Bacillus Calmette-Guérin (BCG) is the most widely used vaccine worldwide and has been used to prevent tuberculosis for a century. BCG also stimulates an anti-tumour immune response, which urologists have harnessed for the treatment of non-muscle-invasive bladder cancer. A growing body of evidence indicates that BCG offers protection against various non-mycobacterial and viral infections. The non-specific effects of BCG occur via the induction of trained immunity and form the basis for the hypothesis that BCG vaccination could be used to protect against the severity of coronavirus disease 2019 (COVID-19). This Perspective article highlights key milestones in the 100-year history of BCG and projects its potential role in the COVID-19 pandemic.

Department of Microbial Pathogenesis and Immunology Texas A and M Health Science Center Bryan TX USA

Department of Surgical Oncology Division of Urology Princess Margaret Cancer Centre University of Toronto and University Health Network Toronto ON Canada

Department of Urology Hospital Motol 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Mayo Clinic Rochester MN USA

Department of Urology MD Anderson Cancer Center Houston TX USA

Department of Urology NYU Langone Health New York NY USA

Department of Urology Radboud University Nijmegen Medical Centre Nijmegen Netherlands

Division of Urology Department of Surgery Sinai Health System University of Toronto Toronto ON Canada

Division of Urology Molinette Hospital University of Torino School of Medicine Torino Italy

Johns Hopkins Greenberg Bladder Cancer Institute Brady Urological Institute Johns Hopkins University Baltimore MD USA

Northwestern University School of Medicine Chicago IL USA

The James Buchanan Brady Urological Institute and Department of Urology The Johns Hopkins School of Medicine Baltimore MD USA

Vancouver Prostate Centre Vancouver BC Canada

See more in PubMed

World Health Organization. BCG vaccine. WHOhttps://www.who.int/biologicals/areas/vaccines/bcg/en/ (2018). PubMed

Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and military tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet. 2006;367:1173–1180. doi: 10.1016/S0140-6736(06)68507-3. PubMed DOI

Babjuk M, et al. EAU Guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) — 2019 update. Eur. Urol. 2019;75:639–657. doi: 10.1016/j.eururo.2019.08.016. PubMed DOI

World Health Organization. Coronavirus disease (COVID-19) pandemic. WHOhttps://www.who.int/emergencies/diseases/novel-coronavirus-2019 (2020).

Dong E, Du H, Gardner L. An interactive web-based dashboard to trace COVID-19 in real time. Lancet. 2020;20:533–534. doi: 10.1016/S1473-3099(20)30120-1. PubMed DOI PMC

van’t Wout J, Poell R, Furth R. The role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand. J. Immunol. 1992;36:713–720. doi: 10.1111/j.1365-3083.1992.tb03132.x. PubMed DOI

Kleinnijenhuis J, Quintin J, Preijers F. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl Acad. Sci. USA. 2012;109:17537–17542. doi: 10.1073/pnas.1202870109. PubMed DOI PMC

Tribouley J, Tribouley-Duret J, Appriou M. Effect of Bacillus Calmette Guerin (BCG) on the receptivity of nude mice to Schistosoma mansoni. C. R. Seances Soc. Biol. Fil. 1978;172:902–904. PubMed

Clark IA, Allison AC, Cox FE. Protection of mice against Babesia and Plasmodium with BCG. Nature. 1976;259:309–311. doi: 10.1038/259309a0. PubMed DOI

Matsumoto S, et al. Mycobacterium bovis Bacillus Calmette-Guerin induces protective immunity against infection by Plasmodium yoelii at blood-stage depending on shifting immunity toward Th1 type and inducing protective IgG2a after the parasite infection. Vaccine. 2000;19:779–787. doi: 10.1016/S0264-410X(00)00257-7. PubMed DOI

Parra M, et al. Molecular analysis of non-specific protection against murine malaria induced by BCG vaccination. PLoS ONE. 2013;8:e66115. doi: 10.1371/journal.pone.0066115. PubMed DOI PMC

Walk J, et al. Outcomes of controlled human malaria infection after BCG vaccination. Nat. Commun. 2019;10:874. doi: 10.1038/s41467-019-08659-3. PubMed DOI PMC

Leentjens J, et al. BCG vaccination enhances the immunogenicity of subsequent influenza vaccination in healthy volunteers: a randomized, placebo-controlled pilot study. J. Infect. Dis. 2015;212:1930–1938. doi: 10.1093/infdis/jiv332. PubMed DOI

Arts RJW, 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.e5. doi: 10.1016/j.chom.2017.12.010. PubMed DOI

Giamarellos-Bourboulis EJ, et al. Activate: randomized clinical trial of BCG vaccination against infection in the elderly. Cell. 2020;183:315–323. doi: 10.1016/j.cell.2020.08.051. PubMed DOI PMC

