Recombinant BCG expressing Mycobacterium tuberculosis major extracellular proteins

Horwitz, Marcus A.

doi:10.1016/j.micinf.2005.04.002

Cited by 52 publications

(27 citation statements)

References 33 publications

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“…Another strategy to improve BCG protective efficacy involves the complementation of BCG by overexpressing antigens not expressed or expressed only at low levels by wild-type BCG (24). rBCG30 is the prototype of this class of vaccines, which utilize BCG Tice as a host organism for expressing and secreting Mycobacterium tuberculosis proteins.…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity ofMycobacterium tuberculosisAntigens inMycobacterium bovisBCG-Vaccinated andM. bovis-Infected Cattle

et al. 2006

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The development of novel vaccine strategies supplementing Mycobacterium bovis BCG (BCG) constitutes an urgent research challenge. To identify potential subunit vaccine candidates, we have tested a series of eight recently identified Mycobacterium tuberculosis antigens in M. bovis-infected and BCG-vaccinated cattle. These antigens were characterized on the basis of their ability to induce in vitro gamma interferon responses in infected or BCG-vaccinated calves. We were able to establish a hierarchy of these antigens based on how frequently they were recognized in both groups of animals. In particular, we were able to prioritize frequently recognized proteins like Rv0287, Rv1174, and Rv1196 for future evaluation as subunit vaccines to be used in BCG-protein heterologous prime-boost vaccination scenarios. In addition, the antigen most dominantly recognized in M. bovis-infected cattle in this study, Rv3616c, was significantly less frequently recognized by BCG vaccinees and could be a target to improve BCG, for example, by increasing its secretion, in a recombinant BCG vaccine.

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Section: Discussionmentioning

confidence: 99%

Immunogenicity ofMycobacterium tuberculosisAntigens inMycobacterium bovisBCG-Vaccinated andM. bovis-Infected Cattle

et al. 2006

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“…tuberculosis H37Rv, a recombinant BCG strain overexpressing the 30-kD major secretory protein (rBCG30) (28,29), and the Tice BCG parent strain were mouse-passaged, frozen in aliquots, and subcultured in Middlebrook 7H9 broth with 10% oleic acid-albumin-dextrosecatalase (Fisher, Pittsburgh, PA) and 0.05% Tween 80 before infection. The rBCG30 and Tice BCG strains were kind gifts from Professor Marcus A. Horwitz.…”

Section: Mycobacterial Strainsmentioning

confidence: 99%

“…The rBCG30 and Tice BCG strains were kind gifts from Professor Marcus A. Horwitz. The rBCG30 strain is a more efficacious vaccine than its parent in guinea pig and bovine models of pulmonary TB (28)(29)(30) and more effective than several commonly used BCG strains in guinea pigs (31).…”

Section: Mycobacterial Strainsmentioning

confidence: 99%

Short-Course Therapy with Daily Rifapentine in a Murine Model of Latent Tuberculosis Infection

Zhang¹,

Zhang²,

Rosenthal³

et al. 2009

Am J Respir Crit Care Med

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Rationale: Regimens recommended to treat latent tuberculosis infection (LTBI) are 3 to 9 months long. A 2-month rifampin1 pyrazinamide regimen is no longer recommended. Shorter regimens are highly desirable. Because substituting rifapentine for rifampin in the standard regimen for active tuberculosis halves the treatment duration needed to prevent relapse in mice, we hypothesized daily rifapentine-based regimens could shorten LTBI treatment to 2 months or less. Objectives: To improve an existing model of LTBI chemotherapy and evaluate the efficacy of daily rifapentine-based regimens. Methods: Mice were immunized with a more immunogenic recombinant Bacille Calmette-Guérin strain (rBCG30) and received very lowdose aerosol infection with Mycobacterium tuberculosis to establish a stable lung bacterial burden below 10 4 CFU without drug treatment. Mice received a control (isoniazid alone, rifampin alone, rifampin1isoniazid, rifampin1pyrazinamide) or test (rifapentine alone, rifapentine1isoniazid, rifapentine1pyrazinamide, rifapentine1 isoniazid1pyrazinamide) regimen for 8 weeks. Rifamycin doses were 10 mg/kg/d, analogous to the same human doses. Outcomes were biweekly lung CFU counts and relapse after 4 to 8 weeks of treatment. Measurements and Main Results: M. tuberculosis CFU counts remained stable around 3.65 log 10 in immunized, untreated mice. Isoniazid or rifampin left all or most mice culture-positive at week 8. Rifampin1 isoniazid cured 0 and 53% of mice and rifampin1pyrazinamide cured 47 and 100% of mice in 4 and 8 weeks, respectively. Rifapentine-based regimens were more active than rifampin1isoniazid and indistinguishable from rifampin1pyrazinamide. Conclusions: In this improved murine model of LTBI chemotherapy with very low lung burden, existing regimens were well represented. Daily rifapentine-based regimens were at least as active as rifampin1pyrazinamide, suggesting they could effectively treat LTBI in 6 to 8 weeks.Keywords: BCG; mouse; isoniazid; rifampin; pyrazinamide Identification and treatment of latent tuberculosis infection (LTBI) is necessary to eliminate tuberculosis (TB) in lowincidence countries (1-4). This strategy may soon be applied more widely now that new diagnostic tests are available to discriminate LTBI from past vaccination with Bacille CalmetteGuérin (BCG) or exposure to nontuberculous mycobacteria (5). Preventive therapy is also effective, though vastly underutilized, in reducing TB risk among HIV-infected persons with LTBI in high-prevalence settings, including persons receiving concomitant highly active antiretroviral therapy (6-9).Current LTBI treatment guidelines generally consider isoniazid (INH) for 6 to 12 months to be the first-line regimen (1, 4, 10). Rifampin (RIF) for 4 months is an alternative in the United States and Canada (1, 4, 11). In the United Kingdom, a 3-month regimen of RIF1INH is used with success (12, 13). The combination of RIF1pyrazinamide (PZA) was first shown to have potent sterilizing activity in a model of LTBI using mice immunized with BCG (14). Aft...

