Fitzpatrick Megan, Ho Mei Mei, Clark Simon, Dagg Belinda, Khatri Bhagwati, Lanni Faye, Williams Ann, Brennan Michael, Laddy Dominick, Walker Barry
Aeras, 1405 Research Boulevard, Rockville, MD, 20850, USA.
Bacteriology Division, MHRA-NIBSC, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK.
Tuberculosis (Edinb). 2019 Jan;114:47-53. doi: 10.1016/j.tube.2018.10.013. Epub 2018 Nov 2.
A global BCG vaccine shortage began in 2013 which impacted availability for infant vaccinations, as well as preclinical studies and clinical trials of new TB vaccines. Stakeholders met in 2015 at McGill University in Montreal to discuss the shortage and potential mitigation strategies. Manufacturing BCG through a more tractable liquid fermentation process instead of the traditional pellicle growth method was considered a potentially viable strategy. This pilot program compared pellicle-grown and shake flask-grown BCG strains (as a first step towards modeling fermenter-produced BCG vaccine) in selected quality control assays, as well as mouse and guinea pig protection studies. Conventional pellicle-grown, lyophilized BCG WHO Reference Reagents (Danish, Moreau, Russian, Tokyo strains) were obtained from the National Institute for Biological Standards and Control (NIBSC), UK. Strains were grown in shake flasks and glycerol stocks prepared. Shake flask-grown BCG culture preparations generally met the requirements of quality control testing at NIBSC. In mouse and guinea pig protection studies there were no significant differences in lung colony forming units (CFUs) between shake flask-grown and pellicle-grown preparations, with the exception of BCG Russian, where the shake flask-grown preparation protected better in mice (P = 0.0042), but the pellicle-grown preparation protected better in guinea pigs (P = 0.0015). Producing BCG vaccines by a more tractable liquid growth process could be a viable solution to the global BCG shortage.
2013年开始出现全球卡介苗短缺，这影响了婴儿疫苗接种的供应，以及新型结核病疫苗的临床前研究和临床试验。2015年，利益相关者在蒙特利尔的麦吉尔大学开会讨论短缺问题和潜在的缓解策略。通过更易于操作的液体发酵工艺而非传统的菌膜生长方法来生产卡介苗被认为是一种潜在可行的策略。该试点项目在选定的质量控制检测中，以及在小鼠和豚鼠保护研究中，比较了菌膜生长和摇瓶培养的卡介苗菌株（作为模拟发酵罐生产卡介苗疫苗的第一步）。传统的菌膜生长、冻干的卡介苗世界卫生组织参考试剂（丹麦、莫罗、俄罗斯、东京菌株）从英国国家生物标准与控制研究所（NIBSC）获得。菌株在摇瓶中培养并制备甘油菌液。摇瓶培养的卡介苗培养制剂一般符合NIBSC的质量控制检测要求。在小鼠和豚鼠保护研究中，除了俄罗斯卡介苗外，摇瓶培养制剂和菌膜生长制剂在肺部集落形成单位（CFU）方面没有显著差异，俄罗斯卡介苗的摇瓶培养制剂在小鼠中保护效果更好（P = 0.0042），但菌膜生长制剂在豚鼠中保护效果更好（P = 0.0015）。通过更易于操作的液体生长工艺生产卡介苗疫苗可能是解决全球卡介苗短缺问题的可行办法。