Hegarty P, et al. COVID-19 and Bacillus Calmette-Guerin: what is the link? Eur Urol Oncol. 2020;3:259–261. doi: 10.1016/j.euo.2020.04.001. PubMed DOI PMC

Berg M, et al. Mandated Bacillus Calmette-Guérin (BCG) vaccination predicts flattened curves for the spread of COVID-19. Sci. Adv. 2020;6:eabc1463. doi: 10.1126/sciadv.abc1463. PubMed DOI PMC

Ozdemir C, Kucuksezer UC, Tamay ZU. Is BCG vaccination affecting the spread and severity of COVID-19? Allergy. 2020;75:1824–1827. doi: 10.1111/all.14344. PubMed DOI

Escobar LE, Molina-Cruz A, Barillas-Mury C. BCG vaccine protection from severe coronavirus disease 2019 (COVID-19) Proc. Natl Acad. Sci. USA. 2020;117:17720–17726. doi: 10.1073/pnas.2008410117. PubMed DOI PMC

Rivas MN, et al. BCG vaccination history associates with decreased SARSCoV-2 seroprevalence across a diverse cohort of healthcare workers. J. Clin. Invest. 2021;131:e145157. doi: 10.1172/JCI145157. PubMed DOI PMC

Calmette A, Bocquet A, Negre L. Contribution a l’etude du bacilli tuberculuex bilie. Ann. Inst. Pasteur. 1921;9:651–670.

Lange B. Nouvelles recherche sur les causes des accidents de Lubeck. Rev. Tuberc. Extrait. 1931;12:1142–1170.

Fine, P. E. M., Carneiro, I. A. M., Milstien, J. B. & Clements, C. J. Issues relating to the use of BCG in immunization programmes. 1–44 (World Health Organization, 1999).

Plotkin, S. A., Orenstein, W. A. & Offit, P. A. Vaccines. 6th Edn. (Elsevier Saunders, 2013).

Brosch RB, et al. Genome plasticity of BCG and impact on vaccine efficacy. PNAS. 2007;104:5596–5601. doi: 10.1073/pnas.0700869104. PubMed DOI PMC

Ritz N, Curtis N. Mapping the global use of different BCG vaccine strains. Tuberculosis. 2009;89:248–251. doi: 10.1016/j.tube.2009.03.002. PubMed DOI

World Health Organization. Information Sheet. Observed rate of vaccine reactions. Bacille Calmette-Guerin (BCG) vaccine. WHOhttps://www.who.int/vaccine_safety/initiative/tools/BCG_Vaccine_rates_information_sheet.pdf (2012).

Messing EM. The BCG shortage. Bladder Cancer. 2017;3:227–228. doi: 10.3233/BLC-179018. PubMed DOI PMC

Roth A, et al. Vaccination technique, PPD reaction and BCG scarring in a cohort of children born in Guinea-Bissau 2000–2002. Vaccine. 2005;23:3991–3998. doi: 10.1016/j.vaccine.2004.10.022. PubMed DOI

Anderson EJ, et al. The influence of BCG vaccine strain on mycobacteria-specific and non-specific immune responses in a prospective cohort of infants in Uganda. Vaccine. 2012;30:2083–2089. doi: 10.1016/j.vaccine.2012.01.053. PubMed DOI PMC

Frankel H, et al. Different effects of BCG strains - a natural experiment evaluating the impact of the Danish and the Russian BCG strains on morbidity and scar formation in Guinea-Bissau. Vaccine. 2016;34:4586–4593. doi: 10.1016/j.vaccine.2016.07.022. PubMed DOI

Shann F. Editorial commentary: different strains of bacillus calmette-guerin vaccine have very different effects on tuberculosis and on unrelated infections. Clin. Infect. Dis. 2015;61:960–962. doi: 10.1093/cid/civ454. PubMed DOI PMC

Funch KM, et al. Determinants of BCG scarification among children in rural Guinea-Bissau: a prospective cohort study. Hum. Vaccin. Immunother. 2018;14:2434–2442. doi: 10.1080/21645515.2017.1421879. PubMed DOI PMC

Schaltz-Buccholzer F, et al. Early vaccination with bacille calmette-guerin-denmark or BCG-Japan versus BCG-Russia to healthy newborns in Guinea-Bissau: randomized controlled trial. Clin. Infec. Dis. 2020;71:1883–1893. doi: 10.1093/cid/ciz1080. PubMed DOI

Comstock GW. Simple, practical ways to assess the protective efficacy of a new tuberculosis vaccine. Clin. Infect. Dis. 2000;30:S250–S253. doi: 10.1086/313870. PubMed DOI

Favorov M, et al. Comparative tuberculosis (TB) prevention effectiveness in children of Bacillus Calmette-Guérin (BCG) vaccines from different sources, Kazakhstan. PLoS ONE. 2012;7:e32567. doi: 10.1371/journal.pone.0032567. PubMed DOI PMC

