COVID-19 is a severe health problem in many countries and has altered day-to-day life in the whole world. This infection is caused by the SARS-CoV-2 virus, and depending on age, sex and health status of the patient, it can present with variety of clinical symptoms such as mild infection, a very severe form or even asymptomatic course of the disease. Similarly to other viruses, innate immune response plays a vital role in protection against COVID-19. However, dysregulation of innate immunity could have a significant influence on the severity of the disease. Despite various efforts, there is no effective vaccine against the disease so far. Recent data have demonstrated that the Bacillus Calmette-Guérin (BCG) vaccine could reduce disease severity and the burden of several infectious diseases in addition to targeting its primary focus tuberculosis. There is growing evidence for the concept of beneficial non-specific boosting of immune responses by BCG or other microbial compounds termed trained immunity, which may protect against COVID-19. In this manuscript, we review data on how the development of innate immune memory due to microbial compounds specifically BCG can result in protection against SARS-CoV-2 infection. We also discuss possible mechanisms, challenges and perspectives of using innate immunity as an approach to reduce COVID-19 severity.

Department for Genomics and Immunoregulation Life and Medical Sciences Institute University of Bonn Bonn Germany

Department of Cardiology 1 Coronary and Peripheral Vascular Disease Heart Failure University Hospital Münster Münster Germany

Department of Internal Medicine and Radboud Centre of Infectious Diseases Radboud University Medical Centre Nijmegen The Netherlands

Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Núcleo de Pesquisa da Faculdade da Polícia Militar do Estado de Goiás Goiânia Brazil

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Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet 2020; 395: 470–473. PubMed PMC

Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS‐CoV‐2. Nat Med 2020; 26: 450–452. PubMed PMC

Huang C, Wang Y, Li X et al Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506. PubMed PMC

Liu K, Chen Y, Lin R, Han K. Clinical features of COVID‐19 in elderly patients: a comparison with young and middle‐aged patients. J Infect 2020; 80: e14–e18. PubMed PMC

Verity R, Okell LC, Dorigatti I et al Estimates of the severity of coronavirus disease 2019: a model‐based analysis. Lancet Infect Dis 2020; 20: 669–677. PubMed PMC

Kai H, Kai M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors‐lessons from available evidence and insights into COVID‐19. Hypertens Res 2020; 43: 648–654. PubMed PMC

Yuki K, Fujiogi M, Koutsogiannaki S. COVID‐19 pathophysiology: a review. Clin Immunol 2020; 215: 108427. PubMed PMC

Sluimer JC, Gasc JM, Hamming I et al Angiotensin‐converting enzyme 2 (ACE2) expression and activity in human carotid atherosclerotic lesions. J Pathol 2008; 215: 273–279. PubMed

Sahu BR, Kampa RK, Padhi A, Panda AK. C‐reactive protein: a promising biomarker for poor prognosis in COVID‐19 infection. Clin Chim Acta 2020; 509: 91–94. PubMed PMC

Qiu F, Ma X, Shin YH et al Pathogenic role of human C‐reactive protein in diabetic retinopathy. Clin Sci (Lond) 2020; 134: 1613–1629. PubMed

Anania JC, Chenoweth AM, Wines BD, Hogarth PM. The human FcγRII (CD32) family of leukocyte FcR in health and disease. Front Immunol 2019; 10: 464. PubMed PMC

Devaraj S, Chen X, Adams‐Huet B, Jialal I. Increased expression of Fc‐γ receptors on monocytes in patients with nascent metabolic syndrome. J Clin Endocrinol Metab 2013; 98: E1510–E1515. PubMed

Tanigaki K, Sundgren N, Khera A, Vongpatanasin W, Mineo C, Shaul PW. Fcγ receptors and ligands and cardiovascular disease. Circ Res 2015; 116: 368–384. PubMed PMC

Walls AC, Xiong X, Park YJ et al Unexpected receptor functional mimicry elucidates activation of coronavirus fusion. Cell 2019; 176: 1026–1039 e1015. PubMed PMC

