Nature Medicine
9, 533 - 539 (2003)
Published online: 14 April 2003; | doi:10.1038/nm859
Recombinant BCG exporting ESAT-6 confers enhanced protection against tuberculosisAlexander S. Pym1, 2, 6, Priscille Brodin1, 6, Laleh Majlessi3, 6, Roland Brosch1, Caroline Demangel1, Ann Williams4, Karen E. Griffiths4, Gilles Marchal5, Claude Leclerc3
& Stewart T. Cole11
Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, Paris, France
2
Liverpool School of Tropical Medicine, Liverpool, UK
3
Unité de Biologie des Régulations Immunitaires, INSERM E0352, Institut Pasteur, Paris, France
4
Centre for Applied Microbiology and Research, Salisbury, UK
5
Laboratoire de Référence des Mycobactéries, Institut Pasteur, Paris, France
6
A.S.P., P.B. and L.M. contributed equally to this work.
Correspondence should be addressed to Stewart T. Cole stcole@pasteur.frThe 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.
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