Vaccine Safety: Neurotoxicity safety test development,

疫苗安全：神经毒性安全测试开发，

• 批准号: 6678775
• 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/6678775
• 关键词: bioassay; biomarker; central nervous system disorders; developmental neurobiology; disease /disorder model; drug adverse effect; drug screening /evaluation; genetic strain; hydrocephalus; iatrogenic disease; immunotherapy; influenza vaccines; laboratory mouse; laboratory rat; mumps virus; neuropathology; neurotropic virus; newborn animals; public health; technology /technique development; vaccinia virus; viral vaccines; virulence; virus genetics

Summary: Background: Human brain continues to develop during the first few years of postnatal life. Since the developing brain is uniquely sensitive to damage following virus infection, administration of neurovirulent vaccines to infants can place the child's nervous system at increased risk for vaccine related injury. There is a need to develop a test to assess the vaccine's human neurotoxicity potential, in order to develop the safest vaccines possible. Such an effective test currently does not exist for most new vaccines. Vaccine neurotoxicity concerns have been raised for mumps virus, vaccinia virus (Smallpox vaccine), influenza virus, human parainfluenza virus III, poliovirus, dengue virus, Japanese encephalitis virus and human immunodeficiency virus. Thus, neurotoxicity safety tests (NVST) are needed to identify a multitude of potentially neurovirulent vaccines that may cause CNS disease following vaccination. Progress: 1. Mumps vaccine: A newborn rat neurotoxicity test was developed we are proceeding with international validation studies with NIBSC in England and with health authorities in Brazil. We have also discovered virus genomic changes associated with neurotoxicity alterations, as well as molecular markers of host neuronal damage following infection. Two manuscripts summarizing these results are in preparation. 2. Influenza vaccine: Although rare, CNS events associated with wild type influenza virus can occur. In this project we are developing an assay to evaluate the relative neurotoxicity of influenza viruses (wild type and vaccine) using our newborn rat model. Our data show that we can differentiate between wild type influenza virus and vaccine strains in our neurotoxicity test. These results have been submitted for review. 3. Smallpox vaccines: We have developed a newborn mouse model for differentiating the toxicity of vaccinia virus strains. We can differentiate between vaccinia strains of greater or lesser neurotoxicity, suggesting this test will have utility as a pre-clinical toxicity test for new smallpox vaccines. A manuscript summarizing these results is in preparation. 4. We have begun to develop a mouse model for measles virus neurotoxicity testing using transgenic mice.

摘要：背景： 人脑在出生后的头几年继续发育。由于发育中的大脑对病毒感染后的损伤特别敏感，给婴儿接种神经毒力疫苗可能会增加儿童神经系统受到疫苗相关损伤的风险。为了开发尽可能安全的疫苗，有必要开发一种测试来评估疫苗的人类神经毒性潜力。对于大多数新疫苗，目前还不存在这样有效的测试。流行性腮腺炎病毒、牛痘病毒(天花疫苗)、流感病毒、人类副流感病毒III、脊髓灰质炎病毒、登革病毒、日本脑炎病毒和人类免疫缺陷病毒等疫苗的神经毒性问题已引起关注。因此，需要进行神经毒性安全试验(NVST)，以确定疫苗接种后可能导致中枢神经系统疾病的多种潜在神经毒力疫苗。 进展： 1.腮腺炎疫苗： 新生大鼠的神经毒性测试已经开发出来，我们正在与英国的NIBSC和巴西的卫生当局进行国际验证研究。我们还发现了与神经毒性改变相关的病毒基因组变化，以及感染后宿主神经元损伤的分子标志物。总结这些结果的两份手稿正在准备中。 2.流感疫苗： 虽然罕见，但与野生型流感病毒相关的中枢神经系统事件可能会发生。在这个项目中，我们正在开发一种使用我们的新生大鼠模型来评估流感病毒(野生型和疫苗)的相对神经毒性的方法。我们的数据表明，在我们的神经毒性测试中，我们可以区分野生型流感病毒和疫苗株。这些结果已提交审查。 3.天花疫苗： 我们已经建立了一个新生的小鼠模型，用于区分痘苗病毒株的毒性。我们可以区分神经毒性较大或较小的痘苗菌株，这表明该测试将作为新天花疫苗的临床前毒性测试。总结这些结果的手稿正在准备中。 4.我们已经开始利用转基因小鼠建立麻疹病毒神经毒性检测的小鼠模型。