A Promising Listeria-Vectored Vaccine Induces Th1-Type Immune Responses and Confers Protection Against Tuberculosis

Abstract

Deaths associated with tuberculosis (TB) is rising and accounted for 1.4 million deaths in 2015 many of which were due to drug-resistant bacteria. Vaccines represent an important medical intervention, but the current Bacilli Calmette-Guerin (BCG) vaccine is not ideal for the protection of teenagers and adults. Therefore, a safe and effective vaccine is urgently needed. In this study, we designed a novel vaccine using an attenuated Listeria monocytogenes strain carrying fusion antigen FbpB-ESAT-6 (rLM) and characterized its safety and protective efficacy against Mycobacterium tuberculosis (M.tb) infection in mice. Compared to the wild type strain yzuLM4 and parental strain LMΔactA/plcB (LM1-2), the virulence of rLM was significantly reduced as judged by its infectious kinetics and LD50 dose. Further characterization of intravenous immunization showed that prime-boost vaccination significantly increased the levels of Th1 cytokines (IFN-γ, IL-17, and IL-6), and enhanced cytotoxic T lymphocyte (CTL) CTLs activity, suggesting that rLM could elicit potent Th1/Th17 responses. More importantly, rLM significantly conferred the protection against M.tb H37Rv challenge. Collectively, our findings indicated that rLM is a novel and useful tool to prevent M.tb infection, and can be potentially be used to boost BCG-primed immunity.

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

“…The failure of an TB vaccine candidate MVA85A that based on a modified Ankara virus vector indicated the need for further study to develop new booster vaccines against TB ( 2 ). Attenuated LM has been developed as a vaccine vector for TB vaccine candidates ( 11 – 14 ). Recently, we constructed two attenuated LI recombinant strains expressing Ag85A or ESAT-6, which induced potent CD4 + and CD8 + T cell responses either in the spleen after intravenous immunization ( 10 ) or in the lung after intranasal vaccination ( 15 ).…”

“…Recently, we constructed two attenuated LI recombinant strains expressing Ag85A or ESAT-6, which induced potent CD4 + and CD8 + T cell responses either in the spleen after intravenous immunization ( 10 ) or in the lung after intranasal vaccination ( 15 ). Therefore, the facultative intracellular Listeria strain is considered as a promising delivery system since it induces strong CD4 + and CD8 + cell-mediated immune response ( 9 – 11 ). Besides, unlike virus-vectored TB vaccines such as MAV85A, human pre-existing immunity to Listeria was lower.…”

“…The notable induction of polyfunctional CD8 + T cell responses in this study suggests a promising immunogenicity of such Listeria -based Mtb delivery system to be a booster of BCG. We are not the first to use Listeria -vector TB vaccine as a booster vaccine for BCG, but few of the others analyzed the quantity of the polyfunctional T cell responses in mice or other animal models ( 11 , 12 ). Yin et al ( 11 ) reported an attenuates LM-vector Tb candidate expressing Mtb FbpB and ESAT-6 that was used as a BCG booster vaccine.…”

“…We are not the first to use Listeria -vector TB vaccine as a booster vaccine for BCG, but few of the others analyzed the quantity of the polyfunctional T cell responses in mice or other animal models ( 11 , 12 ). Yin et al ( 11 ) reported an attenuates LM-vector Tb candidate expressing Mtb FbpB and ESAT-6 that was used as a BCG booster vaccine. It could elevate antigen-specific IFN-γ secretion, but as for polyfunctional T cells they did not investigate.…”

The effect of adjuvants and delivery systems on Th1, Th2, Th17 and Treg cytokine responses in mice immunized with Mycobacterium tuberculosis-specific proteins

“…However, the delivery of these antigens is a key issue that may have influence on the quality of immune responses induced, i.e. protective (Th1) [21,22], pathologic (Th2 and Treg) [23,24], or both protective and pathologic (Th17) [25]. To induce the desired immune responses against protein antigens, adjuvants and delivery systems are often required to deliver the antigens [26].…”