背景:结核分枝杆菌是结核病的主要病原体。BCG,唯一获得许可的疫苗,对肺结核的保护不足。受控的人类感染模型是疫苗开发的有用工具。我们的目的是确定一个安全剂量的气溶胶吸入的活的减毒牛分枝杆菌BCG作为结核分枝杆菌感染的替代品,然后比较使用气雾剂吸入和皮内给药BCG建立的感染模型的安全性和耐受性。
方法:该1期对照人类感染试验在英国的两个临床研究机构进行。健康,18-50岁有免疫能力的成年人,初治结核分枝杆菌和初治卡介苗,无哮喘或其他呼吸道疾病史,有资格参加审判。参与者最初被纳入第1组(接受BCG丹麦菌株);由于全球缺乏BCG丹麦,该试验随后暂停,议定书修正后,使用BCG保加利亚菌株(第2组)重新开始。经过剂量递增研究,在此期间,参与者被依次分配接受1×103、1×104、1×105、1×106或1×107个菌落形成单位(CFU)的气溶胶BCG,在随机对照试验中选择最大耐受剂量.这项试验的参与者被随机分配(9:12),通过可变区组随机化和使用顺序编号的密封信封,接受气雾剂卡介苗(1×107CFU)和皮内盐水或皮内卡介苗(1×106CFU)和气雾剂盐水。参与者被掩盖到治疗分配直到第14天。主要结果是比较基于气雾剂吸入卡介苗的受控人类感染模型与基于皮内给药卡介苗的受控人类感染模型的安全性。次要结局是评估接受气雾剂BCG的参与者在气道中的BCG恢复或接受皮内BCG的参与者的皮肤活检。通过培养和PCR检测BCG。该试验在ClinicalTrials.gov注册,NCT02709278,并且完成。
结果:参与者在2016年4月7日至2018年9月29日之间接受了资格评估。对于第1组,对15名参与者进行了筛查,其中13人入组,10人完成研究;对于第2组,60人进行了筛查,33人入组,所有人都完成了这项研究。高达1×107CFU气雾剂吸入的BCG的剂量具有足够好的耐受性。气雾剂组和皮内组之间的不良事件发生频率没有显著差异(每位参与者所请求的不良事件的中位数百分比,气雾剂后与皮内卡介苗:全身7%[IQR2-11]与4%[1-13],p=0·62;呼吸7%[1-19]vs4%[1-9],p=0·56)。气雾剂卡介苗后2周内发生更严重的全身不良事件(122例报告的全身不良事件中的15例[12%])比皮内卡介苗后(94例[1%];差异11%[95%CI5-17];p=0·0013),但在呼吸道不良事件的严重程度上没有观察到差异(144个中的2个[1%]与97个中的0个[0%];1%[-1至3];p=0·52).气雾剂BCG后的所有不良事件均自发消退。报告了一个严重不良事件-第2组的参与者因先前存在的卵巢囊肿而入院接受镇痛,这被认为与卡介苗感染无关。在第14天,从气溶胶感染后的支气管肺泡灌洗样品和皮内感染后的皮肤活检样品培养BCG。
结论:这种先入人气雾剂BCG控制的人感染模型具有足够好的耐受性。进一步的工作将评估该模型在评估疫苗功效和确定潜在的保护相关方面的实用性。
背景:比尔和梅琳达·盖茨基金会,惠康信托基金,国立卫生研究院牛津生物医学研究中心,泰晤士河谷临床研究网络,和TBVAC2020。
BACKGROUND: Mycobacterium tuberculosis is the main causative agent of tuberculosis. BCG, the only licensed vaccine, provides inadequate protection against pulmonary tuberculosis. Controlled human infection models are useful tools for vaccine development. We aimed to determine a safe dose of aerosol-inhaled live-attenuated Mycobacterium bovis BCG as a surrogate for M tuberculosis infection, then compare the safety and tolerability of infection models established using aerosol-inhaled and intradermally administered BCG.
METHODS: This phase 1 controlled human infection trial was conducted at two clinical research facilities in the UK. Healthy, immunocompetent adults aged 18-50 years, who were both M tuberculosis-naive and BCG-naive and had no history of asthma or other respiratory diseases, were eligible for the trial. Participants were initially enrolled into group 1 (receiving the BCG Danish strain); the trial was subsequently paused because of a worldwide shortage of BCG Danish and, after protocol amendment, was restarted using the BCG Bulgaria strain (group 2). After a dose-escalation study, during which participants were sequentially allocated to receive either 1 × 103, 1 × 104, 1 × 105, 1 × 106, or 1 × 107 colony-forming units (CFU) of aerosol BCG, the maximum tolerated dose was selected for the randomised controlled trial. Participants in this trial were randomly assigned (9:12), by variable block randomisation and using sequentially numbered sealed envelopes, to receive aerosol BCG (1 × 107 CFU) and intradermal saline or intradermal BCG (1 × 106 CFU) and aerosol saline. Participants were masked to treatment allocation until day 14. The primary outcome was to compare the safety of a controlled human infection model based on aerosol-inhaled BCG versus one based on intradermally administered BCG, and the secondary outcome was to evaluate BCG recovery in the airways of participants who received aerosol BCG or skin biopsies of participants who received intradermal BCG. BCG was detected by culture and by PCR. The trial is registered at ClinicalTrials.gov, NCT02709278, and is complete.
RESULTS: Participants were assessed for eligibility between April 7, 2016, and Sept 29, 2018. For group 1, 15 participants were screened, of whom 13 were enrolled and ten completed the study; for group 2, 60 were screened and 33 enrolled, all of whom completed the study. Doses up to 1 × 107 CFU aerosol-inhaled BCG were sufficiently well tolerated. No significant difference was observed in the frequency of adverse events between aerosol and intradermal groups (median percentage of solicited adverse events per participant, post-aerosol vs post-intradermal BCG: systemic 7% [IQR 2-11] vs 4% [1-13], p=0·62; respiratory 7% [1-19] vs 4% [1-9], p=0·56). More severe systemic adverse events occurred in the 2 weeks after aerosol BCG (15 [12%] of 122 reported systemic adverse events) than after intradermal BCG (one [1%] of 94; difference 11% [95% CI 5-17]; p=0·0013), but no difference was observed in the severity of respiratory adverse events (two [1%] of 144 vs zero [0%] of 97; 1% [-1 to 3]; p=0·52). All adverse events after aerosol BCG resolved spontaneously. One serious adverse event was reported-a participant in group 2 was admitted to hospital to receive analgesia for a pre-existing ovarian cyst, which was deemed unrelated to BCG infection. On day 14, BCG was cultured from bronchoalveolar lavage samples after aerosol infection and from skin biopsy samples after intradermal infection.
CONCLUSIONS: This first-in-human aerosol BCG controlled human infection model was sufficiently well tolerated. Further work will evaluate the utility of this model in assessing vaccine efficacy and identifying potential correlates of protection.
BACKGROUND: Bill & Melinda Gates Foundation, Wellcome Trust, National Institute for Health Research Oxford Biomedical Research Centre, Thames Valley Clinical Research Network, and TBVAC2020.