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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1019))

Abstract

BCG vaccines were derived by in vitro passage, during the years 1908–1921, at the Pasteur Institute of Lille. Following the distribution of stocks of BCG to vaccine production laboratories around the world, it was only a few decades before different BCG producers recognized that there were variants of BCG, likely due to different passaging conditions in the different laboratories. This ultimately led to the lyophilization of stable BCG products in the 1950s and 1960s, but not before considerable evolution of the different BCG strains had taken place. The application of contemporary research methodologies has now revealed genomic, transcriptomic and proteomic differences between BCG strains. These molecular differences in part account for phenotypic differences in vitro between BCG strains, such as their variable secretion of antigenic proteins. Yet, the relevance of BCG variability for immunization policy remains elusive. In this chapter we present an overview of what is known about BCG evolution and its resulting strain variability, and provide some speculation as to the potential relevance for a vaccine given to over 100 million newborns each year.

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References

  • Abdallah AM, Gey Van pittius NC, Champion PA, Cox J, Luirink J, Vandenbroucke-Grauls CM, Appelmelk BJ, Bitter W (2007) Type VII secretion – mycobacteria show the way. Nat Rev Microbiol 5:883–891

    Article  CAS  PubMed  Google Scholar 

  • Abdallah AM, Savage ND, Van zon M, Wilson L, Vandenbroucke-Grauls CM, Van Der Wel NN, Ottenhoff TH, Bitter W (2008) The ESX-5 secretion system of Mycobacterium marinum modulates the macrophage response. J Immunol 181:7166–7175

    Article  CAS  PubMed  Google Scholar 

  • Abdallah AM, Hill-Cawthorne GA, Otto TD, Coll F, Guerra-Assuncao JA, Gao G, Naeem R, Ansari H, Malas TB, ADROUB SA, Verboom T, Ummels R, Zhang H, Panigrahi AK, Mcnerney R, Brosch R, Clark TG, Behr MA, Bitter W, Pain A (2015) Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations. Sci Rep 5: 15443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alexander DC, Behr MA (2007) Rv1773 is a transcriptional repressor deleted from BCG-Pasteur. Tuberculosis (Edinb) 87:421–425

    Article  CAS  Google Scholar 

  • Arend SM, Van Soolingen D (2011) Editor’s choice: editorial commentary: low level INH-resistant BCG: a sheep in wolf’s clothing? Clin Infect Dis 52:89–93

    Article  PubMed  Google Scholar 

  • Aronson JD, Aronson CF, Taylor HC (1958) A twenty-year appraisal of BCG vaccination in the control of tuberculosis. AMA Arch Intern Med 101:881–893

    Article  CAS  PubMed  Google Scholar 

  • Ates LS, Ummels R, Commandeur S, Van de Weerd R, Sparrius M, Weerdenburg E, Alber M, Kalscheuer R, Piersma SR, Abdallah AM, Abd el Ghany M, Abdel-Haleem AM, Pain A, Jimenez CR, Bitter W, Houben EN (2015) Essential role of the ESX-5 secretion system in outer membrane permeability of pathogenic mycobacteria. PLoS Genet 11:e1005190

    Article  PubMed  PubMed Central  Google Scholar 

  • Azad AK, Sirakova TD, Fernandes ND, Kolattukudy PE (1997) Gene knockout reveals a novel gene cluster for the synthesis of a class of cell wall lipids unique to pathogenic mycobacteria. J Biol Chem 272:16741–16745

    Article  CAS  PubMed  Google Scholar 

  • Bai G, Gazdik MA, Schaak DD, Mcdonough KA (2007) The Mycobacterium bovis BCG cyclic AMP receptor-like protein is a functional DNA binding protein in vitro and in vivo, but its activity differs from that of its M. tuberculosis ortholog, Rv3676. Infect Immun 75:5509–5517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Behr MA (2002) BCG – different strains, different vaccines? Lancet Infect Dis 2:86–92

    Article  PubMed  Google Scholar 

  • Behr MA, Sherman DR (2007) Mycobacterial virulence and specialized secretion: same story, different ending. Nat Med 13:286–287

