Trends in Immunology
Volume 43, Issue 4, April 2022, Pages 322-335
Journal home page for Trends in Immunology

Review
BCG vaccination induces cross-protective immunity against pathogenic microorganisms

https://doi.org/10.1016/j.it.2021.12.006Get rights and content

Highlights

  • Bacillus Calmette-Guérin (BCG) has been the most widely used vaccine globally to induce immunity against Mycobacterium tuberculosis (M. tb). This vaccine is an important prophylactic measure to reduce the progression of tuberculous pulmonary disease. BCG is administered, in most cases, during the first days of life and has led to a decrease in neonatal tuberculosis deaths.

  • BCG can promote immunity against other non-tuberculosis mycobacteria, such as Mycobacterium leprae, Mycobacterium ulcerans, Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium abscessus. BCG can also contribute to the control of opportunistic pathogens.

  • BCG can induce the expansion of T cells that recognize epitopes against other bacteria (different than M. tb) and viruses [e.g., severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)]. Although the underlying mechanism for cross-protection is not yet fully understood, it is thought to rely on epigenetic changes and metabolic modifications on immune cells.

  • New data have suggested an association between decreased mortality rates due to SARS-CoV-2 infection with a high rate of BCG vaccination, suggesting that this vaccine might potentially generate cross-protective immunity against this virus, which remains to be robustly tested.

Bacillus Calmette-Guérin (BCG) is an attenuated Mycobacterium bovis strain used as a vaccine to prevent Mycobacterium tuberculosis (M. tb) infection. Its ability to potentiate the immune response induced by other vaccines and to promote nonspecific immunomodulatory effects has been described. These effects can be triggered by epigenetic reprogramming and metabolic shifts on innate immune cells, a phenomenon known as trained immunity. The induction of trained immunity may contribute to explain why BCG vaccination effectively decreases disease symptoms caused by pathogens different from M. tb. This article explains the importance of BCG immunization and the possible mechanisms associated with the induction of trained immunity, which might be used as a strategy for rapid activation of the immune system against unrelated pathogens.

Section snippets

Global relevance of BCG

BCG is a live attenuated vaccine that has been used for over 100 years to prevent infections with M. tb, the causative agent of TB [1]. It is estimated that a quarter of the population worldwide is infected with M. tb [2], resulting in about 1.6 million fatalities each year. This number can be considered one of the highest causes of death from a bacterial disease. Therefore, the control of this epidemic continues to be a global public health problem [3]. According to the 2019 international

Molecular and cellular mechanisms underlying BCG-induced immune responses

BGC is a potent stimulator of the mammalian innate immune response [18], known to engage pattern recognition receptors (PRRs), such as Toll-like receptor (TLR)-2 and TLR-4, which are located on the cell membrane surface [19], and nucleotide-binding oligomerization domain (NOD) receptors situated on the cytosol of innate immune cells such as macrophages, dendritic cells (DCs), and lymphocytes [20]. BCG immunization in mice and humans has also been reported to enhance macrophage trained innate

Trained immunity: heterologous protection by BCG vaccination

Trained immunity is a concept used for the first time in 2011 to indicate the training of innate immune cells upon exposure to certain pathogens or molecules in a sort of innate memory profile [35]. This training allows innate immune cells to respond robustly and rapidly upon challenge with molecules different from the original stimuli [35]. Metabolic and epigenetic changes seem to be responsible for establishing trained immunity in various cell types, as evidenced from particular DNA

BCG-induced cross-protection against bacterial and viral infections

Vaccination with BCG has been described to promote cross-protection against other bacterial and viral infections, resulting in decreased disease outcomes (induced by these pathogens) in humans and mice. In this section, we will specifically discuss the cross-protection that has been documented against non-tuberculosis mycobacteria, other bacteria, fungi, and viruses which has been linked to the trained immunity profile described above.

Putative advantages of BCG-induced cross-immunity for vaccine development

The capacity of BCG vaccination to induce a trained immunity profile against several pathogens, and consequently, cross-reactivity antibodies and stimulation of several T cell subsets in host defense, might potentially help develop new vaccine approaches [92]. Specifically, BCG vaccination induces heterologous immunity, which upon infection with different pathogens, induces the production of IFN-γ and TNF, as described earlier [95]. This nonspecific response against several pathogens has

Concluding remarks

Despite the many years of use of BCG in humans and its positive effects in preventing TB infection, there is a lack of knowledge on how this vaccine can protect against other unrelated infections. In this sense, understanding the mechanisms of induced trained immunity from this vaccine strain is essential for reducing the rates of death and hospitalization due to different infectious agents, that is currently of evident interest when considering the SARS-CoV-2 pandemic (see Outstanding questions

Acknowledgments

This work was supported by FONDECYT grants N° 1190830, FONDECYT Postdoctoral grants N° 3190590, CONICYT scholarship 21190183, 21210662, 21210336, the Millennium Institute on Immunology and Immunotherapy (P09/016-F; ICN09_016), the Innovation Fund for Competitiveness FIC-R 2017 (BIP Code: 30488811-0), Regular grants COPEC-UC2019. R.1169, COPEC-UC2020. E.1. and the Biomedical Research Consortium Chile (13CTI-21526/P4).

