Vaccine to prevent E. coli urinary tract infection

预防大肠杆菌尿路感染的疫苗

• 批准号: 9186483
• 负责人: HARRY L. MOBLEY
• 金额: $ 38.79万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186483
• 关键词: Address; Adjuvant; Allergic Reaction; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Antibodies; Antibody titer measurement; Antigens; B-Lymphocytes; Bacteriuria; Binding; Bladder; Canada; Cellular Immunity; Cholera Toxin; Ciprofloxacin; Cystitis; Data; Development; Documentation; Dose; Effectiveness; Epitopes; Escherichia coli; Failure; Fostering; Frequencies; Funding; Goals; Health; Heterogeneity; Human; Immunization; Immunoglobulin G; Incidence; Individual; Infection; Infection prevention; Intestines; Iron; Kidney; Laboratories; Life; Medical; Mission; Morbidity - disease rate; Multi-Drug Resistance; Mus; Outcome; Passive Immunization; Patients; Peer Review; Pharmacologic Substance; Phase; Physicians; Population; Predisposition; Prevalence; Preventive vaccine; Productivity; Public Health; Publishing; Quality of life; Recording of previous events; Recurrence; Research; Resistance; Respiratory System; Respiratory tract structure; Route; Scourge; Serum; Severities; Subunit Vaccines; Surface; Symbiosis; T-Lymphocyte; Testing; Trimethoprim-Sulfamethoxazole; United States National Institutes of Health; Ureter; Urethra; Urinary tract infection; Uropathogenic E. coli; Vaccinated; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; Woman; Work; acute pyelonephritis; adaptive immune response; burden of illness; combat; cost; disability; economic cost; experience; improved; innovation; microbial; pathogen; prevent; public health relevance; resistance mechanism; resistant strain; uptake; urinary; vaccine development

 DESCRIPTION (provided by applicant): Urinary tract infection (UTI) is the second most common infection in humans after those involving the respiratory tract. This results not only in huge annual economic costs, but in decreased workforce productivity, and high patient morbidity. Most infections are caused by uropathogenic Escherichia coli (UPEC). Antibiotic treatment is generally effective for eradication of the infecting strain, however, documentation of increasing antibiotic resistance, allergic reaction to certain pharmaceuticals, alteration of norma gut flora, and failure to prevent recurrent infections, represent significant barriers to treatment As a result, approaches to prevent UTI such as vaccination represent a gap that must be addressed. The laboratory has an outstanding track record in the field of vaccine development and has made progress toward development of a preventive vaccine against UPEC. The long-term research goal is to prevent UTIs in women with recurrent UTI. The objective during this funding period is to identify the optimal combination of protective antigens for inclusion in an effective UTI vaccine, optimal adjuvant, optimal dose, and optimal route of delivery. The central hypothesis states that a multi-subunit vaccine elicits antibody or cell-mediated immunity that protects against experimental challenge with UPEC strains. The rationale for the proposed work is to protect women from the development of UTI by administration of a preventive vaccine. The central hypothesis will be tested and objectives will be completed by carrying out two specific aims: 1) Combine protective antigens to establish an effective multi- subunit vaccine to prevent urinary tract infection. 2) Identify the mechanism of protection for the optimized vaccine against uropathogenic E. coli in urinary tract infection. Previously, we systematically identified four antigens that can individually protect experimentally infected mice from colonization of the bladder and/or kidneys by UPEC when administered intranasally with cholera toxin (CT) as adjuvant. To advance the vaccine for utility in humans, we will group the individual antigens (IreA, Hma, IutA, FyuA) into an effective combination to establish a multi-subunit vaccine, and optimize the adjuvants, doses, and routes of inoculation currently used for immunization of humans. We demonstrated for all four vaccine antigens that antigen-specific serum IgG represents a strong correlate of protection in vaccinated mice. High antibody titers correlate with low CFUs of UPEC following transurethral challenge of vaccinated mice. The contribution of cell-mediated immunity cannot be ruled out and will also be investigated experimentally following vaccination. We propose to assess long-term protection, passive immunization, the involvement of B and T cells in protection, and whether antibodies bind to the surface of UPEC and inhibit iron acquisition and uptake. Sera from women with and without histories of UTI will be tested for antibody levels to vaccine antigens, epitope recognition, and the potential for eliciting opsonophagocytosis of UPEC. At the conclusion of the funding period, our expected result is an optimized vaccine ready for the next phase of development to prevent UTI in women with recurrent UTI.

 描述（由申请方提供）：尿路感染（UTI）是人类第二常见的感染，仅次于呼吸道感染。这不仅导致巨大的年度经济成本，而且降低了劳动力生产率和高患者发病率。大多数感染是由尿路致病性大肠杆菌（UPEC）引起的。抗生素治疗通常对根除感染菌株有效，然而， 抗生素耐药性的增加、对某些药物的过敏反应、正常肠道植物群的改变以及未能预防复发性感染是治疗的重大障碍。因此，预防尿路感染的方法（例如疫苗接种）代表了必须解决的差距。该实验室在疫苗开发领域有着出色的记录，并在开发针对UPEC的预防性疫苗方面取得了进展。长期研究的目标是预防复发性UTI女性的UTI。本资助期的目标是确定有效UTI疫苗中包含的保护性抗原的最佳组合、最佳佐剂、最佳剂量和最佳给药途径。中心假设指出，多亚单位疫苗激发抗体或细胞介导的免疫，保护免受UPEC菌株的实验性攻击。拟议工作的基本原理是通过预防性疫苗的管理来保护妇女免受UTI的发展。将检验中心假设，并通过实施两个具体目标来完成目标：1）联合收割机保护性抗原以建立有效的多亚单位疫苗来预防尿路感染。2)进一步研究优化疫苗的免疫保护机制。大肠埃希菌在尿路感染中的作用。以前，我们系统地确定了四种抗原，可以单独保护实验感染的小鼠，从膀胱和/或肾脏的UPEC定植时，鼻内注射霍乱毒素（CT）作为佐剂。为了推进疫苗在人类中的实用性，我们将单个抗原（IreA，Hma，IutA，FyuA）分组为有效组合以建立多亚单位疫苗，并优化目前用于人类免疫的佐剂，剂量和接种途径。我们证明了对于所有四种疫苗抗原，抗原特异性血清IgG在接种疫苗的小鼠中代表保护的强相关性。高抗体滴度与 接种小鼠经尿道激发后UPEC的CFU较低。不能排除细胞介导免疫的作用，也将在接种后进行实验研究。我们建议评估长期保护，被动免疫，B和T细胞参与保护，以及抗体是否结合到UPEC表面并抑制铁的获得和吸收。将检测有和无UTI病史的女性血清中疫苗抗原的抗体水平、表位识别和引发UPEC调理吞噬作用的潜力。在资助期结束时，我们的预期结果是一种优化的疫苗，可用于下一阶段的开发，以预防复发性UTI女性的UTI。