Vaccine Safety and Neurotoxicity

疫苗安全性和神经毒性

• 批准号: 6545063
• 负责人: K. M CARBONE
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6545063
• 关键词: autism; bioassay; biomarker; biotechnology; communicable disease control; developmental neurobiology; disease /disorder model; disease /disorder proneness /risk; drug screening /evaluation; gene expression; host organism interaction; iatrogenic disease; immunoregulation; laboratory rat; method development; model design /development; mumps; neurogenetics; neurotoxicology; neurotoxins; neurotropic virus; polymerase chain reaction; vaccine development; viral vaccines; virulence; virus infection mechanism

Summary: Since the developing nervous system is uniquely sensitive to damage following virus infection, postnatal CNS development during the first several years of life provides for continued susceptibility of the infant CNS to damage by viral infection after birth. Administering insufficiently attenuated vaccines to infants may place the child's CNS at increased risk for injury. Thus, it is imperative to develop methods of pre-clinical neurovirulence testing with which to predict which vaccines might have significant neurovirulence potential for human CNS. Thus, it is important to develop valid molecular biological, in vitro and in vivo models to evaluate the pathogenesis of the neurotoxic effects of vaccine viruses. Development of these models will lead to improved safety of childhood vaccines, cost saving and improved predictability of neurovirulence testing, and information obtained in these studies will be useful in testing potentially neurovirulent vaccines (e.g., measles, mumps, HIV, parainfluenza, Japanese encephalitis). Progress: 2001 CBER Outstanding Regulatory Research Project 1. Molecular Markers of Neurotoxicity: We have identified vaccine virus-related perturbations in CNS gene expression by standard semiquantitative RT-PCR and by differential display techniques, including endogenous immune mediators of the CNS. We have recovered un-characterized gene products from new genes that are altered by virus infection of the brain. We have initiated RPA to compare changes in endogenous immune mediators in the CNS in animals infected with low and high neurovirulence strains of mumps virus.2. Animal Models of CNS Diseases Following Childhood Virus Infection: Autism. Viruses are known etiologic agents of autism (e.g., rubella). Therefore, concerns are raised regarding a possible relationship between childhood vaccines and autism. Because no valid animal models existed to study the pathogenesis of the neuroanatomical and behavioral signs of autism, we developed a rat model of autism using neonatal infection with neurotropic viruses. We have characterized autistic-like changes in neuroanatomy, neurochemistry, neurological disease and behavior in these rats. In addition, we have identified regional and developmental changes in neurotransmitters, including serotonin and norepinephrine. A developmental study of damage to developing brain (e.g., cerebellum)in virus infected rats was performed demonstrating anatomical, behavioral and neurological consequences.

总结： 由于发育中的神经系统对病毒感染后的损伤特别敏感，因此出生后几年的CNS发育使婴儿CNS在出生后对病毒感染的损伤持续易感。 给婴儿接种不充分的减毒疫苗可能会增加儿童CNS损伤的风险。 因此，迫切需要开发临床前神经毒力测试方法，以预测哪些疫苗可能对人类CNS具有显著的神经毒力潜力。 因此，重要的是开发有效的分子生物学，在体外和体内模型，以评估疫苗病毒的神经毒性作用的发病机制。 这些模型的开发将提高儿童疫苗的安全性，节省成本并提高神经毒力测试的可预测性，这些研究中获得的信息将有助于测试潜在的神经毒力疫苗（例如，麻疹、腮腺炎、HIV、副流感、日本脑炎）。 进展：2001年CBER杰出监管研究项目1。 神经毒性的分子标志物：我们通过标准半定量RT-PCR和差异显示技术，包括CNS的内源性免疫介质，鉴定了CNS基因表达中疫苗病毒相关的扰动。 我们已经从新基因中恢复了未表征的基因产物，这些新基因因病毒感染大脑而改变。 我们已经启动RPA来比较低和高神经毒力腮腺炎病毒株感染动物中枢神经系统内源性免疫介质的变化。 儿童病毒感染后CNS疾病的动物模型：自闭症。 病毒是自闭症的已知病原体（例如，风疹）。 因此，人们对儿童疫苗和自闭症之间可能存在的关系表示担忧。 由于没有有效的动物模型存在研究自闭症的神经解剖学和行为体征的发病机制，我们开发了一个自闭症的新生儿感染嗜神经病毒的大鼠模型。 我们已经在这些大鼠的神经解剖学、神经化学、神经疾病和行为方面描述了自闭症样变化。 此外，我们已经确定了神经递质的区域和发育变化，包括5-羟色胺和去甲肾上腺素。 对发育中大脑损伤的发育研究（例如，小脑）的解剖学、行为学和神经学结果。