Shifting a Paradigm in Vaccine Safety: From Empirical to Rational Attenuation

转变疫苗安全范式：从经验衰减到理性衰减

基本信息

批准号：
8664340
负责人：
William Paul Duprex
金额：
$ 40.42万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8664340
关键词：
Address Adverse event Animal Model Animals Aseptic Meningitis Attenuated Attenuated Live Virus Vaccine Attenuated Vaccines Biological Biological Assay Biological Products Cell Culture Techniques Cell Line Cells Child Clinical Coin Complex Country Data Developed Countries Development Disease Disease Outbreaks Disease Progression Drug Industry Epithelium Europe Failure Gene Targeting Genes Genetic Goals Health Human Immunization In Vitro Incidence Individual Industry Infant Knowledge Licensing Licensure Life Macaca Macaca mulatta Microscopic Modeling Molecular Molecular Profiling Mumps Mumps virus Mutation Neuraxis Neurologic Neurotropism Newborn Infant Organ Pathogenesis Patients Population Process Public Health Rattus Recombinants Research Resistance Resolution Risk Rodent Model Route Safety Secondary to Side Site Staging Study models Swab Symptoms System Testing Therapeutic Agents Tissues Tropism Upper respiratory tract Vaccinated Vaccination Vaccines Virus Virus Replication Withdrawal Work attenuation base bioimaging design enhanced green fluorescent protein gene replacement genome sequencing in vivo in vivo Model interest neurovirulence positional cloning progenitor programs public health relevance research study respiratory respiratory virus safety testing tissue tropism vaccine safety vaccinology virus pathogenesis virus tropism

Address Adverse event Animal Model Animals Aseptic Meningitis Attenuated Attenuated Live Virus Vaccine Attenuated Vaccines Biological Biological Assay Biological Products Cell Culture Techniques Cell Line Cells Child Clinical Coin Complex Country Data Developed Countries Development Disease Disease Outbreaks Disease Progression Drug Industry Epithelium Europe Failure Gene Targeting Genes Genetic Goals Health Human Immunization In Vitro Incidence Individual Industry Infant Knowledge Licensing Licensure Life Macaca Macaca mulatta Microscopic Modeling Molecular Molecular Profiling Mumps Mumps virus Mutation Neuraxis Neurologic Neurotropism Newborn Infant Organ Pathogenesis Patients Population Process Public Health Rattus Recombinants Research Resistance Resolution Risk Rodent Model Route Safety Secondary to Side Site Staging Study models Swab Symptoms System Testing Therapeutic Agents Tissues Tropism Upper respiratory tract Vaccinated Vaccination Vaccines Virus Virus Replication Withdrawal Work attenuation base bioimaging design enhanced green fluorescent protein gene replacement genome sequencing in vivo in vivo Model interest neurovirulence positional cloning progenitor programs public health relevance research study respiratory respiratory virus safety testing tissue tropism vaccine safety vaccinology virus pathogenesis virus tropism

