AUTHOR=Liu Si-Jing , Tian Si-Cheng , Zhang Yun-Wen , Tang Tian , Zeng Ju-Mei , Fan Xiao-Yong , Wang Chuan 

TITLE=Heterologous Boosting With Listeria-Based Recombinant Strains in BCG-Primed Mice Improved Protection Against Pulmonary Mycobacterial Infection

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.02036

DOI=10.3389/fimmu.2020.02036

ISSN=1664-3224

ABSTRACT=<p>While Baccillus Calmette-Guerin (BCG) is used worldwide, tuberculosis (TB) is still a global concern due to the poor efficacy of BCG. Novel vaccine candidates are therefore urgently required. In this study, two attenuated recombinant <italic>Listeria</italic> strains, LMΔ<italic>-msv</italic> and LIΔ<italic>-msv</italic> were constructed by deletion of <italic>actA</italic> and <italic>plcB</italic> and expression of a fusion protein consisting of T cell epitopes from four <italic>Mycobacterium tuberculosis</italic> (<italic>Mtb</italic>) antigens (<italic>Rv2460c, Rv2660c, Rv3875</italic>, and <italic>Rv3804c</italic>). The safety and immunogenicity of the two recombinant strains were evaluated in C57BL/6J mice. After intravenous immunization individually, both recombinant strains entered liver and spleen but eventually were eliminated from these organs after several days. Simultaneously, they induced antigen-specific cell-mediated immunity, indicating that the recombinant <italic>Listeria</italic> strains were immunogenic and safe <italic>in vivo</italic>. LMΔ<italic>-msv</italic> immunization induced stronger cellular immune responses than LIΔ<italic>-msv</italic> immunization, and when boosted with LIΔ<italic>-msv</italic>, antigen-specific IFN-γ CD8<sup>+</sup> T cell responses were notably magnified. Furthermore, we evaluated the protection conferred by the vaccine candidates against mycobacterial infection via challenging the mice with 1 × 10<sup>7</sup> CFU of BCG. Especially, we tested the feasibility of application of them as heterologous BCG supplement vaccine by immunization of mice with BCG firstly, and boosted with LMΔ<italic>-msv</italic> and LIΔ<italic>-msv</italic> sequentially before challenging. Combination immune strategy (LMΔ<italic>-msv</italic> prime-LIΔ<italic>-msv</italic> boost) conferred comparable protection efficacy as BCG alone. More importantly, BCG-vaccinated mice acquired stronger resistance to Mycobacterial challenge when boosted with LMΔ<italic>-msv</italic> and LIΔ<italic>-msv</italic> sequentially. Our results inferred that heterologous immunization with <italic>Listeria</italic>-based recombinant strains boosted BCG-primed protection against pulmonary mycobacterial infection.</p>