Zhou Y, Fu B, Zheng X et al Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID‐19 patients. Natl Sci Rev 2020; 7: 998–1002. nwaa041. PubMed PMC

Croxford AL, Lanzinger M, Hartmann FJ et al The cytokine GM‐CSF drives the inflammatory signature of CCR2+ monocytes and licenses autoimmunity. Immunity 2015; 43: 502–514. PubMed

Guillot L, Le Goffic R, Bloch S et al Involvement of toll‐like receptor 3 in the immune response of lung epithelial cells to double‐stranded RNA and influenza A virus. J Biol Chem 2005; 280: 5571–5580. PubMed

Totura AL, Whitmore A, Agnihothram S et al Toll‐like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. MBio 2015; 6: e00638–e00615. PubMed PMC

Wen W, Su W, Tang H et al Immune cell profiling of COVID‐19 patients in the recovery stage by single‐cell sequencing. Cell Discovery 2020; 6: 31. PubMed PMC

Cavalli G, De Luca G, Campochiaro C et al Interleukin‐1 blockade with high‐dose anakinra in patients with COVID‐19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol 2020; 2: e325–e331. PubMed PMC

Padron‐Regalado E. Vaccines for SARS‐CoV‐2: lessons from other coronavirus strains. Infect Dis Ther 2020; 9: 1–20. PubMed PMC

Gursel M, Gursel I. Is global BCG vaccination‐induced trained immunity relevant to the progression of SARS‐CoV‐2 pandemic? Allergy 2020; 75: 1815–1819. PubMed PMC

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. PubMed PMC

Pereira M, Paixao E, Trajman A et al The need for fast‐track, high‐quality and low‐cost studies about the role of the BCG vaccine in the fight against COVID‐19. Respir Res 2020; 21: 178. PubMed PMC

Milutinovic B, Kurtz J. Immune memory in invertebrates. Semin Immunol 2016; 28: 328–342. PubMed

Netea MG, Joosten LA, Latz E et al Trained immunity: a program of innate immune memory in health and disease. Science 2016; 352: aaf1098. PubMed PMC

Schnack L, Sohrabi Y, Lagache SMM et al Mechanisms of trained innate immunity in oxLDL primed human coronary smooth muscle cells. Front Immunol 2019; 10: 13. PubMed PMC

Naik S, Larsen SB, Gomez NC et al Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 2017; 550: 475–480. PubMed PMC

Lu Y, Sun Y, Drummer CT et al Increased acetylation of H3K14 in the genomic regions that encode trained immunity enzymes in lysophosphatidylcholine‐activated human aortic endothelial cells ‐ Novel qualification markers for chronic disease risk factors and conditional DAMPs. Redox Biol 2019; 24: 101221. PubMed PMC

Quintin J, Saeed S, Martens JHA et al Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 2012; 12: 223–232. PubMed PMC

Arts RJ, Novakovic B, Ter Horst R et al Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab 2016; 24: 807–819. PubMed PMC

Sohrabi Y, Godfrey R, Findeisen HM. Altered cellular metabolism drives trained immunity. Trends Endocrinol Metab 2018; 29: 602–605. PubMed

Dos Santos JC, Barroso de Figueiredo AM, Teodoro Silva MV et al β‐Glucan‐induced trained immunity protects against Leishmania braziliensis infection: a crucial role for IL‐32. Cell Rep 2019; 28: 2659–2672 e2656. PubMed

Di Luzio NR, Williams DL. Protective effect of glucan against systemic Staphylococcus aureus septicemia in normal and leukemic mice. Infect Immun 1978; 20: 804–810. PubMed PMC

Krahenbuhl JL, Sharma SD, Ferraresi RW, Remington JS. Effects of muramyl dipeptide treatment on resistance to infection with Toxoplasma gondii in mice. Infect Immun 1981; 31: 716–722. PubMed PMC

Ribes S, Meister T, Ott M et al Intraperitoneal prophylaxis with CpG oligodeoxynucleotides protects neutropenic mice against intracerebral Escherichia coli K1 infection. J Neuroinflammation 2014; 11: 14. PubMed PMC

