Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
mSphere. 2020 Sep 23;5(5):e00416-20. doi: 10.1128/mSphere.00416-20.
Controlled human infection models (CHIMs) are useful for vaccine development. To improve on existing models, we developed a CHIM using a lyophilized preparation of strain 53G produced using current good manufacturing practice (cGMP). Healthy adults were enrolled in an open-label dose-ranging study. Following administration of a dose of rehydrated strain 53G, subjects were monitored for development of disease. The first cohort received 500 CFU of 53G, and dosing of subsequent cohorts was based on results from the previous cohort. Subjects were administered ciprofloxacin on day 5 and discharged home on day 8. Subjects returned as outpatients for clinical checks and sample collection. Attack rates increased as the dose of was increased. Among those receiving the highest dose (1,760 CFU), 70% developed moderate to severe diarrhea, 50% had dysentery, and 40% had fever. Antilipopolysaccharide responses were observed across all cohorts. An CHIM using a lyophilized lot of strain 53G was established. A dose in the range of 1,500 to 2,000 CFU of 53G was selected as the dose for future challenge studies using this product. This model will enable direct comparison of study results between institutions and ensure better consistency over time in the challenge inoculum. Controlled human infection models (CHIMs) are invaluable tools utilized to understand the human response to infection, potentially leading to protective immune mechanisms and allowing efficacy testing of enteric countermeasures, including vaccines, antibiotics, and other products. The development of an improved CHIM for both and is consistent with international efforts, supported by international donors and the World Health Organization, focused on standardizing CHIMs and using them to accelerate vaccine development. The use of lyophilized challenge strains rather than plate-grown inoculum preparations is considered an important step forward in the standardization process. Furthermore, the results of studies such as this justify the development of lyophilized preparations for additional epidemiologically important serotypes, including 3a and 6.
人体感染控制模型（CHIM）可用于疫苗开发。为了改进现有的模型，我们使用符合现行良好生产规范（cGMP）生产的冻干制剂 53G 株开发了一种 CHIM。健康成年人参加了一项开放标签剂量递增研究。在给予复水 53G 株剂量后，监测受试者疾病的发展情况。第一队列接受 500 CFU 的 53G，随后队列的剂量基于前一队列的结果。在第 5 天给予受试者环丙沙星，并在第 8 天出院回家。受试者作为门诊病人返回进行临床检查和样本采集。随着 的剂量增加，攻击率增加。在接受最高剂量（1760 CFU）的受试者中，70%出现中度至重度腹泻，50%出现痢疾，40%出现发热。在所有队列中都观察到了抗脂多糖反应。建立了使用冻干 53G 株的 CHIM。选择 1500 至 2000 CFU 范围内的剂量作为使用该产品进行未来挑战研究的剂量。该模型将能够在机构之间直接比较研究结果，并确保随着时间的推移，挑战接种物具有更好的一致性。人体感染控制模型（CHIM）是一种非常有价值的工具，可用于了解人体对感染的反应，从而可能产生保护性免疫机制，并能够对肠道对策（包括疫苗、抗生素和其他产品）进行疗效测试。开发一种用于 和 的改进 CHIM 符合国际努力，得到了国际捐助者和世界卫生组织的支持，重点是标准化 CHIM 并利用它们加速 疫苗的开发。使用冻干 挑战株而不是平板培养接种物制剂被认为是标准化过程中的重要一步。此外，此类研究的结果证明了为其他具有流行病学重要性的 血清型（包括 3a 和 6）开发冻干制剂是合理的。
