Advancement of a Defined, Protective, Live Attenuated Tularemia Vaccine

明确的、保护性的、兔热病减毒活疫苗的进展

• 批准号: 8513102
• 负责人: Eileen M. Barry
• 金额: $ 68.31万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513102
• 关键词: Advanced Development; Aerosols; Animal Model; Animals; Anthrax disease; Applications Grants; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Awareness; Biological; Breathing; Categories; Cessation of life; Clinical; Country; Cyclic GMP; Data; Development; Disease; Dose; Engineering; Enzymes; Evaluation; Event; Exclusion; Exposure to; Francisella; Francisella tularensis; Future; Genes; Genetic; Goals; Human; Immunization; Institution; Laboratories; Licensing; Life; Literature; Metabolic; Metabolism; Modeling; Mus; Organism; Oryctolagus cuniculus; Pathology; Recording of previous events; Regimen; Reporting; Research Personnel; Resources; Safety; Series; Testing; Toxicology; Tularemia; Vaccinated; Vaccines; Virulence; Virulence Factors; Virulent; attenuation; base; in vivo; microbial; mouse model; mutant; nonhuman primate; pathogen; prevent; protective efficacy; public health relevance; safety testing; success; vaccine candidate; weapons

DESCRIPTION (provided by applicant): The anthrax bioterror attacks in the US in 2001, led to an awareness of the potentially devastating effects of attack with a bioweapon and the recognition of the need to prepare against possible future nefarious events. F. tularensis is a highly virulent organism that can cause severe and fatal disease in humans following inhalation of as few as 10-100 organisms. It has a history of weaponization by several countries and is a Category A select agent, one of six pathogens that are of highest priority for countermeasure development. One live vaccine strain, LVS, based on a type B strain, was developed and tested in the 1960's and conferred partial protection against exposure to aerosols containing virulent type A F. tularensis. While providing proof of principle that a live attenuated F. tularensis vaccine can protect, LVS is not licensed by the FDA and suffers from several notable drawbacks that render it a sub-optimal tularemia vaccine. The literature supports the superior protective capacity of type A strains against type A challenge. We have engineered a vaccine candidate based on type A strain SchuS4, that contains an unmarked precisely defined deletion in the aroD gene encoding a critical enzyme in microbial metabolic processes. This vaccine is highly attenuated in the mouse model and was protective against a very high challenge dose (1,000 CFU) of wild type (WT) type A strain SchuS4. This is the first report of a live attenuated F. tularensis vaccine capable of protecting against a type A challenge of this magnitude. Furthermore, in preliminary rabbit studies SchuS4¿aroD provided partial protection against a lethal aerosol challenge with SchuS4; this level of protection was superior to that conferred by LVS in this model. The fact that this vaccine strain, SchuS4¿aroD, is more attenuated and more protective than LVS in the mouse model and more protective in the rabbit model supports its potential for success as a human vaccine. We are proposing to perform a set of focused studies to confirm the safety, stability, and protective capacity of the candidate vaccine, SchuS4¿aroD, using the mouse and rabbit models. Parallel studies in the laboratories of collaborating investigators at 3 institutions, with specific expertise in the evaluation of Francisella strains i animal models, will accelerate progress. Our goal is to accumulate sufficient data to support transition of this candidate to advanced development. Advanced development will require a substantial commitment of resources that cannot be justified without the preliminary studies outlined within this proposal to substantiate the potential of this candidate as an efficacious human vaccine.

描述（由适用提供）：2001年在美国的炭疽生物侵蚀攻击，使人们意识到了对生物武器攻击的潜在毁灭性影响，并认识到需要为未来可能的邪恶事件做准备的需求。 F. tularensis是一种高度毒性的生物体，在吸入少于10-100个生物后会导致人类严重和致命疾病。它具有多个国家的武器化历史，并且是选择代理的类别，这是六种病原体之一，是对策开发的最高优先事项。在1960年代开发并测试了一种基于B型菌株的活疫苗菌株LVS，并赋予了对含有毒力A型F. tularensis的气溶胶的部分保护。虽然提供了原则证明，表明活着减毒的tularensis疫苗可以保护，但LVS没有获得FDA的许可，并且遭受了几个值得注意的缺点，这些缺点使其成为优美的Tularemia疫苗。文献支持A型菌株对A型挑战的卓越保护能力。我们已经根据A型菌株Schus4设计了疫苗候选者，该疫苗包含在AROD基因中未标记的精确删除，该缺失编码了微生物代谢过程中的临界酶。该疫苗在小鼠模型中高度减弱，并受到野生型（1,000 CFU）的高挑战剂量（WT）型A型菌株Schus4的保护。这是第一份报告的活体衰减的tularensis疫苗，能够防止这种大小的A挑战。此外，在初步的兔子研究中，schus4¿AROD提供了针对Schus4致命的气溶胶挑战的部分保护。在该模型中，LVS赋予的保护水平优于LV。与小鼠模型中的LV相比，这种疫苗菌株Schus4 arod的事实更受衰减，更受保护，并且在兔模型中受到保护，这一事实支持了其作为人类疫苗成功的潜力。我们建议使用小鼠和兔子模型进行一组集中研究，以确认候选疫苗Schus4 arod的安全性，稳定性和受保护能力。在三个机构合作研究人员的实验室中，与弗朗西斯拉菌株I动物模型评估的特定专家的合作研究人员的平行研究将加速进步。我们的目标是加速足够的数据，以支持该候选人向高级发展的过渡。先进的发展将需要实质性的资源承诺，如果没有本提案中概述的初步研究，就无法证明该候选人作为有效的人类疫苗的潜力。