title: Persistence and protective efficacy of a Mycobacterium tuberculosis auxotroph vaccine.
abstract: New vaccines against tuberculosis are urgently required because of the impressive incidence of this disease worldwide and the highly variable protective efficacy of the current vaccine. The possibility of creating new live vaccines by the rational attenuation of strains from the Mycobacterium tuberculosis complex was investigated. Two auxotrophic mutants of M. tuberculosis and M. bovis BCG were constructed by disruption of one of their purine biosynthetic genes. These mutants appeared unable to multiply in vitro within mouse bone-marrow derived macrophages. They were also attenuated in vivo in the mouse and guinea pig animal models. In guinea pigs, the two mutants induced strong delayed-type hypersensitivity response to purified protein derivative. In a preliminary experiment, the two mutants were compared to the BCG vaccine for their protective efficacy in a challenge against aerosolized virulent M. tuberculosis in the guinea pig model. Both mutants conferred some level of protection. These experiments demonstrate that the rational attenuation of M. tuberculosis could lead to the design of new candidate live vaccines against tuberculosis.
authors.affiliation: Unité de Génétique Mycobactérienne, Institut Pasteur, 75724 Paris Cedex, France. mjackson@pasteur.fr
authors.forename: M
authors.initials: M
authors.lastname: Jackson
authors.forename: S W
authors.initials: SW
authors.lastname: Phalen
authors.forename: M
authors.initials: M
authors.lastname: Lagranderie
authors.forename: D
authors.initials: D
authors.lastname: Ensergueix
authors.forename: P
authors.initials: P
authors.lastname: Chavarot
authors.forename: G
authors.initials: G
authors.lastname: Marchal
authors.forename: D N
authors.initials: DN
authors.lastname: McMurray
authors.forename: B
authors.initials: B
authors.lastname: Gicquel
authors.forename: C
authors.initials: C
authors.lastname: Guilhot
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D006968:Hypersensitivity, Delayed / Q000276:immunology; D008264:Macrophages / Q000382:microbiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D009163:Mycobacterium bovis / Q000235:genetics / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D010453:Peptide Synthases; D011687:Purines; D014376:Tuberculosis / Q000382:microbiology / Q000517:prevention & control*; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology*
chemical_list: D001500:BCG Vaccine; D001426:Bacterial Proteins; D011687:Purines; D014614:Vaccines, Synthetic; D010453:Peptide Synthases; C083513:PurC protein, Bacteria