title: Genome sequencing and analysis of BCG vaccine strains.
abstract: BACKGROUND
  Although the Bacillus Calmette-Guérin (BCG) vaccine against tuberculosis (TB) has been available for more than 75 years, one third of the world's population is still infected with Mycobacterium tuberculosis and approximately 2 million people die of TB every year. To reduce this immense TB burden, a clearer understanding of the functional genes underlying the action of BCG and the development of new vaccines are urgently needed.
  
  
  RESULTS
  Comparative genomic analysis of 19 M. tuberculosis complex strains showed that BCG strains underwent repeated human manipulation, had higher region of deletion rates than those of natural M. tuberculosis strains, and lost several essential components such as T-cell epitopes. A total of 188 BCG strain T-cell epitopes were lost to various degrees. The non-virulent BCG Tokyo strain, which has the largest number of T-cell epitopes (359), lost 124. Here we propose that BCG strain protection variability results from different epitopes. This study is the first to present BCG as a model organism for genetics research. BCG strains have a very well-documented history and now detailed genome information. Genome comparison revealed the selection process of BCG strains under human manipulation (1908-1966).
  
  
  CONCLUSIONS
  Our results revealed the cause of BCG vaccine strain protection variability at the genome level and supported the hypothesis that the restoration of lost BCG Tokyo epitopes is a useful future vaccine development strategy. Furthermore, these detailed BCG vaccine genome investigation results will be useful in microbial genetics, microbial engineering and other research fields.
authors: National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention/State Key Laboratory for Infectious Disease Prevention and Control, Beijing, China ; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
authors: Wen
authors: W
authors: Zhang
authors: Yuanyuan
authors: Y
authors: Zhang
authors: Huajun
authors: H
authors: Zheng
authors: Yuanlong
authors: Y
authors: Pan
authors: Haican
authors: H
authors: Liu
authors: Pengcheng
authors: P
authors: Du
authors: Li
authors: L
authors: Wan
authors: Jun
authors: J
authors: Liu
authors: Baoli
authors: B
authors: Zhu
authors: Guoping
authors: G
authors: Zhao
authors: Chen
authors: C
authors: Chen
authors: Kanglin
authors: K
authors: Wan
mesh_terms: D000595:Amino Acid Sequence; D000940:Antigenic Variation; D001500:BCG Vaccine / Q000145:classification / Q000235:genetics* / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D016680:Genome, Bacterial; D006801:Humans; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000235:genetics* / Q000276:immunology; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*
chemical_list: D001500:BCG Vaccine; D018984:Epitopes, T-Lymphocyte
references: Lancet. 2008 Jul 12;372(9633):164-175
references: 18620952
references: J Gen Microbiol. 1977 Jun;100(2):373-9
references: 302322
references: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7877-82
references: 12788972
references: Ann Dermatol Venereol. 2008 Aug-Sep;135(8-9):587-90
references: 18789295
references: Am J Respir Crit Care Med. 2012 Jan 15;185(2):213-22
references: 22071384
references: Science. 1999 May 28;284(5419):1520-3
references: 10348738
references: Scand J Immunol. 1997 May;45(5):499-503
references: 9160093
references: Mol Biol Evol. 2007 Aug;24(8):1596-9
references: 17488738
references: Nat Genet. 2007 Jan;39(1):120-5
references: 17159978
references: Nat Genet. 2010 Jun;42(6):498-503
references: 20495566
references: Vaccine. 2009 Mar 10;27(11):1710-6
references: 19200449
references: Science. 2000 Apr 14;288(5464):339-44
references: 10764648
references: J Bacteriol. 2011 Jun;193(12):3152-3
references: 21478353
references: JAMA. 1994 Mar 2;271(9):698-702
references: 8309034
references: Infect Immun. 2004 Oct;72(10):5955-62
references: 15385499
references: Nature. 2009 Apr 2;458(7238):641-5
references: 19242411
references: Microbiology (Reading). 2002 Oct;148(Pt 10):2967-2973
references: 12368430
references: Hum Vaccin. 2009 Feb;5(2):70-8
references: 19164935
references: BMC Microbiol. 2008 Jul 17;8:120
references: 18637199
references: Bioinformatics. 2004 Jun 12;20(9):1453-4
references: 14871861
references: Gigascience. 2012 Dec 27;1(1):18
references: 23587118
references: BMC Genomics. 2011 Oct 08;12:493
references: 21981907
references: Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5596-601
references: 17372194
references: Nat Med. 2003 May;9(5):533-9
references: 12692540
references: J Investig Allergol Clin Immunol. 2009;19(6):494-6
references: 20128425
references: J Bacteriol. 2002 Oct;184(19):5479-90
references: 12218036
references: BMC Genomics. 2008 Sep 15;9:413
references: 18793412
references: Bioinformatics. 2009 Aug 1;25(15):1966-7
references: 19497933
references: PLoS One. 2008 Jun 11;3(6):e2375
references: 18584054
references: Nucleic Acids Res. 2003 Jul 1;31(13):3497-500
references: 12824352
references: J Infect Dis. 2006 Feb 15;193(4):531-6
references: 16425132
references: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3684-9
references: 11891304
references: Nature. 1998 Jun 11;393(6685):537-44
references: 9634230
references: Nature. 1997 Sep 11;389(6647):133-4
references: 9296487
references: Genome Res. 2002 Apr;12(4):656-64
references: 11932250
references: Lancet. 1995 Nov 18;346(8986):1339-45
references: 7475776