title: Recombinant BCG exporting ESAT-6 confers enhanced protection against tuberculosis.
abstract: The live tuberculosis vaccines Mycobacterium bovis BCG (bacille Calmette-Guérin) and Mycobacterium microti both lack the potent, secreted T-cell antigens ESAT-6 (6-kDa early secretory antigenic target) and CFP-10 (10-kDa culture filtrate protein). This is a result of independent deletions in the region of deletion-1 (RD1) locus, which is intact in virulent members of the Mycobacterium tuberculosis complex. To increase their immunogenicity and protective capacity, we complemented both vaccines with different constructs containing the esxA and esxB genes, which encode ESAT-6 and CFP-10 respectively, as well as a variable number of flanking genes. Only reintroduction of the complete locus, comprising at least 11 genes, led to full secretion of the antigens and resulted in specific ESAT-6-dependent immune responses; this suggests that the flanking genes encode a secretory apparatus. Mice and guinea pigs vaccinated with the recombinant strain BCG::RD1-2F9 were better protected against challenge with M. tuberculosis, showing less severe pathology and reduced dissemination of the pathogen, as compared with control animals immunized with BCG alone.
authors.affiliation: Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, Paris, France.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Pym
authors.forename: Priscille
authors.initials: P
authors.lastname: Brodin
authors.forename: Laleh
authors.initials: L
authors.lastname: Majlessi
authors.forename: Roland
authors.initials: R
authors.lastname: Brosch
authors.forename: Caroline
authors.initials: C
authors.lastname: Demangel
authors.forename: Ann
authors.initials: A
authors.lastname: Williams
authors.forename: Karen E
authors.initials: KE
authors.lastname: Griffiths
authors.forename: Gilles
authors.initials: G
authors.lastname: Marchal
authors.forename: Claude
authors.initials: C
authors.lastname: Leclerc
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001500:BCG Vaccine / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping; D005260:Female; D017353:Gene Deletion; D006168:Guinea Pigs; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000235:genetics; D021381:Protein Transport; D013601:T-Lymphocytes / Q000276:immunology; D014376:Tuberculosis / Q000517:prevention & control*; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; D001426:Bacterial Proteins; C117940:CFP-10 protein, Mycobacterium tuberculosis; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D014614:Vaccines, Synthetic