Bacillus Calmette-Guérin (BCG) vaccination is routine and near-universal in many low- and middle-income countries (LMIC). It has been suggested that BCG can have a protective effect on COVID-19 morbidity and mortality. This commentary discusses the limitations of the evidence around BCG and COVID-19. We argue that higher-quality evidence is necessary to understand the protective effect of the BCG vaccine from existing, secondary data, while we await results from clinical trials currently conducted in different settings

Barral-Netto, Manoel

Barreto, Florisneide Rodrigues

Barreto, Maurício L

da Natividade, Marcio Santos

Dalcomo, Margareth

de Souza, Ramon Andrade

Ichihara, Maria Yury

Nunes, Ceuci

Paixão, Enny

Pereira, Marcos

Pereira, Susan Martins

Pescarini, Julia M

Trajman, Anete

Ximenes, Ricardo

Respiratory Research

English

LSHTM Research Online

LETTER TO THE EDITOR Open AccessThe need for fast-track, high-quality andlow-cost studies about the role of the BCGvaccine in the fight against COVID-19Marcos Pereira1*, Enny Paixão2,3, Anete Trajman4, Ramon Andrade de Souza1, Marcio Santos da Natividade1,Julia M. Pescarini2, Susan Martins Pereira1, Florisneide Rodrigues Barreto1, Ricardo Ximenes5, Margareth Dalcomo6,Maria Yury Ichihara2, Ceuci Nunes7, Manoel Barral-Netto8,9 and Maurício L. Barreto1,2AbstractBacillus Calmette-Guérin (BCG) vaccination is routine and near-universal in many low- and middle-income countries(LMIC). It has been suggested that BCG can have a protective effect on COVID-19 morbidity and mortality. Thiscommentary discusses the limitations of the evidence around BCG and COVID-19. We argue that higher-qualityevidence is necessary to understand the protective effect of the BCG vaccine from existing, secondary data, whilewe await results from clinical trials currently conducted in different settings.Letter to the editorNeonatal Bacillus Calmette-Guérin (BCG) vaccination isroutine and near-universal in many low- and middle-income countries (LMIC). By the end of March 2020, dur-ing the unpreceded global health crisis generated by theCOVID-19 pandemic, a few ecological studies suggested aprotective effect of the BCG vaccine, with less morbidityand lower mortality from the severe acute respiratory syn-drome coronavirus-2 (SARS-CoV-2) [1–4]. These studieshave drawn attention to this century-old vaccine and a fewclinical trials are underway to repurpose BCG vaccination.According to these studies, the incidence of COVID-19 is four times higher, with a 21-fold increase in deathrates in high- and middle-income countries (HMIC)without universal BCG vaccination when compared tothose with this policy [1]. The earlier the implementa-tion of the policy in the country, the lower the numberof COVID-19 related deaths, possibly due to a largerproportion of vaccinated older adults [1, 2]. However,those studies included countries that were still in earlyphases of the epidemic back then, including Brazil, whichnow accounts with the highest number of daily COVID-19deaths. Also, the observed association was not sustained incountries with high COVID-19 testing rates [3, 4].The potential protective effect of neonatal BCG vac-cination on COVID-19 severity was suggested due to thelower COVID-19 mortality in some European and Asiancountries (China, South Corea, India, Russia and Japan),where the vaccination is mandatory [5, 6]. Additionally,COVID-19 mortality is higher where BCG vaccinationhas been discontinued for more than 20 years [7].France, for instance, registered lower COVID-19 mortal-ity than Italy, where the vaccination is no longermandatory [5–8]. However, there is conflicting data onthe protective effect of BCG vaccination. In Italy, BCGvaccination was interrupted in 2001 and COVID-19mortality rates were high among elders [5–8]. In the UK,where BCG vaccination was recently restarted for TBhigh-risk groups such as migrants and individuals livingin social deprived conditions, COVID-19 mortality rateswere higher in these groups than in the overall popula-tion [5–8]. Finally, countries using the original BCGstrains registered lower COVID-19 case fatality rate if© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.