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

• 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
• 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

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）：在引入腮腺炎减毒活疫苗之前，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，流行性腮腺炎的发病率急剧下降，尽管最近全球流行性腮腺炎的复苏凸显了维持强有力的疫苗接种计划的重要性。尽管 MuV 被确定为该疾病的病原体已有 75 年多了，但实际上人们对病毒向神经性的基础一无所知，并且尚未确定控制减毒的分子决定因素。这使得安全疫苗的开发变得复杂，一些获得许可的腮腺炎疫苗引起无菌性脑膜炎的事实就证明了这一点。流行性腮腺炎最近在美国和欧洲重新出现，导致接种疫苗的人大规模爆发。由于新的 MuV 疫苗目前正在研发中，因此提高疫苗安全性的研究成为当务之急。我们的目标是开发一套经过验证、稳健的体外、离体和体内检测工具包，以预测腮腺炎疫苗在人类中使用是否安全。该工作计划对疫苗学领域具有直接和长期的重要性，这些数据将为目前正在开发的合理减毒 MuV 疫苗的安全测试提供信息。提出了三个协同和连续的目标： 1. 确定体内野生型 MuV 靶向的原代细胞、组织和器官：已知来源的重组 (r) 野生型病毒将用于评估疾病相关原代细胞、组织和啮齿动物神经毒力模型的复制能力和趋向性。我们将通过用表达rMV的增强型绿色荧光蛋白感染恒河猴来测试MuV最初感染上呼吸道上皮细胞的模型，以回答“MuV在体内复制的主要靶位点是什么”的问题？ 2. 确定高减毒和低减毒 MuV 靶向的原代细胞是否彼此不同以及与当前流行的野生型病毒是否不同：了解安全和不安全疫苗之间的差异和相似之处对于安全疫苗的开发和许可至关重要。将在体外、离体和体内模型中评估源自高度减毒和欠减毒毒株的表达增强型绿色荧光蛋白的 MuV，以确定病毒复制、组织向性和体内传播是否与已知的人类疫苗接种者安全性相关。 3. 使用具有不同复制能力和向性的非重组疫苗祖细胞和合理减毒的 rMuV 开发腮腺炎疫苗安全性的体内预测因子：将表征一组具有基因替换和旨在调节复制能力和向性的靶向突变的疫苗祖细胞和 rMuV。根据它们的“减毒特征”，猕猴将接种 rMuV 疫苗，并评估安全性。这将回答“我们能否开发强大的体外、离体和体内模型来预测 MuV 疫苗对人类安全的可能性”的问题。