Mycobacterium tuberculosis H37Rv: Delta RD1 is more virulent than M. bovis bacille Calmette-Guerin in long-term murine infection.
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Region of difference (RD1) genes are present in virulent Mycobacterium tuberculosis but not the vaccine strain M. bovis bacille Calmette-Guerin (BCG). The deletion of RD1 from M. tuberculosis produces an attenuation strikingly like that of BCG, which suggests the use of RD1 mutant strains for improvement of the tuberculosis (TB) vaccine. We performed long-term murine infection with M. tuberculosis H37Rv: Delta RD1 and BCG. Mice infected with H37Rv: Delta RD1 gained less weight than did BCG-infected control mice, and, after >1 year, their lungs harbored many more bacteria and displayed significant levels of inflammation. This difference in virulence has important implications for the pursuit of strains lacking RD1 in the development of the TB vaccine. (+info)
New vaccines against tuberculosis.
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In September 2000, recognizing the effect of communicable diseases as obstacles to development in poorer countries, the European Commission assembled a special round table on 'accelerated action targeted at major communicable diseases within the context of poverty reduction'. The three major communicable diseases discussed were tuberculosis (TB), malaria and HIV. One outcome of this discussion was a workshop examining issues related to the fight against TB in Africa, which took place in Goree, Senegal, in May 2001. The timing was propitious, as new vaccines for TB (recombinant MVA and BCG, and adjuvanated recombinant fusion proteins or peptide constructs), are just beginning to enter human clinical trials. All but the last of these have shown promise in animal models, up to and including non-human primates, and all are strongly immunogenic and apparently safe. Humans trials for safety and efficacy are thus the logical next step. This review summarizes recent advances in tuberculosis vaccine development, with a special emphasis on issues raised at the Goree meeting about testing and deploying new generation vaccines in TB-endemic areas such as Africa. (+info)
Antigenic evidence of prevalence and diversity of Mycobacterium tuberculosis arabinomannan.
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Arabinomannan (AM) is a polysaccharide of the mycobacterial capsule. The capsular polysaccharides of various microorganisms are diverse, and this diversity is important for classification of organisms into serotypes and vaccine development. In the present study we examined the prevalence and diversity of AM among Mycobacterium tuberculosis strains using four AM-binding monoclonal antibodies (MAbs). One of these MAbs, MAb 9d8, is known to bind to AM specifically. By whole-cell enzyme-linked immunosorbent assay (ELISA), the AM recognized by MAb 9d8 was detected on the surfaces of 9 of 11 strains, while 2 strains showed no reactivity with MAb 9d8. However, the AM recognized by MAb 9d8 was found in the culture supernatants of all 11 M. tuberculosis strains tested, as demonstrated by capture ELISA. Other AM-binding MAbs reacted both with the surfaces and with the culture supernatants of all 11 strains. Mice immunized with an experimental AM-recombinant Pseudomonas aeruginosa exoprotein A (rEPA) conjugate vaccine had an increased antibody response to AM and a moderate reduction in the numbers of CFU in their organs 7 days after challenge. Our results indicate that AM was detected in all M. tuberculosis strains tested, with differences in epitope distributions of certain strains. In addition, our results suggest that an experimental AM-rEPA vaccine has a moderate effect on the numbers of CFU in organs early after infection. (+info)
Characterization of a Mycobacterium tuberculosis peptide that is recognized by human CD4+ and CD8+ T cells in the context of multiple HLA alleles.
