Establishment of a Controlled Human Infection Model with a Lyophilized Strain of Shigella sonnei 53G.
Establishment of a Controlled Human Infection Model with a Lyophilized Strain of Shigella sonnei 53G.
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DOI：
10.1128/msphere.00416-20
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发表时间：
2020-09-23
期刊：
影响因子：
4.8
通讯作者：
Porter CK
中科院分区：
文献类型：
--
作者：
Frenck RW Jr;Dickey M;Suvarnapunya AE;Chandrasekaran L;Kaminski RW;Clarkson KA;McNeal M;Lynen A;Parker S;Hoeper A;Mani S;Fix A;Maier N;Venkatesan MM;Porter CK
受控人类感染模型（CHIM）是用于了解人类对感染的反应的宝贵工具，可能导致保护性免疫机制，并允许肠道对策（包括疫苗，抗生素和其他产品）的有效性测试。针对宋内志贺菌和福氏志贺菌的改良志贺菌CHIM的开发与国际捐助者和世界卫生组织支持的国际努力一致，重点是志贺菌CHIM标准化并利用它们加速志贺菌疫苗开发。使用冻干志贺氏菌挑战菌株而不是平板生长的接种物制剂被认为是标准化过程中的重要一步。此外，诸如此类的研究结果证明了开发冻干制剂用于其他流行病学上重要的S。福氏血清型，包括S. flexneri 3a和S.第六章.受控人类感染模型（CHIM）可用于疫苗开发。为了改进现有的模型，我们开发了一个CHIM使用冻干制剂的宋内志贺菌菌株53 G生产使用当前的良好生产规范（cGMP）。健康成人入组了一项开放标签剂量范围研究。在施用一剂再水化的S.在宋内氏菌株53 G中，监测受试者的疾病发展。第一组接受500 CFU的53 G，随后的组的给药基于前一组的结果。受试者在第5天接受环丙沙星给药，第8天出院回家。受试者作为门诊患者返回进行临床检查和样本采集。发病率随S.索尼增加了。在接受最高剂量（1，760 CFU）的患者中，70%出现中度至重度腹泻，50%出现痢疾，40%出现发热。在所有队列中均观察到抗脂多糖应答。色葡萄建立了使用冻干批次的菌株53 G的sonnei CHIM。选择1，500 - 2，000 CFU 53 G的剂量作为使用该产品进行未来挑战研究的剂量。该模型将能够直接比较机构之间的研究结果，并确保挑战接种物随时间推移具有更好的一致性。重要性受控人类感染模型（CHIM）是用于了解人类对感染的反应的宝贵工具，可能导致保护性免疫机制，并允许肠道对策（包括疫苗，抗生素和其他产品）的有效性测试。针对宋内志贺菌和福氏志贺菌的改良志贺菌CHIM的开发与国际捐助者和世界卫生组织支持的国际努力一致，重点是志贺菌CHIM标准化并利用它们加速志贺菌疫苗开发。使用冻干志贺氏菌挑战菌株而不是平板生长的接种物制剂被认为是标准化过程中的重要一步。此外，诸如此类的研究结果证明了开发冻干制剂用于其他流行病学上重要的S。福氏血清型，包括S. flexneri 3a和S.第六章.
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 Shigella CHIM for both Shigella sonnei and Shigella flexneri is consistent with international efforts, supported by international donors and the World Health Organization, focused on standardizing Shigella CHIMs and using them to accelerate Shigella vaccine development. The use of lyophilized Shigella 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 S. flexneri serotypes, including S. flexneri 3a and S. flexneri 6. Controlled human infection models (CHIMs) are useful for vaccine development. To improve on existing models, we developed a CHIM using a lyophilized preparation of Shigella sonnei 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 S. sonnei 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 S. sonnei 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 S. sonnei 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. IMPORTANCE 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 Shigella CHIM for both Shigella sonnei and Shigella flexneri is consistent with international efforts, supported by international donors and the World Health Organization, focused on standardizing Shigella CHIMs and using them to accelerate Shigella vaccine development. The use of lyophilized Shigella 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 S. flexneri serotypes, including S. flexneri 3a and S. flexneri 6.