Tuberculosis is resurgent in most of the world fueled by drug resistance, AIDS, poverty and mobility. The goal of this project is to produce an improved vaccine. It is based on our observations that an antigen 85A deletion mutant of MTB strain H37Rv (Ag85A-) is markedly attenuated and has increased antigen presenting capability. Our rationale has three components: First, the most effective immunity known against tuberculosis is provided by prior infection with MTB itself. Consequently, we propose that an appropriately attenuated MTB will approach the natural limit of efficacy of vaccines for tuberculosis. Second, MTB inhibits phagosome-lysosome (P-L) fusion. Preliminary data demonstrates that deletion of the Ag85A gene of MTB restores P-L fusion, enhances antigen presentation and probably increases the immunogenicity of MTB. Third, since MTB is a clonal organism with no demonstrated ability for horizontal transfer of genes, the safety of attenuated MTB can be assured.
The specific aims are: 1) Evaluate the efficacy and safety of the Ag85A-mutant as a vaccine against tuberculosis. The efficacy (ability to limit primary infection and dissemination) will be investigated by single or multiple immunizations of C57BL/6 mice, outbred mice and guinea pigs prior to aerosol challenge with virulent MTB. Safety will be evaluated by infection of a spectrum of animals including guinea pigs that are naturally more susceptible to disease, genetically heterogeneous outbred mice, immunocomormized SCID mice and steroid treated mice. Safety will be evaluated in terms the capacity of the vaccine organism to produce disease and its effect on persistence and pathogenicity of wild type MTB following challenge. 2) Introduce additional deletion mutations into the Ag85A- strain to improve safety while maintaining immunogenicity. We anticipate that any vaccine with prolonged survival in tissue may produce disease in immunosuppressed people. Consequently, attempts will be made to produce a double knockout mutant MTB that retains the immunogenicity of Ag85A- and is unable to survive in tissue. The 16 kDa alpha crystallin protein gene and nitrate reductase gene will be targeted. We anticipate that a safe live attenuated MTB vaccine with enhanced immunogenicity will prove valuable in combating adult pulmonary tuberculosis as well primary disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Sizemore, Christine F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center Houston
Schools of Medicine
United States
Zip Code
Hunter, Robert L; Actor, Jefrey K; Hwang, Shen-An et al. (2018) Pathogenesis and Animal Models of Post-Primary (Bronchogenic) Tuberculosis, A Review. Pathogens 7:
Bakhru, Pearl; Sirisaengtaksin, Natalie; Soudani, Emily et al. (2014) BCG vaccine mediated reduction in the MHC-II expression of macrophages and dendritic cells is reversed by activation of Toll-like receptors 7 and 9. Cell Immunol 287:53-61
Hunter, Robert L; Actor, Jeffrey K; Hwang, Shen-An et al. (2014) Pathogenesis of post primary tuberculosis: immunity and hypersensitivity in the development of cavities. Ann Clin Lab Sci 44:365-87
Saikolappan, Sankaralingam; Estrella, Jaymie; Sasindran, Smitha J et al. (2012) The fbpA/sapM double knock out strain of Mycobacterium tuberculosis is highly attenuated and immunogenic in macrophages. PLoS One 7:e36198
Jagannath, Chinnaswamy; Bakhru, Pearl (2012) Rapamycin-induced enhancement of vaccine efficacy in mice. Methods Mol Biol 821:295-303
Roche, Cherie M; Smith, Amanda; Lindsey, Devin R et al. (2011) The ?fbpA attenuated candidate vaccine from Mycobacterium tuberculosis, H37Rv primes for a stronger T-bet dependent Th1 immunity in mice. Tuberculosis (Edinb) 91 Suppl 1:S96-104
Vadrevu, Indumathi S; Lofton, Hava; Sarva, Krishna et al. (2011) ChiZ levels modulate cell division process in mycobacteria. Tuberculosis (Edinb) 91 Suppl 1:S128-35
Jagannath, Chinnaswamy; Lindsey, Devin R; Dhandayuthapani, Subramanian et al. (2009) Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med 15:267-76
Lindsey, Devin R; Dhandayuthapani, Subramanian; Jagannath, Chinnaswamy (2009) Anti-tuberculosis immunity induced in mice by vaccination with Mycobacterium smegmatis over-expressing Antigen 85B is due to the increased influx of IFNgamma-positive CD4 T cells into the lungs. Tuberculosis (Edinb) 89 Suppl 1:S46-8
Hunter, Robert L; Armitige, Lisa; Jagannath, Chinnaswamy et al. (2009) TB research at UT-Houston--a review of cord factor: new approaches to drugs, vaccines and the pathogenesis of tuberculosis. Tuberculosis (Edinb) 89 Suppl 1:S18-25

Showing the most recent 10 out of 16 publications