A Small Animal Model for Viscerotropic Disease to Improve Yellow Fever Vaccine

改善黄热病疫苗的嗜内脏疾病小动物模型

• 批准号: 8183819
• 负责人: KATHERINE D RYMAN
• 金额: $ 35.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8183819
• 关键词: Adverse event; Africa; African; Agreement; Alphavirus; Americas; Animal Model; Animals; Attenuated; Attenuated Live Virus Vaccine; Biological Warfare; Bioterrorism; Bite; Contracts; Culicidae; Cultured Cells; Dengue Virus; Development; Disease; Eastern Equine Encephalitis Virus; Emerging Communicable Diseases; Engineering; Etiology; Europe; Family member; Flaviviridae; Flavivirus; Fright; Genes; Genome; Genotype; Goals; Human; Immune response; Immunologic Factors; Immunologics; In Vitro; Incidence; Individual; Infection; Integration Host Factors; Interferon Type I; Interferons; Japanese Encephalitis; Laboratories; Life; Liver; Mediating; Minor; Modeling; Molecular; Mosquito-borne infectious disease; Mus; Mutation; Pathogenesis; Pathology; Peru; Phase II Clinical Trials; Phenotype; Play; Predisposition; Primates; Relative (related person); Reporting; Research; Role; Safety; Serious Adverse Event; Source; Structural Protein; System; Technology; Testing; Universities; Vaccination; Vaccine Research; Vaccines; Vertebral column; Viral; Viral Hemorrhagic Fevers; Virulence; Virulent; Virus; Virus Diseases; Virus Replication; West Nile virus; Yellow Fever; Yellow Fever Vaccine; Yellow Fever Virus Infection; Yellow fever virus; attenuation; authority; base; cytokine; design; immunogenicity; improved; indexing; mouse model; neurotropic; novel vaccines; pathogen; prototype; receptor; response; subcutaneous; vector; virus pathogenesis

DESCRIPTION (provided by applicant): Yellow fever virus (YFV) causes the mosquito-borne disease yellow fever (YF), a viscerotropic disease, i.e., it targets the liver, of primates. The disease is controlled by a very efficacious live attenuated vaccine, strain 17D, which was derived from wild-type strain Asibi and has been administered to over 540 million people in the last 70 years. In the last 10 years a rare, but fatal, condition has been reported due to the vaccine, termed YF vaccine associated viscerotropic disease (YEL-AVD). This condition is associated with uncontrolled replication of the virus in primary vaccinees resulting in pansystemic infection and a disease picture very similar to wild-type YFV. Originally, YEL-AVD was reported to have an incidence of 0.3 per 100,000 vaccinees. However, in October 2007, an incidence of 9 per 100,000 was reported in Peru. This alarming rate of serious adverse events is causing regulatory authorities to re-evaluate the contraindications and use of the 17D vaccine, and a number of individuals are calling for the development of a new YF vaccine. Nonetheless, it is recognized that development of a new vaccine takes at least 15 years. Thus, there is an urgent need to undertake research on the current vaccine to understand YEL-AVD and how the current vaccine could be improved. This urgency is emphasized by the use of 17D vaccine virus to generate chimeric viruses containing the structural protein genes of one flavivirus (e.g. Japanese encephalitis) in a 17D vaccine virus backbone. Such chimeric vaccines are in phase II clinical trials. Surprisingly, little is known about the molecular mechanisms that govern the virulence of wild-type YFV or the attenuation and immunogenicity of the live- attenuated YFV 17D vaccine. This is, in part, due to the lack of a small animal of viscerotropism. The PI has developed a new YFV infection model that readily distinguishes wild-type Asibi strain from the 17D vaccine strain. Our long-term goals are to use this model to understand the immunologic basis of viscerotropism and attenuation. Our specific aims are: i) investigate the steps in the pathogenic sequence at which attenuated 17D virus infection is blocked compared with virulent Asibi virus thereby identifying potential anomalies in the innate immune response that might be important to the development of YEL-AVD; and ii) identify YFV-encoded molecular determinants of viscerotropism present in YEL-AVD isolates by examining their viscerotropic phenotype in the new mouse model developed in this project. PUBLIC HEALTH RELEVANCE: The highly-lethal viral hemorrhagic fever caused by the mosquito-borne yellow fever virus (YFV) was one of the most feared diseases in Africa, Europe and the Americas until the live-attenuated 17D vaccine was developed in the 1930's. Even today, over 200,000 West Africans contract YF annually, with tens of thousands of fatalities. The attenuated 17D vaccine strain was derived by repeatedly growing a wild- type YFV isolate (strain Asibi) in cultured cells. Although 17D is considered to be one of the most effective live-attenuated virus vaccines ever developed, the immunologic mechanisms that control the attenuation and immunogenicity of this live-attenuated vaccine remain a mystery. Our long-term goal is to determine how the host is able to control the 17D infection and investigate mechanisms by which vaccine-associated viscerotropic disease (YEL-AVD) occurs. To achieve this goal, Drs. Ryman and Barrett have proposed a consortium agreement in which Dr. Barrett's laboratory will provide viruses to Dr. Ryman's laboratory, where their virulence will be assessed using a newly developed model of YFV pathogenesis and disease. Our understanding of host- pathogen interactions has increased sufficiently to allow rational design of live- attenuated virus strains and the technology exists to introduce and test mutations in genetically-engineered vector systems. It is anticipated that our findings will improve the safety and efficacy of the YFV vaccine, and additionally facilitate the rational design of other live-attenuated virus vaccines, particularly against other pathogenic flaviviruses (e.g., West Nile and dengue viruses) and the closely-related alphaviruses (e.g., eastern equine encephalitis virus), most of which are agents of both emerging infectious disease and bioterrorism/biowarfare.