    Article  CAS  PubMed  Google Scholar 

  • Behr MA, Small PM (1999) A historical and molecular phylogeny of BCG strains. Vaccine 17:915–922

    Article  CAS  PubMed  Google Scholar 

  • Behr MA, Wilson MA, Gill WP, Salamon H, Schoolnik GK, Rane S, Small PM (1999) Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science 284:1520–1523

    Article  CAS  PubMed  Google Scholar 

  • Behr MA, Schroeder BG, Brinkman JN, Slayden RA, Barry CE 3rd (2000) A point mutation in the mma3 gene is responsible for impaired methoxymycolic acid production in Mycobacterium bovis BCG strains obtained after 1927. J Bacteriol 182:3394–3399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Belley A, Alexander D, Di Pietrantonio T, Girard M, Jones J, Schurr E, Liu J, Sherman DR, Behr MA (2004) Impact of methoxymycolic acid production by Mycobacterium bovis BCG vaccines. Infect Immun 72:2803–2809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brewer TF (2000) Preventing tuberculosis with Bacillus Calmette-Guerin vaccine: a meta-analysis of the literature. Clin Infect Dis 31(Suppl 3):S64–S67

    Google Scholar 

  • Brosch R, Gordon SV, Buchrieser C, Pym AS, Garnier T, Cole ST (2000) Comparative genomics uncovers large tandem chromosomal duplications in Mycobacterium bovis BCG Pasteur. Yeast 17:111–123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brosch R, Gordon SV, Garnier T, Eiglmeier K, Frigui W, VALENTI P, Dos Santos S, Duthoy S, Lacroix C, Garcia-Pelayo C, Inwald JK, Golby P, Garcia JN, Hewinson RG, Behr MA, Quail MA, Churcher C, Barrell BG, Parkhill J, Cole ST (2007) Genome plasticity of BCG and impact on vaccine efficacy. Proc Natl Acad Sci U S A 104:5596–5601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bryder L (1999) ‘We shall not find salvation in inoculation’: BCG vaccination in Scandinavia, Britain and the USA, 1921–1960. Soc Sci Med 49:1157–1167

    Article  CAS  PubMed  Google Scholar 

  • Calmette A (1922) L’ninfection bacillaire et la tuberculose chez l’homme et chez les animaux

    Google Scholar 

  • Calmette A, Guerin C, Weill-Halle B (1924) Essai d’immunisation contre l’infection tuberculeuse. Bull Acad Med Paris 91:787–796

    Google Scholar 

  • Charlet D, Mostowy S, Alexander D, Sit L, Wiker HG, Behr MA (2005) Reduced expression of antigenic proteins MPB70 and MPB83 in Mycobacterium bovis BCG strains due to a start codon mutation in sigK. Mol Microbiol 56:1302–1313

    Article  CAS  PubMed  Google Scholar 

  • Chen JM, Islam ST, Ren H, Liu J (2007) Differential productions of lipid virulence factors among BCG vaccine strains and implications on BCG safety. Vaccine 25:8114–8122

    Article  CAS  PubMed  Google Scholar 

  • Chen JM, Uplekar S, Gordon SV, Cole ST (2012) A point mutation in cycA partially contributes to the D-cycloserine resistance trait of Mycobacterium bovis BCG vaccine strains. PLoS One 7:e43467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Colditz GA, Berkey CS, Mosteller F, Brewer TF, Wilson ME, Burdick E, Fineberg HV (1995) The efficacy of bacillus Calmette-Guerin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature. Pediatrics 96:29–35

    CAS  PubMed  Google Scholar 

  • Corbel MJ, Fruth U, Griffiths E, Knezevic I (2004) Report on a WHO consultation on the characterisation of BCG strains, Imperial College, London 15–16 December 2003. Vaccine 22:2675–2680

    Article  CAS  PubMed  Google Scholar 

  • Dreyer G, Vollum RL (1931) Mutation and pathogenicity experiments with BC G. Lancet 1:9–15

    Article  Google Scholar 

  • Dubos RJ, Pierce CH (1956) Differential characteristics in vitro and in vivo of several substrains of BCG. IV. Immunizing effectiveness. Am Rev Tuberc 74:699–717

