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（由应用程序提供）：尿路感染（UTI）是人类第二大最常见的感染，仅次于涉及呼吸道的人。这不仅造成了巨大的年度经济成本，而且导致劳动力生产率提高和患者发病率高。大多数感染是由肝病大肠杆菌（UPEC）引起的。抗生素治疗通常对于消除感染菌株有效，但是 增加抗生素耐药性，对某些药物的过敏反应，Norma肠道菌群的改变以及未能防止复发感染的未经抗生素反应，因此代表了预防UTI（例如疫苗）的方法，代表了必须解决的空白。该实验室在疫苗开发领域具有出色的往绩，并在开发针对UPEC的预防性疫苗方面取得了进展。长期的研究目标是防止反复发作的UTI女性的UTI。在此资助期间的目的是确定受保护抗原的最佳组合，以纳入有效的UTI疫苗，最佳调整，最佳剂量和最佳输送途径。中央假设指出，多生产疫苗会引起抗体或细胞介导的免疫力，可防止使用UPEC菌株实验性挑战。拟议工作的理由是通过施用预防性疫苗来保护妇女免受UTI的发展。将测试中央假设，并通过执行两个具体目的来完成目标：1）结合受保护的抗原以建立有效的多生产疫苗以防止尿路感染。 2）确定针对尿路感染中针对尿路发育大肠杆菌的优化疫苗保护的机理。以前，我们系统地鉴定了四种抗原，这些抗原可以单独保护被UPEC的膀胱和/或肾脏的实验感染小鼠免受膀胱和/或肾脏的定殖，而用霍乱毒素（CT）进行了调节。为了将疫苗促进人类的效用，我们将对单个抗原（IREA，HMA，IUTA，FYUA）进行分组，以建立多生疫苗的有效组合，并优化当前用于人类免疫接种的调节剂，剂量和接种途径。我们证明了所有四种疫苗抗原，抗原特异性血清IgG代表了疫苗接种小鼠保护的强相关性。高抗体滴度与 接种疫苗的小鼠经尿道挑战后UPEC的低CFU。细胞介导的免疫学的贡献不能排除，也将在疫苗后进行实验研究。我们建议评估长期保护，被动免疫学，B和T细胞参与保护，以及抗体是否与UPEC表面结合并抑制铁的获取和摄取。具有和没有UTI史的女性的血清将测试疫苗抗原，表位识别的抗体水平，以及引起UPEC的吞噬性胞毒性的潜力。在资金期结束时，我们的预期结果是一种优化的疫苗，准备下一阶段的开发疫苗，以防止反复发作的尿路病毒女性的UTI。