Abstract
A single intradermal vaccination with an antibiotic-less version of BCGΔBCG1419c given to guinea pigs conferred a significant improvement in outcome following a low dose aerosol exposure to M. tuberculosis compared to that provided by a single dose of BCG Pasteur. BCGΔBCG1419c was more attenuated than BCG in murine macrophages, athymic, BALB/c, and C57BL/6 mice. In guinea pigs, BCGΔBCG1419c was at least as attenuated as BCG and induced similar dermal reactivity to that of BCG. Vaccination of guinea pigs with BCGΔBCG1419c resulted in increased anti-PPD IgG compared with those receiving BCG. Guinea pigs vaccinated with BCGΔBCG1419c showed a significant reduction of M. tuberculosis replication in lungs and spleens compared with BCG, as well as a significant reduction of pulmonary and extrapulmonary tuberculosis (TB) pathology measured using pathology scores recorded at necropsy. Evaluation of cytokines produced in lungs of infected guinea pigs showed that BCGΔBCG1419c significantly reduced TNF-α and IL-17 compared with BCG-vaccinated animals, with no changes in IL-10. This work demonstrates a significantly improved protection against pulmonary and extrapulmonary TB provided by BCGΔBCG1419c in susceptible guinea pigs together with an increased safety compared with BCG in several models. These results support the continued development of BCGΔBCG1419c as an effective vaccine for TB.
Highlights
A single intradermal vaccination with an antibiotic-less version of BCGΔBCG1419c given to guinea pigs conferred a significant improvement in outcome following a low dose aerosol exposure to M. tuberculosis compared to that provided by a single dose of BCG Pasteur
Using the antibiotic-less version of BCGΔBCG1419c, here we compared its in vitro growth, its replication in murine macrophages, its safety in immunocompetent hosts (BALB/c and C57BL/6 mice, and Hartley guinea pigs) and immunocompromised hosts, to that of parental BCG Pasteur. Considering that both C57BL/6 and BALB/c mice are resistant to M. tuberculosis infection and do not produce caseous granulomas in the lungs, unlike typical lesions found in human TB d isease[13,14], here we employed the guinea pig model for evaluation of vaccine efficacy, which are highly susceptible to M. tuberculosis infection and whose reliability and reproducibility in obtaining efficacy data was independently confirmed in three different laboratories[15]
We recently reported that this novel version of BCGΔBCG1419c maintain changes in antigenic proteins compared with B CG11, fostering our interest in its preclinical characterization
Summary
A single intradermal vaccination with an antibiotic-less version of BCGΔBCG1419c given to guinea pigs conferred a significant improvement in outcome following a low dose aerosol exposure to M. tuberculosis compared to that provided by a single dose of BCG Pasteur. Using the antibiotic-less version of BCGΔBCG1419c, here we compared its in vitro growth, its replication in murine macrophages, its safety in immunocompetent hosts (BALB/c and C57BL/6 mice, and Hartley guinea pigs) and immunocompromised hosts (athymic nu/nu mice), to that of parental BCG Pasteur Considering that both C57BL/6 and BALB/c mice are resistant to M. tuberculosis infection and do not produce caseous granulomas in the lungs, unlike typical lesions found in human TB d isease[13,14], here we employed the guinea pig model for evaluation of vaccine efficacy, which are highly susceptible to M. tuberculosis infection and whose reliability and reproducibility in obtaining efficacy data was independently confirmed in three different laboratories[15]. Comparison of efficacy in guinea pigs showed that the antibiotic-less version of BCGΔBCG1419c provided improved control of both pulmonary and extrapulmonary TB compared with its parental BCG
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