Abstract：
Accumulating evidence has shown that the abnormal toxicity test (ATT) is not suitable as a quality control batch release test for biologics and vaccines. The purpose of the current study was to explore the optimal ATT experimental design for an adenoviral vector-based vaccine product to avoid false positive results following the standard test conditions stipulated in the Pharmacopoeias. ATT were conducted in both mice and guinea pigs based on methods in Pharmacopeias, with modifications to assess effects of dose volume and amount of virus particles (VPs). The results showed intraperitoneal (IP) dosing at human relevant dose and volume (i.e., VPs), as required by pharmacopeia study design, resulted in false positive findings not associated with extraneous contaminants of a product. Considering many gene therapy products use adeno associated virus as the platform for transgene delivery, data from this study are highly relevant in providing convincing evidence to show the ATT is inappropriate as batch release test for biologics, vaccine and gene therapy products. In conclusion, ATT, which requires unnecessary animal usage and competes for resources which otherwise can be spent on innovative medicine research, should be deleted permanently as batch release test by regulatory authorities around the world.
摘要：
越来越多的证据表明，异常毒性试验（ATT）不适合作为生物制剂和疫苗的质量控制批次释放试验。本研究的目的是探索基于腺病毒载体的疫苗产品的最佳ATT实验设计，以避免遵循药典中规定的标准测试条件的假阳性结果。根据药典中的方法，在小鼠和豚鼠中进行了ATT研究，进行修改以评估剂量体积和病毒颗粒（VP）量的影响。结果显示腹膜内(IP)给药在人相关剂量和体积(即，VPs),根据药典研究设计的要求，导致假阳性结果与产品的外来污染物无关。考虑到许多基因治疗产品使用腺相关病毒作为转基因传递的平台，这项研究的数据在提供令人信服的证据表明ATT不适合作为生物制剂的批量发布测试方面具有高度相关性，疫苗和基因治疗产品。总之,ATT,这需要不必要的动物使用，并争夺资源，否则这些资源可以用于创新医学研究，应作为全球监管机构的批量发布测试永久删除。