* Correspondence: pereira.santosm@yahoo.com1Institute of Collective Health, Federal University of Bahia, Salvador, BrazilFull list of author information is available at the end of the articlePereira et al. Respiratory Research          (2020) 21:178 https://doi.org/10.1186/s12931-020-01439-4compared to European countries that are using modifiedBCG strains (Japan - 5.4%; Brazil- 4.7% and Rússia-1.4%vs France-15.1%, Italy- 14.5% and United Kingdom14.0%) [5–8], suggesting that different BCG strains canhave different effects on COVID-19 severity and mortal-ity. Regardless of the controversial findings, ecologicalbias and the large numbers of potential confounders,such as age, socio-economic factors, health system cap-acity, stage of the epidemic and the proportion of thepopulation tested, among others, hamper the confiabilityof these ecological observations and the inference to theindividual level.The alleged protective effect could be the result oftrained immunity stimulation from BCG. BCG vaccin-ation can reduce viremia from other respiratory tractviral infections [9, 10]. This would be achieved by boost-ing non-specific Th1 and Th17 responses for at leastone year after vaccination [9], inducing trained immun-ity, the equivalent of immunological memory for the in-nate immune response. BCG vaccination followed by achallenge with attenuated Yellow Fever Virus leads tomacrophage reprogramming, with a central role of inter-leukin 1 beta (Il-1b), a hallmark of trained immunity [9].Trained immunity results in a long-lasting functionalprogramming of innate immune cells that, even in a qui-escent state, can be recovered by endogenous or exogen-ous stimuli resulting in a better-regulated responseagainst a new challenge [11].In the absence of a specific treatment and vaccine forCOVID-19, even a small protective effect of a cheap andsafe vaccine such as BCG could be a valuable tool forfighting the disease. If this effect can be confirmed byhigher-quality evidence, BCG vaccine could be used toimprove clinical outcomes of the most vulnerable, redu-cing the need for hospital beds, ventilators, and the over-all impact on LMIC countries’ fragile health systems.Additionally, applied to healthcare professionals, it couldprotect the healthcare force, reducing the burden uponthem, and the absenteeism from the disease.High-income countries without BCG vaccination rec-ommendations are planning clinical trials to test theprotective effect of BCG on COVID-19 among health-care workers and older adults [12, 13]. To support therationale of these trials, LMIC such as Brazil, whereBCG vaccination has been used since 1929 - with uni-versal coverage since 1973, are strategic to providetimely evidence on this potential effect of the BCG vac-cine, by conducting large case-control studies, which areusually faster and less expensive than clinical trials. Ourgroup is currently using Brazilian routine programmaticdata from the existing information systems to analysethe effect of neonatal BCG immunization on COVID-19clinical outcomes. In addition, data from a large ran-domized clinical trial (REVAC-BCG), conducted in over350 thousand school-aged children in two large Braziliancities in 1996–1997 to investigate the effect of BCG vac-cination and revaccination on tuberculosis is beinglinked to the COVID-19 database to provide more in-sights on this matter [14]. As the BCG revaccination wasineffective for protection against tuberculosis, the con-trol arm was not revaccinated; thus, the randomizationcarried out in the past is still valid over the years.Producing high-quality evidence of the effect of BCGvaccination on COVID-19 outcomes is essential fordecision-makers to eventually recommend the BCG vac-cination as a possible intervention for COVID-19. Weurge colleagues from LMIC where BCG vaccination pol-icies are in course to produce fast, trustable, and low-cost evidence about the effect of the BCG vaccine on theCOVID-19 pandemic, while trials are underway. In casethe results are positive, it would summ up with the re-sults of the trials in HMIC in course to speed the deci-sions on the best rationale for using BCG in the currentand future possible waves of the pandemics.AbbreviationsBCG: Bacillus Calmette-Guérin; HMIC: High- and middle-income countries; Il-1b: Interleukin 1 beta; LMIC: Low- and middle-income countries; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; REVAC-BCG: Brazilianrendomized trial on revaccination of pre-high school children for protectionagaint tuberculosisAcknowledgementsNot applicable.Authors’ contributionsMP, EP, SMP and MLB developed the study concept. MP and EP wrote thefirst draft of the manuscript, and all authors reviewed and approved the finalmanuscript. MLB supervised the study process.FundingNot applicable.Availability of data and materialsNot applicable.Ethics approval and consent to participateNot applicable.Competing interestsThe authors declare that they have no competing interests.Author details1Institute of Collective Health, Federal University of Bahia, Salvador, Brazil.2Center for Data and Knowledge Integration for Health (CIDACS), Fiocruz,Salvador, Brazil. 