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BCG vaccine’s off-target effects on allergic, inflammatory, and autoimmune diseases: Worth another shot?

  • Asimenia Angelidou
    Affiliations
    Department of Neonatology, Beth Israel Deaconess Medical Center, Boston, Mass

    Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, Mass

    Department of Pediatrics, Harvard Medical School, Boston, Mass
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  • Laure F. Pittet
    Affiliations
    Infectious Diseases Research Group, Murdoch Children’s Research Institute, Royal Children's Hospital Melbourne, Parkville, Australia

    Unit of Pediatric Infectious Diseases, Division of General Pediatrics, Department of Pediatrics, Gynecology and Obstetrics, Children's Hospital, University Hospitals of Geneva, Geneva, Switzerland

    Faculty of Medicine, University of Geneva, Geneva, Switzerland
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  • Denise Faustman
    Affiliations
    Department of Pediatrics, Harvard Medical School, Boston, Mass

    Department of Immunobiology, Massachusetts General Hospital, Boston, Mass
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  • Nigel Curtis
    Affiliations
    Infectious Diseases Research Group, Murdoch Children’s Research Institute, Royal Children's Hospital Melbourne, Parkville, Australia

    Department of Paediatrics, The University of Melbourne, Melbourne, Australia
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  • Ofer Levy
    Correspondence
    Corresponding author: Ofer Levy MD, PhD, 4 Blackfan Circle, HIM Building, Rm 837A, Boston, MA 02115.
    Affiliations
    Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, Mass

    Department of Pediatrics, Harvard Medical School, Boston, Mass

    Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Mass
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Published:October 18, 2021DOI:https://doi.org/10.1016/j.jaci.2021.09.034
      Allergy is an exaggerated immune response to foreign antigens resulting from a combination of genetic, epigenetic and environmental interactions. Immune responses misdirected against intrinsic antigens can lead to autoimmunity. The incidence of allergic and autoimmune diseases is rising, constituting a global public health challenge with broad socioeconomic implications. The Bacille Calmette-Guérin (BCG) vaccine is a live attenuated Mycobacterium bovis vaccine given to millions of newborns worldwide to prevent tuberculosis. It also has immunomodulatory properties that have sparked interest in its use as a preventive or therapeutic tool against allergic and autoimmune diseases (Table I).
      Table IRandomized controlled trials of BCG to prevent or treat allergic and immune-mediated diseases, listed in chronologic order
      Indication Study phase Location Mean age (+SD) or age range N Interventions Outcomes Results Reference
      New-onset type I diabetes Pilot interventional trial, PH 3 IL 11 y (+5 y) 17 Single dose of i.d. BCG-Connaught vaccine vs saline Clinical remission (blood glucose and insulin requirement) until 8 mo after vaccination Transient clinical remission in 65% of patients Shehadeh et al, Lancet 1994
      New-onset type I diabetes RCT, PH 3 IT 14.5 y (+6 y) 72 Single dose of i.d. BCG-Berna vaccine vs no vaccine Insulin dose,

      C-peptide level, and HbA1c at 3, 6, 9, and 12 mo after Dx; clinical remission
      No difference Pozzilli et al, Lancet 1997
      New-onset type I diabetes RCT, PH 3 CA 13.1 y (+3.1 y) 26 Single dose of i.d. BCG-Connaught vaccine vs saline C-peptide level and HbA1c at 1, 3, 6, 9, 12, and 18 mo after vaccination No difference Elliott et al, Diabetes Care 1998
      Relapsing-remitting MS Single-blind crossover trial, PH 3 IT 30.6 y (+5 y) 12 Single dose of i.d. BCG-Berna vaccine MRI activity ≤24 mo after BCG Fewer new enhancing lesions, persistence of lesions and black holes on MRI after BCG vaccine Paolillo et al, J Neurol 2003
      Allergy Single-blind RCT, PH 3 NL 6 wk 121 Single dose of i.d. BCG-Denmark vaccine vs saline at 6 wk, followed by a second dose at 4 mo in some Allergic signs and symptoms, lung function; No. of leukocytes and eosinophils, IgE levels at 6 wk and 4 and 18 mo No difference at 4 mo; significantly lower use of medication for eczema and trend toward less eczema at 18 mo Steenhuis et al, Clin Exp Allergy 2008
      Atopy Long-term follow-up of RCT, PH 3 GB 0-3 d 281 Single dose of i.d. BCG-Denmark vaccine early vs delayed Skin prick testing, signs and symptoms of asthma, eczema, and food allergy at 3-9 y No difference between early vs late BCG vaccination; significantly less atopy in children with a BCG vaccine scar Kiraly et al, Allergy 2013
      First demyelinating episode RCT, PH 2/3 IT 32 y (+8 y) 82 Single dose of i.d. BCG-Pasteur vaccine vs saline MRI lesions at 0 and 6 mo after vaccination Significantly reduced development of gadolinium-enhancing lesions after BCG vaccination Ristori et al, Neurology 2014
      Established type I diabetes Long-term follow-up of RCT, PH 1 US 42 y (+3 y) 12 2 doses of i.d. BCG-Connaught vaccine vs saline at 0 and 4 wk HbA1c at 3, 4, 5, 6, 7, and 8 y; stimulated C-peptide levels at 4 y Lower HbA1c and evidence of pancreas recovery after BCG vaccination Kühtreiber et al, NPJ Vaccines 2018
      Atopic dermatitis Single-blind RCT, PH 3 DK 0-7 d 4262 Single dose of i.d. BCG-Denmark vaccine vs no vaccine Atopic dermatitis at 13 mo Significant decrease in atopic dermatitis in children with predisposition Thostesen et al, Allergy 2018
      Atopy Single-blind RCT, PH 3 AUS 0-7 d 1272 Single dose of i.d. BCG-Denmark vaccine vs no vaccine Food allergy, eczema, asthma, and LRTI at 1 and 5 y Significant decrease in eczema in children with predisposition; analysis of other outcomes ongoing Pittet et al, Allergy 2021
      AUS, Australia; CA, Canada; DK, Denmark, Dx, diagnosis; GB, Guinea Bissau; HbA1c, glycosylated hemoglobin; i.d., intradermal; IL, Israel; IT, Italy; LRTI, lower respiratory tract infection; MS, multiple sclerosis; NL, The Netherlands; PH, phase; RCT, randomized controlled trial; US, United States.

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