J Bacteriol Virol.  2014 Sep;44(3):236-243. 10.4167/jbv.2014.44.3.236.

Mycobacterium bovis Bacillus Calmette-Guerin (BCG) and BCG-based Vaccines Against Tuberculosis

  • 1Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. sjshin@yuhs.ac


Tuberculosis (TB) is the second leading infectious cause of mortality worldwide with about two million deaths per year. The only licensed TB vaccine, Mycobacterium bovis bacillus Calmette-Guerin (BCG) shows limited protection efficacy suggesting an improved vaccination strategy is required. Recently, several TB vaccine candidates have entered clinical trials. These vaccine candidates are live mycobacterial vaccines designed to replace BCG or subunit vaccines designed to boost immunity induced by BCG. Vaccines with different strategy such as therapeutic vaccines, which can also be used in combination with drug therapy, are in the early stages of development to resolve latent TB or reactivation from the latent state. In this review, we discuss about development of BCG and BCG-based vaccines and further studies necessary for novel TB vaccine development to sterilize tuberculosis.


Tuberculosis; Mycobacterium tuberculosis; Mycobacterium bovis bacillus Calmette-Guerin; BCG-based vaccine

MeSH Terms

Drug Therapy
Mycobacterium bovis*
Mycobacterium tuberculosis
Vaccines, Subunit
Vaccines, Subunit