3Faculty of Epidemiology, London School of Hygiene andTropical Medicine, London, UK. 4Instituto de Medicina Social, Universidadedo Estado do Rio de Janeiro, Rio de Janeiro, Brazil. 5Departamento deMedicina Tropical, Universidade Federal de Pernambuco, Recife, Brazil.6Centro de Referência Hélio Fraga, Fundação Oswaldo Cruz, Rio de Janeiro,Brazil. 7Hospital Couto Maia, Secretaria Estadual de Saúde da Bahia, Salvador,Brazil. 8Instituto Gonçalo Moniz - Fundação Oswaldo Cruz (Fiocruz), Salvador,Brazil. 9Faculdade de Medicina, Universidade Federal da Bahia, Salvador,Brazil.Pereira et al. Respiratory Research          (2020) 21:178 Page 2 of 3Received: 10 May 2020 Accepted: 30 June 2020References1. Miller A, Reandelar MJ, Fasciglione K, Roumenova V, Li Y, Otazu GH.Correlation between universal BCG vaccination policy and reducedmorbidity and mortality for COVID-19: an epidemiological study. medRxiv.2020. https://doi.org/10.1101/2020.03.24.20042937.2. Shet A, Ray D, Malavige N, Santosham M, Bar-Zeev N. Differential COVID-19-attributable mortality and BCG vaccine use in countries. medRxiv. 2020.https://doi.org/10.1101/2020.04.01.20049478.3. Szigeti R, Kellermayer D, Kellermayer R. BCG protects against COVID-19? Aword of caution. medRxiv. 2020:2020.04.09.20056903. https://doi.org/10.1101/2020.04.09.20056903.4. Hensel J, McGrail DJ, McAndrews KM, Dowlatshahi D, LeBleu VS, Kalluri R.Exercising caution in correlating COVID-19 incidence and mortality rateswith BCG vaccination policies due to variable rates of SARS CoV-2 testing.medRxiv. 2020. https://doi.org/10.1101/2020.04.08.20056051.5. Zwerling A, Behr MA, Verma A, Brewer TF, Menzies D, Pai M. The BCG worldatlas: a database of global BCG vaccination policies and practices. PLoSMed. 2011;8(3):e1001012. https://doi.org/10.1371/journal.pmed.1001012.6. Johns Hopkins University. Coronavirus Resource Center: Mortality Analyses.Available in: https://coronavirus.jhu.edu/data/mortality. Accessed 20 June2020.7. Iwasaki A, Grubaugh ND. Why does Japan have so few cases of COVID-19?EMBO Mol Med. 2020;12(5):e12481. https://doi.org/10.15252/emmm.202012481.8. Miyasaka M. Is BCG vaccination causally related to reduced COVID-19mortality? EMBO Mol Med. 2020;12(6):e12661. https://doi.org/10.15252/emmm.202012661.9. Arts RJW, Moorlag SJCFM, Novakovic B, et al. BCG Vaccination Protectsagainst Experimental Viral Infection in Humans through the Induction ofCytokines Associated with Trained Immunity. Cell Host Microbe. 2018;23(1):89–100.e5. https://doi.org/10.1016/j.chom.2017.12.010.10. Hollm-Delgado M-G, Stuart EA, Black RE. Acute lower respiratory infectionamong Bacille Calmette-Guerin (BCG)-vaccinated children. Pediatrics. 2014;133(1):e73–81. https://doi.org/10.1542/peds.2013-2218.11. Netea MG, Domínguez-Andrés J, Barreiro LB, Chavakis T, Divangahi M, FuchsE, et al. Defining trained immunity and its role in health and disease. NatRev Immunol. 2020 Mar 4. https://doi.org/10.1038/s41577-020-0285-6 [Epubahead of print].12. Ziekenhuis JB, Ziekenhuis CW, Radboud UMC, et al. Reducing health careworkers absenteeism in Covid-19 pandemic through BCG vaccine (BCG-CORONA). Clinical trial: NCT04328441. Available in: https://clinicaltrials.gov/ct2/show/NCT04328441?term=BCG&cond=COVID&draw=2&rank=1.Accessed 19 Apr 2020.13. Curtis N, Gardiner K. BCG vaccination to protect healthcare workers againstCOVID-19 (BRACE). Clinical trial: NCT04327206. Available in: https://clinicaltrials.gov/ct2/show/NCT04327206?term=BCG&cond=COVID&draw=2&rank=4. Accessed 19 Apr 2020.14. Rodrigues LC, Pereira SM, Cunha SS, et al. Effect of BCG revaccination onincidence of tuberculosis in school-aged children in Brazil: the BCG-REVACcluster-randomised trial. Lancet. 2005;366(9493):1290–5. https://doi.org/10.1016/S0140-6736(05)67145-0.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Pereira et al. Respiratory Research          (2020) 21:178 Page 3 of 3

The need for fast-track, high-quality and low-cost studies about the role of the BCG vaccine in the fight against COVID-19.

https://researchonline.lshtm.ac.uk/id/eprint/4658054/1/The%20need%20for%20fast-track%2C%20high-quality%20and%20low-cost%20studies%20about%20the%20role%20of%20the%20BCG%20vaccine%20in%20the%20fight%20against%20COVID-19.pdf

The need for fast-track, high-quality and low-cost studies about the role of the BCG vaccine in the fight against COVID-19.

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