Gan C, et al. BCG immunotherapy for bladder cancer — the effects of substrain differences. Nat. Rev. Urol. 2013;10:580–588. doi: 10.1038/nrurol.2013.194. PubMed DOI

Rentsch CA, et al. Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy. Eur. Urol. 2014;66:677–688. doi: 10.1016/j.eururo.2014.02.061. PubMed DOI

Witjes JA, et al. The efficacy of BCG TICE and BCG Connaught in a cohort of 2,099 patients with T1G3 non-muscle-invasive bladder cancer. Urol. Oncol. 2016;34:484. doi: 10.1016/j.urolonc.2016.05.033. PubMed DOI PMC

D’Andrea D, et al. Comparative effectiveness of intravesical BCG-Tice and BCG-Moreau in patients with non-muscle-invasive bladder cancer. Clin. Genitourin. Cancer. 2020;18:20–25. doi: 10.1016/j.clgc.2019.10.021. PubMed DOI

Boehm BE, et al. Efficacy of bacillus Calmette-Guerin strains for treatment of nonmuscle invasive bladder cancer: a systematic review and network meta-analysis. J. Urol. 2017;198:503–510. doi: 10.1016/j.juro.2017.01.086. PubMed DOI PMC

World Health Organisation. Tuberculosis. WHOhttps://www.who.int/news-room/fact-sheets/detail/tuberculosis (2021).

Mangtani P, et al. Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials. Clin. Infect. Dis. 2014;58:470–480. doi: 10.1093/cid/cit790. PubMed DOI

Abubakar I, et al. Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guerin vaccination against tuberculosis. Health Technol. Assess. 2013;17:1–372. doi: 10.3310/hta17370. PubMed DOI PMC

Aronson NE, et al. Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: a 60-year follow-up study. JAMA. 2004;291:2086–2091. doi: 10.1001/jama.291.17.2086. PubMed DOI

Nguipdop-Djomo P, Heldal E, Rodrigues LC, Abubakar I, Mangtani P. Duration of BCG protection against tuberculosis and change in effectiveness with time since vaccination in Norway: a retrospective population-based cohort study. Lancet Infect. Dis. 2016;16:219–226. doi: 10.1016/S1473-3099(15)00400-4. PubMed DOI

Swaminathan S, Rekha B. Pediatric tuberculosis: global overview and challenges. Clin. Infect. Dis. 2010;50:S184–S194. doi: 10.1086/651490. PubMed DOI

Fine PE. Variation in protection by BCG: implications of and for heterologous immunity. Lancet. 1995;346:1339–1345. doi: 10.1016/S0140-6736(95)92348-9. PubMed DOI

Brandt L, et al. Failure of the Mycobacterium bovis BCG vaccine: some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis. Infect. Immun. 2002;70:672–678. doi: 10.1128/IAI.70.2.672-678.2002. PubMed DOI PMC

Weir RE, et al. The influence of previous exposure to environmental mycobacteria on the interferon-gamma response to bacille Calmette–Guérin vaccination in southern England and northern Malawi. Clin. Exp. Immunol. 2006;146:390–399. doi: 10.1111/j.1365-2249.2006.03222.x. PubMed DOI PMC

Nemes E, et al. Prevention of M. Tuberculosis infection with H4:IC31 vaccine or BCG revaccination. N. Engl. J. Med. 2018;379:138–149. doi: 10.1056/NEJMoa1714021. PubMed DOI PMC

Van Der Meeren O, et al. Phase 2b controlled trial of M72/AS01E vaccine to prevent tuberculosis. N. Engl. J. Med. 2018;379:1621–1634. doi: 10.1056/NEJMoa1803484. PubMed DOI PMC

Darrah PA, et al. Prevention of tuberculosis in macaques after intravenous BCG immunization. Nature. 2020;577:95–102. doi: 10.1038/s41586-019-1817-8. PubMed DOI PMC

Benn CS, et al. A small jab — a big effect: nonspecific immunomodulation by vaccines. Trends Immunol. 2013;34:431–439. doi: 10.1016/j.it.2013.04.004. PubMed DOI

Naslund, C. Resultats des experiences de vaccination par le BCG poursuivies dans le Norrbotten (Suède) (Septembre 1927–Décembre 1931). Vaccination Preventative de Tuberculose, Rapports et Documents (Institut Pasteur, 1932).