Bardel E, Doucet‐Ladeveze R, Mathieu C, Harandi AM, Dubois B, Kaiserlian D. Intradermal immunisation using the TLR3‐ligand Poly (I:C) as adjuvant induces mucosal antibody responses and protects against genital HSV‐2 infection. NPJ Vaccines 2016; 1: 16010. PubMed PMC

Rieckmann A, Villumsen M, Sorup S et al Vaccinations against smallpox and tuberculosis are associated with better long‐term survival: a Danish case‐cohort study 1971–2010. Int J Epidemiol 2017; 46: 695–705. PubMed PMC

Aaby P, Martins CL, Garly ML et al Non‐specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ 2010; 341: c6495. PubMed PMC

Biering‐Sorensen S, Aaby P, Napirna BM et al Small randomized trial among low‐birth‐weight children receiving bacillus Calmette‐Guerin vaccination at first health center contact. Pediatr Infect Dis J 2012; 31: 306–308. PubMed

Nemes 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: 138–149. PubMed PMC

Biering‐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: 1183–1190. PubMed PMC

Ohrui T, Nakayama K, Fukushima T, Chiba H, Sasaki H. [Prevention of elderly pneumonia by pneumococcal, influenza and BCG vaccinations]. Nihon Ronen Igakkai Zasshi Japanese Journal of Geriatrics 2005; 42: 34–36. PubMed

Kolmel KF, Grange JM, Krone B et al Prior immunisation of patients with malignant melanoma with vaccinia or BCG is associated with better survival. An European Organization for Research and Treatment of Cancer cohort study on 542 patients. Eur J Cancer 2005; 41: 118–125. PubMed

Lankes HA, Fought AJ, Evens AM, Weisenburger DD, Chiu BC. Vaccination history and risk of non‐Hodgkin lymphoma: a population‐based, case‐control study. Cancer Causes Control 2009; 20: 517–523. PubMed PMC

Kleinnijenhuis J, Quintin J, Preijers F et al Bacille Calmette‐Guerin induces NOD2‐dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci USA 2012; 109: 17537–17542. PubMed PMC

Arts 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 e105. PubMed

Walk J, de Bree LCJ, Graumans W et al Outcomes of controlled human malaria infection after BCG vaccination. Nat Commun 2019; 10: 874. PubMed PMC

Pereira LI, Dorta ML, Pereira AJ et al Increase of NK cells and proinflammatory monocytes are associated with the clinical improvement of diffuse cutaneous leishmaniasis after immunochemotherapy with BCG/Leishmania antigens. Am J Trop Med Hyg 2009; 81: 378–383. PubMed

Fortier AH, Mock BA, Meltzer MS, Nacy CA. Mycobacterium bovis BCG‐induced protection against cutaneous and systemic Leishmania major infections of mice. Infect Immun 1987; 55: 1707–1714. PubMed PMC

Leentjens J, Kox M, Stokman R 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. PubMed

Angelidou A, Conti MG, Diray‐Arce J et al Licensed Bacille Calmette‐Guerin (BCG) formulations differ markedly in bacterial viability, RNA content and innate immune activation. Vaccine 2020; 38: 2229–2240. PubMed PMC

Aldovini A, Young RA. Humoral and cell‐mediated immune responses to live recombinant BCG‐HIV vaccines. Nature 1991; 351: 479–482. PubMed

Uno‐Furuta S, Matsuo K, Tamaki S et al Immunization with recombinant Calmette‐Guerin bacillus (BCG)‐hepatitis C virus (HCV) elicits HCV‐specific cytotoxic T lymphocytes in mice. Vaccine 2003; 21: 3149–3156. PubMed

Mukherjee S, Subramaniam R, Chen H, Smith A, Keshava S, Shams H. Boosting efferocytosis in alveolar space using BCG vaccine to protect host against influenza pneumonia. PLoS One 2017; 12: e0180143. PubMed PMC

Buffen K, Oosting M, Quintin J et al Autophagy controls BCG‐induced trained immunity and the response to intravesical BCG therapy for bladder cancer. PLoS Pathog 2014; 10: e1004485. PubMed PMC

