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Tuberculosis Subunit Vaccine EAMMH and Vaccine-induced Immune Memory

Tuberculosis Subunit Vaccine EAMMH and Vaccine-induced Immune Memory. Bingdong Zhu Lanzhou University bdzhu@lzu.edu.cn 2014.09.26 Valencia. The strategies for tuberculosis vaccine development. Boost one or more times. Immunity. ①. ②. Threshold. BCG. 70+. 10-15. Age (year).

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Tuberculosis Subunit Vaccine EAMMH and Vaccine-induced Immune Memory

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  1. Tuberculosis Subunit Vaccine EAMMH and Vaccine-induced Immune Memory Bingdong Zhu Lanzhou University bdzhu@lzu.edu.cn 2014.09.26 Valencia

  2. The strategies for tuberculosis vaccine development Boost one or more times Immunity ① ② Threshold BCG 70+ 10-15 Age (year) Novel subunit vaccine Booster of BCG Replacement of BCG Andersen P, Nature reviews microbiology 2005; 3:656-62.

  3. Ag85B MPT64 Mtb8.4 Rv2626 HspX ESAT-6 Mtb 10.4 Resuscitation, Replication, Dormancy, Death of M. tuberculosis The Yin-Yang model and antigens selection for TB vaccine Reverts Dormant Replicating Persisters Yin-Yang Model Ying Zhang, Clin Pharmacol Ther. 2007;82(5):595-600.

  4. The main fusion proteins constructed in our lab • Ag85B-MPT64（190- 198）-Mtb8.4 (AMM) (Vaccine 2009) • ESAT6-AMM (EAMM) (PLoS One 2013) • Mtb10.4-HspX (MH) (Vaccine 2011) *p < 0.05 vs. PBS. ** p < 0.05 vs. PBS, EAMM and MH.

  5. The novel multistage subunit vaccine candidate Fusion proteins: • EAMM-HspX(EAMMH, LT69) Adjuvant: DDA + Ploy I:C

  6. The immunogenicity and protective efficiency of EAMMH

  7. PBS BCG Subunit Vaccine _ _ _ + + The schedule of immunization and challenge Immune responses H37Rv CFU detection 0W 2W 4W 10w 28w 34W 44W

  8. The immunogenicity of EAMMH IFN-γ production with the stimulation of special antigens in vivo * p < 0.05 vs. PBS，BCG and EAMM+MH groups IL-2 production with the Ag85B stimulation in vivo

  9. The protective efficacy of EAMMH * p < 0.05 vs. PBS，BCG and EAMM+MH groups; ** p < 0.05 vs. PBS and BCG groups.

  10. Regulation the immune responses induced by EAMMH

  11. T cells activation and their cytokine network during M. tuberculosis infection Th1 Th2 Treg Th17 IL-17 IL-21 IL-22 T TGF-β IL-6 IL-23 IFN-γ TNF-α IL-2 GM-CSF γδT IL-12 IL-18 MHC-Ⅱ CD4 Phospholigand IFN-γ IL-4 IL-4 IL-5 IL-13 IL-4 IL-5 IL-13 IL-25 MHC-Ⅰ Peptide CD-1 TGF-β (High concentration) Lipid CD8 IL-10 TGF-β IL-28B

  12. IL-28B down-regulated Tregs following vaccination with EAMMH FoxP3 CD25

  13. IL-28B enhanced short-term protective efficacy induced by the EAMMH vaccination

  14. IL-28B impaired long-term antigen-specific immune memory

  15. Factors that affect the immune memory induced by EAMMH • Antigen dose • Rapamycin

  16. Low dose of antigen generated long-lived cellular immune responses * p < 0.05 vs. PBS，BCG and EAMM+MH groups; ** p < 0.05 vs. PBS and BCG groups.

  17. Rapamycin treatments increased the immune responses and protective efficacy Mice were challenged with BCG by tail vein 30 wk after last immunization The antigen specific IFN-γ expression 24 wk after the last immunization

  18. Vaccine induction of memory T cells Antigen Contraction Expansion Contraction Naïve T cells TEM TCM TCM TE TEM TCM Rapamycin Rapamycin • More antigens stimulate more effector T cells and less memory T cells • Down-regulating Tregs induces more effector T cells, less memory T cells

  19. Conclusion • Subunit vaccine EAMMH induced long-term T cell immune responses in mice, and its protective efficacy against M. tuberculosis was even higher than traditional vaccine BCG. • Down-regulation of regulatory T cells does not benefit to long-term immunity. • Low-dose EAMMH had the benefit to generate long-term immune memory. • The EAMMH-induced immune memory could be enhanced by additional treatment with rapamycin during vaccination.

  20. Acknowledgement Fudan University Prof. WANG Honghai Johns Hopkins University Prof. Ying Zhang MIT Prof Jianzhu Chen ABSL-3 of Wuhan University AERAS Lanzhou University Prof. JING Tao Dr. MA Xingming YU Hongjuan Dr. TANG Jiying Dr. LI Qin Dr. LUO Yu NIU Hongxia LUO Yanping LIU Xun SONG Nannan DA Zejiao XIN Qi JIANG Wenwen PENG Jinxiu LI Zhi ZHANG Guoping LIU Wanbo WANG Yue BAI Chunxiang CHEN Huiyu SUN Hongjia TANG Kefeng BAI Chunxiang Lanzhou Institute of Biological Products Dr. WANG Bingxiang HU Lina Gansu Province CDC Lanzhou Lung Hospital Funding 863 Project of China National Major S&T Projects of China NSFC of China

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