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100 Years of BCG Immunization: Past, Present and Future

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A special issue of Vaccines (ISSN 2076-393X).

Deadline for manuscript submissions: closed (10 April 2022) | Viewed by 30643

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Dr. Aldo Tagliabue

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Guest Editor

Institute of Biomedical Technologies (ITB), National Research Council (CNR), Milano, Italy
Interests: vaccines; adjuvants; infectious diseases; mucosal immunity; cytokines

Dr. Diana Boraschi

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Guest Editor

Shenzhen Institute of Advanced Technologies (SIAT) University, Shenzhen, China
Interests: innate immunity; inflammation; innate memory; adjuvants; immunosafety
Special Issues, Collections and Topics in MDPI journals

Dr. Luciana C. C. Leite

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Laboratório de Desenvolvimento de Vacinas, Instituto Butantan, São Paulo, Brazil
Interests: vaccine-induced immunity; vaccine development; recombinant BCG

Prof. Dr. Stefan H. E. Kaufmann

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Guest Editor

1. Max Planck Institute for Infection Biology, Berlin, Germany
2. Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
3. Faculty Fellow of the Hagler Institute for Advanced Study, Texas A&M University, College Station, TX, USA
Interests: microbiology; tuberculosis; immunology; biology; infection; vaccinology; biosignatures; recombinant BCG

Special Issue Information

Dear Colleagues,

The tuberculosis vaccine Bacille Calmette–Guérin (BCG) has been available for 100 years, but tuberculosis remains a major health threat. BCG vaccine efficacy has been demonstrated when administered to children below 5 years of age, against pulmonary, meningeal, and disseminated tuberculosis (TB), while its efficacy in adults has been shown to vary widely in different epidemiological conditions, and its capacity to prevent infection is still debated. BCG efficacy against leprosy is higher but likewise variable. An additional concern is the increasing appearance of multiple antibiotic-resistant variants of Mycobacterium tuberculosis and Mycobacterium leprae, which urgently calls for effective preventive measures. Thus, better vaccines are needed. Several candidates have been developed in recent decades employing molecular technologies to obtain antigen/adjuvant subunit vaccines, viral vectored vaccines, and whole cell mycobacterial vaccines that come as live recombinant vaccines. In the century of BCG immunization, it has become clear that the administration of live attenuated BCG can have other effects in addition to inducing specific immunity against M. tuberculosis. BCG is also considered the gold standard for primary therapy of carcinoma in situ of the bladder, most likely for its capacity to activate the host innate/inflammatory response against the tumor. Despite its limitations, to date, BCG has not been surpassed by any other treatment. Along the same line, several other interesting findings suggest that BCG can have beneficial non-specific effects (NSE), from controlling hyperglycemia in type 1 diabetes to decreasing childhood mortality. The BCG NSE have received a lot of interest recently in the attempt to find effective treatments for COVID-19. The possibility is currently being investigated that BCG could prime the innate immune system of vaccinees and generate an innate immune memory able to afford a better, pathogen-agnostic antimicrobial resistance. Additionally, the capacity of BCG to interfere with the cellular energy metabolism and epigenetic reprogramming of metabolic, immune, and inflammatory responses could be exploited for treating a variety of non-infectious diseases, in particular autoimmune and chronic inflammatory conditions such as allergic asthma, insulin-dependent diabetes, and multiple sclerosis

Dr. Aldo Tagliabue
Dr. Diana Boraschi
Dr. Luciana C. C. Leite
Prof. Dr. Stefan H. E. Kaufmann
Guest Editors

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Keywords

BCG
TB vaccines
bladder carcinoma
innate memory

Published Papers (10 papers)

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Editorial

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4 pages, 213 KiB

Open AccessEditorial

100 Years of BCG Immunization: Past, Present, and Future

by Aldo Tagliabue, Diana Boraschi, Luciana C. C. Leite and Stefan H. E. Kaufmann

Vaccines 2022, 10(10), 1743; https://doi.org/10.3390/vaccines10101743 - 18 Oct 2022

