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

• Published in: Biomedicine & pharmacotherapy Vol. 142; p. 112047
• Main Authors: Chiwala, Gift, Liu, Zhiyong, Mugweru, Julius N., Wang, Bangxing, Khan, Shahzad Akbar, Bate, Petuel Ndip Ndip, Yusuf, Buhari, Hameed, H.M. Adnan, Fang, Cuiting, Tan, Yaoju, Guan, Ping, Hu, Jinxing, Tan, Shouyong, Liu, Jianxiong, Zhong, Nanshan, Zhang, Tianyu
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.10.2021; Elsevier
• Subjects: Ag85B; Amikacin - pharmacology; Amikacin - therapeutic use; Animals; Antigens, Bacterial - biosynthesis; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Antitubercular Agents - pharmacology; Antitubercular Agents - therapeutic use; BCG Vaccine - biosynthesis; BCG Vaccine - genetics; BCG Vaccine - immunology; BCG Vaccine - therapeutic use; Disease Models, Animal; Drug Resistance, Bacterial - genetics; Drug-resistant tuberculosis; Levofloxacin - pharmacology; Levofloxacin - therapeutic use; Mice; Mice, Inbred BALB C; Mice, SCID; Mycobacterium bovis - chemistry; Mycobacterium bovis - drug effects; Mycobacterium bovis - genetics; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - pathogenicity; Plasmids; Prothionamide - pharmacology; Prothionamide - therapeutic use; Pyrazinamide - pharmacology; Pyrazinamide - therapeutic use; Recombinant drug-resistant BCG; Rv2628; Therapeutic vaccine; Tuberculosis, Pulmonary - drug therapy; Tuberculosis, Pulmonary - pathology; Tuberculosis, Pulmonary - prevention & control; Vaccines, Synthetic - biosynthesis; Vaccines, Synthetic - genetics; Vaccines, Synthetic - immunology; Vaccines, Synthetic - therapeutic use; Virulence; Drug-resistant tuberculosis; Recombinant drug-resistant BCG; Ag85B; Therapeutic vaccine; Rv2628
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.112047

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. [Display omitted] •The RdrBCG-I overexpressing Ag85B + Rv2628 is stable both in vitro and in vivo.•The RdrBCG-I was safe and nonvirulent even to SCID mice.•The RdrBCG-I enhanced the activity of a second-line regimen in a murine model.•The RdrBCG facilitated lung tissue recovery.