Landscape of immunobiological properties of BCG: from vaccine vector to immunotherapy
Tiffany Thurow Bunde, Natasha Rodrigues de Oliveira, Odir Antônio Dellagostin, Thaís Larré Oliveira
Abstract
Bacille Calmette-Guérin (BCG) is an attenuated strain of Mycobacterium bovis. It is derived from 231 in vitro passages conducted at the Pasteur Institute of Lille, France. The first BCG vaccination was performed 100 years ago, and to this day, it remains the only licensed vaccine against tuberculosis (TB). Although it was developed exclusively for conferring protection against tuberculosis, BCG has also shown beneficial effects in several other therapeutic roles, including its use as an immunotherapeutic agent for superficial urothelial carcinoma and melanoma skin cancer. It has also demonstrated potential application as a vaccine vector for the delivery of heterologous antigens and immunological mediators, such as cytokines. Thus, the development of recombinant strains of BCG (rBCG) have been widely explored. Additionally, BCG has demonstrated potential application as an immunotherapeutic agent for autoimmune, allergic, and neurodegenerative diseases, which has been attributed to the induction of memory in innate immune cells (a.k.a. trained immunity). In this review, we provide an update on the immunobiological and immunological aspects involved in bacillus-host interactions in the context of BCG.
Keywords
References
Abdallah, A. M., & Behr, M. A. (2017). Evolution and strain variation in BCG. Advances in Experimental Medicine and Biology, 1019, 155-169. http://dx.doi.org/10.1007/978-3-319-64371-7_8. PMid:29116634.
Arts, R., Moorlag, S., Novakovic, B., Li, Y., Wang, S. Y., Oosting, M., Kumar, V., Xavier, R. J., Wijmenga, C., Joosten, L., Reusken, C., Benn, C. S., Aaby, P., Koopmans, M. P., Stunnenberg, H. G., van Crevel, R., & Netea, M. G. (2018). BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host & Microbe, 23(1), 89-100.e5. http://dx.doi.org/10.1016/j.chom.2017.12.010. PMid:29324233.
Benitez, M. L. R., Bender, C. B., Oliveira, T. L., Schachtschneider, K. M., Collares, T., & Seixas, F. K. (2019). Mycobacterium bovis BCG in metastatic melanoma therapy. Applied Microbiology and Biotechnology, 103(19), 7903-7916. http://dx.doi.org/10.1007/s00253-019-10057-0. PMid:31402426.
Boer, M. C., Prins, C., Van Meijgaarden, K. E., Van Dissel, J. T., Ottenhoff, T. H. M., & Joosten, S. A. (2015). Mycobacterium bovis BCG vaccination induces divergent proinflammatory or regulatory T cell responses in adults. Clinical and Vaccine Immunology; CVI, 22(7), 778-788. http://dx.doi.org/10.1128/CVI.00162-15. PMid:25947145.
Boer, M. C., Van Meijgaarden, K. E., Joosten, S. A., & Ottenhoff, T. H. M. (2014). CD8+ regulatory T cells, and not CD4+ T cells, dominate suppressive phenotype and function after in vitro live Mycobacterium bovis-BCG activation of human cells. PLoS One, 9(4), e94192. http://dx.doi.org/10.1371/journal.pone.0094192. PMid:24714620.
Bontempi, I., Leal, K., Prochetto, E., Díaz, G., Cabrera, G., Bortolotti, A., Morbidoni, H. R., Borsuk, S., Dellagostin, O., & Marcipar, I. (2020). Recombinant Mycobacterium bovis BCG is a promising platform to develop vaccines against Trypansoma cruzi infection. Clinical and Experimental Immunology, 201(3), 306-316. http://dx.doi.org/10.1111/cei.13469. PMid:32464684.
Covián, C., Fernández-Fierro, A., Retamal-Díaz, A., Díaz, F. E., Vasquez, A. E., Lay, M. K., Riedel, C. A., González, P. A., Bueno, S. M., & Kalergis, A. M. (2019). BCG-induced cross-protection and development of trained immunity: implication for vaccine design. Frontiers in Immunology, 10, 2806. http://dx.doi.org/10.3389/fimmu.2019.02806. PMid:31849980.