Author contributions

Conceptualization, J.A.S, A.M.K., S.M.B.; Writing – original draft, J.A.S., N.M.S.G., C.A.P., M.A.R.; Review and editing, J.A.S., N.M.S.G., C.A.P., C.A.R, A.M.K, S.M.B.

Declaration of interests

The authors declare no conflict of interest.

Glossary

5'-methyl-thioadenosine
a histone methyltransferase inhibitor.
Arabinomannan
a polysaccharide of the mycobacterial capsule; important for the classification of different serotypes of the organism, and for vaccine development.
Buruli ulcer
disease caused by M. ulcerans that affects the skin and sometimes the bones.
DC1 phenotype
a less abundant population of DCs found in peripheral blood. They are noted for their ability to cross-present, effectively prime CD8+ T cells against extracellular antigens

References (105)

  • H. Schlums

    Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function

    Immunity

    (2015)
  • B. Foley

    Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function

    Blood

    (2012)
  • S. Moorlag

    (2020) BCG vaccination induces long-term functional reprogramming of human neutrophils

    Cell Rep.

    (2020)
  • J. Kleinnijenhuis

    BCG-induced trained immunity in NK cells: Role for non-specific protection to infection

    Clin. Immunol.

    (2014)
  • R. Richardus

    Effectiveness of single-dose rifampicin after BCG vaccination to prevent leprosy in close contacts of patients with newly diagnosed leprosy: A cluster randomized controlled trial

    Int. J. Infect. Dis.

    (2019)
  • L. Pittet

    Mycobacterium ulcerans-specific immune response after immunisation with bacillus Calmette-Guérin (BCG) vaccine

    Vaccine

    (2021)
  • J. Heinzmann

    Mycobacterium avium subsp. paratuberculosis-specific mpt operon expressed in M. bovis BCG as vaccine candidate

    Vet. Microbiol.

    (2008)
  • N. Curtis

    Considering BCG vaccination to reduce the impact of COVID-19

    Lancet

    (2020)
  • Y. Tomita

    BCG vaccine may generate cross-reactive T cells against SARS-CoV-2: in silico analyses and a hypothesis

    Vaccine

    (2020)
  • K. Parmar

    Bacillus Calmette-Guerin vaccine and nonspecific immunity

    Am. J. Med. Sci.

    (2021)
  • C. Counoupas

    Protective efficacy of recombinant BCG over-expressing protective, stage-specific antigens of Mycobacterium tuberculosis

    Vaccine

    (2018)
  • M. Vierboom

    Stronger induction of trained immunity by mucosal BCG or MTBVAC vaccination compared to standard intradermal vaccination

    Cell Rep. Med.

    (2021)
  • C. Locht et al.

    Good old BCG – what a century-old vaccine can contribute to modern medicine

    J. Intern. Med.

    (2020)
  • J.R. Mascola et al.

    Novel vaccine technologies for the 21st century

    Nat. Rev. Immunol.

    (2020)
  • S. Fatima

    Tuberculosis vaccine: a journey from BCG to present

    Life Sci.

    (2020)
  • A.N. Chard

    Routine vaccination coverage – worldwide

    MMWR Surveill. Summ.

    (2019)
  • A.J. Olive

    Mycobacterium tuberculosis evasion of guanylate binding protein-mediated host defense in mice 1 requires the ESX1 secretion system

    bioRxiv

    (2020)
  • N. Iakobachvili

    Mycobacteria-host interactions in human bronchiolar airway organoids

    Mol. Microbiol.

    (2020)
  • L. Charlotte

    Circadian rhythm influences induction of trained immunity by BCG vaccination

    J. Clin. Invest.

    (2020)
  • M.A. Yamazaki-Nakashimada

    BCG: a vaccine with multiple faces

    Hum. Vaccines Immunother.

    (2020)
  • Y. Li

    The correlation between BCG immunization coverage and the severity of COVID-19

    SSRN Electron. J.