描述（由申请人提供）：黄热病病毒（YFV）引起蚊媒疾病黄热病（YF），这是一种内脏疾病，即以肝脏为目标的灵长类动物。该疾病由一种非常有效的减毒活疫苗 17D 株控制，该疫苗源自野生型 Asibi 株，在过去 70 年中已为超过 5.4 亿人接种。在过去 10 年中，报告了一种由疫苗引起的罕见但致命的疾病，称为 YF 疫苗相关内脏疾病 (YEL-AVD)。这种情况与病毒在初次接种者体内不受控制的复制有关，导致全系统感染，并且疾病情况与野生型 YFV 非常相似。最初，据报道，YEL-AVD 的发病率为每 100,000 名疫苗接种者中 0.3 人。然而，2007 年 10 月，秘鲁报告发病率为每 100,000 人中有 9 例。这种令人震惊的严重不良事件发生率正促使监管机构重新评估 17D 疫苗的禁忌症和使用情况，许多人呼吁开发新的 YF 疫苗。尽管如此，人们认识到新疫苗的开发至少需要15年的时间。因此，迫切需要对现有疫苗进行研究，以了解 YEL-AVD 以及如何改进现有疫苗。使用17D疫苗病毒来生成在17D疫苗病毒骨架中含有一种黄病毒（例如日本脑炎）的结构蛋白基因的嵌合病毒，强调了这种紧迫性。此类嵌合疫苗正处于II期临床试验中。令人惊讶的是，人们对控制野生型 YFV 毒力或减毒活 YFV 17D 疫苗的减毒和免疫原性的分子机制知之甚少。这部分是由于小动物缺乏趋内脏性。 PI 开发了一种新的 YFV 感染模型，可以轻松区分野生型 Asibi 毒株和 17D 疫苗毒株。我们的长期目标是利用该模型来了解趋内脏性和减毒的免疫学基础。我们的具体目标是：i) 与强毒阿西比病毒相比，研究减毒 17D 病毒感染被阻断的致病序列步骤，从而识别先天免疫反应中可能对 YEL-AVD 的发展很重要的潜在异常； ii) 通过检查本项目开发的新小鼠模型中的趋内脏表型，鉴定 YEL-AVD 分离株中存在的 YFV 编码的趋内脏性分子决定因素。 公共卫生相关性：由蚊媒黄热病病毒 (YFV) 引起的高度致命的病毒性出血热是非洲、欧洲和美洲最令人恐惧的疾病之一，直到 1930 年代开发出减毒活疫苗 17D 为止。即使在今天，每年仍有超过 20 万西非人感染黄热病，造成数万人死亡。 17D 减毒疫苗株是通过在培养细胞中反复培养野生型 YFV 分离株（Asibi 株）而获得的。尽管17D被认为是迄今为止开发的最有效的减毒活病毒疫苗之一，但控制这种减毒活疫苗的减毒和免疫原性的免疫机制仍然是个谜。我们的长期目标是确定宿主如何控制 17D 感染并研究疫苗相关内脏疾病 (YEL-AVD) 发生的机制。为了实现这一目标，博士。莱曼和巴雷特提出了一项联合协议，巴雷特博士的实验室将向莱曼博士的实验室提供病毒，并使用新开发的 YFV 发病机制和疾病模型来评估病毒的毒力。我们对宿主-病原体相互作用的了解已经充分增加，可以合理设计减毒活病毒株，并且存在在基因工程载体系统中引入和测试突变的技术。预计我们的研究结果将提高 YFV 疫苗的安全性和有效性，并进一步促进其他减毒活病毒疫苗的合理设计，特别是针对其他致病性黄病毒（例如西尼罗河病毒和登革热病毒）以及密切相关的疫苗甲病毒（例如东部马脑炎病毒），其中大多数是新出现的传染病和生物恐怖主义/生物战的病原体。