Vaccine to prevent E. coli urinary tract infection

目前，在美国还没有获得许可的疫苗来保护人类免受尿路感染（UTI）。 UTI是人类第二大常见的感染，仅次于呼吸道感染。这种高频率的 感染不仅导致巨大的年度经济成本，而且导致劳动力生产率降低和患者高风险。 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。我们的长期研究目标是开发 通过接种疫苗预防UTI的方法，这代表了必须解决的差距。我们的目标是 加强抗原组合以包括铁载体和新的佐剂， 鼻内UTI疫苗。在当前的资助期内，我们确定用两种UPEC进行鼻内免疫， 抗原，Hma和IutA，使用dmLT [E.大肠杆菌不耐热毒素：（R192 G/L211 A）]作为佐剂， 减少UPEC攻击后的膀胱细菌负荷。我们的中心假设是一个多亚基 疫苗激发免疫应答，保护免受UPEC菌株的实验性攻击。工作 为了获得更有效的疫苗，我们已经鉴定了另外的保护性抗原，铁载体受体FyuA 以及两种铁载体，耶尔森菌素和需氧菌素，也靶向UPEC。LTA 1也被确定为 有效新型佐剂。尽管许多女性经历复发性UTI和UPEC异质性， 疫苗设计，我们的动物模型和人体研究数据为成功的UPEC提供了鼓励 疫苗研发。拟议工作的理由是，保护妇女免受经常性暴力的发展， UTI通过简单的疫苗管理。我们将测试我们的中心假设，并完成我们的目标， 实现两个特定目的：1）将保护性抗原Hma和IutA与FyuA和铁载体结合， 用于建立预防复发性尿路的有效鼻内多亚单位疫苗的新佐剂 感染; 2）确定优化的疫苗对尿路致病性E.杆菌 尿路感染对于具体的目标1，我们将建立在我们的决心，鼻内疫苗含有 铁获得蛋白Hma和IutA可以保护小鼠免受UPEC引起的UTI， 粘膜佐剂。对于具体目标2，我们将进行具体的免疫学和生理学实验， 确定宿主如何通过疫苗接种保护免受UPEC感染。建议的研究是创新的 因为我们建议将两种保护性抗原的发现与铁载体和新佐剂结合联合收割机， 通过UPEC预防UTI。这是重要的，因为它将允许开发疫苗，以防止 感染不同的UPEC菌株，提供广泛的保护，对UTI。积极的影响将是防止 这种公共卫生灾难的妇女与复发性UTI和那些容易受到他们的第一个UTI。

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.