Cited by 5 | Viewed by 1625

Abstract

The 100th anniversary of the introduction of Bacille–Calmette–Guérin (BCG) as a tuberculosis (TB) vaccine is an occasion warranting further investigation of the early attempts which culminated in the introduction of BCG as a TB vaccine, as well as of subsequent recognition of failures, new findings that broaden its applications, outstanding questions, and approaches towards the development of novel vaccine candidates [...] Full article

(This article belongs to the Special Issue 100 Years of BCG Immunization: Past, Present and Future)

Research

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13 pages, 1995 KiB

Open AccessArticle

Characterization of the Protective Immune Responses Conferred by Recombinant BCG Overexpressing Components of Mycobacterium tuberculosis Sec Protein Export System

by Annuurun Nisa, Claudio Counoupas, Rachel Pinto, Warwick J. Britton and James A. Triccas

Vaccines 2022, 10(6), 945; https://doi.org/10.3390/vaccines10060945 - 14 Jun 2022

Cited by 4 | Viewed by 1970

Abstract

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is the only approved vaccine against tuberculosis (TB). However, its efficacy in preventing pulmonary TB in adults is limited. Despite its variable efficacy, BCG offers a number of unique and beneficial characteristics, which make it suitable as a vaccine vehicle to express recombinant molecules. In Mycobacterium tuberculosis, the general Sec pathway is an essential cellular process, and it is responsible for exporting the majority of proteins across the cytoplasmic membrane, including potent immune-protective antigens, such as members of the antigen 85 (Ag85) complex. We engineered BCG to overexpress the M. tuberculosis SecDFG proteins in order to improve the efficiency of the Sec-dependent export system and, thus, enhance the secretion of immunogenic proteins. BCG^SecDFG displayed increased intracellular survival within macrophages in vitro and greater persistence in the lymphoid organs of vaccinated mice than parental BCG. In addition, vaccination with BCG^SecDFG generated higher numbers of IFN-γ-secreting T cells in response to secreted mycobacterial antigens compared to BCG, particularly members of the Ag85 complex. Furthermore, vaccination with BCG^SecDFG significantly reduced the bacterial load in the lungs and spleens of M. tuberculosis-infected mice, which was comparable to the protection afforded by parental BCG. Therefore, the modification of protein secretion in BCG can improve antigen-specific immunogenicity. Full article

(This article belongs to the Special Issue 100 Years of BCG Immunization: Past, Present and Future)

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14 pages, 2312 KiB

Open AccessArticle

Recombinant BCG-LTAK63 Vaccine Candidate for Tuberculosis Induces an Inflammatory Profile in Human Macrophages

by Carina C. dos Santos, Kimberley V. Walburg, Suzanne van Veen, Louis G. Wilson, Carlos E. M. Trufen, Ivan P. Nascimento, Tom H. M. Ottenhoff, Luciana C. C. Leite and Mariëlle C. Haks

Vaccines 2022, 10(6), 831; https://doi.org/10.3390/vaccines10060831 - 24 May 2022

Cited by 5 | Viewed by 2275

Abstract

Tuberculosis (TB) is one of the top 10 leading causes of death worldwide. The recombinant BCG strain expressing the genetically detoxified A subunit of the thermolabile toxin from Escherichia coli (LTAK63) adjuvant (rBCG-LTAK63) has previously been shown to confer superior protection and immunogenicity compared to BCG in a murine TB infection model. To further investigate the immunological mechanisms induced by rBCG-LTAK63, we evaluated the immune responses induced by rBCG-LTAK63, BCG, and Mycobacterium tuberculosis (Mtb) H37Rv strains in experimental infections of primary human M1 and M2 macrophages at the transcriptomic and cytokine secretion levels. The rBCG-LTAK63-infected M1 macrophages more profoundly upregulated interferon-inducible genes such as IFIT3, OAS3, and antimicrobial gene CXCL9 compared to BCG, and induced higher levels of inflammatory cytokines such as IL-12(p70), TNF-β, and IL-15. The rBCG-LTAK63-infected M2 macrophages more extensively upregulated transcripts of inflammation-related genes, TAP1, GBP1, SLAMF7, TNIP1, and IL6, and induced higher levels of cytokines related to inflammation and tissue repair, MCP-3 and EGF, as compared to BCG. Thus, our data revealed an important signature of immune responses induced in human macrophages by rBCG-LTAK63 associated with increased inflammation, activation, and tissue repair, which may be correlated with a protective immune response against TB. Full article

