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）是人类第二常见的细菌感染。对于大多数感染，超过 10% 的感染者会出现复发性 (rec) UTI。尿路感染的复发率许多尿路感染疫苗正在接受测试，有些现已进入临床试验。经过近三十年的努力，目前尚未出现有效的尿路感染疫苗。针对细菌疫苗抗原产生的抗体在清除膀胱细菌方面部分有效，在消灭细菌之前，有必要将病原体特异性 Th1 免疫细胞招募到膀胱中。发现我们可以通过以下方式将大量的病原体清除 CD4 T 细胞招募到小鼠膀胱中经尿道滴注尿路致病疫苗抗原 (FimH) 和 Th1 极化佐剂 CpG 这种疫苗接种策略具有高度保护性，因为除了诱发 FimH 之外。全身特异性抗体，它们可以有效地将消灭病原体的 Th1 细胞招募到膀胱中，重要的是，这种疫苗不仅对幼鼠有效，而且对小鼠也有效。已经经历过多次尿路感染的患者，代表最有可能发生尿路感染的患者群体在进行临床研究之前，我们寻求进行更多的小鼠研究以优化疫苗。膀胱疫苗递送并确定从以下来源获得的保护和疫苗功效的适当替代物即使在有限的 1 期临床试验中也可以部署尿液和血液采样，因此，如下。提出了具体目标： (i) 检查膀胱疫苗接种是否采用含有疫苗抗原的疫苗纳米粒子可有效激发针对 UPEC 感染的局部保护性免疫力，无论是初次感染还是三次感染受感染的小鼠，以及（ii）确定小鼠保护的替代物和相关性，这些替代物和相关性可潜在用于评估膀胱疫苗接种效果。