Novel Live Attenuated Cholera-Tetanus Bivalent Vaccine

新型霍乱破伤风二价减毒活疫苗

• 批准号: 7154683
• 负责人: ANISIA J SILVA
• 金额: $ 14.32万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154683
• 关键词: Clostridium; Vibrio cholerae; attenuated microorganism; bacterial antigens; bacterial genetics; bacterial vaccines; bacteriolysis; biotechnology; cholera; cholera vaccine; clostridial tetanus; genetic promoter element; germ free condition; infant animal; intestines; laboratory mouse; mature animal; quorum sensing; vaccine development; vaccine evaluation

Cholera continues to be a major public health problem in developing countries. During 2003 forty five countries officially reported to WHO 111,575 cases of cholera and 1,984 deaths. Unfortunately, there is still not an inexpensive and safe cholera vaccine affording long term protection in all age groups particularly in children under five years old. The live genetically attenuated cholera vaccine candidate Vibrio cholerae 638 adhere strongly to mucosal surfaces in vitro and in vivo and induces strong local and systemic immune responses and protection against cholera in animal models and humans without inducing significant side effects (reactogenicity). Tetanus continues to be a global health problem that accounts for 14% of vaccinepreventable deaths and 500,000 cases of neonatal tetanus per year. Cholera and tetanus share similar geographic distribution. In this project we will develop a novel cholera-tetanus vaccine that lyses in the gut to deliver a tetanus protective antigen rather than being shed to the environment. To achieve this goal we will manipulate the bacterial quorum sensing system so that the live vaccine strain will only sense its cell density in vivo (low iron or anaerobiosis) to express a phage lysis gene under the control of a cell density-dependent promoter. Programmed cell lysis in the gut will allow the massive delivery of immunogenic and protective tetanus C fragment (TCP) to mucosal inductive sites. The capacity of this new vaccine to lyse in the small intestine, deliver TCP and induce protective immunity to cholera and tetanus will be determined using the suckling mouse model, adult rabbits ileal loops and the adult germ-free mice model. The development of the above cholera-tetanus combination vaccine could significantly improve the cost-benefit ratio of a massive vaccination program in endemic areas. In addition, lysis of the vaccine strain in the gut will reduce shedding of live vaccine strain to the environment. The novelty of our approach consists in manipulating a bacterial quorum sensing pathway to alter the course of an infective process and to achieve programmed antigen delivery and lysis of the vaccine vector in the host.

霍乱仍然是发展中国家的一个主要公共卫生问题。 2003年期间四十五 各国向世卫组织正式报告了 111,575 例霍乱病例和 1,984 例死亡。不幸的是，仍然有 不是一种廉价且安全的霍乱疫苗，可以为所有年龄段的人提供长期保护，特别是在 五岁以下儿童。候选霍乱弧菌 638 基因减毒活疫苗 在体外和体内强烈粘附于粘膜表面，并诱导强大的局部和全身免疫 动物模型和人类对霍乱的反应和保护，而不引起明显的副作用 效应（反应原性）。破伤风仍然是一个全球性健康问题，占疫苗可预防疾病的 14% 每年有 50 万例新生儿破伤风死亡和 50 万例新生儿破伤风病例。霍乱和破伤风有相似之处 地理分布。在这个项目中，我们将开发一种新型霍乱破伤风疫苗，它可以在肠道中裂解，从而 提供破伤风保护性抗原而不是释放到环境中。为了实现这一目标，我们将 操纵细菌群体感应系统，使活疫苗株只能感知其细胞密度 体内（低铁或厌氧）在细胞密度依赖性控制下表达噬菌体裂解基因 发起人。肠道内的程序性细胞裂解将允许大量递送免疫原性和保护性物质 破伤风 C 片段 (TCP) 至粘膜诱导位点。这种新疫苗在小细胞中裂解的能力 肠道，输送 TCP 并诱导对霍乱和破伤风的保护性免疫力将使用 乳鼠模型、成年兔回肠环和成年无菌小鼠模型。的发展 上述霍乱破伤风联合疫苗可显着提高大规模疫苗的成本效益比 流行地区的疫苗接种计划。此外，疫苗株在肠道中裂解会减少脱落 活疫苗株对环境的影响。我们方法的新颖之处在于操纵细菌 群体感应途径改变感染过程并获得程序化抗原 疫苗载体在宿主体内的递送和裂解。