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项目摘要

DESCRIPTION (provided by applicant): Prior to the introduction of live attenuated mumps vaccines, mumps virus (MuV) was the leading cause of aseptic meningitis. Mumps incidence declined sharply due to vaccine use, although the recent global resurgence highlights the importance of maintaining robust vaccination programs. Even though it has been over 75 years since MuV was identified as the etiological agent of the disease, virtually nothing is known about the basis of virus neurotropism and the molecular determinants governing attenuation have not been identified. This complicates the development of safe vaccines as demonstrated by the fact that some licensed mumps vaccines caused aseptic meningitis. Mumps has recently reemerged in the US and Europe causing large outbreaks in vaccinated individuals. Since new MuV vaccines are currently in the pipeline this makes research to advance vaccine safety a priority. Our goal is to develop a toolkit of validated, robust in vitro, ex vivo and in vivo assays which predict whether or not mumps vaccines are safe for use in humans. The program of work has both immediate and long term importance for the field of vaccinology and the data will inform safety testing of rationally-attenuated MuV vaccines which are currently in development. Three synergistic and sequential aims are proposed: 1. Determine the primary cells, tissues and organs targeted by wild-type MuV in vivo: Recombinant (r) wild-type viruses of known provenance will be used to assess replicative capacity and tropism in disease- relevant primary cells, tissues and a rodent model of neurovirulence. We will test the model that MuV initially infects epithelia in the upper respiratory tract by infecting rhesus macaques with an rMV-expressing enhanced green fluorescent protein to answer the question, "what are the primary target sites of MuV replication in vivo"? 2. Determine if the primary cells targeted by highly attenuated and under-attenuated MuVs differ from each other and from the currently circulating wild-type virus: Understanding differences and similarities between safe and unsafe vaccines is critical for the development and licensing of safe vaccines. Enhanced green fluorescent protein-expressing MuVs derived from highly attenuated and under-attenuated strains will be assessed in the in vitro, ex vivo and in vivo models to determine if virus replication, tissue tropism and dissemination in vivo correlate with the known safety profile in human vaccinees. 3. Develop in vivo predictors for mumps vaccine safety using non-recombinant vaccine progenitors and rationally attenuated rMuVs which have differing replicative capacity and tropism: A set of vaccine progenitors and rMuVs with gene replacements and targeted mutations designed to modulate replicative capacity and tropism will be characterized. Based on their "attenuation signature" macaques will be vaccinated with the rMuVs and the safety profile will be assessed. This will answer the question "can we develop robust in vitro, ex vivo and in vivo models which predict the likelihood that MuV vaccines will be safe in humans".

描述（由申请人提供）：在引入活肿瘤疫苗之前，腮腺炎病毒（MUV）是无菌性脑膜炎的主要原因。由于疫苗的使用，肿瘤发病率急剧下降，尽管最近的全球复兴强调了维持强大的疫苗接种计划的重要性。即使自MUV被确定为疾病的病因学药物以来已经超过75年，但实际上尚未鉴定出关于病毒神经性的基础和控制衰减的分子决定因素的知之甚少。这使安全疫苗的发展变得复杂，这证明了一些有执照的腮腺炎疫苗引起了无菌性脑膜炎。腮腺炎最近在美国和欧洲重新出现，导致接种疫苗的人爆发大量爆发。由于目前正在企业中新的MUV疫苗，因此可以将研究提高疫苗安全性。我们的目标是开发一个经过验证，健壮的体外，体内和体内测定的工具包，以预测腮腺炎疫苗是否可以安全地用于人类。工作计划对疫苗学领域具有直接和长期的重要性，数据将为当前正在开发的合理增长的MUV疫苗的安全测试提供信息。提出了三个协同和顺序的目标：1。确定由野生型MUV靶向的原代细胞，组织和器官：重组（R）已知出处的重组（R）野生型病毒将用于评估疾病相关细胞中的复制能力和型号的复制能力和型号 - 组织，组织，组织和神经病毒的啮齿动物模型。我们将测试MUV最初感染上呼吸道上皮的模型，通过感染恒河猕猴，表达RMV的增强的增强的绿色荧光蛋白来回答这个问题：“体内MUV复制的主要目标位点是什么？ 2.确定由高度减弱和侵蚀性不足的MUV靶向的主要细胞彼此不同，并且与当前循环的野生型病毒不同：了解安全和不安全疫苗之间的差异和相似性对于安全疫苗的开发和许可至关重要。将在体外，体内和体内模型中评估源自高度减弱和侵蚀性菌株的增强绿色荧光蛋白表达MUV，以确定病毒复制，组织疗法和在人疫苗中与已知的安全概况相关。 3。使用非重组疫苗祖细胞和合理减弱的RMUV来开发体内预测因子，这些疫苗安全性具有不同的复制能力和tropism：一组疫苗祖细胞和rmuvs，旨在调节复制能力和tropisis的基因更换和靶向突变。根据他们的“衰减签名”猕猴将接种RMUV，并将评估安全性。这将回答一个问题：“我们可以在体外，体内和体内模型中发展出强大的体外模型，从而预测MUV疫苗在人类中是安全的可能性”。