(This article belongs to the Special Issue 100 Years of BCG Immunization: Past, Present and Future)

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19 pages, 3946 KiB

Open AccessArticle

BCG-Based Vaccines Elicit Antigen-Specific Adaptive and Trained Immunity against SARS-CoV-2 and Andes orthohantavirus

by Jorge A. Soto, Fabián E. Díaz, Angello Retamal-Díaz, Nicolás M. S. Gálvez, Felipe Melo-González, Alejandro Piña-Iturbe, Mario A. Ramírez, Karen Bohmwald, Pablo A. González, Susan M. Bueno and Alexis M. Kalergis

Vaccines 2022, 10(5), 721; https://doi.org/10.3390/vaccines10050721 - 4 May 2022

Cited by 12 | Viewed by 3493

Abstract

Background:Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine mainly administered to newborns and used for over 100 years to prevent the disease caused by Mycobacterium tuberculosis (M. tb). This vaccine can induce immune response polarization towards a Th1 profile, which is desired for counteracting M. tb, other mycobacteria, and unrelated intracellular pathogens. The vaccine BCG has been used as a vector to express recombinant proteins and has been shown to protect against several diseases, particularly respiratory viruses. Methods: BCG was used to develop recombinant vaccines expressing either the Nucleoprotein from SARS-CoV-2 or Andes orthohantavirus. Mice were immunized with these vaccines with the aim of evaluating the safety and immunogenicity parameters. Results: Immunization with two doses of 1 × 10⁸ CFU or one dose of 1 × 10⁵ CFU of these BCGs was safe in mice. A statistically significant cellular immune response was induced by both formulations, characterized as the activation of CD4⁺ and CD8⁺ T cells. Stimulation with unrelated antigens resulted in increased expression of activation markers by T cells and secretion of IL-2 and IFN-γ, while increased secretion of IL-6 was found for both recombinant vaccines; all of these parameters related to a trained immunity profile. The humoral immune response elicited by both vaccines was modest, but further exposure to antigens could increase this response. Conclusions: The BCG vaccine is a promising platform for developing vaccines against different pathogens, inducing a marked antigen-specific immune response. Full article

(This article belongs to the Special Issue 100 Years of BCG Immunization: Past, Present and Future)

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15 pages, 3424 KiB

Open AccessArticle

Protease-Based Subunit Vaccine in Mice Boosts BCG Protection against Mycobacterium tuberculosis

by Ana Paula Junqueira-Kipnis, Carine de Castro Souza, Ana Carolina de Oliveira Carvalho, Fabio Muniz de Oliveira, Vinnycius Pereira Almeida, Alisson Rodrigues de Paula, Mara Rubia Celes and André Kipnis

Vaccines 2022, 10(2), 306; https://doi.org/10.3390/vaccines10020306 - 16 Feb 2022

Cited by 2 | Viewed by 2968

Abstract

The significant number of people with latent and active tuberculosis infection requires further efforts to develop new vaccines or improve the Bacillus Calmette-Guérin (BCG), which is the only approved vaccine against this disease. In this study, we developed a recombinant fusion protein (PEPf) containing high-density immunodominant epitope sequences from Rv0125, Rv2467, and Rv2672 Mycobacterium tuberculosis (Mtb) proteases that proved immunogenic and used it to develop a recombinant BCG vaccine expressing the fusion protein. After challenging using Mtb, a specific immune response was recalled, resulting in a reduced lung bacterial load with similar protective capabilities to BCG. Thus BCG PEPf failed to increase the protection conferred by BCG. The PEPf was combined with Advax4 adjuvant and tested as a subunit vaccine using a prime-boost strategy. PEPf + Advax4 significantly improved protection after Mtb challenge, with a reduction in bacterial load in the lungs. Our results confirm that Mtb proteases can be used to develop vaccines against tuberculosis and that the use of the recombinant PEPf subunit protein following a prime-boost regimen is a promising strategy to improve BCG immunity. Full article