Hirve S, et al. Non-specific and sex-differential effects of vaccinations on child survival in rural western India. Vaccine. 2012;30:7300–7308. doi: 10.1016/j.vaccine.2012.09.035. PubMed DOI

Moulton LH, et al. Evaluation of non-specific effects of infant immunizations on early infant mortality in a southern Indian population. Trop. Med. Int. Health. 2005;10:947–955. doi: 10.1111/j.1365-3156.2005.01434.x. PubMed DOI

Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ. 2000;321:1435–1438. doi: 10.1136/bmj.321.7274.1435. PubMed DOI PMC

de Castro MJ, Pardo-Seco J, Martinon-Torrest F. Nonspecific (heterologous) protection of neonatal BCG vaccination against hospitalization due to respiratory infection and sepsis. Clin. Infect. Dis. 2015;60:1611–1619. doi: 10.1093/cid/civ144. PubMed DOI

Roth A, et al. Low birth weight infants and Calmette Guerin bacillus vaccination at birth: community study from Guinea-Bissau. Pediatr. Infect. Dis. J. 2004;23:544–550. doi: 10.1097/01.inf.0000129693.81082.a0. PubMed DOI

Aaby P, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: Beneficial nonspecific effects in the neonatal period? J. Infect. Dis. 2011;2:245–252. doi: 10.1093/infdis/jir240. PubMed DOI

Biering-Sørensen S, et al. Small randomized trial among low-birth-weight children receiving bacillus Calmette-Guérin vaccination at first health center contact. Pediatr. Infect. Dis. J. 2012;31:306–308. doi: 10.1097/INF.0b013e3182458289. PubMed DOI

Jensen KJ, et al. Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: a randomized-controlled trial. J. Infect. Dis. 2014;211:956–967. doi: 10.1093/infdis/jiu508. PubMed DOI PMC

Netea MG, van der Meer JW, van Deuren M, Kullberg BJ. Proinflammatory cytokines and sepsis syndrome: not enough, or too much of a good thing? Trends Immunol. 2003;24:254–258. doi: 10.1016/S1471-4906(03)00079-6. PubMed DOI

van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat. Rev. Immunol. 2017;17:407–420. doi: 10.1038/nri.2017.36. PubMed DOI

Van Puffelen JH, et al. Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer. Nat. Rev. Urol. 2020;17:513–525. doi: 10.1038/s41585-020-0346-4. PubMed DOI

Aaby P, et al. Early BCG vaccination and reduction in atopy in Guinea-Bissau. Clin. Exp. Allergy. 2000;30:644–650. doi: 10.1046/j.1365-2222.2000.00803.x. PubMed DOI

Steenhuis TJ, et al. Bacille-Calmette-Guerin vaccination and the development of allergic disease in children: a randomized, prospective, single-blind study. Clin. Exp. Allergy. 2008;38:79–85. PubMed

Thøstesen LM, et al. Neonatal BCG vaccination and atopic dermatitis before 13 months of age: a randomized clinical trial. Allergy. 2018;73:498–504. doi: 10.1111/all.13314. PubMed DOI

Usher NT, et al. Association of BCG vaccination in childhood with subsequent cancer diagnoses: a 60 year follow-up of a clinical trial. JAMA Netw. Open. 2019;2:e1912014. doi: 10.1001/jamanetworkopen.2019.12014. PubMed DOI PMC

Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin. Orthop. Relat. Res. 1991;262:3–11. PubMed

Coley WB. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus) Proc. R. Soc. Med. 1910;3:1–48. PubMed PMC

Pearl R. Cancer and tuberculosis. Am. J. Hygiene. 1929;9:97.

Old LJ, Clarke DA, Benacerraf B. Effect of bacillus Calmette-Guerin infection on transplanted tumours in the mouse. Nature. 1959;184:291–292. doi: 10.1038/184291a0. PubMed DOI

Zbar B, Tanaka T. Immunotherapy of cancer: regression of tumors after intralesional injection of living Mycobacterium bovis. Science. 1971;172:271–273. doi: 10.1126/science.172.3980.271. PubMed DOI

Zbar B, Rapp HJ. Immunotherapy of guinea pig cancer with BCG. Cancer. 1974;34:1532–1540. doi: 10.1002/1097-0142(197410)34:8+<1532::AID-CNCR2820340827>3.0.CO;2-H. PubMed DOI

Mathe G, et al. Active immunotherapy for acute lymphoblastic leukemia. Lancet. 1969;1:697–699. doi: 10.1016/S0140-6736(69)92648-8. PubMed DOI

Morton DL. BCG immunotherapy of malignant melanoma: summary of a seven-year experience. Ann. Surg. 1974;180:635–641. doi: 10.1097/00000658-197410000-00029. PubMed DOI PMC

Galligioni E, et al. Adjuvant immunotherapy treatment of renal carcinoma patients with autologous tumor cells and bacillus Calmette-Guerin: five year results of a prospective randomized study. Cancer. 1996;12:2560–2566. doi: 10.1002/(SICI)1097-0142(19960615)77:12<2560::AID-CNCR20>3.0.CO;2-P. PubMed DOI

Gray BN, et al. Controlled clinical trial of adjuvant immunotherapy with BCG and neuraminidase-treated autologous tumour cells in large bowel cancer. J. Surg. Oncol. 1989;40:34–37. doi: 10.1002/jso.2930400109. PubMed DOI

