VACCINE SAFETY: NEUROVIRULENCE SAFETY TEST DEVELOPMENT, VALIDATION AND EVALUATIO

疫苗安全：神经病毒安全测试的开发、验证和评估

• 批准号: 6293713
• 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/6293713
• 关键词: active immunization; brain injury; developmental neurobiology; drug adverse effect; histopathology; laboratory rat; microorganism culture; mumps virus; neurotropic virus; newborn animals; viral vaccines; virulence

Congenital brain damage due to intrauterine virus infections is a significant pediatric problem. In addition, the brain continues to develop during the first year of postnatal life. Since the developing nervous system is uniquely sensitive to damage following virus infection, administering neurovirulent vaccines to infants can place the child's nervous system at increased risk for vaccine related injury. Mumps virus, and certain strains of mumps vaccine (Urabe Am9, Leningrad 3), are among the most neurotropic of the early childhood viruses, and new MMR combinations continue to be proposed, including new strains of mumps vaccine virus. In addition, vaccine neurovirulence concerns have been raised about other viruses including influenza virus, human parainfluenza virus III, poliovirus, dengue virus, Japanese encephalitis virus and human immunodeficiency virus. Neurovirulence safety tests (NVST) are needed to identify neurovirulent vaccines that may cause CNS disease following vaccination. Progress: NSVT Development: Primate: Developed and tested a simplified, biologically relevant, standardized primate NVST. Animals inoculated with various doses of wild type and vaccine strains of mumps virus developed inflammation. Licensed mumps vaccines were statistically no different from experimental mumps vaccine. The test was unable to differentiate vaccine from wild type strains at a single dose. These studies support the conclusion that neurovirulence safety testing of mumps vaccines in primates may not be helpful in discriminating the neurovirulence potention in human CNS of mumps vaccine strains. Small animal: A newborn rat NVST was developed and tested with neurovirulent (Kilham, Strain 88-1961, Urabe AM9) and relatively non-neurovirulent (Jeryl-Lynn) strains of mumps viruses. Using physiological, neuroanatomical and behavioral endpoints, significant differences were identified in rats infected at birth with relatively neurovirulent and non neurovirulent viruses. This preliminary model system development was able to discriminate among vaccine strains and wild type strains based upon their known human neurovirulence clinical outcomes. Additional experiments are underway to complete validation of this model system and to evaluate a dose-response curve for neurovirulence induction by wild type and vaccine mumps virus strains.

由于宫内病毒感染引起的先天性脑损伤是一个重要的儿科问题。 此外，大脑在出生后的第一年继续发育。由于发育中的神经系统对病毒感染后的损伤特别敏感，因此对婴儿接种神经毒性疫苗可能会增加儿童神经系统发生疫苗相关损伤的风险。 流行性腮腺炎病毒和某些流行性腮腺炎疫苗株（Urabe Am 9，Leningrad 3）是最嗜神经的幼儿病毒之一，新的MMR组合不断被提出，包括新的流行性腮腺炎疫苗病毒株。 此外，疫苗的神经毒力问题还涉及其他病毒，包括流感病毒、人类副流感病毒III、脊髓灰质炎病毒、登革热病毒、日本脑炎病毒和人类免疫缺陷病毒。需要进行神经毒力安全性试验（NVST）来鉴定接种后可能导致CNS疾病的神经毒力疫苗。 进展：NSVT开发：灵长类动物：开发并测试了一种简化的、生物学相关的、标准化的灵长类动物NVST。 接种不同剂量的野生型和疫苗株腮腺炎病毒的动物出现炎症。许可的腮腺炎疫苗与实验性腮腺炎疫苗在统计学上没有差异。 该试验无法在单次给药时区分疫苗和野生型菌株。 这些研究支持以下结论：在灵长类动物中进行腮腺炎疫苗的神经毒力安全性试验可能无助于区分腮腺炎疫苗株在人CNS中的神经毒力潜力。 小动物：开发了新生大鼠NVST，并用神经毒性（Kilham，菌株88-1961，Urabe AM 9）和相对非神经毒性（Jeryl-Lynn）腮腺炎病毒株进行了测试。 使用生理，神经解剖学和行为终点，显着差异，确定在出生时感染相对神经毒力和非神经毒力病毒的大鼠。 该初步模型系统开发能够基于其已知的人类神经毒力临床结果来区分疫苗株和野生型株。 目前正在进行其他实验，以完成该模型系统的验证，并评估野生型和疫苗腮腺炎病毒株诱导神经毒力的剂量-反应曲线。