The BCGΔBCG1419c strain, which produces more pellicle in vitro, improves control of chronic tuberculosis in vivo

The BCGΔBCG1419c Vaccine Candidate Reduces Lung Pathology, IL-6, TNF-α, and IL-10 During Chronic TB Infection

“…In order to explore the hypothesis that mycobacterial biofilms resemble aspects of chronic TB infection ( Flores-Valdez, 2016 ), we deleted the cyclic di-GMP phosphodiesterase-encoding gene BCG1419c , to create the BCGΔBCG1419c Pasteur-derivative strain ( Flores-Valdez et al, 2015 ). We previously showed that in immunocompromised nu/nu mice, BCGΔBCG1419c was as safe as parental BCG, and that in a mouse model of progressive infection with M. tuberculosis H37Rv, compared to BCG, vaccination with BCGΔBCG1419c increased the levels of CD4 + and CD8 + T lymphocytes, and reduced 1-log 10 bacterial burden in lungs after 24 weeks post-infection, with reduced pneumonia, indicating its potential as a preventive vaccine against chronic TB ( Pedroza-Roldán et al, 2016 ). Furthermore, in a model resembling reactivation from chronic infection, H37Rv bacillary loads were reduced more than 1-log 10 after 1 month of corticosteroid treatment, and TB pneumonia was reduced by 30% ( Pedroza-Roldán et al, 2016 ), suggesting that BCGΔBCG1419c could also be considered as a candidate for a post-exposure vaccine.…”

“…We previously showed that in immunocompromised nu/nu mice, BCGΔBCG1419c was as safe as parental BCG, and that in a mouse model of progressive infection with M. tuberculosis H37Rv, compared to BCG, vaccination with BCGΔBCG1419c increased the levels of CD4 + and CD8 + T lymphocytes, and reduced 1-log 10 bacterial burden in lungs after 24 weeks post-infection, with reduced pneumonia, indicating its potential as a preventive vaccine against chronic TB ( Pedroza-Roldán et al, 2016 ). Furthermore, in a model resembling reactivation from chronic infection, H37Rv bacillary loads were reduced more than 1-log 10 after 1 month of corticosteroid treatment, and TB pneumonia was reduced by 30% ( Pedroza-Roldán et al, 2016 ), suggesting that BCGΔBCG1419c could also be considered as a candidate for a post-exposure vaccine. In this regard, immunization with BCG in PPD-positive humans who received a preventive therapy with isoniazid resulted in increased levels of CD3 + CD56 + NKT-like cells ( Suliman et al, 2016 ), suggesting that BCG, a recombinant BCG or other vaccine candidate could be applied to and protect human beings with presumptive or confirmed latent infection.…”

BCG and BCGΔBCG1419c protect type 2 diabetic mice against tuberculosis via different participation of T and B lymphocytes, dendritic cells and pro-inflammatory cytokines

“…In fact, in the early 2000s, it was shown that in vivo lethality following M. tuberculosis challenge sometimes dissociated from its replication in organs for strains devoid of some genes, such as whiB3 34 , sigH 35 , and sigC 36 , to mention some examples. We hypothesize that the protection conferred by vaccination with BCGΔBCG1419c against lung pathology in mouse models of TB, already observed in non-diabetic mice 12,15 , might potentially contribute to a more prolonged median survival time of T2D mice with TB as compared with those receiving BCG, which remains a matter of future investigation. Moreover, as sterilization is not achieved in murine models of TB, it could well be that reduction of lung pathology translates into a clinically meaningful phenotype for vaccine efficacy in mice.…”

“…T2D generates a series of changes that compromises the host response against M. tuberculosis, as recently reviewed by some authors 6,7 , including altered capacity to present antigens by macrophages 8 , activation of monocytes 9 , and chemoattraction of immune cells to lung during infection 10 . Furthermore, T2D favors more severe manifestations of TB as compared with those occurring in patients without T2D 11 , including extended lung damage especially at chronic stages of the comorbidity 12,13 . Despite this, the evaluation of new treatments or preventive measures against TB in the context of T2D constitutes a poorly explored area 14 , with no report available as of today about the efficacy of protection of any vaccine candidate against TB in the context of T2D.…”

“…The BCGΔBCG1419c mutant strain, a BCG Pasteur derivative, has been shown to reduce lung pathology at the chronic stage in two murine models of TB 12,15 , and also reduced reactivation after immusuppression induced by corticosterone administration in a mouse model of latent TB infection (LTBI) 12 . Furthermore, BCGΔBCG1419c reduced lung damage at 6 months post reactivation from latent lymphatic TB 16 .…”