    CAS  PubMed  Google Scholar 

  • Fernandes ND, Wu QL, Kong D, Puyang X, Garg S, Husson RN (1999) A mycobacterial extracytoplasmic sigma factor involved in survival following heat shock and oxidative stress. J Bacteriol 181:4266–4274

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fine PE (1995) Variation in protection by BCG: implications of and for heterologous immunity. Lancet 346:1339–1345

    Article  CAS  PubMed  Google Scholar 

  • Frothingham R, Hills HG, Wilson KH (1994) Extensive DNA sequence conservation throughout the Mycobacterium tuberculosis complex. J Clin Microbiol 32:1639–1643

    CAS  PubMed  PubMed Central  Google Scholar 

  • Garnier T, Eiglmeier K, Camus JC, Medina N, Mansoor H, Pryor M, Duthoy S, Grondin S, Lacroix C, Monsempe C, Simon S, Harris B, Atkin R, Doggett J, Mayes R, Keating L, Wheeler PR, Parkhill J, Barrell BG, Cole ST, Gordon SV, Hewinson RG (2003) The complete genome sequence of Mycobacterium bovis. Proc Natl Acad Sci U S A 100:7877–7882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gheorghiu M, Augier J, Lagrange PH (1983) Maintenance and control of the French Bcg strain 1173-P2 (primary and secondary seed-lots). Bull Inst Pasteur 81: 281–288

    Google Scholar 

  • Gordon SV, Brosch R, Billault A, Garnier T, Eiglmeier K, Cole ST (1999) Identification of variable regions in the genomes of tubercle bacilli using bacterial artificial chromosome arrays. Mol Microbiol 32:643–655

    Article  CAS  PubMed  Google Scholar 

  • Grange JM, Gibson J, Osborn TW, Collins CH, Yates MD (1983) What is BCG? Tubercle 64:129–139

    Article  CAS  PubMed  Google Scholar 

  • Griffin JF, Chinn DN, Rodgers CR, Mackintosh CG (2001) Optimal models to evaluate the protective efficacy of tuberculosis vaccines. Tuberculosis (Edinb) 81:133–139

    Article  CAS  Google Scholar 

  • Guinn KM, Hickey MJ, Mathur SK, Zakel KL, Grotzke JE, Lewinsohn DM, Smith S, Sherman DR (2004) Individual RD1-region genes are required for export of ESAT-6/CFP-10 and for virulence of Mycobacterium tuberculosis. Mol Microbiol 51:359–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta S, Sinha A, Sarkar D (2006) Transcriptional autoregulation by Mycobacterium tuberculosis PhoP involves recognition of novel direct repeat sequences in the regulatory region of the promoter. FEBS Lett 580:5328–5338

    Article  CAS  PubMed  Google Scholar 

  • Hsu T, Hingley-Wilson SM, Chen B, Chen M, Dai AZ, Morin PM, Marks CB, Padiyar J, Goulding C, Gingery M, Eisenberg D, Russell RG, Derrick SC, Collins FM, Morris SL, King CH, Jacobs WR Jr (2003) The primary mechanism of attenuation of bacillus Calmette-Guerin is a loss of secreted lytic function required for invasion of lung interstitial tissue. Proc Natl Acad Sci U S A 100:12420–12425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huard RC, Fabre M, De Haas P, Lazzarini LCO, Van Soolingen D, Cousins D, Ho JL (2006) Novel genetic polymorphisms that further delineate the phylogeny of the Mycobacterium tuberculosis complex. J Bacteriol 188:4271–4287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hunt DM, Saldanha JW, Brennan JF, Benjamin P, Strom M, Cole JA, Spreadbury CL, Buxton RS (2008) Single nucleotide polymorphisms that cause structural changes in the cyclic AMP receptor protein transcriptional regulator of the tuberculosis vaccine strain Mycobacterium bovis BCG alter global gene expression without attenuating growth. Infect Immun 76:2227–2234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imaeda T, Coppola KM, Furness G (1985) Deoxyribonucleic acids of Corynebacterium genitalium and Corynebacterium pseudogenitalium: their genome molecular weights, base ratios, and DNA relatedness with other corynebacteria involved in urinary tract infections. Can J Microbiol 31:1068–1070

