Yersinia pseudotuberculosis-based vaccines for plague and yersiniosis

基于假结核耶尔森氏菌的鼠疫和耶尔森氏菌疫苗

• 批准号: 9471106
• 负责人: Wei Sun
• 金额: $ 44.36万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9471106
• 关键词: Acute; Adjuvant; Animals; Antigens; Attention; Attenuated; Bacterial Vaccines; Biological Warfare; Blood Circulation; Cellular Immunity; Cessation of life; Dose; Economic Burden; Enteral; Fleas; Food Safety; Health; Heterophile Antigens; Hour; Human; Humoral Immunities; Immune response; Immunity; Immunization; Immunize; Infection; Innate Immune Response; Knowledge; Legal patent; Livestock; Modernization; Mus; Needles; Onset of illness; Oral; Oral Administration; Outcome; Pasteurella pseudotuberculosis; Persons; Plague; Plague Vaccine; Pneumonic Plague; Production; Public Health; Recombinants; Recording of previous events; Risk; Rodent; Safety; Salmonella Vaccines; Supplementation; Symptoms; System; Systemic infection; United States; Vaccine Production; Vaccines; Yersinia; Yersinia enterocolitica; Yersinia pestis; Zoonoses; adaptive immune response; attenuation; base; cost; experimental study; foodborne; immunogenicity; improved; mortality; pandemic disease; pathogen; prevent; protective efficacy; vaccine candidate; vaccine development; vector; vector vaccine; weapons

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.

项目概要 鼠疫耶尔森氏菌（Yersinia pestis）是鼠疫的病原体，它通过引起 据估计，三大流行病导致 2 亿人死亡。鼠疫耶尔森氏菌被认为是一种重新出现的病原体 仍然是一个公共卫生问题，每年造成全球数千例鼠疫病例。 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持续存在。在 除了通过跳蚤自然传播之外，鼠疫耶尔森氏菌还拥有广泛的生物战操作历史 并被归类为现代武器化的主要威胁。肺鼠疫是最严重、最严重的鼠疫 具有威胁性的表现，具有高度传染性，很容易通过空气在人与人之间传播 飞沫，导致疾病迅速发作，如果治疗延迟，死亡率接近 100% 24 症状出现后数小时。目前，美国还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物种引起的肠道感染。有两种亚型 引起耶尔森氏菌病、小肠结肠炎耶尔森氏菌 (Ye) 和假结核耶尔森氏菌 (Yptb)。叶和Yptb 是粪口人畜共患病原体，在环境和多种动物之间循环 水库。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，并导致大量牲畜死亡 生产损失。然而，对耶尔森氏菌病疫苗开发的关注有限。 我们之前在重组 Yptb 载体疫苗的构建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。基于我们已建立的重组 减毒沙门氏菌疫苗平台，一种基于 Yptb 的针对鼠疫和耶尔森氏菌病的疫苗将传授 几个关键优势包括（1）无针口服给药，（1）低成本疫苗生产，以及（3） 强烈诱导体液和细胞免疫反应，以及（4）人类和环境诱饵递送。 此外，我们努力在不补充佐剂的情况下通过单剂量激发保护性免疫力。我们 先前证明，用减毒 Yptb 菌株进行免疫可引发针对 Y 的交叉保护。 鼠疫和叶。此外，3 型分泌系统很容易增强针对鼠疫耶尔森氏菌的免疫原性 递送异源抗原。因此，使用改良的减毒活 Yptb 菌株进行免疫应 刺激针对引起鼠疫的鼠疫耶尔森氏菌以及引起耶尔森氏菌病的Ye和Yptb的交叉保护性免疫力。