Barton ES, White DW, Cathelyn JS et al Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 2007; 447: 326–329. PubMed

Hong M, Sandalova E, Low D et al Trained immunity in newborn infants of HBV‐infected mothers. Nat Commun 2015; 6: 6588. PubMed PMC

Kleinnijenhuis J, Quintin J, Preijers F et al BCG‐induced trained immunity in NK cells: role for non‐specific protection to infection. Clin Immunol 2014; 155: 213–219. PubMed PMC

Kleinnijenhuis J, Quintin J, Preijers F et al Long‐lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J Innate Immun 2014; 6: 152–158. PubMed PMC

Mitroulis I, Ruppova K, Wang B et al Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 2018; 172: 147–161 e112. PubMed PMC

Bai W, Liu H, Ji Q et al TLR3 regulates mycobacterial RNA‐induced IL‐10 production through the PI3K/AKT signaling pathway. Cell Signal 2014; 26: 942–950. PubMed

Speth MT, Repnik U, Muller E et al Poly(I:C)‐encapsulating nanoparticles enhance innate immune responses to the tuberculosis vaccine bacille Calmette‐Guerin (BCG) via synergistic activation of innate immune receptors. Mol Pharm 2017; 14: 4098–4112. PubMed

Novakovic B, Habibi E, Wang SY et al β‐Glucan reverses the epigenetic state of LPS‐induced immunological tolerance. Cell 2016; 167: 1354–1368 e1314. PubMed PMC

Fanucchi S, Fok ET, Dalla E et al Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Nat Genet 2019; 51: 138–150. PubMed

Cheng SC, Quintin J, Cramer RA et al mTOR/HIF1α‐mediated aerobic glycolysis as metabolic basis for trained immunity. Science 2014; 345: 1250684. PubMed PMC

Arts RJW, Carvalho A, La Rocca C et al Immunometabolic pathways in BCG‐induced trained immunity. Cell Rep 2016; 17: 2562–2571. PubMed PMC

Keating ST, El‐Osta A. Epigenetics and metabolism. Circ Res 2015; 116: 715–736. PubMed

Kaufmann E, Sanz J, Dunn JL et al BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell 2018; 172: 176–190 e119. PubMed

Ventura L, Vitali M, Romano Spica V. BCG vaccination and socioeconomic variables vs COVID‐19 global features: clearing up a controversial issue. Allergy 2020. 10.1111/all.14524. Online ahead of print. PubMed DOI

Ozdemir C, Kucuksezer UC, Tamay ZU. Is BCG vaccination effecting the spread and severity of COVID‐19? Allergy 2020; 75: 1824–1827. PubMed

Weng CH, Saal A, Butt WW et al Bacillus Calmette‐Guerin vaccination and clinical characteristics and outcomes of COVID‐19 in Rhode Island, United States: a cohort study. Epidemiol Infect 2020; 148: e140. PubMed PMC

Moorlag SJCFM, van Deuren RC, van Werkhoven CH et al Safety and COVID‐19 symptoms in individuals recently vaccinated with BCG: a retrospective cohort study. Cell Rep Med 2020; 1: 100073. PubMed PMC

Kinoshita M, Tanaka M. Impact of routine infant BCG vaccination in young generation on prevention of local COVID‐19 spread in Japan. J Infect 2020; 81: 625–633. PubMed PMC

Hamiel U, Kozer E, Youngster I. SARS‐CoV‐2 Rates in BCG‐Vaccinated and Unvaccinated Young Adults. JAMA 2020; 323: 2340–2341. PubMed PMC

Pollard AJ, Finn A, Curtis N. Non‐specific effects of vaccines: plausible and potentially important, but implications uncertain. Arch Dis Child 2017; 102: 1077–1081. PubMed

Barreto ML, Cunha SS, Pereira SM et al Neonatal BCG protection against tuberculosis lasts for 20 years in Brazil. Int J Tuberc Lung Dis 2005; 9: 1171–1173. PubMed

