A novel vaccination strategy to curb recUTIs

摘要 尿路感染(UTIs)是人类第二常见的细菌感染。女性账户 对于大多数感染，超过10%的感染者经历反复(REC)尿路感染。因为有这么高 尿路感染的复发率许多尿路感染疫苗正在进行测试，有些正在进行临床试验。然而，在 经过近三十年的努力，还没有出现有效的尿路感染疫苗。最近我们发现，虽然 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，它是 在细菌被根除之前，有必要将病原体特异性的Th1免疫细胞招募到膀胱中。我们 我们发现，我们可以通过以下方式将大量清除病原体的CD4T细胞招募到小鼠的膀胱中 经尿路注射尿路致病疫苗抗原(FimH)和Th1极化佐剂CpG 寡聚脱氧核苷酸。这种疫苗接种策略具有高度的保护性，因为除了唤起FimH 从系统上讲，它们能有效地招募病原体，将Th1细胞根除到膀胱内， 潜在地防止了未来的复发。重要的是，这种疫苗对幼稚的小鼠有效，但对小鼠也有效。 已经经历过多次尿路感染的患者，代表最有可能接受尿路感染的患者群体 疫苗。在我们进行临床研究之前，我们寻求进行更多的小鼠研究，以优化 膀胱疫苗的投放和确定合适的替代物的保护和疫苗效力从 采样尿液和血液，即使在有限的第一阶段临床试验中也可以使用。因此，以下是 具体目标被提出：(I)检查使用疫苗抗原进行的膀胱疫苗接种是否含有 纳米粒在幼稚和三次激发对UPEC感染的局部保护性免疫方面有效 受感染的小鼠和(Ii)确定在小鼠中可能被用来 评价膀胱疫苗接种效果。

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.