Recombinant BCG exporting ESAT-6 confers enhanced protection against tuberculosis.
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.
Pym
Alexander S
AS
Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, Paris, France.
Brodin
Priscille
P
Majlessi
Laleh
L
Brosch
Roland
R
Demangel
Caroline
C
Williams
Ann
A
Griffiths
Karen E
KE
Marchal
Gilles
G
Leclerc
Claude
C
Cole
Stewart T
ST
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*
D000942:Antigens, Bacterial; D001500:BCG Vaccine; D001426:Bacterial Proteins; C117940:CFP-10 protein, Mycobacterium tuberculosis; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D014614:Vaccines, Synthetic