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“…Since r30 is a mycolyl transferase involved in the synthesis of the key cell wall component TDM, overexpression of r30 could endow rBCG30 with greater resistance to clearance by host antimicrobial defense mechanisms; persistence of the organism might allow it to induce stronger immunity. Consistent with this idea, rBCG30 is more resistant than BCG to the cell wall active antibiotic isoniazid (46). However, studies in the guinea pig have shown that rBCG30 is cleared at the same rate as is BCG (5).…”

Section: Discussionmentioning

confidence: 82%

rBCG30-Induced Immunity and Cross-Protection against Mycobacterium leprae Challenge Are Enhanced by Boosting with the Mycobacterium tuberculosis 30-Kilodalton Antigen 85B

2014

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bLeprosy remains a major global health problem and typically occurs in regions in which tuberculosis is endemic. Vaccines are needed that protect against both infections and do so better than the suboptimal Mycobacterium bovis BCG vaccine. Here, we evaluated rBCG30, a vaccine previously demonstrated to induce protection superior to that of BCG against Mycobacterium tuberculosis and Mycobacterium bovis challenge in animal models, for efficacy against Mycobacterium leprae challenge in a murine model of leprosy. rBCG30 overexpresses the M. tuberculosis 30-kDa major secretory protein antigen 85B, which is 85% homologous with the M. leprae homolog (r30ML). Mice were sham immunized or immunized intradermally with BCG or rBCG30 and challenged 2.5 months later by injection of viable M. leprae into each hind footpad. After 7 months, vaccine efficacy was assessed by enumerating the M. leprae bacteria per footpad. Both BCG and rBCG30 induced significant protection against M. leprae challenge. In the one experiment in which a comparison between BCG and rBCG30 was feasible, rBCG30 induced significantly greater protection than did BCG. Immunization of mice with purified M. tuberculosis or M. leprae antigen 85B also induced protection against M. leprae challenge but less so than BCG or rBCG30. Notably, boosting rBCG30 with M. tuberculosis antigen 85B significantly enhanced r30ML-specific immune responses, substantially more so than boosting BCG, and significantly augmented protection against M. leprae challenge. Thus, rBCG30, a vaccine that induces improved protection against M. tuberculosis, induces cross-protection against M. leprae that is comparable or potentially superior to that induced by BCG, and boosting rBCG30 with antigen 85B further enhances immune responses and protective efficacy. L eprosy, caused by the bacterium Mycobacterium leprae, remains a major global health problem. Although the reported incidence has decreased over the past few decades, the annual decline has leveled off. The World Health Organization reported 232,875 new cases in 2012 with 71% of the cases occurring in the southeast Asian region of the world (1). In many parts of the world, including Southeast Asia, the number of new cases reported increased over the previous year.Leprosy presents across a clinical and immunopathological disease spectrum ranging from multibacillary lepromatous leprosy, characterized by many skin lesions with numerous bacilli and an absence of cell-mediated immunity to M. leprae, to paucibacillary tuberculoid leprosy, characterized by few lesions and a paucity of bacilli but the presence of specific cell-mediated immunity. Infection of peripheral nerves and nerve damage are a frequent and often debilitating manifestation of leprosy. Leprosy is treated with a prolonged course of antibiotics used in combination. As in the case of tuberculosis (TB), drug resistance has emerged, although worldwide levels of resistance to the major drugs dapsone and rifampin have stabilized in recent years. Nevertheless, because of the extrem...

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Recombinant BCG expressing Mycobacterium tuberculosis major extracellular proteins

Cited by 52 publications

References 33 publications

Immunogenicity ofMycobacterium tuberculosisAntigens inMycobacterium bovisBCG-Vaccinated andM. bovis-Infected Cattle

Immunogenicity ofMycobacterium tuberculosisAntigens inMycobacterium bovisBCG-Vaccinated andM. bovis-Infected Cattle

Short-Course Therapy with Daily Rifapentine in a Murine Model of Latent Tuberculosis Infection

rBCG30-Induced Immunity and Cross-Protection against Mycobacterium leprae Challenge Are Enhanced by Boosting with the Mycobacterium tuberculosis 30-Kilodalton Antigen 85B

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