Vaccine to prevent E. coli urinary tract infection

 描述(申请人提供)：尿路感染(UTI)是人类第二常见的感染，仅次于涉及呼吸道的感染。这不仅导致每年巨大的经济成本，而且导致劳动力生产率下降和患者发病率上升。大多数感染是由尿路致病性大肠埃希菌(UPEC)引起的。抗生素治疗通常对根除感染菌株是有效的，然而， 抗生素耐药性的增加，对某些药物的过敏反应，正常肠道菌群的改变，以及未能预防复发感染，都是治疗的重大障碍。因此，预防尿路感染的方法，如疫苗接种，是一个必须解决的缺口。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。长期的研究目标是预防复发尿路感染妇女的尿路感染。在这一资助期间的目标是确定有效的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。中心假说指出，多亚单位疫苗可诱导抗体或细胞介导的免疫，以抵御UPEC菌株的实验挑战。拟议工作的基本原理是通过接种预防性疫苗来保护妇女免受尿路感染的影响。中心假设将得到检验，目标将通过实现两个具体目标来完成：1)结合保护性抗原，建立有效的多亚单位疫苗，以预防尿路感染。2)确定优化疫苗对尿路感染致病大肠杆菌的保护作用机制。在此之前，我们系统地确定了四种抗原，当以霍乱毒素(CT)为佐剂鼻腔给药时，它们可以单独保护实验感染的小鼠免受UPEC对膀胱和/或肾脏的定植。为了推进疫苗在人类中的应用，我们将把单个抗原(IREA、HMA、Iuta、FyuA)组合成一个有效的组合，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，抗原特异性血清免疫球蛋白在免疫小鼠中表现出很强的保护性。高抗体滴度与 免疫小鼠经尿路攻击后UPEC的低CFU。不能排除细胞免疫的作用，也将在接种疫苗后进行实验研究。我们建议评估长期保护、被动免疫、B和T细胞参与保护，以及抗体是否与UPEC表面结合并抑制铁的获取和摄取。来自有和没有尿路感染病史的妇女的血清将被测试疫苗抗原的抗体水平、表位识别以及诱发UPEC吞噬细胞的可能性。在资助期结束时，我们的预期结果是一种优化的疫苗，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妇女的尿路感染。

 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.