Rifapentine, Moxifloxacin, or DNA Vaccine Improves Treatment of Latent Tuberculosis in a Mouse Model

Abstract

Rationale: Priorities for developing improved regimens for treatment of latent tuberculosis (TB) infection include (1 ) developing shorter and/or more intermittently administered regimens that are easier to supervise and (2 ) developing and evaluating regimens that are active against multidrug-resistant organisms. Objectives and Methods: By using a previously validated murine model that involves immunizing mice with Mycobacterium bovis bacillus Calmette-Guérin to augment host immunity before infection with virulent Mycobacterium tuberculosis, we evaluated new treatment regimens including rifapentine and moxifloxacin, and assessed the potential of the Mycobacterium leprae heat shock protein-65 DNA vaccine to augment the activity of moxifloxacin. Measurements: Quantitative spleen colony-forming unit counts, and the proportion of mice with culture-positive relapse after treatment, were determined. Main Results: Three-month, once-weekly regimens of rifapentine combined with either isoniazid or moxifloxacin were as active as daily isoniazid for 6-9 mo. Six-month daily combinations of moxifloxacin with pyrazinamide, ethionamide, or ethambutol were more active than pyrazinamide plus ethambutol, a regimen recommended for latent TB infection after exposure to multidrug-resistant TB. The combination of moxifloxacin with the experimental nitroimidazopyran PA-824 was especially active. Finally, the heat shock protein-65 DNA vaccine had no effect on colony-forming unit counts when given alone, but augmented the bactericidal activity of moxifloxacin. Conclusions: Together, these findings suggest that rifapentine, moxifloxacin, and, perhaps, therapeutic DNA vaccination have the potential to improve on the current treatment of latent TB infection.Keywords: DNA vaccine; latency; moxifloxacin; rifapentine; tuberculosisThe objective of treatment for latent tuberculosis infection (LTBI) is to prevent the development of overt tuberculosis (TB) disease in infected, but asymptomatic, individuals. At present, a 9-mo course of daily isoniazid (INH) is recommended as firstline therapy for LTBI (1). Alternative regimens include a shorter 6-mo course of INH, which is likely inferior to a 9-mo course (2), or a 4-mo course of daily rifampin (RIF), which is largely untested (1, 3). Although it is comparable in efficacy to 6 or 12 mo of INH (4-6), a 2-mo course of RIF plus pyrazinamide (PZA) is no longer recommended for use because of concerns over excessive hepatotoxicity (7). Priorities for developing improved regimens for treatment of LTBI include (1 ) developing shorter and/or more intermittently administered regimens that are easier to supervise and (2 ) developing and evaluating regimens that are active against multidrug-resistant organisms (8).(Received in original form July 6, 2005; accepted in final form September 7, 2005) Supported by the National Institutes of Health (grant AI58993 and supplement to grant AI43846), the Global Alliance for TB Drug Development, and the Potts Memorial Foundation. Regarding the first objective, the l...

Phase I trial of DNA-hsp65 immunotherapy for advanced squamous cell carcinoma of the head and neck

“…This is the first clinical trial using the hsp65 gene from mycobacterial origin, previously shown by different groups to be efficient against tuberculosis and in preventing and reducing tumor growth in preclinical models. [24][25][26]28,30,34,35 We have had the care to create GMP conditions in our laboratory exclusively to produce DNA-hsp65 vaccine for clinical use. The vaccine injections were ultrasound guided, which guaranteed the injection in solid parts of the tumor, avoiding necrotic areas and vessels.…”

“…However, preclinical data from our group and others using different animal models show no evidence of autoimmune disease when DNA-hsp65 was used for immunization. [24][25][26]30 It is relevant to point that the immunogenicity of tumor-derived HSP-peptide complexes has been shown to be individually tumor specific and not tumor-type specific. This suggests that the relevant immunoprotective peptides are most likely derived from individual tumorspecific antigens rather than from shared tumor antigens.…”

No Evidence of Pathological Autoimmunity following Mycobacterium Leprae Heat-Shock Protein 65-Dna Vaccination in Mice

“…These results have not been observed by other groups and, on the contrary, several subsequent reports have provided increasing evidence in favour of the potential therapeutic use of Hsp65 against tuberculosis (13)(14)16). However, it is mandatory to thoroughly exclude any possible harmful effects mediated by this vaccine, including the development of autoimmune diseases.…”

Latent Tuberculosis Infection: Myths, Models, and Molecular Mechanisms

“…The M. bovis BCG vaccine has limited efficacy in protecting against reactivation of LTBI (320-322). DNA vaccines have shown promise in their ability to enhance the activity of antibiotic treatment and reduce reactivation of LTBI and transmission (323)(324)(325). Adjunctive immunotherapy with a DNA vaccine containing the LTBI marker ␣-crystallin (233,(328)(329)(330) reduces the duration of antibiotic treatment in chronically infected mice (331).…”