    Article  CAS  PubMed  Google Scholar 

  • Kaufmann SHE, Winau F (2005) From bacteriology to immunology: the dualism of specificity. Nat Immunol 6:1063–1066

    Article  CAS  PubMed  Google Scholar 

  • Kaufmann SHE, Hussey G, Lambert PH (2010) New vaccines for tuberculosis. Lancet 375:2110–2119

    Article  PubMed  Google Scholar 

  • Keating LA, Wheeler PR, Mansoor H, Inwald JK, Dale J, Hewinson RG, Gordon SV (2005) The pyruvate requirement of some members of the Mycobacterium tuberculosis complex is due to an inactive pyruvate kinase: implications for in vivo growth. Mol Microbiol 56:163–174

    Article  CAS  PubMed  Google Scholar 

  • Keller PM, Bottger EC, Sander P (2008) Tuberculosis vaccine strain Mycobacterium bovis BCG Russia is a natural recA mutant. BMC Microbiol 8:120

    Article  PubMed  PubMed Central  Google Scholar 

  • Kolibab K, Derrick SC, Morris SL (2011) Sensitivity to isoniazid of Mycobacterium bovis BCG strains and BCG disseminated disease isolates. J Clin Microbiol 49:2380–2381

    Article  PubMed  PubMed Central  Google Scholar 

  • Kozak R, Behr MA (2011) Divergence of immunologic and protective responses of different BCG strains in a murine model. Vaccine 29:1519–1526

    Article  CAS  PubMed  Google Scholar 

  • Kozak RA, Alexander DC, Liao R, Sherman DR, Behr MA (2011) Region of difference 2 contributes to virulence of Mycobacterium tuberculosis. Infect Immun 79:59–66

    Article  CAS  PubMed  Google Scholar 

  • Ladefoged A, Bunch-Christensen K, Guld J (1976) Tuberculin sensitivity in guinea-pigs after vaccination with varying doses of BCG of 12 different strains. Bull World Health Organ 53:435–443

    CAS  PubMed  PubMed Central  Google Scholar 

  • Leung AS, Tran V, Wu Z, Yu X, Alexander DC, Gao GF, Zhu B, Liu J (2008) Novel genome polymorphisms in BCG vaccine strains and impact on efficacy. BMC Genomics 9:413

    Article  PubMed  PubMed Central  Google Scholar 

  • Lewis KN, Liao R, Guinn KM, Hickey MJ, Smith S, Behr MA, Sherman DR (2003) Deletion of RD1 from Mycobacterium tuberculosis mimics bacille Calmette-Guerin attenuation. J Infect Dis 187:117–123

    Article  PubMed  Google Scholar 

  • Lind A (1983) The Swedish strain of Bcg. Tubercle 64:233–234

    Article  Google Scholar 

  • Liu J, Tran V, Leung AS, Alexander DC, Zhu B (2009) BCG vaccines: their mechanisms of attenuation and impact on safety and protective efficacy. Hum Vaccin 5:70–78

    Article  CAS  PubMed  Google Scholar 

  • Lotte A, Wasz-Hockert O, Poisson N, Dumitrescu N, Verron M, Couvet E (1984) BCG complications. Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv Tuberc Res 21:107–193

    CAS  PubMed  Google Scholar 

  • Mahairas GG, Sabo PJ, Hickey MJ, Singh DC, Stover CK (1996) Molecular analysis of genetic differences between Mycobacterium bovis BCG and virulent M-bovis. J Bacteriol 178:1274–1282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsunaga I, Bhatt A, Young DC, Cheng TY, Eyles SJ, Besra GS, Briken V, Porcelli SA, Costello CE, Jacobs WR Jr, Moody DB (2004) Mycobacterium tuberculosis pks12 produces a novel polyketide presented by CD1c to T cells. J Exp Med 200:1559–1569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mcshane H (2011) Tuberculosis vaccines: beyond bacille Calmette-Guerin. Philos Trans R Soc Lond Ser B Biol Sci 366:2782–2789

    Article  CAS  Google Scholar 

  • Milstien JB, Gibson JJ (1990) Quality control of BCG vaccine by WHO: a review of factors that may influence vaccine effectiveness and safety. Bull World Health Organ 68:93–108

