Subunit Vaccine ESAT-6:c-di-AMP Delivered by Intranasal Route Elicits Immune Responses and Protects Against Mycobacterium tuberculosis Infection.

Huanhuan Ning,Yanzhi Lu,Huapeng Wang,Wei Zhang,Tianbing Ding,Jian Kang,Xuan Liang,Lixin Shen,Chengxuan Guo,Wenjie Sun,Yinlan Bai

doi:10.3389/fcimb.2021.647220

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, remains the most common cause of death from a single infectious disease. More safe and effective vaccines are necessary for preventing the prevalence of TB. In this study, a subunit vaccine of ESAT-6 formulated with c-di-AMP (ESAT-6:c-di-AMP) promoted mucosal and systemic immune responses in spleen and lung. ESAT-6:c-di-AMP inhibited the differentiations of CD8+ T cells as well as macrophages, but promoted the differentiations of ILCs in lung. The co-stimulation also enhanced inflammatory cytokines production in MH-S cells. It was first revealed that ESAT-6 and c-di-AMP regulated autophagy of macrophages in different stages, which together resulted in the inhibition of Mtb growth in macrophages during early infection. After Mtb infection, the level of ESAT-6-specific immune responses induced by ESAT-6:c-di-AMP dropped sharply. Finally, inoculation of ESAT-6:c-di-AMP led to significant reduction of bacterial burdens in lungs and spleens of immunized mice. Our results demonstrated that subunit vaccine ESAT-6:c-di-AMP could elicit innate and adaptive immune responses which provided protection against Mtb challenge, and c-di-AMP as a mucosal adjuvant could enhance immunogenicity of antigen, especially for innate immunity, which might be used for new mucosal vaccine against TB.

Highlights

Tuberculosis (TB) remains the most common cause of death from a single infectious disease
These results indicated that subunit vaccine ESAT-6:c-di-AMP induces high systemic IgG and higher local mucosal secreted IgA (sIgA), and c-di-AMP as a mucosal
We have demonstrated that Ag85BESAT-6 adjuvanted with monophosphoryl lipid A (MPLA) induces significant humoral and cellular immune response via s.c. administration, which mainly caused by Ag85B (Xu, 2014)

Summary

Introduction

Tuberculosis (TB) remains the most common cause of death from a single infectious disease. Two billion people worldwide are infected with Mycobacterium tuberculosis (Mtb), with around 10 million new cases of TB emerging each year and approximately 1.4 million deaths in 2019 (WHO, 2020). As of 2020, there are 14 new TB vaccines in clinical trials, and four of those are subunit vaccines composed of serial Mtb antigens with different adjuvants (WHO, 2020). Subunit vaccine exhibits superior safety and activates stronger antigens-specific immune response compared with other vaccines such as DNA vaccine and attenuated live mycobacterial vaccine (Zhu et al, 2018). More efforts are being made in the formulation, adjuvants, and delivery methods of subunit vaccine to improve the protection against Mtb infection

Methods

Results

Conclusion