    (2020)
  • S. Muthuvelu

    Measles infection causing Bacillus Calmette-Guérin reactivation: a case report

    BMC Pediatr.

    (2019)
  • H. Hozouri

    An investigation into improvement of stability and efficacy of intravesical BCG formulations using freeze-drying technique

    Trends Pept. Protein Sci.

    (2021)
  • Y. Chang

    Therapeutic effects of BCG vaccination on type 1 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials

    J. Diabetes Res.

    (2020)
  • P. Eggenhuizen

    BCG vaccine derived peptides induce SARS-CoV-2 T cell cross-reactivity

    Front. Immunol.

    (2021)
  • T. Bickett

    Characterizing the BCG induced macrophage and neutrophil mechanisms for defense against Mycobacterium tuberculosis

    Front. Immunol.

    (2020)
  • S. Grassin-Delyle

    The role of Toll-like receptors in the production of cytokines by human lung macrophages

    J. Innate Immun.

    (2020)
  • S. Joosten

    Mycobacterial growth inhibition is associated with trained innate immunity

    J. Clin. Invest.

    (2018)
  • N. Iqbal et al.

    Non-specific immunity of BCG vaccine: a perspective of BCG immunotherapy

    Trials Vaccinol.

    (2014)
  • A. Gela

    Effects of BCG vaccination on donor unrestricted T cells in humans

    bioRxiv

    (2021)
  • D. Melandri

    The γδTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness

    Nat. Immunol.

    (2018)
  • L. Moreira-Teixeira

    Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

    Nat. Commun.

    (2020)
  • B. Freyne

    Neonatal BCG vaccination reduces interferon-γ responsiveness to heterologous pathogens in infants from a randomized controlled trial

    J. Infect. Dis.

    (2020)
  • R. Sutiwisesak

    A natural polymorphism of Mycobacterium tuberculosis in the esxH gene disrupts immunodomination by the TB10.4-specific CD8 T cell response

    PLoS Pathog.

    (2020)
  • T. Chen

    Association of human antibodies to arabinomannan with enhanced mycobacterial opsonophagocytosis and intracellular growth reduction

    J. Infect. Dis.

    (2016)
  • K. Zhou

    Mycobacterial mannose-capped lipoarabinomannan: a modulator bridging innate and adaptive immunity

    Emerg. Microbes Infect.

    (2019)
  • N. Beveridge

    Immunisation with BCG and recombinant MVA85A induces long-lasting, polyfunctional Mycobacterium tuberculosis-specific CD4 + memory T lymphocyte populations

    Eur. J. Immunol.

    (2007)
  • R. Tanner

    The humoral immune response to BCG vaccination

    Front. Immunol.

    (2019)
  • N. Zimmermann

    Human isotype-dependent inhibitory antibody responses against Mycobacterium tuberculosis

    EMBO Mol. Med.

    (2016)
  • A. Tjärnlund

    Polymeric IgR knockout mice are more susceptible to mycobacterial infections in the respiratory tract than wild-type mice

    Int. Immunol.

    (2006)
  • Cited by (19)

    • Implications of the non-specific effect induced by Bacillus Calmette-Guerin (BCG) vaccine on vaccine recommendations

      2023, Jornal de Pediatria
      Citation Excerpt :

      In countries where BCG is not part of the vaccination schedule, nontuberculous mycobacterial respiratory infections are more frequent, particularly in patients with cystic fibrosis and bronchiectasis of other etiologies.1 Protection against C. albicans and other bacteria such as S. pneumoniae and H. influenzae possibly occur through cross-protection.35 Epidemiological studies in several countries have shown that the BCG vaccine was associated with a reduction in childhood morbidity and mortality beyond what would be expected for protection against TB.

    • Trained immunity-related vaccines: innate immune memory and heterologous protection against infections

      2022, Trends in Molecular Medicine
      Citation Excerpt :

      Additionally, activation of trained immunity conferred wide-spectrum protection against a broad panel of clinically relevant bacterial infections [43]. Similar effects were also observed to be induced by vaccines, with most of our knowledge regarding trained immunity in humans deriving from studies with Bacille Calmette–Guérin (BCG) vaccine, a live attenuated strain derived from an isolate of Mycobacterium bovis, developed a century ago against TB [44,45]. Trained immunity properties induced by vaccines were first identified almost a decade ago in a mouse model of lethal Candida albicans infection in which BCG-treated mice exhibited significantly better survival rates and decreased fungal burden after vaccination compared with controls [8].

    View all citing articles on Scopus
    View full text