Vaccine Safety: Neurovirulence test development

疫苗安全：神经毒力测试开发

• 批准号: 6545064
• 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/6545064
• 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 neurovirulence potential, in order to develop the safest vaccines possible. Such an effective test currently does not exist for most new vaccines. Vaccine neurovirulence concerns have been raised for mumps virus, vaccinia virus, influenza virus, human parainfluenza virus III, poliovirus, dengue virus, Japanese encephalitis virus and human immunodeficiency virus. Thus, neurovirulence 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 neurovirulence test was developed and neuropathological abnormalities were present. The most prominent abnormality was hydrocephalus. All strains induced some degree of hydrocephalus in rat brain and the severity of hydrocephalus tracked with the known human clinical histories of the virus strains. Using hydrocephalus as a marker of neurovirulence, wild-type strains could be distinguished from vaccine strains and the relative neurovirulence among wild type strains and among vaccine strains could be distinguished as well. These experiments in other laboratories outside of CBER are underway to initiate early stages of validation of this model system. In addition, virus genome correlates of neurovirulence are being investigated. 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 neurovirulence of influenza viruses (wild type and vaccine) using our newborn rat model. Preliminary results suggest we can differentiate between wild type influenza virus and vaccine strains in our neurovirulence test. 3. Vaccinia-derived vaccines: We have developed a newborn mouse model for differentiating the virulence of vaccinia virus strains. Preliminary results suggest we can differentiate between vaccinia strains of greater or lesser virulence, suggesting this test will have utility as a pre-clinical virulence test.

摘要：背景：人类的大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，因此对婴儿施用神经毒性疫苗可使儿童的神经系统处于疫苗相关损伤的增加的风险中。有必要开发一种测试来评估疫苗的人类神经毒性潜力，以开发尽可能安全的疫苗。目前，大多数新疫苗都没有这种有效的检测方法。疫苗的神经毒力问题已引起腮腺炎病毒、牛痘病毒、流感病毒、人副流感病毒III、脊髓灰质炎病毒、登革热病毒、日本脑炎病毒和人免疫缺陷病毒的关注。因此，需要神经毒力安全性试验（NVST）来鉴定大量可能在接种疫苗后引起CNS疾病的潜在神经毒力疫苗。 进度：1.流行性腮腺炎疫苗：开展了新生大鼠神经毒力试验，发现存在神经病理学异常。最突出的异常是脑积水。所有病毒株在大鼠脑中均诱导一定程度的脑积水，并且脑积水的严重程度与病毒株的已知人类临床历史一起跟踪。以脑积水作为神经毒力的标志物，可以区分野生型菌株和疫苗株，也可以区分野生型菌株和疫苗株之间的相对神经毒力。CBER以外的其他实验室正在进行这些实验，以启动该模型系统验证的早期阶段。此外，正在研究病毒基因组与神经毒力的相关性。 2.流感疫苗：尽管罕见，但可能发生与野生型流感病毒相关的CNS事件。 在这个项目中，我们正在开发一种检测方法，使用我们的新生大鼠模型来评估流感病毒（野生型和疫苗）的相对神经毒力。 初步结果表明，我们可以区分野生型流感病毒和疫苗株在我们的神经毒力测试。 3.牛痘衍生疫苗：我们开发了一种新生小鼠模型，用于区分牛痘病毒株的毒力。 初步结果表明，我们可以区分更大或更小的毒力牛痘菌株，这表明该测试将作为一个临床前的毒力测试的效用。