VACCINE SAFETY: PATHOGENESIS OF VIRUS VACCINE NEUROTOXICITY

疫苗安全性：病毒疫苗神经毒性的发病机制

• 批准号: 6293712
• 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/6293712
• 关键词: brain disorders; developmental neurobiology; disease /disorder model; genetic strain; microorganism growth; mumps virus; neurotropic virus; tissue /cell culture; viral vaccines; virulence; virus replication

Since the developing nervous system is uniquely sensitive to damage following virus infection, postnatal CNS development during the first year of life provides continued susceptibility of the infant CNS to damage by viral infection after birth. Administering neurovirulent vaccines to infants also places the child's CNS at increased risk for injury. However, it is very difficult to predict which vaccines have significant neurovirulence potential for human CNS. Wild type mumps viruses are among the most neurotropic of the early childhood viruses. Mumps vaccine virus strains also have neurovirulence potential (e.g., Urabe Am9) and new MMR combinations continue to be proposed that include new strains of mumps vaccine virus. 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 cost saving and improved predictability of neurovirulence testing, and information obtained in these studies about mumps virus vaccines will likely be useful in generalizing to other potentially neurovirulent vaccines (e.g., measles, Japanese encephalitis). Progress: 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: CNS genes that are altered by the presence of viruses in the CNS include neurotrophic hormones, cellular adhesion molecules and molecules involved in metabolism. In addition, we have identified several genes, not previously known to be affected by CNS virus infection, that are responsible for immunological responses, nucleotide synthesis and cell migration in the CNS. We have sequenced gene products from new genes that are altered by virus infection of the brain. 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, neurological disease and behavior in these rats. 3. Pathogenesis of neurotoxicity of neurovirulent vaccine virus infections. We have documented a relationship between state of CNS maturity and neurotoxic effects of virus infection. 4. Pathogenesis of behavioral and anatomical developmental brain disease following neonatal virus infection. We have identified regional abnormalities in cytokines, cytokine receptors, neuropeptides and neurotransmitters in neonatally virus-infected rat brain.

由于发育中的神经系统对病毒感染后的损伤特别敏感，因此出生后第一年的CNS发育使婴儿CNS在出生后对病毒感染的损伤持续易感。 给婴儿接种神经毒性疫苗也会增加儿童中枢神经系统受伤的风险。 然而，很难预测哪些疫苗对人类CNS具有显著的神经毒力潜力。 野生型腮腺炎病毒是最嗜神经的幼儿病毒之一。 腮腺炎疫苗病毒株也具有神经毒性潜力（例如，Urabe Am 9）和新的MMR组合仍在继续提出，其中包括新的腮腺炎疫苗病毒株。 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。 这些模型的开发将节省成本并提高神经毒力测试的可预测性，并且在这些研究中获得的关于腮腺炎病毒疫苗的信息可能有助于推广到其他潜在的神经毒力疫苗（例如，麻疹、日本脑炎）。 进度：1. 神经毒性的分子标志物：我们已经通过标准半定量RT-PCR和差异显示技术鉴定了CNS基因表达中疫苗病毒相关的扰动：CNS中存在病毒改变的CNS基因包括神经营养激素、细胞粘附分子和参与代谢的分子。 此外，我们已经确定了几个基因，以前不知道会受到CNS病毒感染，负责免疫反应，核苷酸合成和细胞迁移的CNS。 我们已经对新基因的基因产物进行了测序，这些新基因被大脑的病毒感染所改变。 2. 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，神经系统疾病和行为的特征性自闭症样变化。 3. 神经毒性疫苗病毒感染神经毒性的发病机制。 我们已经证明了CNS成熟状态与病毒感染的神经毒性作用之间的关系。4.新生儿病毒感染后行为和解剖发育性脑疾病的发病机制。 我们已经确定了区域异常的细胞因子，细胞因子受体，神经肽和神经递质在脑病毒感染的大鼠大脑。