The yellow fever vaccine saga: Defining the viral and host determinants responsible for success versus failure

黄热病疫苗传奇：定义导致成功与失败的病毒和宿主决定因素

• 批准号: 9225162
• 负责人: Charles M Rice
• 金额: $ 79.88万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9225162
• 关键词: Adverse event; Adverse reactions; Affect; Amino Acids; Animal Model; Attenuated; B-Lymphocytes; Biological Assay; Cell model; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Sequence Alteration; Data; Defect; Development; Disease; Elements; Failure; Flavivirus; Generations; Genetic; Genetic Determinism; Genetic Transcription; Genome; Genomic approach; Goals; Hepatocyte; Human; Immune; Immune response; Immunologic Factors; In Vitro; Inbred NOD Mice; Individual; Infection; Innate Immune Response; Innate Immune System; Integration Host Factors; Kidney Diseases; Knock-out; Knowledge; Lead; Libraries; Life; Liver diseases; Maps; Mediating; Minority; Molecular; Molecular Virology; Mus; Mutation; Natural Immunity; Natural Killer Cells; Outcome; Pathway interactions; Phenotype; Primary Infection; Process; Proteins; RNA; Risk; Safety; Sampling; Serial Passage; Serious Adverse Event; Stem cells; System; T-Lymphocyte; Testing; Untranslated RNA; Vaccinated; Vaccination; Vaccines; Viral; Virulence; Virulent; Virus; Virus Activation; Work; Yellow Fever; Yellow Fever Vaccine; Yellow Fever Virus Infection; Yellow fever virus; attenuation; base; fetal; fetal infection; genome-wide analysis; improved; knockout gene; mouse model; neurotropic; nonhuman primate; novel; public health relevance; response; success; vaccine evaluation; vaccine safety; virus genetics; virus pathogenesis

 DESCRIPTION (provided by applicant): The live-attenuated yellow fever virus (YFV) vaccine 17D, developed by serial passaging in vitro of the virulent Asibi strain, is one of the most successful vaccines, providing an essentially life-long protection from disease caused by infection with wildtype YFV. While the vaccine strain is markedly less viscerotropic and neurotropic than virulent strains, the mechanism of attenuation remains completely unknown despite more than 70 years of successful 17D vaccine use and knowledge of the sequences of both virus strains. New preliminary studies using NRG mice (non-obese diabetic mice harboring the Rag1null and IL2rγnull mutations), which lack B, T and NK cells, but retain a functional innate immune system, demonstrate that infection with Asibi results in 100% lethality, while 17D infection is non-lethal. Moreover, infection of primary fetal hepatocytes or iHEPs with Asibi results in persistent replication, while 17D is cleared. We hypothesize that Asibi virulence is related to the ability to counteract (or not induce) anti-YFV innate immunity, which is lost in 17D leading to its attenuation. Moreover, we posit that otherwise healthy individuals suffering from severe vaccine adverse reactions harbor genetic mutations in components of innate immune pathway(s) that normally control 17D, but are counteracted by Asibi and other virulent strains. Using molecular virologic and genomic approaches in cell-based and small animal model-based systems, as well studies on human samples, this project will 1) identify the differences between Asibi and 17D in their interaction with host innate immune pathways, 2) map the genetic determinants responsible for 17D attenuation, and 3) characterize the host genetic determinants associated with serious adverse events to 17D vaccination. The work will provide information on responses to the YFV 17D vaccine, the mechanism of vaccine attenuation, and may uncover novel innate immune antagonism mechanisms. Knowledge of genetic defects predisposing to adverse events will allow pre-vaccine testing to identify at-risk individuals. All together the wor will support the development of safe and effective vaccines for YFV and other flaviviruses.

 描述（由申请人提供）：黄热病减毒活疫苗 17D 是通过毒力 Asibi 毒株在体外连续传代而开发的，是最成功的疫苗之一，可提供基本上终生的保护，防止因野生型 YFV 感染引起的疾病。虽然该疫苗株的亲内脏性和亲神经性明显低于强毒株，但尽管 17D 疫苗已成功使用 70 多年并且了解两种病毒株的序列，但减毒机制仍然完全未知。使用 NRG 小鼠（携带 Rag1null 和 IL2rγnull 突变的非肥胖糖尿病小鼠）进行的新的初步研究表明，Asibi 感染导致 100% 致死，而 17D 感染则不致死。NRG 小鼠缺乏 B、T 和 NK 细胞，但保留了功能性先天免疫系统。此外，Asibi 感染原代胎儿肝细胞或 iHEP 会导致持续复制，而 17D 则被清除。我们假设 Asibi 毒力与抵消（或不诱导）抗 YFV 先天免疫的能力有关，这种能力在 17D 中丢失，导致其减弱。此外，我们假设，遭受严重疫苗不良反应的其他健康个体的先天免疫途径成分中存在基因突变，这些成分通常控制 17D，但会被 Asibi 和其他强毒株所抵消。该项目将利用基于细胞和小动物模型的系统中的分子病毒学和基因组方法，以及对人类样本的研究，1) 确定 Asibi 和 17D 在与宿主先天免疫途径相互作用方面的差异，2) 绘制导致 17D 减毒的遗传决定因素，以及 3) 表征与 17D 疫苗接种严重不良事件相关的宿主遗传决定因素。这项工作将提供有关 YFV 17D 疫苗反应、疫苗减毒机制的信息，并可能揭示新的先天免疫拮抗机制。了解导致不良事件的遗传缺陷将使疫苗前测试能够识别高危个体。全世界将共同支持开发安全有效的 YFV 和其他黄病毒疫苗。