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. PubMed

Netea MG, Schlitzer A, Placek K, Joosten LAB, Schultze JL. Innate and adaptive immune memory: an evolutionary continuum in the host's response to pathogens. Cell Host Microbe 2019; 25: 13–26. PubMed

Ritz N, Dutta B, Donath S et al The influence of bacille Calmette‐Guerin vaccine strain on the immune response against tuberculosis: a randomized trial. Am J Respir Crit Care Med 2012; 185: 213–222. PubMed

Curtis N, Sparrow A, Ghebreyesus TA, Netea MG. Considering BCG vaccination to reduce the impact of COVID‐19. Lancet 2020; 395: 1545–1546. PubMed PMC

Cernuschi T, Malvolti S, Nickels E, Friede M. Bacillus Calmette‐Guerin (BCG) vaccine: a global assessment of demand and supply balance. Vaccine 2018; 36: 498–506. PubMed PMC

Kandeel W, Abdelal A, Elmohamady BN et al A comparative study between full‐dose and half‐dose intravesical immune bacille Calmette‐Guerin injection in the management of superficial bladder cancer. Arab J Urol 2015; 13: 233–237. PubMed PMC

Roy P, Vekemans J, Clark A, Sanderson C, Harris RC, White RG. Potential effect of age of BCG vaccination on global paediatric tuberculosis mortality: a modelling study. Lancet Glob Health 2019; 7: e1655–e1663. PubMed PMC

Hoft DF, Xia M, Zhang GL et al PO and ID BCG vaccination in humans induce distinct mucosal and systemic immune responses and CD4+ T cell transcriptomal molecular signatures. Mucosal Immunol 2018; 11: 486–495. PubMed PMC

Goonetilleke NP, McShane H, Hannan CM, Anderson RJ, Brookes RH, Hill AV. Enhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette‐Guerin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus Ankara. J Immunol 2003; 171: 1602–1609. PubMed

Verreck FAW, Tchilian EZ, Vervenne RAW et al Variable BCG efficacy in rhesus populations: pulmonary BCG provides protection where standard intra‐dermal vaccination fails. Tuberculosis 2017; 104: 46–57. PubMed

de Bree LCJ, Marijnissen RJ, Kel JM et al Bacillus Calmette‐Guerin‐induced trained immunity is not protective for experimental influenza A/Anhui/1/2013 (H7N9) infection in mice. Front Immunol 2018; 9: 869. PubMed PMC

Darrah PA, Zeppa JJ, Maiello P et al Prevention of tuberculosis in macaques after intravenous BCG immunization. Nature 2020; 577: 95–102. PubMed PMC

Lieberman J, Krauthammer M, Sastre A. Serum angiotensin‐converting‐enzyme in rabbits with and without pulmonary granulomatosis. Granulomatosis induced with complete‐Freund's‐adjuvant or BCG. Sarcoidosis 1986; 3: 60–66. PubMed

Rea TH, Narayanan RB, Turk JL. Lysozyme and angiotensin converting enzyme levels in experimental mycobacterial granulomas. J Pathol 1983; 139: 207–216. PubMed

Guo W, Li M, Dong Y, et al Diabetes is a risk factor for the progression and prognosis of COVID ‐19. Diabetes Metab Res Rev 2020; e3319. PubMed PMC

Chang YC, Lin CJ, Hsiao YH, Chang YH, Liu SJ, Hsu HY. Therapeutic effects of BCG vaccination on type 1 diabetes mellitus: a systematic review and meta‐analysis of randomized controlled trials. J Diabetes Res 2020; 2020: 8954125. PubMed PMC

Kodama S, Kuhtreiber W, Fujimura S, Dale EA, Faustman DL. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science 2003; 302: 1223–1227. PubMed

Radhakrishnan RK, Thandi RS, Tripathi D et al BCG vaccination reduces the mortality of Mycobacterium tuberculosis‐infected type 2 diabetes mellitus mice. JCI Insight 2020; 5: e133788. PubMed PMC

Faustman DL, Wang L, Okubo Y et al Proof‐of‐concept, randomized, controlled clinical trial of Bacillus‐Calmette‐Guerin for treatment of long‐term type 1 diabetes. PLoS One 2012; 7: e41756. PubMed PMC

