Genome plasticity of BCG and impact on vaccine efficacy

Roland Brosch, Stephen V. Gordon, Thierry Garnier, Karin Eiglmeier, Wafa Frigui, Philippe Valenti, Sandrine Dos Santos, Stéphanie Duthoy, Céline Lacroix, Carmen Garcia-Pelayo, Jacqueline K. Inwald, Paul Golby, Javier Nuñez Garcia, R. Glyn Hewinson, Marcel A. Behr, Michael A. Quail, Carol Churcher, Bart G. Barrell, Julian Parkhill, Stewart T. Cole*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

447 Citations (SciVal)

Abstract

To understand the evolution, attenuation, and variable protective efficacy of bacillus Calmette-Guérin (BCG) vaccines, Mycobacterium bovis BCG Pasteur 1173P2 has been subjected to comparative genome and transcriptome analysis. The 4,374,522-bp genome contains 3,954 protein-coding genes, 58 of which are present in two copies as a result of two independent tandem duplications, DU1 and DU2. DU1 is restricted to BCG Pasteur, although four forms of DU2 exist; DU2-I is confined to early BCG vaccines, like BCG Japan, whereas DU2-III and DU2-IV occur in the late vaccines. The glycerol-3-phosphate dehydrogenase gene, glpD2, is one of only three genes common to all four DU2 variants, implying that BCG requires higher levels of this enzyme to grow on glycerol. Further amplification of the DU2 region is ongoing, even within vaccine preparations used to immunize humans. An evolutionary scheme for BCG vaccines was established by analyzing DU2 and other markers. Lesions in genes encoding σ-factors and pleiotropic transcriptional regulators, like PhoR and Crp, were also uncovered in various BCG strains; together with gene amplification, these affect gene expression levels, immunogenicity, and, possibly, protection against tuberculosis. Furthermore, the combined findings suggest that early BCG vaccines may even be superior to the later ones that are more widely used.

Original languageEnglish
Pages (from-to)5596-5601
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number13
Early online date19 Mar 2007
DOIs
Publication statusPublished - 27 Mar 2007

Keywords

  • Glycerol metabolism
  • Live vaccines
  • Tandem duplications
  • Tuberculosis

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