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（由申请人提供）：尿路感染（UTI）是人类继呼吸道感染之后的第二大常见感染，这不仅导致巨大的年度经济成本，而且导致劳动力生产力下降和患者发病率高。感染是由尿路致病性大肠杆菌 (UPEC) 引起的，抗生素治疗通常可以有效根除感染菌株，但有文献记载。 抗生素耐药性的增加、对某些药物的过敏反应、正常肠道菌群的改变以及无法预防反复感染，都是治疗的重大障碍。因此，预防尿路感染的方法（例如疫苗接种）是实验室必须解决的一个空白。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。长期研究目标是预防患有复发性尿路感染的女性发生尿路感染。本次资助期间的目标是确定最佳的治疗方法。保护性抗原的组合包含在有效的 UTI 疫苗中的最佳佐剂、最佳剂量和最佳递送途径的中心假设指出，多亚单位疫苗可引发抗体或细胞介导的免疫，从而防止 UPEC 菌株的实验攻击。通过接种预防性疫苗来保护女性免受尿路感染的侵害 将通过实现两个具体目标来检验中心假设并完成目标： 1) 结合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) 确定针对尿路感染中尿路致病性大肠杆菌的优化疫苗的保护机制 之前，我们系统地确定了四种抗原，它们可以单独保护实验感染的小鼠免受 UPEC 定植。与霍乱毒素 (CT) 作为佐剂鼻内给药 为了推进疫苗在人类中的应用，我们将单独的抗原（IreA、Hma、IutA、FyuA）分组。有效组合建立多亚单位疫苗，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，对于所有四种疫苗抗原，抗原特异性血清 IgG 与呼吸道小鼠的保护作用密切相关。 .高抗体滴度与 肺炎小鼠经尿道攻击后 UPEC 的 CFU 较低，不能排除细胞介导的免疫的影响，我们建议在接种疫苗后进行实验研究，以评估长期保护、被动免疫、B 细胞和 T 细胞的参与。保护作用，以及抗体是否与 UPEC 表面结合并抑制有或无 UTI 病史的女性的血清，将测试疫苗抗原的抗体水平、表位识别以及引发的可能性。 UPEC 的调理吞噬作用在资助期结束时，我们的预期结果是为下一阶段的开发做好准备，以预防患有复发性尿路感染的女性的尿路感染。