Development of a novel live attenuated vaccine for eastern equine encephalitis virus

新型东部马脑炎病毒减毒活疫苗的研制

• 批准号: 8869837
• 负责人: WILLIAM B KLIMSTRA
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8869837
• 关键词: Address; Aerosols; Alphavirus; Animal Disease Models; Animals; Antibody Response; Antiviral Agents; Arboviruses; Arthropods; Attenuated; Attenuated Live Virus Vaccine; Competence; Culicidae; Development; Disease; Domestic Animals; Dose; Eastern Equine Encephalitis Virus; Encephalitis Viruses; Equine Encephalomyelitis; Evaluation; Formalin; Genetic; Human; Immune; In Vitro; Inactivated Vaccines; Incidence; Individual; Infection; Injection of therapeutic agent; Licensing; Life; Measures; Mediating; Modeling; Mus; Mutagenesis; Mutation; Neurologic; Nucleotides; Parents; Reporter; Risk; Route; Testing; Therapeutic; Time; Vaccinated; Vaccines; Viral Genome; Virulence; Virulent; Virus; Virus Replication; adaptive immunity; attenuation; base; blind; design; epizootic; immunogenic; immunogenicity; in vivo; mortality; mutant; neurovirulence; novel; preclinical study; public health relevance; vaccine candidate; vaccine development; vector; vector vaccine

 DESCRIPTION (provided by applicant): Eastern (EEEV), Venezuelan (VEEV), and Western (WEEV) equine encephalitis viruses are mosquito-transmitted alphaviruses with the potential to cause fatal neuroinvasive disease in humans and domesticated animals. These viruses also can be spread by the aerosol route and thus, have significant potential as bioterrorist agents. Currently, there are no antiviral agents approved for alphaviruses. The existing investigational live-attenuated VEEV vaccine (LAV; TC-83) was generated >40 years ago, is highly reactogenic, poorly immunogenic, and causes disease in up to 20% of recipients. For EEEV and WEEV, investigational formalin-inactivated vaccines have been given to at-risk workers. While both elicit antibody responses, they provide uncertain protection, require multiple booster injections, and in fact, the WEEV vaccine is no longer available. Here, we propose to develop a safe and effective LAV vaccine against EEEV using recent advances in understanding of the virulence mechanisms of the virus. These advances have allowed mutagenesis of EEEV that specifically reduces neurovirulence and increases immunogenicity. We plan to combine mutations to create an optimal vaccine strain and we propose this strategy as a platform for LAV versus other alphaviruses. We will identify correlates of protection against EEEV and address the extent of cross- protection against VEEV. The development of safe and protective vaccines against the encephalitic alphaviruses will provide an immediate counter-measure against disease emergence or bioterrorist introduction. For the first time with alphaviruses, the individua and combined effects of mutations with known mechanisms of action will be tested for effects on virus replication, disease and immunogenicity in animals.

 描述（由申请人提供）：东部（EEEV）、委内瑞拉（VEEV）和西部（WEEV）马脑炎病毒是蚊子传播的甲病毒，有可能在人类和家养动物中引起致命的神经侵袭性疾病。这些病毒也可以传播。通过气溶胶途径，因此具有作为生物恐怖分子的巨大潜力，目前，还没有批准用于甲病毒的现有研究性减毒活疫苗。 （LAV；TC-83）产生于 40 年前，反应性高，免疫原性差，导致高达 20% 的接种者患病。对于 EEEV 和 WEEV，已向高危工人接种了研究性福尔马林灭活疫苗。虽然两者都会引起抗体反应，但它们提供的保护不确定，需要多次加强注射，而且事实上，WEEV 疫苗已不再可用。在这里，我们建议利用最新进展开发一种安全有效的针对 EEEV 的 LAV 疫苗。这些进展使得 EEEV 的突变能够特异性地降低神经毒力并增加免疫原性。我们计划结合突变来创建最佳疫苗株，并且我们建议将这一策略作为 LAV 与其他甲病毒的平台。我们将确定针对 EEEV 的保护的相关性，并解决针对 VEEV 的交叉保护的程度。针对脑炎甲病毒的安全和保护性疫苗的开发将为疾病的出现或预防提供直接的对策。首次使用甲病毒，测试具有已知作用机制的突变的个体和组合效应对动物中病毒复制、疾病和免疫原性的影响。