Conlan J Wayne, Sjöstedt Anders, Gelhaus H Carl, Fleming Perry, McRae Kevan, Cobb Ronald R, De Pascalis Roberto, Elkins Karen L
Department of Human Health and Therapeutics, National Research Council-Canada, Ottawa, ON K1A 0R6, Canada.
Laboratory for Molecular Infection Medicine Sweden (MIMS), Department of Clinical Microbiology, Umeå University, SE-901 85 Umeå, Sweden.
Pathogens. 2021 Jun 23;10(7):795. doi: 10.3390/pathogens10070795.
Inhalation of small numbers of subspecies () in the form of small particle aerosols causes severe morbidity and mortality in people and many animal species. For this reason, was developed into a biological weapon by the USA, by the former USSR, and their respective allies during the previous century. Although such weapons were never deployed, the 9/11 attack quickly followed by the Amerithrax attack led the U.S. government to seek novel countermeasures against a select group of pathogens, including . Between 2005-2009, we pursued a novel live vaccine against by deleting putative virulence genes from a fully virulent strain of the pathogen, SCHU S4. These mutants were screened in a mouse model, in which the vaccine candidates were first administered intradermally (ID) to determine their degree of attenuation. Subsequently, mice that survived a high dose ID inoculation were challenged by aerosol or intranasally (IN) with virulent strains of . We used the current unlicensed live vaccine strain (LVS), first discovered over 70 years ago, as a comparator in the same model. After screening 60 mutants, we found only one, SCHU S4 , that outperformed LVS in the mouse ID vaccination-respiratory-challenge model. Currently, SCHU S4 has been manufactured under current good manufacturing practice conditions, and tested for safety and efficacy in mice, rats, and macaques. The steps necessary for advancing SCHU S4 to this late stage of development are detailed herein. These include developing a body of data supporting the attenuation of SCHU S4 to a degree sufficient for removal from the U.S. Select Agent list and for human use; optimizing SCHU S4 vaccine production, scale up, and long-term storage; and developing appropriate quality control testing approaches.
吸入少量呈小颗粒气溶胶形式的亚种（）会导致人类和许多动物物种出现严重发病和死亡情况。因此，在上个世纪，美国、前苏联及其各自盟友将其开发成了一种生物武器。尽管此类武器从未被部署，但9·11袭击后紧接着发生的美国炭疽袭击事件促使美国政府寻求针对包括在内的一组特定病原体的新型应对措施。在2005年至2009年期间，我们通过从该病原体的一个完全有毒力的菌株SCHU S4中删除假定的毒力基因，来研发一种针对的新型活疫苗。这些突变体在小鼠模型中进行筛选，在该模型中，候选疫苗首先通过皮内注射（ID）给药，以确定其减毒程度。随后，在高剂量ID接种后存活的小鼠通过气溶胶或鼻内（IN）途径用的有毒力菌株进行攻击。我们将70多年前首次发现的当前未获许可的活疫苗株（LVS）作为同一模型中的对照。在筛选了60个突变体后，我们仅发现一个，即SCHU S4，在小鼠ID疫苗接种 - 呼吸道攻击模型中其表现优于LVS。目前，SCHU S4已按照现行良好生产规范条件进行生产，并在小鼠、大鼠和猕猴中进行了安全性和有效性测试。本文详细介绍了将SCHU S4推进到这一后期开发阶段所需的步骤。这些步骤包括生成一系列数据，以支持将SCHU S4减毒到足以从美国选择生物剂清单中移除并供人类使用的程度；优化SCHU S4疫苗的生产、扩大规模和长期储存；以及开发适当的质量控制测试方法。
