Vaccine to prevent E. coli urinary tract infection

预防大肠杆菌尿路感染的疫苗

基本信息

批准号：
10464436
负责人：
HARRY L. MOBLEY
金额：
$ 42.31万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10464436
关键词：
Address Adjuvant Allergic Reaction Animal Model Antibiotic Resistance Antibiotic Therapy Antigen Targeting Antigens Appearance Applied Research Bacteriuria Basic Science Bladder Canada Ciprofloxacin Collection Communicable Diseases Cystitis Data Development Dose Effectiveness Escherichia coli Escherichia coli Infections Escherichia coli Vaccines Escherichia coli heat-labile toxin Failure Frequencies Funding Goals Heterogeneity Human Immune response Immunization Immunologics Incidence Infection Infection prevention Intestines Iron Kidney Lead Life Mission Morbidity - disease rate Mucous Membrane Multi-Drug Resistance Mus National Institute of Allergy and Infectious Disease Nitrofurantoin Outcome Patients Peer Review Pharmacologic Substance Physiological Prevention Preventive therapy Productivity Proteins Public Health Publishing Quality of life Recurrence Research Resistance Respiratory System Route Scourge Severities Siderophores Subunit Vaccines Testing Trimethoprim-Sulfamethoxazole United States National Institutes of Health Ureter Urethra Urinary tract infection Urine Uropathogenic E. coli Vaccination Vaccine Design Vaccines Woman Work acute pyelonephritis aerobactin barrier to care burden of illness combat cost disability economic cost experience experimental study gut microbiota improved infection management innovation mutant novel pathogen prevent receptor recurrent infection siderophore receptors small molecule societal costs vaccine development yersiniabactin

项目摘要

Currently, there is no licensed vaccine to protect humans against urinary tract infection (UTI) in the U.S. Indeed, UTI is the second most common infection in humans after those of the respiratory tract. This high frequency of infection results not only in huge annual economic costs, but in decreased workforce productivity and high patient morbidity. At least 80% of these infections are caused by uropathogenic Escherichia coli (UPEC). Antibiotic treatment is generally effective for eradication of the infecting strain. However, increasing antibiotic resistance, allergic reaction to certain pharmaceuticals, alteration of normal gut flora, and failure to prevent recurrent infections, represent significant barriers to treatment. Our long-term research goal is to develop approaches to prevent UTI by vaccination, which represents a gap that must be addressed. Our objective is to strengthen antigen combinations to include siderophores and novel adjuvants for inclusion in an effective intranasal UTI vaccine. In the current funding period, we determined that intranasal immunization with two UPEC antigens, Hma and IutA, using dmLT [double mutant of E. coli heat-labile toxin: (R192G/L211A)] as adjuvant, reduces bladder bacterial load following challenge with UPEC. Our central hypothesis states that a multi-subunit vaccine elicits an immune response that protects against experimental challenge with UPEC strains. Working toward a more effective vaccine, we have identified additional protective antigens, siderophore receptor FyuA and two siderophores, yersiniabactin and aerobactin that also target UPEC. LTA1 has also been identified as an effective novel adjuvant. Although many women experience recurrent UTI and UPEC heterogeneity complicates vaccine design, data from our animal model and human studies offer encouragement for successful UPEC vaccine development. The rationale for the proposed work is to protect women from the development of recurrent UTI by simple administration of a vaccine. We will test our central hypothesis and complete our objectives by carrying out two specific aims: 1) Combine protective antigens Hma and IutA with FyuA and siderophores and novel adjuvants to establish an effective intranasal multi-subunit vaccine for prevention of recurrent urinary tract infection; and 2) Identify the mechanism of protection for the optimized vaccine against uropathogenic E. coli in urinary tract infection. For specific aim 1, we will build on our determination that an intranasal vaccine containing iron acquisition proteins Hma and IutA can protect mice from UTI by UPEC when delivered intranasally with a mucosal adjuvant. For specific aim 2, we will conduct specific immunological and physiological experiments to determine how the host is protected from UPEC infection by vaccination. The proposed research is innovative because we propose to combine discovery of two protective antigens with siderophores and novel adjuvant to protect against UTI by UPEC. This is significant because it will allow for development of a vaccine to prevent infection by diverse UPEC strains, providing broad protection against UTI. The positive impact will be to prevent this public health scourge in women with recurrent UTI and those susceptible to their first UTI.

目前，美国还没有获得许可的疫苗可以保护人类免受尿路感染 (UTI)。事实上，尿路感染是人类第二常见的感染，仅次于呼吸道感染。这种高频度感染不仅导致每年巨大的经济成本，而且导致劳动力生产力下降和患者高发病率。这些感染中至少 80% 是由尿路致病性大肠杆菌 (UPEC) 引起的。抗生素治疗通常可有效根除感染菌株。然而，增加抗生素耐药性、对某些药物的过敏反应、正常肠道菌群的改变以及未能预防反复感染是治疗的重大障碍。我们的长期研究目标是开发通过疫苗接种来预防尿路感染的方法，这是一个必须解决的差距。我们的目标是加强抗原组合，包括铁载体和新型佐剂，以包含在有效的鼻内尿路感染疫苗。在当前资助期间，我们确定使用两种 UPEC 进行鼻内免疫抗原，Hma 和 IutA，使用 dmLT [大肠杆菌不耐热毒素双突变体：(R192G/L211A)] 作为佐剂，减少 UPEC 攻击后的膀胱细菌负荷。我们的中心假设指出，多亚基疫苗引发免疫反应，防止 UPEC 菌株的实验挑战。在职的为了开发更有效的疫苗，我们已经确定了额外的保护性抗原，铁载体受体 FyuA 以及两种铁载体，耶尔森菌素和气杆菌素，也针对 UPEC。 LTA1 也被确定为有效的新型佐剂。尽管许多女性经历过复发性尿路感染，但 UPEC 的异质性使情况变得复杂疫苗设计、动物模型数据和人体研究为 UPEC 的成功提供了鼓励疫苗开发。拟议工作的理由是保护妇女免受复发性通过简单地注射疫苗即可感染尿路感染。我们将测试我们的中心假设并通过以下方式完成我们的目标实现两个具体目标：1) 将保护性抗原 Hma 和 IutA 与 FyuA 和铁载体结合，新型佐剂建立有效的鼻内多亚单位疫苗以预防尿路复发感染; 2) 确定针对尿路致病性大肠杆菌的优化疫苗的保护机制尿路感染。对于具体目标 1，我们将基于我们的决定，即鼻内疫苗含有当用 UPEC 鼻内递送时，铁获取蛋白 Hma 和 IutA 可以保护小鼠免受尿路感染粘膜佐剂。针对具体目标2，我们将进行具体的免疫学和生理学实验确定如何通过疫苗接种保护宿主免受 UPEC 感染。所提出的研究具有创新性因为我们建议将两种保护性抗原的发现与铁载体和新型佐剂结合起来通过 UPEC 预防尿路感染。这很重要，因为它将有助于开发疫苗来预防多种 UPEC 菌株的感染，提供针对 UTI 的广泛保护。积极影响将是防止对于患有复发性尿路感染和易患首次尿路感染的女性来说，这是一种公共卫生祸害。