Heterologous Boost Vaccination Improves BCG Priming Protection Against Latent Tuberculosis Infection Rather than Primary Infection

Adults are the leading population affected by tuberculosis (TB) epidemic and death. Developing an effective vaccine against adult TB is urgently needed. BCG prime-heterologous boost strategy has been explored extensively to protect adults against primary TB infection, but the majority of experimental regimens have not improved the protection primed by the BCG vaccine with unknown reason. In this study, CTT3H-based vaccines, namely recombinant adenovirus rAdCTT3H, DMT adjuvanted subunit or DNA vaccine were constructed. Protective efficacy and immunogenicity of BCG prime-CTT3H based boosters were compared in C57BL/c mice models of primary TB and latent TB infection. Heterologous boosters did not enhance the protection primed by the BCG vaccine against primary infection, but they conferred stronger protection against latent TB infection than BCG alone, regardless of vaccine types. BCG prime-boosters elicited Th1-biased responses and increased the number of CTT3H-sepcific IFN-γ T cells and IFN-γ TEM cells in the spleen before exposure to M. tuberculosis infection, while IFN-γ and IL-2 T cells and memory T cells, including IL-2-expressing TCM cells and IFN-γ-expressing TEM cells, in the spleen and lung were significantly increased post-exposure vaccination. Therefore, BCG prime-boost strategy might be a promising measure to protect adult against latent TB infection. Funding Statement: This work was supported by grants of the National Megaproject of Science Research for both the 13th Five-year Plan of China (No. 2018ZX10302302002-001) and the 12th Five-year Plan of China (No. 2012ZX10003008-005), and the National Natural Science Foundation of China (No.81772147). The funders had no role in study design, data collection, data analysis,interpretation, and writing of the report. Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: The study protocol involving animal experiments were performed in accordance with the guidelines of the Chinese Council on Animal Care. The Committee on the Ethics of Animal Experiments and the School Committee on Biosaftey of Tongji Medical College (Wuhan, China) approved the research protocols.