Somogyi I, Rigo J, Sos J. The prevention of experimental hypertension and arteriosclerosis with B.C.G. and tuberculin. Lancet 1962; 2: 280–281. PubMed

Lamb DJ, Ferns GA. The magnitude of the immune response to heat shock protein‐65 following BCG immunisation is associated with the extent of experimental atherosclerosis. Atherosclerosis 2002; 165: 231–240. PubMed

van Dam AD, Bekkering S, Crasborn M et al BCG lowers plasma cholesterol levels and delays atherosclerotic lesion progression in mice. Atherosclerosis 2016; 251: 6–14. PubMed

Ovchinnikova OA, Berge N, Kang C et al Mycobacterium bovis BCG killed by extended freeze‐drying induces an immunoregulatory profile and protects against atherosclerosis. J Intern Med 2014; 275: 49–58. PubMed

Goyal P, Choi JJ, Pinheiro LC et al Clinical characteristics of Covid‐19 in New York City. N Engl J Med 2020; 382: 2372–2374. PubMed PMC

Choi IS, Koh YI. Therapeutic effects of BCG vaccination in adult asthmatic patients: a randomized, controlled trial. Ann Allergy Asthma Immunol 2002; 88: 584–591. PubMed

Park SS, Heo EY, Kim DK, Chung HS, Lee CH. The association of BCG vaccination with atopy and asthma in adults. Int J Med Sci 2015; 12: 668–673. PubMed PMC

El‐Zein M, Parent ME, Benedetti A, Rousseau MC. Does BCG vaccination protect against the development of childhood asthma? A systematic review and meta‐analysis of epidemiological studies. Int J Epidemiol 2010; 39: 469–486. PubMed

Datau EA, Mewengkang H, Matheos JC et al Clinical efficacy and laboratory improvement of bacillus calmette‐guerin vaccination on adult atopic asthma: a cohort study. World Allergy Organ J 2008; 1: 63–69. PubMed PMC

Linehan MF, Nurmatov U, Frank TL, Niven RM, Baxter DN, Sheikh A. Does BCG vaccination protect against childhood asthma? Final results from the Manchester Community Asthma Study retrospective cohort study and updated systematic review and meta‐analysis. J Allergy Clin Immunol 2014; 133: 688–695 e614. PubMed

Chyczewska E, Chyczewski L, Bankowski E, Sulkowski S, Niklinski J. Stimulation of alveolar macrophages by BCG vaccine enhances the process of lung fibrosis induced by bleomycin. Folia Histochem Cytobiol 1993; 31: 113–116. PubMed

Hatherill M, Geldenhuys H, Pienaar B et al Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults. Vaccine 2014; 32: 3982–3988. PubMed PMC

Venkataraman A, Yusuff M, Liebeschuetz S, Riddell A, Prendergast AJ. Management and outcome of Bacille Calmette‐Guerin vaccine adverse reactions. Vaccine 2015; 33: 5470–5474. PubMed PMC

Decaestecker K, Oosterlinck W. Managing the adverse events of intravesical bacillus Calmette‐Guerin therapy. Res Rep Urol 2015; 7: 157–163. PubMed PMC

Talbot EA, Perkins MD, Silva SF, Frothingham R. Disseminated bacille Calmette‐Guerin disease after vaccination: case report and review. Clin Infect Dis 1997; 24: 1139–1146. PubMed

Hesseling AC, Marais BJ, Gie RP et al The risk of disseminated Bacille Calmette‐Guerin (BCG) disease in HIV‐infected children. Vaccine 2007; 25: 14–18. PubMed

Croce E, Hatz C, Jonker EF, Visser LG, Jaeger VK, Buhler S. Safety of live vaccinations on immunosuppressive therapy in patients with immune‐mediated inflammatory diseases, solid organ transplantation or after bone‐marrow transplantation – a systematic review of randomized trials, observational studies and case reports. Vaccine 2017; 35: 1216–1226. PubMed