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The secreted Mycobacterium tuberculosis 10-kDa culture filtrate protein (CFP)10 is a potent T cell Ag that is recognized by a high percentage of persons infected with M. tuberculosis. We determined the molecular basis for this widespread recognition by identifying and characterizing a 15-mer peptide, CFP10(71-85), that elicited IFN-gamma production and CTL activity by both CD4(+) and CD8(+) T cells from persons expressing multiple MHC class II and class I molecules, respectively. CFP10(71-85) contained at least two epitopes, one of 10 aa (peptide T1) and another of 9 aa (peptide T6). T1 was recognized by CD4(+) cells in the context of DRB1*04, DR5*0101, and DQB1*03, and by CD8(+) cells of A2(+) donors. T6 elicited responses by CD4(+) cells in the context of DRB1*04 and DQB1*03, and by CD8(+) cells of B35(+) donors. Deleting a single amino acid from the amino or carboxy terminus of either peptide markedly reduced IFN-gamma production, suggesting that they are minimal epitopes for both CD4(+) and CD8(+) cells. As far as we are aware, these are the shortest microbial peptides that have been found to elicit responses by both T cell subpopulations. The capacity of CFP10(71-85) to stimulate IFN-gamma production and CTL activity by CD4(+) and CD8(+) cells from persons expressing a spectrum of MHC molecules suggests that this peptide is an excellent candidate for inclusion in a subunit antituberculosis vaccine. (+info)
Magnetic resonance imaging of pulmonary lesions in guinea pigs infected with Mycobacterium tuberculosis.
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We utilized magnetic resonance imaging to visualize lesions in the lungs of guinea pigs infected by low-dose aerosol exposure to Mycobacterium tuberculosis. Lesions were prominent in such images, and colorized three-dimensional reconstructions of images revealed a very uniform distribution in the lungs. Lesion numbers after 1 month were approximately similar to the aerosol exposure algorithm, suggesting that each was established by a single bacterium. Numbers of lesions in unprotected and vaccinated animals were similar over the first month but increased thereafter in the control animals, indicating secondary lesion development. Whereas lesion sizes increased progressively in control guinea pigs, lesions remained small in BCG-vaccinated animals. A prominent feature of the disease pathology in unprotected animals was rapid and severe lymphadenopathy of the mediastinal lymph node cluster, which is paradoxical given the strong state of cellular immunity at this time. Further development of this technical approach could be very useful in tracking lesion size, number, and progression in the search for new tuberculosis vaccines. (+info)
Protective effect of a tuberculosis subunit vaccine based on a fusion of antigen 85B and ESAT-6 in the aerosol guinea pig model.
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A fusion protein of antigen 85B (Ag85B) and ESAT-6 administered in cationic lipid vesicles conferred a highly significant level of protection against Mycobacterium tuberculosis in the guinea pig aerosol model of infection. The protection was manifested as delayed clinical illness and prolonged survival. Neither Ag85B nor ESAT-6 (independently or as a cocktail) induced significant protection in this model. (+info)
Potential public health impact of new tuberculosis vaccines.
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Developing effective tuberculosis (TB) vaccines is a high priority. We use mathematical models to predict the potential public health impact of new TB vaccines in high-incidence countries. We show that preexposure vaccines would be almost twice as effective as postexposure vaccines in reducing the number of new infections. Postexposure vaccines would initially have a substantially greater impact, compared to preexposure vaccines, on reducing the number of new cases of disease. However, the effectiveness of postexposure vaccines would diminish over time, whereas the effectiveness of preexposure vaccines would increase. Thus, after 20 to 30 years, post- or preexposure vaccination campaigns would be almost equally effective in terms of cumulative TB cases prevented. Even widely deployed and highly effective (50%-90% efficacy) pre- or postexposure vaccines would only be able to reduce the number of TB cases by one third. We discuss the health policy implications of our analyses. (+info)
RNA encoding the MPT83 antigen induces protective immune responses against Mycobacterium tuberculosis infection.
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We have previously demonstrated that vaccination of mice with plasmid DNA vectors expressing immunodominant mycobacterial genes induced cellular immune responses and significant protection against challenge with Mycobacterium tuberculosis. We demonstrate here, using in vitro-synthesized RNA, that vaccination with DNA or RNA constructs expressing the M. tuberculosis MPT83 antigen are capable of inducing specific humoral and T-cell immune responses and confer modest but significant protection against M. tuberculosis challenge in mice. This is the first report of protective immunity conferred against intracellular bacteria by an RNA vaccine. This novel approach avoids some of the drawbacks of DNA vaccines and illustrates the potential for developing new antimycobacterial immunization strategies. (+info)