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）引起蚊子传播疾病黄热病（YF），一种内脏疾病，即，它针对灵长类动物的肝脏。该疾病受到一种非常有效的活衰减疫苗17D的控制，该疫苗是源自野生型Asibi的菌株，在过去的70年中已对超过5.4亿人施用。在过去的十年中，由于疫苗称为YF疫苗相关的内脏疾病（Yel-AVD），据报道了一种罕见但致命的状况。这种情况与原发性疫苗中病毒的不受控制的复制有关，导致脑系统感染和与野生型YFV非常相似的疾病图片。据报道，最初，Yel-Avd的发病率为每100,000个疫苗0.3。但是，在2007年10月，秘鲁报告了每10万人的发病率。严重不良事件的这种令人震惊的速度正在导致监管机构重新评估17D疫苗的禁忌症和使用，许多人呼吁开发新的YF疫苗。但是，人们认识到，新疫苗的开发至少需要15年。因此，迫切需要对当前疫苗进行研究，以了解Yel-avd以及如何改善当前的疫苗。通过使用17D疫苗病毒在17D疫苗病毒骨链中产生一种含有一种黄病毒（例如日本脑炎）的结构蛋白基因的嵌合病毒来强调这种紧迫性。这种嵌合疫苗正在II期临床试验中。令人惊讶的是，关于控制野生型YFV的毒力的分子机制，或活减弱的YFV 17D疫苗的衰减和免疫原性，知之甚少。这部分是由于缺乏内脏性的小动物。 PI开发了一种新的YFV感染模型，该模型很容易区分野生型ASIBI菌株与17D疫苗菌株。我们的长期目标是使用该模型来了解内脏和衰减的免疫学基础。我们的具体目的是：i）研究致病序列中的步骤，即减毒17D病毒感染与有毒的ASIBI病毒相比被阻断，从而识别先天免疫反应中可能对Yel-AVD发展重要的潜在异常； ii）通过检查其在该项目中开发的新小鼠模型中检查其内脏表型，从而确定YEL-AVD分离株中内脏性的YFV编码的分子决定因素。 公共卫生相关性：由蚊子传播的黄热病病毒（YFV）引起的高致命病毒出血热是非洲，欧洲和美洲最令人恐惧的疾病之一，直到1930年代开发了现场直播的17D疫苗。即使在今天，每年有超过200,000西非人签订YF，数以万计的死亡人数。通过反复在培养的细胞中种植野生型YFV分离株（菌株ASIBI）来得出减毒的17D疫苗菌株。尽管17D被认为是有史以来开发的最有效的生命衰减病毒疫苗之一，但控制这种实时侵入疫苗的衰减和免疫原性的免疫机制仍然是一个谜。我们的长期目标是确定宿主如何控制17D感染并研究与疫苗相关的内脏疾病（Yel-AVD）进行的机制。为了实现这一目标，博士。莱曼（Ryman）和巴雷特（Barrett）提出了一项财团协议，其中巴雷特（Barrett）博士的实验室将向莱曼（Ryman）博士的实验室提供病毒，在那里将使用新开发的YFV发病机理和疾病模型来评估其毒力。我们对宿主病原体相互作用的理解已经充分增加了，以允许对生物衰减病毒菌株的合理设计，并且该技术的存在以引入和测试基因工程载体系统中的突变。可以预料，我们的发现将提高YFV疫苗的安全性和功效，并促进其他活衰减的病毒疫苗的合理设计，尤其是针对其他致病性黄酮病毒（例如西尼罗河和登革热病毒），以及密切相关的α，Easterteme seemene Enceention（例如，Eastern sore sere sepeents in Capeent seemention sere sere inse sepeents in Capeine sore seerians sore inse inse sepeents）疾病和生物恐怖主义/生物贸易。