As countries race to develop a vaccine for COVID-19, there is avid interest, and debate, regarding the possible role of the existing bacille Calmette-Guérin (BCG) vaccine to prevent or reduce the severity of viral infection by SARS-CoV-2.
What is the BCG vaccine?
BCG vaccine is an attenuated strain of Mycobacterium bovis, which is administered at birth or to infants in countries with a high burden of tuberculosis (TB) under national BCG vaccination programs to prevent TB meningitis and disseminated TB. BCG vaccine is also used as adjuvant immunotherapy for patients with non-muscle-invasive bladder cancer.
BCG Vaccine and COVID-19
One of the first observational studies (not peer reviewed) looked at all reported cases and fatalities of COVID-19 from March 9-24, 2020 across 178 countries. It found that countries with a national program of whole population BCG vaccination have a lower incidence and death rate from COVID-19.  Most striking is that COVID-19-related deaths are significantly higher in countries with higher quality of life, contradicting the expected rates of mortality in countries with improved health care systems even after correcting for confounding factors and age. 
Previous epidemiological studies have shown that although BCG was developed to combat TB, it also reduces all-cause mortality due to infections from non-related pathogens. More recent studies have demonstrated the effect of BCG on an experimental viral infection in humans. These effects are thought to be mediated via metabolic and epigenetic changes leading to trained immunity with the induction of innate immune memory and heterologous lymphocyte activation, enhanced cytokine production, macrophage activity, T-cell responses, and antibody titers. [3,4] The BCG vaccine, therefore, might reduce viremia after SARS-COV-2 exposure, with consequently less severe COVID-19 and more rapid recovery. 
Concerns are being raised, however, as there is insufficient evidence establishing causality between BCG vaccination and protection from severe COVID-19. A recent large observational study from Israel did not support the idea that BCG vaccination in childhood has a protective effect against COVID-19 in adulthood.  Nonetheless, as the BCG vaccine is widely used with remarkable safety, any human studies to determine efficacy would only require Phase III clinical trials, making this a low-risk, high-benefit proposition.
Currently, the World Health Organization (WHO) does not recommend BCG vaccination for the prevention of COVID-19 except in randomized control trials. Absence of concrete evidence, a short supply for known indications, a potential false sense of security, and the remote possibility of exacerbating COVID-19 in a minority of patients with severe disease due to upregulation of immunity are valid reasons to adhere to WHO advice. 
More than ten randomized, clinical trials are in progress to assess the effectiveness of BCG vaccine, including the BADAS Trial (U.S.), BRACE Trial (Australia), and BCG-Corona (Netherlands). In these trials, healthcare workers are administered either the BCG vaccine or a placebo saline injection to determine the extent to which BCG vaccination in adults confers protection from COVID-19. [8,9,10]
The results of ongoing studies are eagerly awaited and, if successful, the age-old, faithful BCG vaccine could have a measurable and favorable impact on COVID-19 and possibly future pandemics.
- Hegarty, Paul et al. (2020). BCG vaccination may be protective against Covid-19. 10.13140/RG.2.2.35948.10880.
- Escobar, LE et al. BCG vaccine-induced protection from COVID-19 infection, wishful thinking or a game changer? doi: https://doi.org/10.1101/2020.05.05.20091975
- Moorlag SJCFM, et al. Non-specific effects of BCG vaccine on viral infections. Clin Microbiol Infect. 2019;25(12):1473‐1478. doi:10.1016/j.cmi.2019.04.020
- Netea MG et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020; (published online March 4, 2020.) DOI:10.1038/s41577-020-0285-6
- Curtis N, Sparrow A, Ghebreyesus TA, Netea MG. Considering BCG vaccination to reduce the impact of COVID-19 [published online ahead of print, 2020 Apr 30]. Lancet. 2020;S0140-6736(20)31025-4. doi:10.1016/S0140-6736(20)31025-4
- Hamiel, U et al. SARS-CoV-2 rates in BCG-vaccinated and unvaccinated young adults. JAMA, research letter. doi:10.1001/jama.2020.8189 (13 May 2020).
- Bacille Calmette-Guérin (BCG) vaccination and COVID 19. https://www.who.int/news-room/commentaries/detail/bacille-calmette-gu%C3%A9rin-(bcg)-vaccination-and-covid-19 (accessed 16 May 2020)
- BCG Vaccine for Health Care Workers as Defense Against COVID 19 (BADAS) https://clinicaltrials.gov/ct2/show/NCT04348370 (accessed 16 May 2020)
- NLM Vaccine Trials (2020) Reducing Health Care Workers Absenteeism in Covid-19 Pandemic Through BCG Vaccine (BCG-CORONA). https://clinicaltrials.gov/ct2/show/NCT04328441 (accessed 16 May 2020)
- NLM Vaccine Trials (2020) BCG Vaccination to Protect Healthcare Workers Against COVID-19 (BRACE). https://clinicaltrials.gov/ct2/show/NCT04327206 (accessed 16 May 2020)