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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 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.

* Corresponding author. Mailing address: Institut Pasteur, Unité de Génétique Mycobactérienne, 25 rue du Dr. Roux, 75724 Paris cedex 15, France. Phone: 1 45 68 88 77. Fax: 1 45 68 88 43. 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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