Mycobacterium tuberculosis, the primary agent of tuberculosis, kills 2 million people annually, making it one of the world's leading causes of death. Moreover, it is a major cause of disease and death in AIDS patients, particularly in developing nations. Finally, multidrug resistant strains of M. tuberculosis (MDRTB) are potential agents of bioterrorism and have been designated Category C Priority Pathogens. Even in the absence of bioterrorism, the rapid global emergence of strains resistant to the major antibiotics used to treat tuberculosis poses a serious threat to public health. The highest priority in the fight against tuberculosis is the development of a vaccine that is more efficacious than the current vaccine - BCG. A vaccine more potent than BCG would have an impact on human health greater than virtually any other conceivable development in the fight against infectious diseases. During the previous grant period, we developed and characterized the first vaccine against tuberculosis more potent than BCG in a rigorous animal model. This vaccine, named rBCG30, is a live recombinant BCG vaccine expressing the M. tuberculosis 30 kDa major secretory protein. Compared with BCG, guinea pigs immunized with rBCG30 have significantly fewer tuberculous lesions in their lungs, livers, and spleens, significantly fewer M. tuberculosis organisms in their lungs and spleens, and significantly enhanced survival after aerosol challenge with highly virulent M. tuberculosis. rBCG30 was selected by the Aeras Global TB Vaccine Foundation and the Gates Foundation for further study in humans. In collaboration with Aeras, we successfully manufactured the vaccine by Good Manufacturing Practices (GMP) and completed studies required for an Investigational New Drug (IND) application from the Food and Drug Administration (FDA). rBCG30 is currently in human clinical trials. The guinea pig is highly susceptible to M. tuberculosis and develops a disease that closely resembles human tuberculosis clinically, immunologically and pathologically. Hence, it seems reasonable to postulate that the more potent a vaccine is in guinea pigs, the more potent it will be in humans as well. With this postulate in mind, and our having already developed a vaccine more potent in animals than BCG, the goal of this application is to develop a vaccine more potent than rBCG30 in the guinea pig model of pulmonary tuberculosis and ultimately, a vaccine that prevents or at least markedly reduces primary infection of the lung with M. tuberculosis. Lay Summary: Tuberculosis is a major worldwide public health problem. This proposal seeks to develop a more potent vaccine with which to combat this disease. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Lacourciere, Karen A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Jia, Qingmei; Dillon, Barbara Jane; Masleša-Gali?, Saša et al. (2017) Listeria-vectored vaccine expressing the Mycobacterium tuberculosis 30 kDa major secretory protein via the constitutively active prfA* regulon boosts BCG efficacy against tuberculosis. Infect Immun :
Gillis, Thomas P; Tullius, Michael V; Horwitz, Marcus A (2014) rBCG30-induced immunity and cross-protection against Mycobacterium leprae challenge are enhanced by boosting with the Mycobacterium tuberculosis 30-kilodalton antigen 85B. Infect Immun 82:3900-9
Horwitz, Marcus A; Harth, Günter; Dillon, Barbara Jane et al. (2009) Commonly administered BCG strains including an evolutionarily early strain and evolutionarily late strains of disparate genealogy induce comparable protective immunity against tuberculosis. Vaccine 27:441-5
Hoft, Daniel F; Blazevic, Azra; Abate, Getahun et al. (2008) A new recombinant bacille Calmette-Guerin vaccine safely induces significantly enhanced tuberculosis-specific immunity in human volunteers. J Infect Dis 198:1491-501
Tullius, Michael V; Harth, Gunter; Maslesa-Galic, Sasa et al. (2008) A Replication-Limited Recombinant Mycobacterium bovis BCG vaccine against tuberculosis designed for human immunodeficiency virus-positive persons is safer and more efficacious than BCG. Infect Immun 76:5200-14
Horwitz, Marcus A; Harth, Gunter; Dillon, Barbara Jane et al. (2006) A novel live recombinant mycobacterial vaccine against bovine tuberculosis more potent than BCG. Vaccine 24:1593-600
Horwitz, Marcus A; Harth, Gunter; Dillon, Barbara Jane et al. (2006) Extraordinarily few organisms of a live recombinant BCG vaccine against tuberculosis induce maximal cell-mediated and protective immunity. Vaccine 24:443-51
Horwitz, Marcus A (2005) Recombinant BCG expressing Mycobacterium tuberculosis major extracellular proteins. Microbes Infect 7:947-54
Harth, Gunter; Maslesa-Galic, Sasa; Tullius, Michael V et al. (2005) All four Mycobacterium tuberculosis glnA genes encode glutamine synthetase activities but only GlnA1 is abundantly expressed and essential for bacterial homeostasis. Mol Microbiol 58:1157-72
Horwitz, Marcus A; Harth, Gunter; Dillon, Barbara Jane et al. (2005) Enhancing the protective efficacy of Mycobacterium bovis BCG vaccination against tuberculosis by boosting with the Mycobacterium tuberculosis major secretory protein. Infect Immun 73:4676-83

Showing the most recent 10 out of 33 publications