Mycobacterium tuberculosis multistage antigens confer comprehensive protection against pre- and post-exposure infections by driving Th1-type T cell immunity

// Jilei Ma 1, * , Maopeng Tian 1, * , Xionglin Fan 1 , Qi Yu 1 , Yukai Jing 1 , Weihua Wang 2 , Li Li 2 , Zijie Zhou 1 1 Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China 2 Wuhan Pulmonary Hospital, Wuhan Institute for Tuberculosis Control, Wuhan 430030, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Xionglin Fan, email: xlfan@hust.edu.cn Keywords: TB, subunit vaccine, primary infection, post-exposure, Th1 Received: May 08, 2016     Accepted: August 11, 2016     Published: August 23, 2016 ABSTRACT There is an urgent need for a vaccine against tuberculosis (TB) that is more effective than the current sole licensed option. However, target antigens of Mycobacterium tuberculosis with the vaccine potential remain elusive. Five immunodominant antigens with characteristic expressions at the stages of primary infection (Ag85A), the regulation of nutrition and metabolism when transferring from rapid growth to latency (PhoY2 and Rv3407), latency (Rv2626c), and reactivation (RpfB) were selected to construct the fusion polyprotein WH121, which has better immunogenicity and protection than each multistage antigen. DMT adjuvanted WH121 vaccinated C57BL/6 mice could confer persistent and significant protection against the respiratory challenge with 80 CFU of virulent M. tuberculosis H37Rv at 9 and 18 weeks after immunization, as the BCG vaccine did. Moreover, WH121/DMT could boost the BCG primed mice against post-exposure infection, and more significantly inhibit the growth of M. tuberculosis in the spleen than BCG repeat vaccination. The protection elicited by WH121/DMT is attributed to the WH121-specific Th1-type biased immune responses, characterized by increased antigen-specific IgG2a/IgG1 ratio and high levels of IFN-γ secreted by the splenocytes of vaccinated mice. In particular, high levels of IFN-γ + T EM cells in the spleen are an effective biomarker for the vaccine-induced early protection, and the persistent protection mainly depends on the increasing IL-2 + IFN-γ + CD4 + and CD8 + T cells, especially IL-2 + T CM cells. These findings demonstrate that multistage-specific antigens might be promising targets for the next generation TB vaccine, and a combination of these antigens such as WH121/DMT is required for further preclinical evaluation.