Grade system.

BackgroundThe Bacillus Calmette-Guérin (BCG) vaccine has shown potential non-specific protection against infectious diseases through “trained immunity”, which may offer cross-protection against viral infections. However, there is no consensus on whether BCG vaccination could prevent COVID-19 or reduce its symptoms.MethodsPubMed, Cochrane Library, Embase and Web of Science were searched for randomized controlled trials on BCG vaccination and COVID-19 prevention, covering studies from the inception of each database to 2 May 2024. We included studies where participants, not infected with COVID-19, were vaccinated with BCG or placebo. We excluded non-randomized trials, studies without full texts, unrelated interventions, and those not reporting relevant outcomes. Clinical data on COVID-19 infection, severity, hospitalization, mortality, and other adverse events, were extracted and analyzed. The DerSimonian–Laird random-effects model and the Cochrane Collaboration’s risk of Bias Tool were used for analysis and risk of bias assessment.ResultsA total of 12 RCTs involving 18,086 patients were finally included. For the prophylactic effect of BCG on COVID-19, pooled results showed no statistically significant difference between BCG and placebo (pooled RR 1.02; 95%CI: 0.91–1.14). There was no statistically significant difference between non-health care workers (pooled RR 0.91; 95%CI: 0.67–1.24) and health care workers (pooled RR 1.03; 95%CI: 0.93–1.15). Regarding COVID-19 severity, no significant difference were found for asymptomatic (pooled RR 1.18; 95%CI: 0.81–1.72), mild to moderate (pooled RR 0.99; 95%CI: 0.84–1.17), severe COVID-19 (pooled RR 1.25; 95%CI: 0.92–1.70), hospitalization (pooled RR 0.93; 95%CI: 0.58–1.50) or all-cause mortality (pooled RR 0.60; 95%CI: 0.18–1.95) between BCG and placebo groups. Subgroup analysis also showed no significant difference between BCG and placebo in non-health care workers or health care workers.ConclusionsVaccination of BCG could not effectively prevent COVID-19 infection or decrease COVID-19 symptoms both in non-health care workers and health care workers.