A recombinant selective drug-resistant M. bovis BCG enhances the bactericidal activity of a second-line anti-tuberculosis regimen.

Abstract

Drug-resistant tuberculosis (DR-TB) poses a new threat to global health; to improve the treatment outcome, therapeutic vaccines are considered the best chemotherapy adjuvants. Unfortunately, there is no therapeutic vaccine approved against DR-TB. Our study assessed the therapeutic efficacy of a recombinant drug-resistant BCG (RdrBCG) vaccine in DR-TB. We constructed the RdrBCG overexpressing Ag85B and Rv2628 by selecting drug-resistant BCG strains and transformed them with plasmid pEBCG or pIBCG to create RdrBCG-E and RdrBCG-I respectively. Following successful stability testing, we tested the vaccine's safety in severe combined immune deficient (SCID) mice that lack both T and B lymphocytes plus immunoglobulins. Finally, we evaluated the RdrBCG's therapeutic efficacy in BALB/c mice infected with rifampin-resistant M. tuberculosis and treated with a second-line anti-TB regimen. We obtained M. bovis strains which were resistant to several second-line drugs and M. tuberculosis resistant to rifampin. Notably, the exogenously inserted genes were lost in RdrBCG-E but remained stable in the RdrBCG-I both in vitro and in vivo. When administered adjunct to a second-line anti-TB regimen in a murine model of DR-TB, the RdrBCG-I lowered lung M. tuberculosis burden by 1 log10. Furthermore, vaccination with RdrBCG-I adjunct to chemotherapy minimized lung tissue pathology in mice. Most importantly, the RdrBCG-I showed almost the same virulence as its parent BCG Tice strain in SCID mice. Our findings suggested that the RdrBCG-I was stable, safe and effective as a therapeutic vaccine. Hence, the "recombinant" plus "drug-resistant" BCG strategy could be a useful concept for developing therapeutic vaccines against DR-TB.

• Authors: Gift Chiwala, Zhiyong Liu, Julius N Mugweru, Bangxing Wang, Shahzad Akbar Khan, Petuel Ndip Ndip Bate, Buhari Yusuf, H M Adnan Hameed, Cuiting Fang, Yaoju Tan, Ping Guan, Jinxing Hu, Shouyong Tan, Jianxiong Liu, Nanshan Zhong, Tianyu Zhang
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 142 Pg. 112047 (Oct 2021) ISSN: 1950-6007 [Electronic] France
• PMID: 34426260 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Antigens, Bacterial
• Antitubercular Agents
• BCG Vaccine
• Vaccines, Synthetic
• Pyrazinamide
• Levofloxacin
• Prothionamide
• Amikacin

Topics

• Amikacin (pharmacology, therapeutic use)
• Animals
• Antigens, Bacterial (biosynthesis, genetics, immunology)
• Antitubercular Agents (pharmacology, therapeutic use)
• BCG Vaccine (biosynthesis, genetics, immunology, therapeutic use)
• Disease Models, Animal
• Drug Resistance, Bacterial (genetics)
• Levofloxacin (pharmacology, therapeutic use)
• Mice, Inbred BALB C
• Mice, SCID
• Mycobacterium bovis (chemistry, drug effects, genetics)
• Mycobacterium tuberculosis (drug effects, pathogenicity)
• Plasmids
• Prothionamide (pharmacology, therapeutic use)
• Pyrazinamide (pharmacology, therapeutic use)
• Tuberculosis, Pulmonary (drug therapy, pathology, prevention & control)
• Vaccines, Synthetic (biosynthesis, genetics, immunology, therapeutic use)
• Virulence