Darrah, P. A., Zeppa, J. J., Maiello, P., Hackney, J. A., Wadsworth 2nd, M. H., Hughes, T. K., Pokkali, S., Swanson 2nd, P. A., Grant, N. L., Rodgers, M. A., Kamath, M., Causgrove, C. M., Laddy, D. J., Bonavia, A., Casimiro, D., Lin, P. L., Klein, E., White, A. G., Scanga, C. A., Shalek, A. K., Roederer, M., Flynn, J. L., & Seder, R. A. (2020). Prevention of tuberculosis in macaques after intravenous BCG immunization. Nature, 577(7788), 95-102. http://dx.doi.org/10.1038/s41586-019-1817-8. PMid:31894150.
Dijkman, K., Sombroek, C. C., Vervenne, R. A. W., Hofman, S. O., Boot, C., Remarque, E. J., Kocken, C. H. M., Ottenhoff, T. H. M., Kondova, I., Khayum, M. A., Haanstra, K. G., Vierboom, M. P. M., & Verreck, F. A. W. (2019). Prevention of tuberculosis infection and disease by local BCG in repeatedly exposed rhesus macaques. Nature Medicine, 25(2), 255-262. http://dx.doi.org/10.1038/s41591-018-0319-9. PMid:30664782.
Divangahi, M., Aaby, P., Khader, S. A., Barreiro, L. B., Bekkering, S., Chavakis, T., van Crevel, R., Curtis, N., DiNardo, A. R., Dominguez-Andres, J., Duivenvoorden, R., Fanucchi, S., Fayad, Z., Fuchs, E., Hamon, M., Jeffrey, K. L., Khan, N., Joosten, L. A. B., Kaufmann, E., Latz, E., Matarese, G., van der Meer, J. W. M., Mhlanga, M., Moorlag, S. J. C. F. M., Mulder, W. J. M., Naik, S., Novakovic, B., O’Neill, L., Ochando, J., Ozato, K., Riksen, N. P., Sauerwein, R., Sherwood, E. R., Schlitzer, A., Schultze, J. L., Sieweke, M. H., Benn, C. S., Stunnenberg, H., Sun, J., van de Veerdonk, F. L., Weis, S., Williams, D. L., Xavier, R., & Netea, M. G. (2021). Trained immunity, tolerance, priming and differentiation: distinct immunological processes. Nature Immunology, 22(1), 2-6. http://dx.doi.org/10.1038/s41590-020-00845-6. PMid:33293712.
Dorneles, J., Madruga, A. B., Seixas Neto, A. C. P., Rizzi, C., Bettin, É. B., Hecktheuer, A. S., Castro, C. C., Fernandes, C. G., Oliveira, T. L., & Dellagostin, O. A. (2020). Protection against leptospirosis conferred by Mycobacterium bovis BCG expressing antigens from Leptospira interrogans. Vaccine, 38(51), 8136-8144. http://dx.doi.org/10.1016/j.vaccine.2020.10.086. PMid:33176938.
Fatima, S., Kumari, A., Das, G., & Dwivedi, V. P. (2020). Tuberculosis vaccine: a journey from BCG to present. Life Sciences, 252, 117594. http://dx.doi.org/10.1016/j.lfs.2020.117594. PMid:32305522.
Fletcher, H. A., Snowden, M. A., Landry, B., Rida, W., Satti, I., Harris, S. A., Matsumiya, M., Tanner, R., Oshea, M. K., Dheenadhayalan, V., Bogardus, L., Stockdale, L., Marsay, L., Chomka, A., HarringtonKandt, R., Manjaly-Thomas, Z. R., Naranbhai, V., Stylianou, E., Darboe, F., Penn-Nicholson, A., Nemes, E., Hatherill, M., Hussey, G., Mahomed, H., Tameris, M., McClain, J. B., Evans, T. G., Hanekom, W. A., Scriba, T. J., & McShane, H. (2016). T-cell activation is an immune correlate of risk in BCG vaccinated infants. Nature Communications, 7(11290), 11290. http://dx.doi.org/10.1038/ncomms11290. PMid:27068708.
