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)。 尿路感染是人类仅次于呼吸道感染的第二大常见感染。这种高频率的 感染不仅会导致每年巨大的经济成本，而且会导致劳动力生产率下降和患者人数增加 发病率。这些感染中至少有80%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是有效的。然而，增加抗生素 耐药性、对某些药物的过敏反应、正常肠道菌群改变以及未能预防 反复感染是治疗的重大障碍。我们的长期研究目标是发展 通过接种疫苗预防尿路感染的方法，这是一个必须解决的差距。我们的目标是 加强抗原组合，包括铁载体和新佐剂，以纳入有效的 鼻腔UTI疫苗。在目前的筹资期间，我们确定了两种UPEC鼻腔免疫 抗原HMA和IutA，以dmLT[大肠杆菌不耐热毒素双突变体(R192G/L211A)]为佐剂， 减少UPEC挑战后的膀胱细菌负荷。我们的中心假设是，一个多亚基 疫苗可引起免疫反应，以抵御UPEC菌株的实验挑战。劳作 为了更有效的疫苗，我们已经确定了额外的保护性抗原，铁载体受体FyuA 还有两个铁载体，也是针对UPEC的yersiniabactin和Aerobactin。LTA1也已被确定为 有效的新型佐剂。尽管许多女性经历了反复的尿路感染和UPEC，但异质性变得复杂 疫苗设计、我们动物模型和人体研究的数据为UPEC的成功提供了鼓舞 疫苗研发。拟议工作的基本原理是保护妇女免受复发的影响。 通过简单地接种疫苗来治疗尿路感染。我们将测试我们的中心假设并通过以下方式完成我们的目标 执行两个具体目标：1)将保护性抗原HMA和IutA与FyuA和铁载体结合，并 新型佐剂构建预防尿路复发的鼻腔多亚单位疫苗 2)确定优化疫苗对尿路致病性大肠杆菌的保护作用机制。 尿路感染。对于特定的目标1，我们将建立在我们的决心基础上，鼻腔疫苗含有 铁获取蛋白HMA和IutA经鼻给药可保护小鼠免受UPEC的尿路感染 粘膜佐剂。针对特定目标2，我们将进行特定的免疫和生理实验，以 确定如何通过接种疫苗保护宿主免受UPEC感染。建议的研究具有创新性。 因为我们建议将发现的两种具有铁载体的保护性抗原和新型佐剂结合起来 通过UPEC预防UTI。这一点意义重大，因为它将允许开发一种疫苗来预防 被不同的UPEC菌株感染，提供对尿路感染的广泛保护。积极的影响将是防止 这一公共卫生祸害发生在患有复发性尿路感染的妇女和首次尿路感染易感人群中。

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.