BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial.

OBJECTIVES: 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. DESIGN: Phase III double-blind randomised controlled trial. SETTING: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic. PARTICIPANTS: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG. INTERVENTION: 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). MAIN OUTCOME MEASURES: 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.

Antecedent and persistent symptoms in COVID-19 and other respiratory illnesses: Insights from prospectively collected data in the BRACE trial.

BACKGROUND: Some individuals have a persistence of symptoms following both COVID-19 (post-acute COVID-19 syndrome; PACS) and other viral infections. This study used prospectively collected data from an international trial to compare symptoms following COVID-19 and non-COVID-19 respiratory illness, to identify factors associated with the risk of PACS, and to explore symptom patterns before and after COVID-19 and non-COVID-19 respiratory illnesses. METHODS: Data from a multicentre randomised controlled trial (BRACE trial) involving healthcare workers across four countries were analysed. Symptom data were prospectively collected over 12 months, allowing detailed characterisation of symptom patterns. Participants with COVID-19 and non-COVID-19 respiratory illness episodes were compared, focussing on symptom severity, duration (including PACS using NICE and WHO definitions), and pre-existing symptoms. FINDINGS: Compared to those with a non-COVID-19 illness, participants with COVID-19 had significantly more severe illness (OR 7·4, 95%CI 5·6-9·7). Symptom duration meeting PACS definitions occurred in a higher proportion of COVID-19 cases than non-COVID-19 respiratory controls using both the NICE definition (2·5% vs 0·5%, OR 6·6, 95%CI 2·4-18·3) and the WHO definition (8·8% vs 3·7%, OR 2·5, 95%CI 1·4-4·3). When considering only participants with COVID-19, age 40-59 years (aOR 2·8, 95%CI 1·3-6·2), chronic respiratory disease (aOR 5·5, 95%CI 1·3-23·1), and pre-existing symptoms (aOR 3·0, 95%CI 1·4-6·3) were associated with an increased risk of developing PACS. Symptoms associated with PACS were also reported by participants in the months preceding their COVID-19 or non-COVID-19 respiratory illnesses (32% fatigue and muscle ache, 11% intermittent cough and shortness of breath). INTERPRETATION: Healthcare workers with COVID-19 were more likely to have severe and longer-lasting symptoms than those with a non-COVID-19 respiratory illness, with a higher proportion meeting the WHO or NICE definitions of PACS. Age, chronic respiratory disease, and pre-existing symptoms increased the risk of developing PACS following COVID-19.

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.