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1). Song CH. Cell Death and Bacterial Infection. J Bacteriol Virol. 2013; 43:85–91.
2). Fine PE. Variation in protection by BCG: implications of and for heterologous immunity. Lancet. 1995; 346:1339–45.
3). Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV, et al. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA. 1994; 271:698–702.
4). Frick M. The tuberculosis vaccines pipeline. TAG Pipeline Report. 2013. 263–83.
5). Song JH, Shin SJ, Kim JS. Leptin: A Multifunctional Role as an Immunomodulator in Mycobacterial Lung Disease. J Bacteriol Virol. 2013; 43:1–8.
6). Jang B, Shin SJ. Peptidylarginine Deiminase and Citrullination: Potential Therapeutic Targets for Inflammatory Diseases. J Bacteriol Virol. 2013; 43:159–67.
7). Calmette A. Preventive vaccination against tuberculosis with BCG. Proc R Soc Med. 1931; 24:1481–90.
8). Lewis KN, Liao R, Guinn KM, Hickey MJ, Smith S, Behr MA, et al. Deletion of RD1 from Mycobacterium tuberculosis mimics bacille Calmette-Guérin attenuation. J Infect Dis. 2003; 187:117–23.
9). Joung SM, Ryoo S. BCG vaccine in Korea. Clin Exp Vaccine Res. 2013; 2:83–91.
10). Fine PEM, Carneiro IAM, Milstein JB, Clements CJ. “Chapter 8: Reasons for variable efficacy”. Issues relating to the use of BCG in immunization programmes. Geneva, Switzerland: World Health Organization;1999. p. 18–20.
11). Hesseling AC, Marais BJ, Gie RP, Schaaf HS, Fine PE, Godfrey-Faussett P, et al. The risk of disseminated Bacille Calmette-Guerin (BCG) disease in HIV-infected children. Vaccine. 2007; 25:14–8.
12). Grode L, Seiler P, Baumann S, Hess J, Brinkmann V, Nasser Eddine A, et al. Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guérin mutants that secrete listeriolysin. J Clin Invest. 2005; 115:2472–9.
13). Desel C, Dorhoi A, Bandermann S, Grode L, Eisele B, Kaufmann SH. Recombinant BCG ΔureC hly+ induces superior protection over parental BCG by stimulating a balanced combination of type 1 and type 17 cytokine responses. J Infect Dis. 2011; 204:1573–84.
14). Grode L, Ganoza CA, Brohm C, Weiner J 3rd, Eisele B, Kaufmann SH. Safety and immunogenicity of the recombinant BCG vaccine VPM1002 in a phase 1 open-label randomized clinical trial. Vaccine. 2013; 31:1340–8.
15). Gonzalo Asensio J, Maia C, Ferrer NL, Barilone N, Laval F, Soto C Y, et al. The virulence-associated two-component PhoP-PhoR system controls the biosynthesis of polyketide-derived lipids in Mycobacterium tuberculosis. J Biol Chem. 2006; 281:1313–6.
16). Frigui W, Bottai D, Majlessi L, Monot M, Josselin E, Brodin P, et al. Control of M. tuberculosis ESAT-6 secretion and specific T cell recognition by PhoP. PLoS Pathog. 2008; 4:e33.
17). Astarie-Dequeker C, Le Guyader L, Malaga W, Seaphanh FK, Chalut C, Lopez A, et al. Phthiocerol dimycocerosates of M. tuberculosis participate in macrophage invasion by inducing changes in the organization of plasma membrane lipids. PLoS Pathog. 2009; 5:e1000289.
18). Arbues A, Aguilo JI, Gonzalo-Asensio J, Marinova D, Uranga S, Puentes E, et al. Construction, characterization and preclinical evaluation of MTBVAC, the first live-attenuated M. tuberculosis-based vaccine to enter clinical trials. Vaccine. 2013; 31:4867–73.
19). Horwitz MA, Harth G, Dillon BJ, Maslesa-Galic S. Recombinant Bacillus Calmette-Guérin (BCG) vaccines expressing the Mycobacterium tuberculosis 30-kDa major secretory protein induce greater protective immunity against tuberculosis than conventional BCG vaccines in a highly susceptible animal model. Proc Natl Acad Sci U S A. 2000; 97:13853–8.
20). Hoft DF, Blazevic A, Abate G, Hanekom WA, Kaplan G, Soler JH, et al. A new recombinant bacille Calmette-Guérin vaccine safely induces significantly enhanced tuberculosis-specific immunity in human volunteers. J Infect Dis. 2008; 198:1491–501.
21). Kaufmann SH. Tuberculosis vaccine development: strength lies in tenacity. Trends Immunol. 2012; 33:373–9.
22). Sun R, Skeiky YA, Izzo A, Dheenadhayalan V, Imam Z, Penn E, et al. Novel recombinant BCG expressing perfringolysin O and the over-expression of key immunodominant antigens; pre-clinical characterization, safety and protection against challenge with Mycobacterium tuberculosis. Vaccine. 2009; 27:4412–23.
23). Johansen P, Fettelschoss A, Amstutz B, Selchow P, Waeckerle-Men Y, Keller P, et al. Relief from Zmp1-mediated arrest of phagosome maturation is associated with facilitated presentation and enhanced immunogenicity of mycobacterial antigens. Clin Vaccine Immunol. 2011; 18:907–13.
24). Li Z, Howard A, Kelley C, Delogu G, Collins F, Morris S. Immunogenicity of DNA vaccines expressing tuberculosis proteins fused to tissue plasminogen activator signal sequences. Infect Immun. 1999; 67:4780–6.