Goulart, C., Rodriguez, D., Kanno, A. I., Converso, T. R., Lu, Y.-J., Malley, R., & Leite, L. C. C. (2017). A Combination of recombinant Mycobacterium bovis BCG strains expressing pneumococcal proteins induces cellular and humoral immune responses and protects against pneumococcal colonization and sepsis. Clinical and Vaccine Immunology; CVI, 24(10), e00133-e17. http://dx.doi.org/10.1128/CVI.00133-17. PMid:28768668.
Hoft, D. F., Xia, M., Zhang, G. L., Blazevic, A., Tennant, J., Kaplan, C., Matuschak, G., Dube, T. J., Hill, H., Schlesinger, L. S., Andersen, P. L., & Brusic, V. (2018). PO and ID BCG vaccination in humans induce distinct mucosal and systemic immune responses and CD4+ T cell transcriptomal molecular signatures. Mucosal Immunology, 11(2), 486-495. http://dx.doi.org/10.1038/mi.2017.67. PMid:28853442. Kaufmann, E., Sanz, J., Dunn, J. L., Khan, N., Mendonça, L. E., Pacis, A., Tzelepis, F., Pernet, E., Dumaine, A., Grenier, J. C., Mailhot-Léonard, F., Ahmed, E., Belle, J., Besla, R., Mazer, B., King, I. L., Nijnik, A., Robbins, C. S., Barreiro, L. B., & Divangahi, M. (2018). BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell, 172(1-2), 176-190.e19. http://dx.doi.org/10.1016/j.cell.2017.12.031. PMid:29328912.
Khader, S. A., Divangahi, M., Hanekom, W., Hill, P. C., Maeurer, M., Makar, K. W., Mayer-Barber, K. D., Mhlanga, M. M., Nemes, E., Schlesinger, L. S., Van Crevel, R., Vankalayapati, R., Xavier, R. J., & Netea, M. G. (2019). Targeting innate immunity for tuberculosis vaccination. The Journal of Clinical Investigation, 129(9), 3482-3491. http://dx.doi.org/10.1172/JCI128877. PMid:31478909.
Kühtreiber, W. M., & Faustman, D. L. (2019). BCG therapy for type 1 diabetes: restoration of balanced immunity and metabolism. Trends in Endocrinology and Metabolism, 30(2), 80-92. http://dx.doi.org/10.1016/j.tem.2018.11.006. PMid:30600132.
Kühtreiber, W. M., Tran, L., Kim, T., Dybala, M., Nguyen, B., Plager, S., Huang, D., Janes, S., Defusco, A., Baum, D., Zheng, H., & Faustman, D. L. (2018). Long-Term reduction in hyperglycemia in advanced type 1 diabetes: The value of induced aerobic glycolysis with BCG vaccinations. Npj Vaccines, 3(1), 23. http://dx.doi.org/10.1038/s41541-018-0062-8. PMid:29951281.
Lardone, R. D., Chan, A. A., Lee, A. F., Foshag, L. J., Faries, M. B., Sieling, P. A., & Lee, D. J. (2017). Mycobacterium bovis bacillus Calmette-Guérin alters melanoma microenvironment favoring antitumor T cell responses and improving M2 macrophage function. Frontiers in Immunology, 8, 965. http://dx.doi.org/10.3389/fimmu.2017.00965. PMid:28848560.
Larsen, E. S., Joensen, U. N., Poulsen, A. M., Goletti, D., & Johansen, I. S. (2020). Bacillus Calmette–Guérin immunotherapy for bladder cancer: A review of immunological aspects, clinical effects and BCG infections. APMIS. Acta Pathologica, Microbiologica, et Immunologica Scandinavica, 128(2), 92-103. http://dx.doi.org/10.1111/apm.13011. PMid:31755155.