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mostowy S, Tsolaki AG, Small PM, Behr MA (2003) The in vitro evolution of BCG vaccines. Vaccine 21:4270–4274

    Article  CAS  PubMed  Google Scholar 

  • Munoz ME, Ponce E (2003) Pyruvate kinase: current status of regulatory and functional properties. Comp Biochem Physiol B Biochem Mol Biol 135:197–218

    Article  PubMed  Google Scholar 

  • Naka T, Maeda S, Niki M, Ohara N, Yamamoto S, Yano I, Maeyama J, Ogura H, Kobayashi K, Fujiwara N (2011) Lipid phenotype of two distinct subpopulations of Mycobacterium bovis Bacillus Calmette-Guerin Tokyo 172 substrain. J Biol Chem 286:44153–44161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Obayashi Y (1955) Dried BCG vaccine. Monogr Ser World Health Organ, 1–220

    Google Scholar 

  • Oettinger T, Jorgensen M, Ladefoged A, Haslov K, Andersen P (1999) Development of the Mycobacterium bovis BCG vaccine: review of the historical and biochemical evidence for a genealogical tree. Tuber Lung Dis 79:243–250

    Article  CAS  PubMed  Google Scholar 

  • Ottenhoff TH (2009) Overcoming the global crisis: “yes, we can”, but also for TB ... ? Eur J Immunol 39:2014–2020

    Article  CAS  PubMed  Google Scholar 

  • Ottenhoff THM, Kaufmann SHE (2012) Vaccines against tuberculosis: where are we and where do we need to go? PLoS Pathog 8

    Google Scholar 

  • Parish T, Smith DA, Kendall S, Casali N, Bancroft GJ, Stoker NG (2003) Deletion of two-component regulatory systems increases the virulence of Mycobacterium tuberculosis. Infect Immun 71:1134–1140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pelayo MCG, Uplekar S, Keniry A, Lopez PM, Garnier T, Garcia JN, Boschiroli L, Zhou XM, Parkhill J, Smith N, Hewinson RG, Cole ST, Gordon SV (2009) A comprehensive survey of single nucleotide polymorphisms (SNPs) across Mycobacterium bovis strains and M. bovis BCG vaccine strains refines the genealogy and defines a minimal set of SNPs that separate virulent M. bovis strains and M. bovis BCG strains. Infect Immun 77:2230–2238

    Article  CAS  Google Scholar 

  • Pym AS, Brodin P, Majlessi L, Brosch R, Demangel C, Williams A, Griffiths KE, Marchal G, Leclerc C, Cole ST (2003) Recombinant BCG exporting ESAT-6 confers enhanced protection against tuberculosis. Nat Med 9:533–539

    Article  CAS  PubMed  Google Scholar 

  • Rosenthal SR, Loewinsohne, Graham ML, Liveright D, Thorne G, Johnson V (1961) BCG vaccination against tuberculosis in Chicago. A twenty-year study statistically analyzed. Pediatrics 28:622–641

    CAS  PubMed  Google Scholar 

  • Sakula A (1983) BCG: who were Calmette and Guerin? Thorax 38:806–812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salamon H, Kato-Maeda M, Small PM, Drenkow J, Gingeras TR (2000) Detection of deleted genomic DNA using a semiautomated computational analysis of GeneChip data. Genome Res 10:2044–2054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sherman DR, Guinn KM, Hickey MJ, Mathur SK, Zakel KL, Smith S (2004) Mycobacterium tuberculosis H37Rv: Delta RD1 is more virulent than M. bovis bacille Calmette-Guerin in long-term murine infection. J Infect Dis 190:123–126

    Article  PubMed  PubMed Central  Google Scholar 

  • Singh A, Crossman DK, Mai D, Guidry L, Voskuil MI, Renfrow MB, Steyn AJ (2009) Mycobacterium tuberculosis WhiB3 maintains redox homeostasis by regulating virulence lipid anabolism to modulate macrophage response. PLoS Pathog 5:e1000545