(This article belongs to the Special Issue 100 Years of BCG Immunization: Past, Present and Future)

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14 pages, 1152 KiB

Open AccessArticle

Recombinant BCG Expressing the Subunit 1 of Pertussis Toxin Induces Innate Immune Memory and Confers Protection against Non-Related Pathogens

by Alex I. Kanno, Diana Boraschi, Luciana C. C. Leite and Dunia Rodriguez

Vaccines 2022, 10(2), 234; https://doi.org/10.3390/vaccines10020234 - 3 Feb 2022

Cited by 7 | Viewed by 2103

Abstract

BCG has shown the ability to induce protection against unrelated pathogens, which likely depends on an immune mechanism known as innate immune memory or trained immunity. In this study, we evaluated the induction of innate memory by a recombinant BCG strain expressing the genetically detoxified S1 subunit of the pertussis toxin (rBCG-S1PT). In vitro pre-exposure of naïve murine macrophages to rBCG-S1PT increased their innate/inflammatory response (IL-6, TNF-α, and IL-10) to a subsequent challenge with unrelated pathogens, as compared to pre-exposure to wild-type BCG. Following LPS challenge, mice immunized with rBCG-S1PT produced higher levels of IFN-γ, while the release of other inflammatory cytokines was comparable to that measured after BCG immunization. SCID mice previously immunized with rBCG-S1PT and challenged with pathogenic Candida albicans displayed a similar survival curve as BCG-immunized mice but a lower CFU burden in the kidneys, suggesting an innate memory-dependent control of C. albicans infection. This study highlights the potential of recombinant BCG to increase innate immune memory and, ultimately, non-specific protection, more effectively than wild-type BCG. To our knowledge, this is the first report describing the potential of a recombinant BCG strain to strengthen innate immune memory responses. Full article

(This article belongs to the Special Issue 100 Years of BCG Immunization: Past, Present and Future)

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8 pages, 2988 KiB

Open AccessCommunication

BCG Substrains Change Their Outermost Surface as a Function of Growth Media

by Sandra Guallar-Garrido, Farners Almiñana-Rapún, Víctor Campo-Pérez, Eduard Torrents, Marina Luquin and Esther Julián

Vaccines 2022, 10(1), 40; https://doi.org/10.3390/vaccines10010040 - 29 Dec 2021

Cited by 6 | Viewed by 2322

Abstract

Mycobacterium bovis bacillus Calmette-Guérin (BCG) efficacy as an immunotherapy tool can be influenced by the genetic background or immune status of the treated population and by the BCG substrain used. BCG comprises several substrains with genetic differences that elicit diverse phenotypic characteristics. Moreover, modifications of phenotypic characteristics can be influenced by culture conditions. However, several culture media formulations are used worldwide to produce BCG. To elucidate the influence of growth conditions on BCG characteristics, five different substrains were grown on two culture media, and the lipidic profile and physico-chemical properties were evaluated. Our results show that each BCG substrain displays a variety of lipidic profiles on the outermost surface depending on the growth conditions. These modifications lead to a breadth of hydrophobicity patterns and a different ability to reduce neutral red dye within the same BCG substrain, suggesting the influence of BCG growth conditions on the interaction between BCG cells and host cells. Full article

(This article belongs to the Special Issue 100 Years of BCG Immunization: Past, Present and Future)

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Review

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39 pages, 464 KiB

Open AccessReview

Recombinant BCG to Enhance Its Immunomodulatory Activities

by Magdalena Kowalewicz-Kulbat and Camille Locht

Vaccines 2022, 10(5), 827; https://doi.org/10.3390/vaccines10050827 - 23 May 2022

