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

• Published in: bioRxiv
• Main Authors: Gift Chiwala, Liu, Zhiyong, Mugweru, Julius N, Wang, Bangxing, Shahzad Akbar Khan, Petuel Ndip Ndip Bate, Buhari Yusuf, Hm Adnan Hameed, Fang, Cuiting, Tan, Yaoju, Guan, Ping, Hu, Jinxing, Tan, Shouyong, Liu, Jianxiong, Zhong, Nanshan, Zhang, Tianyu
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 05.03.2021
• Subjects: Animal models; Bactericidal activity; Chemotherapy; Combined vaccines; Complications; Drug resistance; Immune clearance; Immunization; Immunosuppressive agents; Isoniazid; Rifampin; Tuberculosis; Vaccines; Virulence
• DOI: 10.1101/2021.03.04.434024

Abstract Drug-resistant tuberculosis (DR-TB) results from infection by Mycobacterium tuberculosis strains resistant to at least rifampin or isoniazid. To improve the treatment outcome in DR-TB, therapeutic vaccines are considered an ideal choice as they can enhance pathogen clearance and minimize disease sequelae. To date, there is no therapeutic vaccine reported to be effective when combined with a chemotherapy regimen against DR-TB. The only available TB vaccine, the M. bovis BCG (BCG) is susceptible to several anti-TB drugs hence not a perfect option for therapeutic vaccination. Herein, we developed a recombinant BCG (RdrBCG) overexpressing Ag85B and Rv2628 with resistance to selected anti-TB drugs. When administered three times adjunct to a second-line anti-TB regimen in a classical murine model of DR-TB, the RdrBCG lowered lung M. tuberculosis colony-forming units by 1 log10. Furthermore, vaccination with the RdrBCG adjunct to TB chemotherapy minimized lung tissue pathology in mice. Most importantly, the RdrBCG maintained the exogenously inserted genes and showed almost the same virulence as its parent BCG Tice strain in severe combined immune-deficient mice. All these suggested that the RdrBCG was stable, safe and effective. Hence, the “recombinant” plus “drug-resistant” BCG strategy could be a useful concept for developing therapeutic vaccines against DR-TB.