Maurer LH, et al. Combined modality therapy with radiotherapy, chemotherapy, and immunotherapy in limited small-cell carcinoma of the lung: a Phase III Cancer and Leukemia Group B Study. J. Clin. Oncol. 1985;7:969–976. doi: 10.1200/JCO.1985.3.7.969. PubMed DOI

Gandhi NM, Morales A, Lamm DL. Bacillus Calmette-Guerin immunotherapy for genitourinary cancer. BJU Int. 2013;112:288–297. doi: 10.1111/j.1464-410X.2012.11754.x. PubMed DOI

Coe JE, Feldman JD. Extracutaneous delayed hypersensitivity, particularly in the guinea-pig bladder. Immunology. 1966;10:127–136. PubMed PMC

Dekernion JB, et al. Successful transurethral intralesional BCG therapy of a bladder melanoma. Cancer. 1975;36:1662–1667. doi: 10.1002/1097-0142(197511)36:5<1662::AID-CNCR2820360520>3.0.CO;2-6. PubMed DOI

Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol. 1976;116:180–183. doi: 10.1016/S0022-5347(17)58737-6. PubMed DOI

Lamm DL, et al. Bacillus Calmette-Guerin immunotherapy of superficial bladder cancer. J. Urol. 1980;124:38–40. doi: 10.1016/S0022-5347(17)55282-9. PubMed DOI

Pinsky CM, et al. Intravesical administration of bacillus Calmette-Guerin in patients with recurrent superficial carcinoma of the urinary bladder: report of a prospective, randomized trial. Cancer. Treat. Rep. 1985;69:47–53. PubMed

Shelley MD, et al. A systematic review of intravesical bacillus Calmette-Guerin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU Int. 2001;88:209. doi: 10.1046/j.1464-410x.2001.02306.x. PubMed DOI

Han RF, et al. Can intravesical bacillus Calmette-Guerin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology. 2006;67:1216–1223. doi: 10.1016/j.urology.2005.12.014. PubMed DOI

Bohle A, et al. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J. Urol. 2003;169:90–95. doi: 10.1016/S0022-5347(05)64043-8. PubMed DOI

Shelley MD, et al. Intravesical bacillus Calmette-Guerin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU Int. 2004;93:485–490. doi: 10.1111/j.1464-410X.2003.04655.x. PubMed DOI

Malmstrom PU, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. Eur. Urol. 2009;56:247–256. doi: 10.1016/j.eururo.2009.04.038. PubMed DOI

Sylvester RJ, et al. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J. Urol. 2002;168:1964–1970. doi: 10.1016/S0022-5347(05)64273-5. PubMed DOI

Bohle A, et al. Intravesical bacille Calmette-Guerin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression. Urology. 2004;63:682–686. doi: 10.1016/j.urology.2003.11.049. PubMed DOI

Ehdaie B, Sylvester R, Herr HW. Maintenance Bacillus Calmette-Guerin treatment of non-muscle invasive bladder cancer: a critical evaluation of the evidence. Eur. Urol. 2013;64:579–585. doi: 10.1016/j.eururo.2013.05.027. PubMed DOI

Lamm DL, et al. Maintenance BCG immunotherapy in recurrent Ta, T1 and carcinoma in situ transitional cell carcinoma: a randomized Southwest Oncology Group Study. J. Urol. 2000;163:1124–1129. doi: 10.1016/S0022-5347(05)67707-5. PubMed DOI

Oddens J, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one third dose versus full dose and 1 year versus 3 years of maintenance. Eur. Urol. 2013;63:462–472. doi: 10.1016/j.eururo.2012.10.039. PubMed DOI

Chang SS, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J. Urol. 2016;196:1021–1029. doi: 10.1016/j.juro.2016.06.049. PubMed DOI

Lamm DL, et al. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. N. Engl. J. Med. 1991;325:1205–1209. doi: 10.1056/NEJM199110243251703. PubMed DOI

Lamm DL. Long-term results of intravesical therapy for superficial bladder cancer. Urol. Clin. North Am. 1992;19:573–580. doi: 10.1016/S0094-0143(21)00424-9. PubMed DOI

Cambier S, et al. EORTC nomograms and risk groups for predicting recurrence, progression and disease-specific and overall survival in non-muscle-invasive stage Ta-T1 urothelial bladder cancer patients treated with 1-3 years of maintenance Bacillus Calmette-Guerin. Eur. Urol. 2016;69:60–69. doi: 10.1016/j.eururo.2015.06.045. PubMed DOI

Van der Meijden AP, et al. Maintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial. Eur. Urol. 2003;44:429–434. doi: 10.1016/S0302-2838(03)00357-9. PubMed DOI

Brausi M, et al. Side Effects of Bacillus Calmette-Guérin (BCG) in the Treatment of Intermediate- and High-risk Ta, T1 papillary carcinoma of the bladder: results of the EORTC genito-urinary cancers group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance BCG. Eur. Urol. 2014;65:69–76. doi: 10.1016/j.eururo.2013.07.021. PubMed DOI