Lebacle, C., Loriot, Y., & Irani, J. (2021). BCG-unresponsive high-grade non-muscle invasive bladder cancer: What does the practicing urologist need to know? World Journal of Urology. In press. http://dx.doi.org/10.1007/s00345-021-03666-w. PMid:33772322.
Lippens, C., Garnier, L., Guyonvarc’h, P. M., Santiago-Raber, M. L., & Hugues, S. (2018). Extended freeze-dried BCG instructed pDCs induce suppressive tregs and dampen EAE. Frontiers in Immunology, 9, 2777. http://dx.doi.org/10.3389/fimmu.2018.02777. PMid:30555468.
Liu, K., Sun, E., Lei, M., Li, L., Gao, J., Nian, X., & Wang, L. (2019). BCG-induced formation of neutrophil extracellular traps play an important role in bladder cancer treatment. Clinical Immunology (Orlando, Fla.), 201, 4-14. http://dx.doi.org/10.1016/j.clim.2019.02.005. PMid:30771501.
Liu, Y., Liang, S., Ding, R., Hou, Y., Deng, F., Ma, X., Song, T., & Yan, D. (2020). BCG-induced trained immunity in macrophage: reprograming of glucose metabolism. International Reviews of Immunology, 39(3), 83-96. http://dx.doi.org/10.1080/08830185.2020.1712379. PMid:31933415.
Moorlag, S. J. C. F. M., Arts, R. J. W., van Crevel, R., & Netea, M. G. (2019). Non-specific effects of BCG vaccine on viral infections. Clinical Microbiology and Infection, 25(12), 1473-1478. http://dx.doi.org/10.1016/j.cmi.2019.04.020. PMid:31055165.
Moulson, A. J., & Av-Gay, Y. (2021). BCG immunomodulation: from the ‘hygiene hypothesis’ to COVID-19. Immunobiology, 226(1), 152052. http://dx.doi.org/10.1016/j.imbio.2020.152052. PMid:33418320.
Netea, M. G., Domínguez-Andrés, J., Barreiro, L. B., Chavakis, T., Divangahi, M., Fuchs, E., Joosten, B., van der Meer, J. W. M., Mhlanga, M. M., Mulder, W. J. M., Riksen, N. P., Schlitzer, A., Schultze, J. L., Stabell Benn, C., Sun, J. C., Xavier, R. J., & Latz, E. (2020). Defining trained immunity and its role in health and disease. Nature Reviews. Immunology, 20(6), 375-388. http://dx.doi.org/10.1038/s41577-020-0285-6. PMid:32132681.
Nieuwenhuizen, N. E., & Kaufmann, S. H. E. (2018). NextGeneration Vaccines Based on Bacille Calmette-Guérin. Frontiers in Immunology, 9, 121. http://dx.doi.org/10.3389/fimmu.2018.00121. PMid:29459859.
O’Neill, L. A. J., & Netea, M. G. (2020). BCG-induced trained immunity: Can it offer protection against COVID-19? Nature Reviews. Immunology, 20(6), 335-337. http://dx.doi.org/10.1038/s41577-020-0337-y. PMid:32393823.
Oliveira, T. L., Rizzi, C., da Cunha, C. E. P., Dorneles, J., Seixas Neto, A. C. P., Amaral, M. G., Hartwig, D. D., & Dellagostin, O. A. (2019). Recombinant BCG strains expressing chimeric proteins derived from Leptospira protect hamsters against leptospirosis. Vaccine, 37(6), 776-782. http://dx.doi.org/10.1016/j.vaccine.2018.12.050. PMid:30630695.
Penkov, S., Mitroulis, I., Hajishengallis, G., & Chavakis, T. (2019). Immunometabolic crosstalk: an ancestral principle of trained immunity? Trends in Immunology, 40(1), 1-11. http://dx.doi.org/10.1016/j.it.2018.11.002. PMid:30503793.
