Yersinia pseudotuberculosis-based vaccines for plague and yersiniosis

项目摘要 鼠疫耶尔森氏菌是鼠疫的病原体，它通过引起一种疾病而深刻地塑造了人类历史。 估计有两亿人死于三大流行病。被认为是一个重新出现的病原体，Y。鼠疫 仍然是一个公共卫生问题，并造成全球每年数千例鼠疫病例。 地方性鼠疫疫源地通过啮齿动物宿主和跳蚤媒介之间的人畜共患循环而持续存在。在 除自然蚤传外，Y.鼠疫有着悠久的生物战操纵历史 并被列为现代武器化的主要威胁。鼠疫是世界上最急性、 具有威胁性的表现，具有高度传染性，很容易通过空气传播在人与人之间传播 飞沫，导致疾病迅速发作，如果治疗延误，死亡率接近100% 24 几小时后才出现症状目前，美国没有获得许可的鼠疫疫苗。 耶尔森氏菌病是指由耶尔森氏菌属的物种引起的肠道感染。有两种亚型 导致耶尔森氏菌病、小肠结肠炎耶尔森氏菌（Ye）和假结核耶尔森氏菌（Yptb）。Ye和Yptb 是一种在环境和多种动物中循环的粪-口人兽共患病病原体 后备役军人通过偶然的食源性接触，人类可能会患上耶尔森氏菌病，最终可能导致 全身感染和感染后肠外后遗症。除了直接的人类健康风险外， 耶尔森氏菌病造成相当大的食品安全经济负担， 生产损失。然而，对耶尔森氏菌病疫苗开发的关注有限。 我们以前在构建重组Yptb载体疫苗方面取得了实质性进展 旨在预防鼠疫和耶尔森氏菌病的候选人。基于我们建立的重组 减毒沙门氏菌疫苗平台，一种针对鼠疫和耶尔森氏菌病的Yptb疫苗将赋予 几个关键优势包括（1）无针口服给药，（1）低成本疫苗生产，和（3） 体液和细胞免疫应答的强力诱导，和（4）人类和环境诱饵递送。 此外，我们努力在没有佐剂补充的情况下单剂量引发保护性免疫。我们 先前证明用减毒Yptb菌株免疫可增强抗Y. 鼠疫和叶此外，免疫原性对Y.鼠疫杆菌很容易被3型分泌系统增强 递送异源抗原。因此，用改进的减毒活Yptb菌株免疫应 刺激针对Y交叉保护免疫。鼠疫菌引起鼠疫，Ye和Yptb引起耶尔森氏病。

PROJECT SUMMARY Yersinia pestis, the causative agent of plague, has profoundly shaped human history by causing an estimated 200 million deaths amid three major pandemics. Considered to be a re-emerging pathogen, Y. pestis remains a public health issue and is responsible for several thousand worldwide annual cases of plague. Endemic plague foci persist through zoonotic circulation among rodent reservoir hosts and flea vectors. In addition to natural flea-borne acquisition, Y. pestis has an extensive history of biological warfare manipulations and is categorized as a prime threat for modern weaponization. Pneumonic plague, the most acute and threatening manifestation, is highly contagious and easily transmitted from person-to-person through airborne droplets, resulting in a rapid onset of disease and a mortality rate approaching 100% if treatment is delayed 24 hours beyond symptom onset. Currently, no licensed plague vaccines are available in the United States. Yersiniosis refers to an enteric infection by species of the genus Yersinia. There are two subtypes responsible for yersiniosis, Yersinia enterocolitica (Ye) and Yersinia pseudotuberculosis (Yptb). Ye and Yptb are fecal-oral zoonotic pathogens which ciruclate among environmental and a broad range of animal reserviors. Through incidental food-borne exposure, humans can develop yersiniosis, potentially culminating in systemic infection and postinfectious extraintestinal sequelae. In addition to direct human health risks, yersiniosis confers a considerable food-safety economic burden and is responsible for substantial livestock production loss. However, limited attention has been devoted toward vaccine development for yersiniosis. We have previously made substantial headway in the construction of a recombinant Yptb vector vaccine candidate aimed at preventing both plague and yersiniosis. Based upon our established recombinant attenuated Salmonella vaccine platform, a Yptb-based vaccine against plague and yersiniosis will impart several key advantages including (1) needle-free oral administration, (1) low-cost vaccine production, and (3) robust induction of humoral and cellular immune responses, and (4) human and environmental bait delivery. Additionally, we strive to elicit protective immunity upon a single dose without adjuvant supplementation. We previously demonstrated that immunization with attenuated Yptb strains elicits cross-protection against Y. pestis and Ye. Furthermore, immunogenicity against Y. pestis is readily enhanced by type 3 secretion system delivering heterologous antigens. Therefore, immunization with improved live attenuated Yptb strains shall stimulate cross-protective immunity against Y. pestis causing plague, and Ye and Yptb causing yersinosis.