Gonzalez OY, et al. Spectrum of Bacille Calmette-Guerin (BCG) infection after intravesical BCG immunotherapy. Clin. Infect. Dis. 2003;36:140–148. doi: 10.1086/344908. PubMed DOI

Marquez-Batalla S, Fraile-Villarejo E, Belhassen-Garcia M, Gutierrez-Zubiaurre N, Cordero-Sanchez M. Disseminated infection due to Mycobacterium bovis after intravesical BCG instillation. World J. Clin. Cases. 2014;2:301–303. doi: 10.12998/wjcc.v2.i7.301. PubMed DOI PMC

Lamm DL, et al. Incidence and treatment of complications of Bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer. J. Urol. 1992;147:596–600. doi: 10.1016/S0022-5347(17)37316-0. PubMed DOI

Kavoussi LR, Brown EJ, Ritchey JK, Ratliff TL. Fibronectin-mediated Calmette-Guerin bacillus attachment to murine bladder mucosa. Requirement for the expression of an antitumor response. J. Clin. Invest. 1990;85:62–67. doi: 10.1172/JCI114434. PubMed DOI PMC

Witjes JA, et al. Influence of fibrin clot inhibitors on the efficacy of intravesical Bacillus Calmette-Guerin in the treatment of superficial bladder cancer. The Dutch Southeast Cooperative Urological Group. Eur. Urol. 1993;23:366–370. doi: 10.1159/000474631. PubMed DOI

Lipsky MJ, et al. The effect of fibrin clot inhibitors on the immunomodulatory efficacy of Bacillus Calmette-Guerin therapy for non-muscle invasive bladder cancer. Urology. 2013;81:1273–1278. doi: 10.1016/j.urology.2012.09.065. PubMed DOI

Pettenati C, Ingersoll MA. Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat. Rev. Urol. 2018;15:615–625. doi: 10.1038/s41585-018-0055-4. PubMed DOI

El-Demiry MI, et al. Local immune responses after intravesical BCG treatement for carcinoma in situ. Br. J. Urol. 1987;60:543–548. doi: 10.1111/j.1464-410X.1987.tb05039.x. PubMed DOI

Prescott S, et al. HLA-DR expression by high grade superficial bladder cancer treated with BCG. Br. J. Urol. 1989;63:264–2269. doi: 10.1111/j.1464-410X.1989.tb05187.x. PubMed DOI

Jackson AM, et al. Induction of ICAM 1 expression on bladder tumours by BCG immunotherapy. J. Clin. Pathol. 1994;47:309–312. doi: 10.1136/jcp.47.4.309. PubMed DOI PMC

Kamat AM, et al. Cytokine panel for response to intravesical therapy (CyPRIT): nomogram of changes in urinary cytokine levels predicts patient response to Bacillus Calmette-Guerin. Eur. Urol. 2016;69:197–200. doi: 10.1016/j.eururo.2015.06.023. PubMed DOI PMC

Redelman-Sidi G, Glickman MS, Bochner BH. The mechanism of action of BCG therapy for bladder cancer- a current perspective. Nat. Rev. Urol. 2014;11:153–162. doi: 10.1038/nrurol.2014.15. PubMed DOI

Netea MG, Quintin J, Van Der Meer JWM. Trained immunity: a memory for innate host defense. Cell Host Microbe. 2011;9:355–361. doi: 10.1016/j.chom.2011.04.006. PubMed DOI

Kleinnijenhuis J, Quintin J, Preijers F. BCG-induced trained immunity in NK cells: role for non-specific protection to infection. Clin. Immunol. 2014;155:213–219. doi: 10.1016/j.clim.2014.10.005. PubMed DOI PMC

Netea MG, et al. Trained immunity: a program of innate immune memory in health and disease. Science. 2016;352:aaf1098. doi: 10.1126/science.aaf1098. PubMed DOI PMC

Arts RJW, et al. Immunometabolic pathways in BCG-induced trained immunity. Cell Rep. 2016;17:2562–2571. doi: 10.1016/j.celrep.2016.11.011. PubMed DOI PMC

Kaufmann, E. et al. BCG educates haematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell172, 176-190. PubMed

Cirovic B, et al. BCG vaccination in humans elicits trained immunity vi the haematopoietic progenitor compartment. Cell Host Microbe. 2020;28:322–334. doi: 10.1016/j.chom.2020.05.014. PubMed DOI PMC

Cheng S, et al. mTOR/HIF1a-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014;345:1250684. doi: 10.1126/science.1250684. PubMed DOI PMC

Li T, Chen ZJ. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J. Exp. Med. 2018;215:1287–1299. doi: 10.1084/jem.20180139. PubMed DOI PMC

Paludan SR, Bowie AJ. Immune sensing of DNA. Immunity. 2013;38:70–80. doi: 10.1016/j.immuni.2013.05.004. PubMed DOI PMC

Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008;455:674–678. doi: 10.1038/nature07317. PubMed DOI PMC

Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 2009;461:788–792. doi: 10.1038/nature08476. PubMed DOI PMC

Li XD, et al. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science. 2013;341:1390–1394. doi: 10.1126/science.1244040. PubMed DOI PMC

Dey RJ, et al. Bacillus Calmette-Guerin overexpressing an endogenous stimulator of interferon genes agonist provides enhanced protection against pulmonary tuberculosis. J. Infect. Dis. 2020;221:1048–1056. doi: 10.1093/infdis/jiz116. PubMed DOI PMC

Gröschel MI, et al. Recombinant BCG expressing ESX-1 of Mycobacterium marinum combines low virulence with cytosolic immune signaling and improved TB protection. Cell Rep. 2017;18:2752–2765. doi: 10.1016/j.celrep.2017.02.057. PubMed DOI

Loxton AG, et al. Safety and immunogenicity of the recombinant Mycobacterium bovis BCG vaccine VPM1002 in HIV-unexposed newborn infants in South Africa. Clin. Vaccine Immunol. 2017;24:e00439–16. doi: 10.1128/CVI.00439-16. PubMed DOI PMC

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04387409 (2020)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04439045 (2021)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04435379 (2021)

Conti P, et al. Bacillus Calmette–Guerin potentiates monocyte responses to lipopolysaccharide- induced tumor necrosis factor and interleukin-1, but not interleukin-6 in bladder cancer patients. Cancer Immunol. Immunother. 1994;38:365–371. doi: 10.1007/BF01517205. PubMed DOI PMC

Kim CI, Shin JS, Kim HI, Lee JM, Kim SJ. Production of tumor necrosis factor by intravesical administration of bacillus Calmette–Guerin in patients with superficial bladder cancer. Yonsei Med. J. 1993;34:356–364. doi: 10.3349/ymj.1993.34.4.356. PubMed DOI

Calais da Silva FM, et al. Systemic humoral responses of non-muscle-invasive bladder cancer during BCG treatment: less is more. J. Cancer Metastasis Treat. 2017;3:116–126. doi: 10.20517/2394-4722.2017.25. DOI

Reale M, et al. Production of MCP-1 and RANTES in bladder cancer patients after bacillus Calmette–Guerin immunotherapy. Cancer Immunol. Immunother. 2002;51:91–98. doi: 10.1007/s00262-001-0254-2. PubMed DOI PMC

de Reijke TM, et al. Urinary cytokines during intravesical bacillus Calmette–Guerin therapy for superficial bladder cancer: processing, stability and prognostic value. J. Urol. 1996;155:477–482. doi: 10.1016/S0022-5347(01)66424-3. PubMed DOI

Koti M, et al. Investigating the STING pathway to explain mechanisms of BCG failures in non-muscle invasive bladder cancer: prognostic and therapeutic implications. Bladder Cancer. 2019;5:225–234. doi: 10.3233/BLC-190228. DOI

Singh AK, Praharaj M, Lombardo KA. Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved anti-tumour efficacy in non-muscle invasive bladder cancer. Urol. Oncol. 2020;38:899. doi: 10.1016/j.urolonc.2020.10.030. DOI

McKibbin, W. J. & Fernando, R. The global macroeconomic impacts of COVID-19: seven scenarios. Preprint at SSRN10.2139/ssrn.3547729 (2020).

Gilbert M, et al. Preparedness and vulnerability of African countries against importations of COVID-19: a modelling study. Lancet. 2020;395:871–877. doi: 10.1016/S0140-6736(20)30411-6. PubMed DOI PMC

Moore, K. A., Lipsitch, M., Barry, J. M. & Osterholm, M. T. COVID-19: the CIDRAP Viewpoint. https://www.cidrap.umn.edu/sites/default/files/public/downloads/cidrap-covid19-viewpoint-part1_0.pdf (2020).

Wu C, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern. Med. 2020;180:934–943. doi: 10.1001/jamainternmed.2020.0994. PubMed DOI PMC

Kamat AM, et al. Bladder cancer. Lancet. 2016;388:2796–2810. doi: 10.1016/S0140-6736(16)30512-8. PubMed DOI

Ribal, M. J. et al. EAU Guidelines Office Rapid Reaction Group: An organization wide collaborative effort to adapt the EAU guidelines recommendations to the COVID-19 era. https://uroweb.org/wp-content/uploads/EAU-Guidelines-Office-Rapid-Reaction-Group-An-organisation-wide-collaborative-effort-to-adapt-the-EAU-guidelines-recommendations-to-the-COVID-19-era.pdf (2020). PubMed PMC

Lenfant L, et al. Adjustments in the use of intravesical instillations of Bacillus Calmette-Guerin for high-risk non-muscle-invasive bladder cancer during the COVID-19 pandemic. Eur. Urol. 2020;78:1–3. doi: 10.1016/j.eururo.2020.04.039. PubMed DOI PMC

