B Cell-Based Vaccine Transduced With ESAT6-Expressing Vaccinia Virus and Presenting α-Galactosylceramide Is a Novel Vaccine Candidate Against ESAT6-Expressing Mycobacterial Diseases

Abstract

Early secretory antigenic target-6 (ESAT6) is a potent immunogenic antigen expressed in Mycobacterium tuberculosis as well as in some non-tuberculous mycobacteria (NTM), such as M. kansasii. M. kansasii is one of the most clinically relevant species of NTM that causes mycobacterial lung disease, which is clinically indistinguishable from tuberculosis. In the current study, we designed a novel cell-based vaccine using B cells that were transduced with vaccinia virus expressing ESAT6 (vacESAT6), and presenting α-galactosylceramide (αGC), a ligand of invariant NKT cells. We found that B cells loaded with αGC had increased levels of CD80 and CD86 after in vitro stimulation with NKT cells. Immunization of mice with B/αGC/vacESAT6 induced CD4+ T cells producing TNF-α and IFN-γ in response to heat-killed M. tuberculosis. Immunization of mice with B/αGC/vacESAT6 ameliorated severe lung inflammation caused by M. kansasii infection. We also confirmed that immunization with B/αGC/vacESAT6 reduced M. kansasii bacterial burden in the lungs. In addition, therapeutic administration of B/αGC/vacESAT6 increased IFN-γ+ CD4+ T cells and inhibited the progression of lung pathology caused by M. kansasii infection. Thus, B/αGC/vacESAT6 could be a potent vaccine candidate for the prevention and treatment of ESAT6-expressing mycobacterial infection caused by M. kansasii.

The role of donor‐unrestricted T‐cells, innate lymphoid cells, and NK cells in anti‐mycobacterial immunity

“…Administration of a novel B-cell targeting vaccine expressing ESAT6 and loaded with α-GalCer showed both preventive and therapeutic effects in M kansasii infected mice, mediated by enhanced B-cell and CD4 + T-cell function. 181 Additional efforts are underway to design lipid-based vaccine strategies able to induce NKT-cell responses. 182…”

“…However, at later time points, the treatment had no benefits, possibly as a consequence of apoptotic or irresponsive NKT‐cells, underscoring their relevance as an early immune response component against Mtb infection, akin to the above observations for MAITs. Administration of a novel B‐cell targeting vaccine expressing ESAT6 and loaded with α‐GalCer showed both preventive and therapeutic effects in M kansasii infected mice, mediated by enhanced B‐cell and CD4 + T‐cell function 181 . Additional efforts are underway to design lipid‐based vaccine strategies able to induce NKT‐cell responses 182 …”

Autophagy and Host Defense in Nontuberculous Mycobacterial Infection

“…Additionally, BCG vaccination currently in use for immunization against Mtb could be exploited against NTM ( 117 , 118 ). However, BCG vaccine interference by NTM mycobacterial species is thought to be a potential cause of its reduced efficacy against Mtb ( 119 ).…”

Host Immune Response and Novel Diagnostic Approach to NTM Infections

“…NKT cells recognize lipid antigens (e.g., MA, LAM, PIM, glucose monomycolate, and GroMN, a member of the CD1 family [54,55]) and can produce several cytokines immediately after activation [56]. NKT cells might play roles in modulating immune response after NTM infection, as well as Mtb infection [57].…”