Thirty years of recombinant BCG: new trends for a centenary vaccine

ABSTRACT

Introduction: Global perception of the potential for Bacille Calmette-Guérin (BCG), and consequently recombinant BCG (rBCG), in a variety of prophylactic and therapeutic applications has been increasing. A century of information on BCG, and three decades of experience with rBCG, has generated solid knowledge in this field.

Area covered: Here, we review the current state of knowledge of BCG and rBCG development. Molecular tools have facilitated the expression of a variety of molecules in BCG, with the aim of improving its efficacy as a tuberculosis vaccine, generating polyvalent vaccines against other pathogens, including viruses, bacteria, and parasites, and developing immunotherapy approaches against noninvasive bladder cancer. BCG’s recently appraised heterologous effects and prospects for expanding its application to other diseases are also addressed.

Expert opinion: There are high expectations for new tuberculosis vaccines currently undergoing advanced clinical trials, which could change the prospects of the field. Systems biology could reveal effective biomarkers of protection, which would greatly support vaccine development. The development of appropriate large-scale production processes would further support implementation of new vaccines and rBCG products. The next few years should consolidate the broader applications of BCG and produce insights into improvements using the recombinant BCG technology.

KEYWORDS:

• BCG vaccine
• immunotherapy
• polyvalent vaccines
• recombinant BCG

Article highlights

•We are approaching 100 years of BCG use in humans and 30 years of research on recombinant BCG to improve its efficacy as a tuberculosis vaccine and expand its use to other diseases.

•The progress of genetic manipulation of mycobacteria has enabled the expression of foreign viral, bacterial, and parasitic pathogens—besides the tuberculosis antigens—and immunomodulatory molecules, many of which have shown improved protection in animal models.

•A large set of molecular tools are available and have led to more specific gene editing; CRISPR is a promising strategy.

•rBCG strains expressing immunomodulatory factors have been investigated with the aim of improving immunotherapy against bladder cancer and other diseases.

•Studies that show induction of innate immune memory by BCG suggest that rBCG vaccines may incorporate and expand these properties.

•The expert opinion discusses the issues that will be important to progress toward the broader application of the rBCG platform.

Declaration of interest

L M Marques-Netohas, L Moraes, M M Trentini and J L S C Silva received fellowships from FAPESP. L C C Leite has received a FAPESP grant (No. 17/24832-6). Z Piwowarska registered in the EMJMD LIVE (Erasmus+ Mundus Joint Master Degree Leading International Vaccinology Education), co-funded by the EACEA (Education, Audiovisual and Culture Executive Agency) of the European commission and received a scholarship from Sanofi Pasteur. L C C Leite has a patent on rBCG-LTAK63 as vaccine for Tuberculosis.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

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Additional information

Funding

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grant No 17/24832-6), and Fundação Butantan. Z Piwowarska was registered in the EMJMD LIVE (Erasmus+ Mundus Joint Master Degre Leading International Vaccinology Education), co-funded by the EACEA (Education Audiovisual and Culture Executive Agency) of the European commission and received scholarship from Sanofi Pasteur.