Cited by 3 | Viewed by 3254

Abstract

The bacillus Calmette–Guérin (BCG) is an attenuated Mycobacterium bovis derivative that has been widely used as a live vaccine against tuberculosis for a century. In addition to its use as a tuberculosis vaccine, BCG has also been found to have utility in the prevention or treatment of unrelated diseases, including cancer. However, the protective and therapeutic efficacy of BCG against tuberculosis and other diseases is not perfect. For three decades, it has been possible to genetically modify BCG in an attempt to improve its efficacy. Various immune-modulatory molecules have been produced in recombinant BCG strains and tested for protection against tuberculosis or treatment of several cancers or inflammatory diseases. These molecules include cytokines, bacterial toxins or toxin fragments, as well as other protein and non-protein immune-modulatory molecules. The deletion of genes responsible for the immune-suppressive properties of BCG has also been explored for their effect on BCG-induced innate and adaptive immune responses. Most studies limited their investigations to the description of T cell immune responses that were modified by the genetic modifications of BCG. Some studies also reported improved protection by recombinant BCG against tuberculosis or enhanced therapeutic efficacy against various cancer forms or allergies. However, so far, these investigations have been limited to mouse models, and the prophylactic or therapeutic potential of recombinant BCG strains has not yet been illustrated in other species, including humans, with the exception of a genetically modified BCG strain that is now in late-stage clinical development as a vaccine against tuberculosis. In this review, we provide an overview of the different molecular engineering strategies adopted over the last three decades in order to enhance the immune-modulatory potential of BCG. Full article

(This article belongs to the Special Issue 100 Years of BCG Immunization: Past, Present and Future)

12 pages, 585 KiB

Open AccessReview

Auxotrophic Mycobacterium bovis BCG: Updates and Perspectives

by Odir Antônio Dellagostin, Sibele Borsuk, Thaís Larré Oliveira and Fabiana Kömmling Seixas

Vaccines 2022, 10(5), 802; https://doi.org/10.3390/vaccines10050802 - 19 May 2022

Cited by 5 | Viewed by 2212

Abstract

Mycobacterium bovis BCG has been used for a century as the only licensed vaccine against tuberculosis. Owing to its strong adjuvant properties, BCG has also been employed as an oncological immunotherapeutic as well as a live vaccine vector against other pathogens. However, BCG vaccination has limited efficacy in protecting against adult forms of tuberculosis (TB), raises concerns about its safety in immunocompromised populations, compromises the diagnosis of TB through the tuberculin test and lacks predictability for successful antigen expression and immune responses to heterologous antigens. Together, these factors propelled the construction and evaluation of auxotrophic BCG strains. Auxotrophs of BCG have been developed from mutations in the genes required for their growth using different approaches and have shown the potential to provide a model to study M. tuberculosis, a more stable, safe, and effective alternative to BCG and a vector for the development of recombinant live vaccines, especially against HIV infection. In this review, we provide an overview of the strategies for developing and using the auxotrophic BCG strains in different scenarios. Full article

(This article belongs to the Special Issue 100 Years of BCG Immunization: Past, Present and Future)

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9 pages, 471 KiB

Open AccessReview

After 100 Years of BCG Immunization against Tuberculosis, What Is New and Still Outstanding for This Vaccine?

by Mario Alberto Flores-Valdez

Vaccines 2022, 10(1), 57; https://doi.org/10.3390/vaccines10010057 - 31 Dec 2021

Cited by 10 | Viewed by 7029

Abstract

In 2021, most of the world was reasonably still concerned about the COVID-19 pandemic, how cases were up and down in different countries, how the vaccination campaigns were ongoing, and most people were familiar with the speed with which vaccines against SARS-Co-V2 were developed, analyzed, and started to be applied in an attempt to curb the pandemic. Because of this, it may have somehow passed relatively inadvertently for people outside of the field that the vaccine used to control tuberculosis (TB), Mycobacterium bovis Bacille Calmette-Guérin (BCG), was first applied to humans a century ago. Over these years, BCG has been the vaccine applied to most human beings in the world, despite its known lack of efficacy to fully prevent respiratory TB. Several strategies have been employed in the last 20 years to produce a novel vaccine that would replace, or boost, immunity and protection elicited by BCG. In this work, to avoid potential redundancies with recently published reviews, I only aim to present my current thoughts about some of the latest findings and outstanding questions that I consider worth investigating to help develop a replacement or modified BCG in order to successfully fight TB, based on BCG itself. Full article

(This article belongs to the Special Issue 100 Years of BCG Immunization: Past, Present and Future)

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