Persistence and Protective Efficacy of a Mycobacterium tuberculosis Auxotroph Vaccine

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Infection and Immunity, June 1999, p. 2867-2873, Vol. 67, No. 6
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Persistence and Protective Efficacy of a Mycobacterium tuberculosis Auxotroph Vaccine

Mary Jackson,¹^,^* Susan W. Phalen,² Micheline Lagranderie,³ Danielle Ensergueix,¹ Pierre Chavarot,⁴ Gilles Marchal,³^,⁴ David N. McMurray,² Brigitte Gicquel,¹^,³ and Christophe Guilhot¹

Unité de Génétique Mycobactérienne,¹ Laboratoire du BCG,³ and Unité de Physiopathologie de l'Infection,⁴ Institut Pasteur, 75724 Paris Cedex, France, and Department of Medical Microbiology and Immunology, Texas A&M University Health Science Center, College Station, Texas²

Received 21 October 1998/Returned for modification 14 December 1998/Accepted 12 March 1999

New vaccines against tuberculosis are urgently required because of the impressive incidence of this disease worldwide andthe highly variable protective efficacy of the current vaccine.The possibility of creating new live vaccines by the rationalattenuation of strains from the Mycobacterium tuberculosis complexwas investigated. Two auxotrophic mutants of M. tuberculosis andM. bovis BCG were constructed by disruption of one of their purinebiosynthetic genes. These mutants appeared unable to multiplyin vitro within mouse bone-marrow derived macrophages. They werealso attenuated in vivo in the mouse and guinea pig animal models.In guinea pigs, the two mutants induced strong delayed-type hypersensitivityresponse to purified protein derivative. In a preliminary experiment,the two mutants were compared to the BCG vaccine for their protectiveefficacy in a challenge against aerosolized virulent M. tuberculosisin the guinea pig model. Both mutants conferred some level ofprotection. These experiments demonstrate that the rational attenuationof M. tuberculosis could lead to the design of new candidate livevaccines againsttuberculosis.

^* Corresponding author. Mailing address: Institut Pasteur, Unité de Génétique Mycobactérienne, 25 rue du Dr. Roux, 75724Paris cedex 15, France. Phone: 1 45 68 88 77. Fax: 1 45 68 8843. E-mail: mjackson{at}pasteur.fr.

Infection and Immunity, June 1999, p. 2867-2873, Vol. 67, No. 6
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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