Considering BCG vaccination to reduce the impact of COVID-19
Authors: Nigel Curtis, Annie Sparrow, Tedros A Ghebreyesus, Mihai G Netea
Journal: The Lancet (2020)

In addition to its specific effect against tuberculosis, the BCG vaccine has beneficial nonspecific (off-target) effects on the immune system that protect against a wide range of other infections and are used routinely to treat bladder cancer.1Pollard AJ Finn A Curtis N Non-specific effects of vaccines: plausible and potentially important, but implications uncertain.Arch Dis Child. 2017; 102: 1077-1081Crossref PubMed Scopus (86) Google Scholar, 2Goodridge HS Ahmed SS Curtis N et al.Harnessing the beneficial heterologous effects of vaccination.Nat Rev Immunol. 2016; 16: 392-400Crossref PubMed Scopus (187) Google Scholar This has led to the suggestion that vaccination with BCG might have a role in protecting health-care workers and other vulnerable individuals against severe coronavirus disease 2019 (COVID-19). Randomised controlled trials have provided evidence that the BCG vaccine's immunomodulatory properties can protect against respiratory infections. In Guinea-Bissau, a high-mortality setting, BCG-Danish reduced all-cause neonatal mortality by 38% (95% CI 17–54), mainly because there were fewer deaths from pneumonia and sepsis.3Biering-Sorensen S Aaby P Lund N et al.Early BCG-Denmark and neonatal mortality among infants weighing <2500 g: a randomized controlled trial.Clin Infect Dis. 2017; 65: 1183-1190Crossref PubMed Scopus (192) Google Scholar In South Africa, BCG-Danish reduced respiratory tract infections by 73% (95% CI 39–88) in adolescents.4Nemes E Geldenhuys H Rozot V et al.Prevention of M. tuberculosis infection with H4:IC31 vaccine or BCG revaccination.N Engl J Med. 2018; 379: 138-149Crossref PubMed Scopus (464) Google Scholar Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded positive-sense RNA virus, and the BCG vaccine has been shown to reduce the severity of infections by other viruses with that structure in controlled trials. For example, the BCG vaccine reduced yellow fever vaccine viraemia by 71% (95% CI 6–91) in volunteers in the Netherlands,5Arts RJW Moorlag S Novakovic B et al.BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity.Cell Host Microbe. 2018; 23: 89-100.e5Summary Full Text Full Text PDF PubMed Scopus (737) Google Scholar and it markedly reduced the severity of mengovirus (encephalomyocarditis virus) infection in two studies in mice.6Old LJ Benacerraf B Clarke DA Carswell EA Stockert E The role of the reticuloendothelial system in the host reaction to neoplasia.Cancer Res. 1961; 21: 1281-1300PubMed Google Scholar, 7Floc'h F Werner GH Increased resistance to virus infections of mice inoculated with BCG (Bacillus Calmette-Guérin).Ann Immunol. 1976; 127: 173-186PubMed Google Scholar Many of the mechanisms underlying the beneficial off-target effects of the BCG vaccine are now understood. The BCG vaccine and some other live vaccines induce metabolic and epigenetic changes that enhance the innate immune response to subsequent infections, a process termed trained immunity.8Netea MG Dominguez-Andres J Barreiro LB et al.Defining trained immunity and its role in health and disease.Nat Rev Immunol. 2020; (published online March 4.)DOI:10.1038/s41577-020-0285-6Crossref PubMed Scopus (1207) Google Scholar The BCG vaccine might therefore reduce viraemia after SARS-COV-2 exposure, with consequent less severe COVID-19 and more rapid recovery. Randomised controlled trials are underway in the Netherlands and Australia to assess whether BCG-Danish reduces the incidence and severity of COVID-19 in health-care workers, and the effect this has on time away from work (NCT04327206, NCT04328441). It is possible that BCG-Tokyo would be preferable to BCG-Danish.9Ritz N Hanekom WA Robins-Browne R Britton WJ Curtis N Influence of BCG vaccine strain on the immune response and protection against tuberculosis.FEMS Microbiol Rev. 2008; 32: 821-841Crossref PubMed Scopus (162) Google Scholar Until these trials are complete, there are four main reasons why it is very important to adhere to WHO's recommendation that the BCG vaccine is used for COVID-19 only in randomised controlled trials.10WHOBacille Calmette-Guérin (BCG) vaccination and COVID-19.https://www.who.int/news-room/commentaries/detail/bacille-calmette-gu%C3%A9rin-(bcg)-vaccination-and-covid-19Date: April 12, 2020Date accessed: April 29, 2020Google Scholar First, the BCG vaccine is already in short supply, and indiscriminate use could jeopardise the supply needed to protect children against tuberculosis in high-risk areas. Second, whether BCG will be effective remains unknown: findings from the ecological studies suggesting less COVID-19 in countries with routine BCG immunisation are weak evidence because they are based on population rather than individual data and are prone to confounding.11Faust L Huddart S MacLean E Svadzian A Universal BCG vaccination and protection against COVID-19: critique of an ecological study.https://naturemicrobiologycommunity.nature.com/users/36050-emily-maclean/posts/64892-universal-bcg-vaccination-and-protection-against-covid-19-critique-of-an-ecological-studyDate: April 1, 2020Date accessed: April 5, 2020Google Scholar Also, it is unlikely that a BCG vaccine given decades ago in childhood will ameliorate COVID-19 now. One reason for this is that the beneficial off-target effects of the BCG vaccine might be altered by subsequent administration of a different vaccine.1Pollard AJ Finn A Curtis N Non-specific effects of vaccines: plausible and potentially important, but implications uncertain.Arch Dis Child. 2017; 102: 1077-1081Crossref PubMed Scopus (86) Google Scholar Third, if the BCG vaccine is not effective against COVID-19, BCG vaccination could engender a false sense of security. Fourth, careful safety monitoring in randomised trials is needed to guard against the remote possibility that up-regulation of immunity by BCG will exacerbate COVID-19 in a minority of patients with severe disease. If the BCG vaccine or another inducer of trained immunity provides non-specific protection to bridge the gap before a disease-specific vaccine is developed, this would be an important tool in the response to COVID-19 and future pandemics. NC is the lead investigator of the BRACE trial (NCT04327206), and MGN is one of the lead investigators of the BCG-CORONA trial (NCT04328441). TAG is Director General of WHO. AS declares no competing interests.