This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tullius, M. V.
Right arrow Articles by Horwitz, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tullius, M. V.
Right arrow Articles by Horwitz, M. A.

 Previous Article  |  Next Article 

Infection and Immunity, November 2008, p. 5200-5214, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.00434-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Replication-Limited Recombinant Mycobacterium bovis BCG Vaccine against Tuberculosis Designed for Human Immunodeficiency Virus-Positive Persons Is Safer and More Efficacious than BCG{triangledown} ,{dagger}

Michael V. Tullius, Günter Harth, Sasa Maslesa-Galic, Barbara J. Dillon, and Marcus A. Horwitz*

Division of Infectious Diseases, Department of Medicine, School of Medicine, University of California—Los Angeles, Los Angeles, California 90095-1688

Received 7 April 2008/ Returned for modification 28 May 2008/ Accepted 15 August 2008

Tuberculosis is the leading cause of death in AIDS patients, yet the current tuberculosis vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is contraindicated for immunocompromised individuals, including human immunodeficiency virus-positive persons, because it can cause disseminated disease; moreover, its efficacy is suboptimal. To address these problems, we have engineered BCG mutants that grow normally in vitro in the presence of a supplement, are preloadable with supplement to allow limited growth in vivo, and express the highly immunoprotective Mycobacterium tuberculosis 30-kDa major secretory protein. The limited replication in vivo renders these vaccines safer than BCG in SCID mice yet is sufficient to induce potent cell-mediated and protective immunity in the outbred guinea pig model of pulmonary tuberculosis. In the case of one vaccine, rBCG(mbtB)30, protection was superior to that with BCG (0.3-log fewer CFU of M. tuberculosis in the lung [P < 0.04] and 0.6-log fewer CFU in the spleen [P = 0.001] in aerosol-challenged animals [means for three experiments]); hence, rBCG(mbtB)30 is the first live mycobacterial vaccine that is both more attenuated than BCG in the SCID mouse and more potent than BCG in the guinea pig. Our study demonstrates the feasibility of developing safer and more potent vaccines against tuberculosis. The novel approach of engineering a replication-limited vaccine expressing a recombinant immunoprotective antigen and preloading it with a required nutrient, such as iron, that is capable of being stored should be generally applicable to other live vaccine vectors targeting intracellular pathogens.

* Corresponding author. Mailing address: Division of Infectious Diseases, Department of Medicine, School of Medicine, UCLA, CHS 37-121, 10833 Le Conte Ave., Los Angeles, CA 90095-1688. Phone: (310) 206-0074. Fax: (310) 794-7156. E-mail: MHorwitz{at}mednet.ucla.edu

{triangledown} Published ahead of print on 25 August 2008.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: J. L. Flynn

Infection and Immunity, November 2008, p. 5200-5214, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.00434-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Mir, F.-A., Kaufmann, S. H. E., Eddine, A. N. (2009). A Multicistronic DNA Vaccine Induces Significant Protection against Tuberculosis in Mice and Offers Flexibility in the Expressed Antigen Repertoire. CVI 16: 1467-1475 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»