Dourado I, Rios MH, Pereira SM et al Rates of adverse reactions to first and second doses of BCG vaccination: results of a large community trial in Brazilian schoolchildren. Int J Tuberc Lung Dis 2003; 7: 399–402. PubMed

Kato S, Tokunaga O, Yoshiyama T. Analysis of Koch's phenomenon by BCg vaccination with the multi‐puncture method in Japan. Kekkaku 2010; 85: 777–782. PubMed

Ferreira AA, Ferreira Mde F, Macedo EA et al [BCG revaccination in school children: evolution of the lesion at the vaccination site between 48 hours and 10 weeks]. J Pediatr 2002; 78: 289–294. PubMed

Boer MC, Prins C, van Meijgaarden KE, van Dissel JT, Ottenhoff TH, Joosten SA. Mycobacterium bovis BCG vaccination induces divergent proinflammatory or regulatory T cell responses in adults. Clin Vaccine Immunol 2015; 22: 778–788. PubMed PMC

Marakalala MJ, Williams DL, Hoving JC, Engstad R, Netea MG, Brown GD. Dectin‐1 plays a redundant role in the immunomodulatory activities of β‐glucan‐rich ligands in vivo. Microbes Infect 2013; 15: 511–515. PubMed PMC

Kumaki Y, Salazar AM, Wandersee MK, Barnard DL. Prophylactic and therapeutic intranasal administration with an immunomodulator, Hiltonol((R)) (Poly IC:LC), in a lethal SARS‐CoV‐infected BALB/c mouse model. Antiviral Res 2017; 139: 1–12. PubMed PMC

Ishihara C, Mizukoshi N, Iida J, Kato K, Yamamoto K, Azuma I. Suppression of Sendai virus growth by treatment with Nα‐acetylmuramyl‐L‐alanyl‐D‐isoglutaminyl‐Nε‐stearoyl‐L‐lysine in mice. Vaccine 1987; 5: 295–301. PubMed

Dietrich FM, Hochkeppel HK, Lukas B. Enhancement of host resistance against virus infections by MTP‐PE, a synthetic lipophilic muramyl peptide–I. Increased survival in mice and guinea pigs after single drug administration prior to infection, and the effect of MTP‐PE on interferon levels in sera and lungs. Int J Immunopharmacol 1986; 8: 931–942. PubMed

Cheng SC, Scicluna BP, Arts RJ et al Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat Immunol 2016; 17: 406–413. PubMed

Floc'h F, Werner GH. Increased resistance to virus infections of mice inoculated with BCG (Bacillus calmette‐guerin). Ann Immunol 1976; 127: 173–186. PubMed

Sorup S, Benn CS, Poulsen A, Krause TG, Aaby P, Ravn H. Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections. JAMA 2014; 311: 826–835. PubMed

Tielemans S, de Melker HE, Hahne SJM et al Non‐specific effects of measles, mumps, and rubella (MMR) vaccination in high income setting: population based cohort study in the Netherlands. BMJ 2017; 358: j3862. PubMed PMC

Sorup S, Benn CS, Stensballe LG, Aaby P, Ravn H. Measles‐mumps‐rubella vaccination and respiratory syncytial virus‐associated hospital contact. Vaccine 2015; 33: 237–245. PubMed PMC

Sorup S, Stensballe LG, Krause TG, Aaby P, Benn CS, Ravn H. Oral polio vaccination and hospital admissions with non‐polio infections in Denmark: Nationwide retrospective cohort study. Open Forum Infect Dis 2016; 3: ofv204. PubMed PMC

Tarancon R, Dominguez‐Andres J, Uranga S et al New live attenuated tuberculosis vaccine MTBVAC induces trained immunity and confers protection against experimental lethal pneumonia. PLoS Pathog 2020; 16: e1008404. PubMed PMC

Yao Y, Jeyanathan M, Haddadi S et al Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell 2018; 175: 1634–1650 e1617. PubMed

Deadly COVID-19 among the elderly: Innate immune memory helping those most in need

Altered Cholesterol and Lipid Synthesis Mediates Hyperinflammation in COVID-19