Rakshit, S., Ahmed, A., Adiga, V., Sundararaj, B. K., Sahoo, P. N., Kenneth, J., D’Souza, G., Bonam, W., Johnson, C., Franken, K. L. M. C., Ottenhoff, T. H. M., Finak, G., Gottardo, R., Stuart, K. D., De Rosa, S. C., McElrath, M. J., & Vyakarnam, A. (2019). BCG revaccination boosts adaptive polyfunctional Th1/Th17 and innate effectors in IGRA + and IGRA-Indian adults. JCI Insight, 4(24), e130540. http://dx.doi.org/10.1172/jci.insight.130540. PMid:31743110.
Redelman-Sidi, G. (2020). Could BCG be used to protect against COVID-19? Nature Reviews. Urology, 17(6), 316-317. http://dx.doi.org/10.1038/s41585-020-0325-9. PMid:32341531.
Rosser, C. J., Tikhonenkov, S., Nix, J. W., Chan, O. T. M., Ianculescu, I., Reddy, S., & Soon-Shiong, P. (2021). Safety, tolerability, and long-term clinical outcomes of an IL-15 analogue (N-803) admixed with Bacillus Calmette-Guérin (BCG) for the treatment of bladder cancer. OncoImmunology, 10(1), 1912885. http://dx.doi.org/10.1080/2162402X.2021.1912885. PMid:33996264.
Soto, J. A. S., Gálvez, N. M., Rivera, C. A., Palavecino, C. E., Céspedes, P. F., Rey-Jurado, E., Bueno, S. M., & Kalergis, A. M. (2018). Recombinant BCG vaccines reduce pneumovirus-caused airway pathology by inducing protective humoral immunity. Frontiers in Immunology, 9(2875), 2875. http://dx.doi.org/10.3389/fimmu.2018.02875. PMid:30581437.
Sun, E., Liu, K., Lei, M., Wang, L., Nian, X., Li, L., & Gao, J. (2020). BCG induced neutrophil extracellular traps formation and its regulatory mechanism. Research Square. In press. https://doi.org/10.21203/rs.2.15638/v2.
Tanner, R., Villarreal-Ramos, B., Vordermeier, H. M., & McShane, H. (2019). The humoral immune response to BCG vaccination. Frontiers in Immunology, 10, 1317. http://dx.doi.org/10.3389/fimmu.2019.01317. PMid:31244856.
Trauer, J. M., Kawai, A., Coussens, A. K., Datta, M., Williams, B. M., Mcbryde, E. S., & Ragonnet, R. (2021). Timing of Mycobacterium tuberculosis exposure explains variation in BCG effectiveness: a systematic review and meta-analysis Tuberculosis. Thorax. In press. https://doi.org/10.1136/thoraxjnl-2020-216794.
World Health Organization – WHO. (2020). WHO-UNICEF estimates of BCG coverage. WHO Vaccine-preventable diseases: monitoring system 2020 global summary. Geneva: WHO-UNICEF. https://apps. who.int/immunization_monitoring/globalsummary/timeseries/tswucoveragebcg.html
Xu, H., Jia, Y., Li, Y., Wei, C., Wang, W., Guo, R., Jia, J., Wu, Y., Li, Z., Wei, Z., Qi, X., Li, Y., & Gao, X. (2019). IL-10 dampens the Th1 and Tc activation through modulating DC functions in BCG vaccination. Mediators of Inflammation, 2019, 8616154. http://dx.doi.org/10.1155/2019/8616154. PMid:31281230.
Zimmermann, P., & Curtis, N. (2018). The influence of BCG on vaccine responses - a systematic review. Expert review of vaccines, 17(6), 547-554. https://doi.org/10.1080/14760584.2018.1483727.
Submitted date:
06/29/2021
Reviewed date:
08/23/2021
Accepted date:
09/22/2021
Facebook
Google+
Twitter
LinkedIn
Mendeley
StumbleUpon
CiteULike
Reddit
Email