Abstract：
OBJECTIVE: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19.
METHODS: Phase III double-blind randomised controlled trial.
METHODS: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic.
METHODS: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG.
METHODS: Randomised 1:1 using a web-based procedure to receive a single 0.1 mL intradermal dose of BCG-Denmark (BCG group, n = 1999) or saline (placebo group, n = 1989).
METHODS: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12 months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion).
RESULTS: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6 to 24.5%) compared with the placebo group (19.6%; 95% CI 17.6 to 21.5%); adjusted difference +3.0% points (95% CI 0.2 to 5.8%; p = 0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95% CI 9.5 to 12.4%) compared with 9.6% in the placebo group (95% CI 8.3 to 11.1%); adjusted difference +1.3% points (95% CI -0.7 to 3.3%, p = 0.2). Breakthrough COVID-19 (post COVID-19 vaccination) and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95% CI 0.60 to 4.02, p = 0.4) and two deaths due to COVID-19, both in the placebo group.
CONCLUSIONS: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among healthcare workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19.
BACKGROUND: ClinicalTrials.gov NCT04327206.
METHODS: Phase III double-blind randomised controlled trial.
METHODS: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic.
METHODS: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG.
METHODS: Randomised 1:1 using a web-based procedure to receive a single 0.1 mL intradermal dose of BCG-Denmark (BCG group, n = 1999) or saline (placebo group, n = 1989).
METHODS: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12 months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion).
RESULTS: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6 to 24.5%) compared with the placebo group (19.6%; 95% CI 17.6 to 21.5%); adjusted difference +3.0% points (95% CI 0.2 to 5.8%; p = 0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95% CI 9.5 to 12.4%) compared with 9.6% in the placebo group (95% CI 8.3 to 11.1%); adjusted difference +1.3% points (95% CI -0.7 to 3.3%, p = 0.2). Breakthrough COVID-19 (post COVID-19 vaccination) and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95% CI 0.60 to 4.02, p = 0.4) and two deaths due to COVID-19, both in the placebo group.
CONCLUSIONS: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among healthcare workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19.
BACKGROUND: ClinicalTrials.gov NCT04327206.
摘要：
目的：卡介苗（BCG）具有免疫调节作用，可能对无关的传染病提供保护。我们的目的是确定卡介苗接种是否能保护成年人免受COVID-19的侵害。
方法：III期双盲随机对照试验。
方法：澳大利亚的医疗保健中心，巴西,荷兰,西班牙,以及COVID-19大流行期间的英国。
方法：3988名没有既往COVID-19且没有卡介苗禁忌症的医护人员。
方法：使用基于网络的程序以1：1随机分组，接受单次0.1mL皮内剂量的BCG-Denmark（BCG组，n=1999)或盐水(安慰剂组，n=1989)。
方法：在改良意向治疗（mITT）人群（确诊为SARS-CoV-2未纳入）中，随机化后12个月内（i）症状性和（ii）重度COVID-19的发生率差异。
结果：在随机分组的3988名参与者中，3386的基线SARS-CoV-2测试为阴性，并包括在mITT人群中。与安慰剂组（19.6%；95CI17.6%至21.5%）相比，卡介苗组有症状COVID-19的12个月调整后估计风险较高（22.6%；95%置信区间[CI]20.6%至24.5%）；调整后差异+3.0个百分点（95CI0.2%至5.8%；p=0.04）。卡介苗组12个月调整后的重度COVID-19（主要包括报告连续3天不能工作的人群）估计风险为11.0%（95CI9.5%至12.4%），而安慰剂组为9.6%（95CI8.3%至11.1%）；调整后差异+1.3个百分点（95CI-0.7%至3.3%，p=0.2)。突破COVID-19（COVID-19疫苗接种后），两组无症状的SARS-CoV-2感染相似。有18例因COVID-19住院(卡介苗组11例，安慰剂组为7；调整后的风险比1.56，95CI0.60至4.02，p=0.4）和2例因COVID-19而死亡，均在安慰剂组中。
结论：与安慰剂相比，在12个月内，在医护人员中，接种BCG-丹麦疫苗会增加有症状的COVID-19的风险，但并未降低严重COVID-19或疫苗接种后突破性COVID-19的风险。
背景：ClinicalTrials.govNCT04327206。
方法：III期双盲随机对照试验。
方法：澳大利亚的医疗保健中心，巴西,荷兰,西班牙,以及COVID-19大流行期间的英国。
方法：3988名没有既往COVID-19且没有卡介苗禁忌症的医护人员。
方法：使用基于网络的程序以1：1随机分组，接受单次0.1mL皮内剂量的BCG-Denmark（BCG组，n=1999)或盐水(安慰剂组，n=1989)。
方法：在改良意向治疗（mITT）人群（确诊为SARS-CoV-2未纳入）中，随机化后12个月内（i）症状性和（ii）重度COVID-19的发生率差异。
结果：在随机分组的3988名参与者中，3386的基线SARS-CoV-2测试为阴性，并包括在mITT人群中。与安慰剂组（19.6%；95CI17.6%至21.5%）相比，卡介苗组有症状COVID-19的12个月调整后估计风险较高（22.6%；95%置信区间[CI]20.6%至24.5%）；调整后差异+3.0个百分点（95CI0.2%至5.8%；p=0.04）。卡介苗组12个月调整后的重度COVID-19（主要包括报告连续3天不能工作的人群）估计风险为11.0%（95CI9.5%至12.4%），而安慰剂组为9.6%（95CI8.3%至11.1%）；调整后差异+1.3个百分点（95CI-0.7%至3.3%，p=0.2)。突破COVID-19（COVID-19疫苗接种后），两组无症状的SARS-CoV-2感染相似。有18例因COVID-19住院(卡介苗组11例，安慰剂组为7；调整后的风险比1.56，95CI0.60至4.02，p=0.4）和2例因COVID-19而死亡，均在安慰剂组中。
结论：与安慰剂相比，在12个月内，在医护人员中，接种BCG-丹麦疫苗会增加有症状的COVID-19的风险，但并未降低严重COVID-19或疫苗接种后突破性COVID-19的风险。
背景：ClinicalTrials.govNCT04327206。