Wallis CJD, et al. Risks from deferring treatment for genitourinary cancers: a collaborative review to aid trige and management during the COVID-19 pandemic. Eur. Urol. 2020;78:29–42. doi: 10.1016/j.eururo.2020.04.063. PubMed DOI PMC

Hensel J, et al. Protection against SARS-CoV-2 by BCG vaccination is not supported by epidemiological analyses. Sci. Rep. 2020;10:18377. doi: 10.1038/s41598-020-75491-x. PubMed DOI PMC

Hamiel U, Kozer E, Youngster I. SARS-CoV-2 rates in BCG-vaccinated and unvaccinated young adults. JAMA. 2020;323:2340–2341. doi: 10.1001/jama.2020.8189. PubMed DOI PMC

Szigeti R, Kellermayer D, Trakimas G, Kellermayer R. BCG epidemiology supports its protection against COVID-19? A word of caution. PLoS ONE. 2020;15:e0240203. doi: 10.1371/journal.pone.0240203. PubMed DOI PMC

Wassenaar TM, Buzard GS, Newman DJ. BCG vaccination early in life does not improve COVID-19 outcome of elderly populations, based on nationally reported data. Lett. Appl. Microbiol. 2020;71:498–505. doi: 10.1111/lam.13365. PubMed DOI PMC

Lindestam Arlehamn CS, Sette A, Peters B. Lack of evidence for BCG vaccine protection from severe COVID-19. Proc. Natl Acad. Sci. USA. 2020;117:25203–25204. doi: 10.1073/pnas.2016733117. PubMed DOI PMC

De Chaisemartin C, de Chaisemartin L. BCG vaccination in infancy does not protect against COVID-19. Evidence from a natural experiment in Sweden. Clin. Infect. Dis. 2020 doi: 10.1093/cid/ciaa1223. PubMed DOI PMC

Fu W, et al. Reconcile the debate over protective effects of BCG against COVID-19. Sci. Rep. 2021;11:8356. doi: 10.1038/s41598-021-87731-9. PubMed DOI PMC

Moorlag S, et al. Safety and COVID-19 symptoms in individuals recently vaccinated with BCG: a retrospective cohort study. Cell Rep. Med. 2020;1:100073. doi: 10.1016/j.xcrm.2020.100073. PubMed DOI PMC

Weng C, Chan PA. BCG as an adjunct or alternative vaccine to prevent COVID-19? J. Travel Med. 2021;27:taaa175. doi: 10.1093/jtm/taaa175. PubMed DOI PMC

Curtis N, et al. Considering BCG vaccination to reduce the impact of COVID-19. Lancet. 2020;395:1545–1546. doi: 10.1016/S0140-6736(20)31025-4. PubMed DOI PMC

Polack FP, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 2020;383:2603–2615. doi: 10.1056/NEJMoa2034577. PubMed DOI PMC

Baden LR, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 2021;384:403–416. doi: 10.1056/NEJMoa2035389. PubMed DOI PMC

Voysey M, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV2: an interim analysis of four randomized controlled trials in Brazil, South Africa and the UK. Lancet. 2021;397:99–111. doi: 10.1016/S0140-6736(20)32661-1. PubMed DOI PMC

Netea MG, van der Meer JWM, van Crevel R. BCG vaccination in healthcare providers and the protection against COVID-19. J. Clin. Invest. 2021;131:e145545. doi: 10.1172/JCI145545. PubMed DOI PMC

So AD, Woo J. Reserving coronavirus disease 2019 vaccines for global access: cross sectional analysis. BMJ. 2020;371:m4750. doi: 10.1136/bmj.m4750. PubMed DOI PMC

World Health Organization. Bacille Calmette-Guerin (BCG) vaccination and COVID-19. WHOhttps://www.who.int/news-room/commentaries/detail/bacille-calmette-gu%C3%A9rin-(bcg)-vaccination-and-covid-19 (2020).

Brooks NA, et al. The role of the urologist, BCG vaccine administration and SARS-CoV-2: an overview. BJUI Compass. 2020;1:87–92. doi: 10.1002/bco2.21. PubMed DOI PMC

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04350931 (2020)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04384549 (2020)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04328441 (2021)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04379336 (2020)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04537663 (2021)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04648800 (2020)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04414267 (2021)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04417335 (2020)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04373291 (2021)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04641858 (2020)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04542330 (2020)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04659941 (2020)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04534803 (2021)

US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04369794 (2020)

O’Neill LAJ, Netea MG. BCG-induced trained immunity: can it offer protection against COVID-19? Nat. Rev. Immunol. 2020;20:335–337. doi: 10.1038/s41577-020-0337-y. PubMed DOI PMC

Young age and adequate BCG are key factors for optimal BCG treatment efficacy in non-muscle-invasive bladder cancer