25). Shoen CM, DeStefano MS, Hager CC, Tham KT, Braunstein M, Allen AD, et al. A modified Bacillus Calmette-Guérin (BCG) vaccine with reduced activity of antioxidants and glutamine synthetase exhibits enhanced protection of mice despite diminished in vivo persistence. Vaccines. 2013; 1:34–57.
26). Castañon-Arreola M, López-Vidal Y, Espitia-Pinzón C, Hernández-Pando R. A new vaccine against tuberculosis shows greater protection in a mouse model with progressive pulmonary tuberculosis. Tuberculosis (Edinb). 2005; 85:115–26.
27). Sweeney KA, Dao DN, Goldberg MF, Hsu T, Venkataswamy MM, Henao-Tamayo M, et al. A recombinant Mycobacterium smegmatis induces potent bactericidal immunity against Mycobacterium tuberculosis. Nat Med. 2011; 17:1261–8.
28). Jensen K, Ranganathan UD, Van Rompay KK, Canfield DR, Khan I, Ravindran R, et al. A recombinant attenuated Mycobacterium tuberculosis vaccine strain is safe in immunosuppressed simian immunodeficiency virus-infected infant macaques. Clin Vaccine Immunol. 2012; 19:1170–81.
29). Flatz L, Hegazy AN, Bergthaler A, Verschoor A, Claus C, Fernandez M, et al. Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8+ T cell immunity. Nat Med. 2010; 16:339–45.
30). Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet. 2013; 381:1021–8.
31). Kaufmann SH, Hussey G, Lambert PH. New vaccines for tuberculosis. Lancet. 2010; 375:2110–9.
32). Von Eschen K, Morrison R, Braun M, Ofori-Anyinam O, De Kock E, Pavithran P, et al. The candidate tuberculosis vaccine Mtb72F/AS02A: Tolerability and immunogenicity in humans. Hum Vaccin. 2009; 5:475–82.
33). van Dissel JT, Arend SM, Prins C, Bang P, Tingskov PN, Lingnau K, et al. Ag85B-ESAT-6 adjuvanted with IC31 promotes strong and long-lived Mycobacterium tuberculosis specific T cell responses in naïve human volunteers. Vaccine. 2010; 28:3571–81.
34). Holten-Andersen L, Doherty TM, Korsholm KS, Andersen P. Combination of the cationic surfactant dimethyl dioctadecyl ammonium bromide and synthetic mycobacterial cord factor as an efficient adjuvant for tuberculosis subunit vaccines. Infect Immun. 2004; 72:1608–17.
35). Dietrich J, Aagaard C, Leah R, Olsen AW, Stryhn A, Doherty TM, et al. Exchanging ESAT6 with TB10.4 in an Ag85B fusion molecule-based tuberculosis subunit vaccine: efficient protection and ESAT6-based sensitive monitoring of vaccine efficacy. J Immunol. 2005; 174:6332–9.
36). Aagaard C, Hoang T, Dietrich J, Cardona PJ, Izzo A, Dolganov G, et al. A multistage tuberculosis vaccine that confers efficient protection before and after exposure. Nat Med. 2011; 17:189–94.
37). Bertholet S, Ireton GC, Ordway DJ, Windish HP, Pine SO, Kahn M, et al. A defined tuberculosis vaccine candidate boosts BCG and protects against multidrug-resistant Mycobacterium tuberculosis. Sci Transl Med. 2010; 2:53ra74.
38). Temmerman S, Pethe K, Parra M, Alonso S, Rouanet C, Pickett T, et al. Methylation-dependent T cell immunity to Mycobacterium tuberculosis heparin-binding hemagglutinin. Nat Med. 2004; 10:935–41.
39). Vilaplana C, Gil O, Cáceres N, Pinto S, Díaz J, Cardona PJ. Prophylactic effect of a therapeutic vaccine against TB based on fragments of Mycobacterium tuberculosis. PLoS One. 2011; 6:e20404.
40). Bakhru P, Sirisaengtaksin N, Soudani E, Mukherjee S, Khan A, Jagannath C. BCG vaccine mediated reduction in the MHC-II expression of macrophages and dendritic cells is reversed by activation of Toll-like receptors 7 and 9. Cell Immunol. 2014; 287:53–61.
41). Fulton SA, Reba SM, Pai RK, Pennini M, Torres M, Harding CV, et al. Inhibition of major histocompatibility complex II expression and antigen processing in murine alveolar macrophages by Mycobacterium bovis BCG and the 19-kilodalton mycobacterial lipoprotein. Infect Immun. 2004; 72:2101–10.
42). Delogu G, Manganelli R, Brennan MJ. Critical research concepts in tuberculosis vaccine development. Clin Microbiol Infect. 2014; 5:59–65.
43). Elkington PT. Tuberculosis: time for a new perspective? J Infect. 2013; 66:299–302.
44). Helke KL, Mankowski JL, Manabe YC. Animal models of cavitation in pulmonary tuberculosis. Tuberculosis (Edinb). 2006; 86:337–48.
45). Hiyama J, Marukawa M, Shiota Y, Ono T, Mashiba H. Factors influencing response to treatment of pulmonary tuberculosis. Acta Med Okayama. 2000; 54:139–45.
46). Lee JS, Lee JY, Choi HH, Son JW, Kim KH, Paik TH, et al. Elevated Levels of Interferon-inducible Protein-10 (IP)-10/CXCL10, but not of Interferon-γ, in Patients with Pulmonary Tuberculosis. J Bacteriol Virol. 2007; 37:137–46.
47). Nunes-Alves C, Booty MG, Carpenter SM, Jayaraman P, Rothchild AC, Behar SM. In search of a new paradigm for protective immunity to TB. Nat Rev Microbiol. 2014; 12:289–99.
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