Osowicki Joshua, Azzopardi Kristy I, Fabri Loraine, Frost Hannah R, Rivera-Hernandez Tania, Neeland Melanie R, Whitcombe Alana L, Grobler Anneke, Gutman Sarah J, Baker Ciara, Wong Janet M F, Lickliter Jason D, Waddington Claire S, Pandey Manisha, Schuster Tibor, Cheng Allen C, Pollard Andrew J, McCarthy James S, Good Michael F, Dale James B, Batzloff Michael, Moreland Nicole J, Walker Mark J, Carapetis Jonathan R, Smeesters Pierre R, Steer Andrew C
Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Infectious Diseases Unit, Department of General Medicine, Royal Children's Hospital Melbourne, Melbourne, VIC, Australia.
Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
Lancet Microbe. 2021 Jul;2(7):e291-e299. doi: 10.1016/S2666-5247(20)30240-8. Epub 2021 Apr 15.
Streptococcus pyogenes is a leading cause of infection-related morbidity and mortality. A reinvigorated vaccine development effort calls for new clinically relevant human S pyogenes experimental infection models to support proof of concept evaluation of candidate vaccines. We describe the initial Controlled Human Infection for Vaccination Against S pyogenes (CHIVAS-M75) study, in which we aimed to identify a dose of emm75 S pyogenes that causes acute pharyngitis in at least 60% of volunteers when applied to the pharynx by swab.
This observational, dose-finding study was done in a clinical trials facility in Melbourne (VIC, Australia). Groups of healthy volunteers aged 18-40 years, at low risk of complicated S pyogenes disease, and without high type-specific anti-emm75 IgG antibodies against the challenge strain were challenged and closely monitored as inpatients for up to 6 days, and then as outpatients for 6 months. Antibiotics were started upon diagnosis (clinical signs and symptoms of pharyngitis and a positive rapid molecular test) or after 5 days in those without pharyngitis. Rapid test results were confirmed by standard bacterial culture. After a sentinel participant, cohorts of five and then ten participants were challenged, with protocol-directed dose-escalation or de-escalation for subsequent cohorts. The primary outcome was the proportion of participants at each dose level with pharyngitis by day 5 after challenge. The study is registered with ClinicalTrials.gov, NCT03361163.
Between July 10, 2018, and Sept 23, 2019, 25 healthy adults were challenged with emm75 S pyogenes and included in analyses. Pharyngitis was diagnosed in 17 (85%; 95% CI 62-97) of 20 participants at the starting dose level (1-3 × 10 colony-forming units [CFU]/mL). This high proportion prompted dose de-escalation. At the lower dose level (1-3 × 10 CFU/mL), pharyngitis was diagnosed in one of five participants. Immunological, biochemical, and microbiological results supported the clinical picture, with acute symptomatic pharyngitis characterised by pharyngeal colonisation by S pyogenes accompanied by significantly elevated C-reactive protein and inflammatory cytokines (eg, interferon-γ and interleukin-6), and modest serological responses to streptolysin O and deoxyribonuclease B. There were no severe (grade 3) or serious adverse events related to challenge.
We have established a reliable pharyngitis human infection model with reassuring early safety findings to accelerate development of vaccines and other interventions to control disease due to S pyogenes.
Australian National Health and Medical Research Council.
化脓性链球菌是感染相关发病和死亡的主要原因。疫苗研发工作的重新兴起需要新的具有临床相关性的人类化脓性链球菌实验感染模型，以支持候选疫苗的概念验证评估。我们描述了最初的针对化脓性链球菌的疫苗接种人体对照感染（CHIVAS-M75）研究，其目的是确定当通过拭子将一定剂量的emm75化脓性链球菌应用于咽部时，至少60%的志愿者会发生急性咽炎。
这项观察性剂量探索研究在墨尔本（澳大利亚维多利亚州）的一个临床试验机构进行。年龄在18至40岁、患复杂化脓性链球菌疾病风险较低且针对攻击菌株没有高滴度型特异性抗emm75 IgG抗体的健康志愿者组，作为住院患者接受攻击并密切监测长达6天，然后作为门诊患者监测6个月。一旦诊断（咽炎的临床体征和症状以及快速分子检测呈阳性）或在无咽炎的志愿者中5天后开始使用抗生素。快速检测结果通过标准细菌培养确认。在一名哨兵参与者之后，对每组5名和随后每组10名参与者进行攻击，后续组根据方案指导进行剂量递增或递减。主要结局是每个剂量水平的参与者在攻击后第5天发生咽炎的比例。该研究已在ClinicalTrials.gov注册，注册号为NCT03361163。
在2018年7月10日至2019年9月23日期间，25名健康成年人接受了emm75化脓性链球菌攻击并纳入分析。在起始剂量水平（1 - 3×10菌落形成单位[CFU]/mL）的20名参与者中，有17名（85%；95%CI 62 - 97）被诊断为咽炎。这一高比例促使剂量递减。在较低剂量水平（1 - 3×10 CFU/mL），5名参与者中有1名被诊断为咽炎。免疫学、生化和微生物学结果支持临床情况，急性症状性咽炎的特征是化脓性链球菌在咽部定植，同时C反应蛋白和炎性细胞因子（如干扰素-γ和白细胞介素-6）显著升高，以及对链球菌溶血素O和脱氧核糖核酸酶B的适度血清学反应。没有与攻击相关的严重（3级）或严重不良事件。
我们建立了一个可靠的咽炎人体感染模型，早期安全性结果令人放心，以加速疫苗和其他控制化脓性链球菌疾病的干预措施的开发。
澳大利亚国家卫生与医学研究委员会。
