Li Zhongqi, Rubin Steven A, Taffs Rolf E, Merchlinsky Michael, Ye Zhiping, Carbone Kathryn M
Laboratory of Pediatric and Respiratory Viral Diseases, OD/Center for Biologics Evaluation and Research, Food and Drug Administration, HFM-460, Bldg. 29B, Room 5NN22, 8800 Rockville Pike, Bethesda, MD 20892, USA.
Vaccine. 2004 Mar 29;22(11-12):1486-93. doi: 10.1016/j.vaccine.2003.10.022.
The only US FDA licensed smallpox vaccine, Dryvax, was associated with rare but serious neurological adverse events. After smallpox was eradicated in the United States, mass vaccination ceased in 1971. As counter-bioterrorism/biowarfare measures, new smallpox vaccines are now being investigated. However, there are no established pre-clinical neurotoxicity assays with which to evaluate these new vaccines prior to licensure. Here we report the development and initial characterization of a small animal neurotoxicity assay for vaccinia-based smallpox vaccines using Dryvax virus as a reference vaccine strain and the neuroadapted Western Reserve (WR) strain as a neurotoxic positive control. In neonatally inoculated mice, the WR strain produced significantly greater and more rapid onset of mortality than the Dryvax vaccine reference. Expression of virus antigen in neural cells and infectious virus replication in the brain was also significantly different between the two strains. In addition, the appearance of high titer virus antibody correlated with the clearance of virus from brain. With further validation, this assay incorporating a licensed vaccine reference standard and positive control strain may provide important pre-clinical neurotoxicity data on new vaccinia-based smallpox vaccine strains.
美国食品药品监督管理局（FDA）唯一批准的天花疫苗Dryvax，与罕见但严重的神经不良事件相关。在美国消灭天花后，大规模疫苗接种于1971年停止。作为反生物恐怖主义/生物战措施，新型天花疫苗目前正在研究中。然而，在疫苗获批之前，尚无成熟的临床前神经毒性检测方法来评估这些新型疫苗。在此，我们报告了一种针对基于痘苗的天花疫苗的小动物神经毒性检测方法的开发及初步特性研究，该方法使用Dryvax病毒作为参考疫苗株，并使用神经适应性西方储备（WR）株作为神经毒性阳性对照。在新生小鼠中，WR株比Dryvax疫苗参考株导致显著更高且更迅速的死亡。两种毒株在神经细胞中的病毒抗原表达以及脑中的感染性病毒复制也存在显著差异。此外，高滴度病毒抗体的出现与脑中病毒的清除相关。通过进一步验证，这种纳入了获批疫苗参考标准和阳性对照株的检测方法，可能会为新型基于痘苗的天花疫苗株提供重要的临床前神经毒性数据。