    Article  PubMed  PubMed Central  Google Scholar 

  • Sinha A, Gupta S, Bhutani S, Pathak A, Sarkar D (2008) PhoP-PhoP interaction at adjacent PhoP binding sites is influenced by protein phosphorylation. J Bacteriol 190:1317–1328

    Article  CAS  PubMed  Google Scholar 

  • Stanley SA, Raghavan S, Hwang WW, Cox JS (2003) Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system. Proc Natl Acad Sci U S A 100:13001–13006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stewart GR, Snewin VA, Walzl G, Hussell T, Tormay P, O’Gaora P, Goyal M, Betts J, Brown IN, Young DB (2001) Overexpression of heat-shock proteins reduces survival of Mycobacterium tuberculosis in the chronic phase of infection. Nat Med 7:732–737

    Article  CAS  PubMed  Google Scholar 

  • Stewart GR, Wernisch L, Stabler R, Mangan JA, Hinds J, Laing KG, Young DB, Butcher PD (2002) Dissection of the heat-shock response in Mycobacterium tuberculosis using mutants and microarrays. Microbiology 148:3129–3138

    Article  CAS  PubMed  Google Scholar 

  • Steyn AJ, Collins DM, Hondalus MK, Jacobs WR Jr, Kawakami RP, Bloom BR (2002) Mycobacterium tuberculosis WhiB3 interacts with RpoV to affect host survival but is dispensable for in vivo growth. Proc Natl Acad Sci U S A 99:3147–3152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takayama K, Wang L, David HL (1972) Effect of isoniazid on the in vivo mycolic acid synthesis, cell growth, and viability of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2:29–35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tran V, Ahn SK, Ng M, Li M, Liu J (2016) Loss of lipid virulence factors reduces the efficacy of the BCG vaccine. Sci Rep 6:29076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trunz BB, Fine P, Dye C (2006) Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet 367:1173–1180

    Article  PubMed  Google Scholar 

  • Vallishayee RS, Shashidhara AN, Bunch-Christensen K, Guld J (1974) Tuberculin sensitivity and skin lesions in children after vaccination with 11 different BCG strains. Bull World Health Organ 51:489–494

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wallgren A (1928) Intradermal vaccinations with BCG virus – preliminary note. J Am Med Assoc 91:1876–1881

    Article  Google Scholar 

  • Walters SB, Dubnau E, Kolesnikova I, Laval F, Daffe M, Smith I (2006) The Mycobacterium tuberculosis PhoPR two-component system regulates genes essential for virulence and complex lipid biosynthesis. Mol Microbiol 60:312–330

    Article  CAS  PubMed  Google Scholar 

  • Wang S, Engohang-Ndong J, Smith I (2007) Structure of the DNA-binding domain of the response regulator PhoP from Mycobacterium tuberculosis. Biochemistry 46:14751–14761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wernisch L, Kendall SL, Soneji S, Wietzorrek A, Parish T, Hinds J, Butcher PD, Stoker NG (2003) Analysis of whole-genome microarray replicates using mixed models. Bioinformatics 19:53–61

    Article  CAS  PubMed  Google Scholar 

  • Wiker HG, Nagai S, Hewinson RG, Russell WP, Harboe M (1996) Heterogenous expression of the related MPB70 and MPB83 proteins distinguish various substrains of Mycobacterium bovis BCG and Mycobacterium tuberculosis H37Rv. Scand J Immunol 43:374–380

    Article  CAS  PubMed  Google Scholar 

  • Zwaig N, Kistler WS, Lin EC (1970) Glycerol kinase, the pacemaker for the dissimilation of glycerol in Escherichia coli. J Bacteriol 102:753–759

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zwerling A, Behr MA, Verma A, Brewer TF, Menzies D, Pai M (2011) The BCG world atlas: a database of global BCG vaccination policies and practices. PLoS Med 8:e1001012

    Article  PubMed  PubMed Central  Google Scholar 

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Abdallah, A.M., Behr, M.A. (2017). Evolution and Strain Variation in BCG. In: Gagneux, S. (eds) Strain Variation in the Mycobacterium tuberculosis Complex: Its Role in Biology, Epidemiology and Control. Advances in Experimental Medicine and Biology, vol 1019. Springer, Cham. https://doi.org/10.1007/978-3-319-64371-7_8

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