗的不溶性不溶以及这些抗原可以在粘膜上皮上递送到潜在的淋巴样组织的低效率，因此对疫苗发育带来了重大挑战。当前的建议将通过将新型IRP抗原组成与几种创新的CPG输送系统相结合，以最大程度地提高对EXPEC的粘膜免疫反应并提供对UTI的保护，以解决这些问题。在AIM 1中，IRP将从选定的，广泛表达的Expec菌株中纯化，并掺入壳聚糖纳米颗粒的纳米脂蛋白颗粒或衍生物中。这些纳米颗粒制剂将对小鼠进行免疫，以筛选产生抗原特异性分泌IgA，从而确定哪种类型的纳米颗粒刺激了对IRP的强大粘膜免疫反应。 AIM 2将继续评估在临床相关的UTI小鼠模型中有希望疫苗的保护性疗效。该提案中概述的工作的成功完成将为一种新型的UTI疫苗提供概念验证，以纳米颗粒递送工具包装的铁受体，提高我们对粘膜免疫的理解，并为通过细菌蛋白质亚基的开发提供了基于循证的基本原理，以通过细菌蛋白质亚基疫苗发育，以通过粉碎端口进入粉碎端口。