A novel vaccination strategy to curb recUTIs

遏制复发尿路感染的新型疫苗接种策略

基本信息

批准号：
10665990
负责人：
Soman N Abraham
金额：
$ 24.15万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-12 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10665990
关键词：
Adjuvant Age Antibodies Antigens Bacteria Bacterial Adhesins Bacterial Infections Bacterial Vaccines Bladder Bladder mucosa Blood CD4 Positive T Lymphocytes Cells Clinical Clinical Research Clinical Trials Country Data Defect Epithelial Cells Epithelium Escherichia coli Escherichia coli Infections Escherichia coli Vaccines Female Flare Formulation Future Hair Human IgG1 Immune Immune response Immunity Immunization Immunize Immunoglobulin A Immunoglobulin G Infection Interferon Type II Interleukin-2 Intramuscular Intravesical Administration Invaded Longevity Mediating Methods Mucous Membrane Mus Nature Patients Phase I Clinical Trials Positioning Attribute Property Recurrence Sampling Suppositories Testing Th1 Cells Time Urethra Urinary tract infection Urine Uropathogenic E. coli Vaccinated Vaccination Vaccine Antigen Vaccinee Vaccines Vagina Woman appendage cytokine draining lymph node effectiveness testing experience first-in-human nanoparticle novel novel vaccines oral bacteria pathogen patient population prevent recruit response success trafficking type 1 fimbriae vaccination strategy vaccine delivery vaccine efficacy vaccine strategy vaccine trial

项目摘要

ABSTRACT Urinary tract infections (UTIs) are the second most common bacterial infections in humankind. Women account for most infections with over 10% of infected subjects experiencing recurrent (rec)UTIs. Because of the high recurrence rates of UTIs many UTI vaccines are being tested and some are now in clinical trials. However, after almost three decades of effort, no effective UTI vaccine has yet emerged. Recently, we found that while antibodies raised against bacterial vaccine antigens are partially effective in clearing bladder bacteria, it is necessary to recruit pathogen-specific Th1 immune cells into the bladder before bacteria are eradicated. We found that we could recruit robust numbers of pathogen-clearing CD4 T cells into mouse bladders by transurethral instillation of a uropathogenic vaccine antigen (FimH) along with a Th1 polarizing adjuvant, CpG oligodeoxynucleotides. This vaccination strategy was highly protective because in addition to evoking FimH specific antibodies systemically, they were effective in recruiting pathogen eradicating Th1 cells into the bladder, potentially preventing future recurrence. Importantly, this vaccine was efficacious in naïve mice but also, in mice that have already experienced multiple UTIs, representing the population of patients most likely to receive a UTI vaccine. Before we advance to clinical studies, we seek to undertake additional mouse studies to optimize the bladder vaccine delivery and to identify appropriate surrogates of protection and vaccine efficacy obtained from sampling urine and blood that can be deployed even in a limited phase 1 clinical trial. Therefore, the following specific aims are proposed: (i), examine if bladder vaccination employing vaccine antigen containing nanoparticles is effective in evoking local protective immunity against UPEC infections in both naïve and thrice infected mice and (ii), identify surrogates and correlates of protection in mice that can potentially be used to evaluate bladder vaccination efficacy.

抽象的尿路感染（UTI）是人类中第二大常见的细菌感染。妇女帐户对于大多数感染，超过10％的感染受试者会经历复发性（REC）UTI。因为很高 UTI的复发率正在测试许多UTI疫苗，现在有些正在临床试验中。但是，之后将近三十年的努力，尚未出现有效的UTI疫苗。最近，我们发现针对细菌疫苗抗原提出的抗体在清除膀胱细菌方面有效，是在发出细菌之前，将病原体特异性TH1免疫细胞募集到膀胱中所需。我们发现我们可以通过尿道疾病疫苗抗原（FIMH）以及Th1极化调节，CpG的尿道渗透滴注寡脱氧核苷酸。这种疫苗接种策略受到了高度保护，因为除了唤起FIMH之外特异性抗体从系统上有效地募集了将Th1细胞根除到膀胱中的病原体，有可能防止未来复发。重要的是，这种疫苗在幼稚的小鼠中有效，但在小鼠中也有效已经经历了多个UTI，代表最有可能接受UTI的患者人群疫苗。在进行临床研究之前，我们试图进行其他小鼠研究以优化膀胱疫苗输送并确定从中获得的适当的保护和疫苗效率即使在有限的1阶段临床试验中，可以采样尿液和血液。因此，以下内容提出了具体目的：（i）检查是否采用含有疫苗抗原的膀胱疫苗纳米颗粒可有效诱发局部保护性免疫，以抗幼稚和三次的UPEC感染受感染的小鼠和（ii），识别小鼠保护的替代物和相关性评估膀胱疫苗接种效率。