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: 8635973
• 负责人: Eileen M. Barry
• 金额: $ 70.77万
• 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/8635973
• 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（由申请人提供）：2001 年美国发生的炭疽生物恐怖袭击使人们认识到生物武器攻击的潜在破坏性影响，并认识到需要做好准备以应对未来可能出现的土拉热炭疽事件。它是一种剧毒生物体，人类吸入 10-100 种生物体后即可导致严重和致命的疾病，并且有多个国家将其武器化的历史。 A 类选择剂，是对抗措施开发中最优先考虑的六种病原体之一，一种基于 B 型菌株的活疫苗菌株 LVS 于 1960 年代开发并进行了测试，可提供部分保护，防止接触含有有毒物质的气溶胶。虽然 LVS 提供了减毒活土拉菌疫苗可以保护 A 型土拉菌的原理证据，但 LVS 并未获得 FDA 许可，并且存在几个显着的缺点，使其成为一种次优兔热病疫苗。文献支持 A 型毒株对 A 型攻击具有卓越的保护能力。我们基于 A 型毒株 SchuS4 设计了一种候选疫苗，该疫苗在编码关键酶的 aroD 基因中含有未标记的精确定义的缺失。该疫苗在小鼠模型中高度减毒，并且对野生型 (WT) A 型菌株 SchuS4 的攻击剂量非常高 (1,000 CFU) 具有保护作用。此外，在初步的兔子研究 SchuS4¿ aroD 提供了针对 SchuS4 致命气溶胶攻击的部分保护；这种保护水平优于 LVS 在此模型中所提供的保护水平，事实上，该疫苗株 SchuS4¿ aroD 在小鼠模型中比 LVS 具有更强的减毒效果和更强的保护性，在兔子模型中也具有更强的保护性，这支持了其作为人类疫苗的成功潜力，我们建议进行一系列重点研究以确认其安全性、稳定性和保护性。候选疫苗 SchuS4 的容量aroD 使用小鼠和兔子模型在 3 个机构的合作研究人员的实验室进行平行研究，这些研究人员在评估动物模型中的弗朗西斯菌菌株方面具有特定的专业知识，我们的目标是积累足够的数据以支持这一转变。高级开发将需要投入大量资源，如果没有本提案中概述的初步研究来证实该候选疫苗作为有效人类疫苗的潜力，这些资源是不合理的。