Nanoparticle-Fusion Protein Complexes Protect against Mycobacterium tuberculosis Infection

作者：Hart Peter; Copland Alastair; Diogo Gil Reynolds; Harris Shane; Spallek Ralf; Oehlmann Wulf; Singh Mahavir; Basile Juan; Rottenberg Martin; Paul Matthew John; Reljic Rajko^*

来源：Molecular Therapy, 2018, 26(3): 822-833.

DOI：10.1016/j.ymthe.2017.12.016

Tuberculosis (TB) is the leading cause of death from infectious disease, and the current vaccine, Bacillus Cahnette-Guerin (BCG), is inadequate. Nanoparticles (NPs) are an emerging vaccine technology, with recent successes in oncology and infectious diseases. NPs have been exploited as antigen delivery systems and also for their adjuvantic properties. However, the mechanisms underlying their immunological activity remain obscure. Here, we developed a novel mucosal TB vaccine (Nano-FP1) based upon yellow carnauba wax NPs (YC-NPs), coated with a fusion protein consisting of three Mycobacterium tuberculosis (Mtb) antigens: Acr, Ag85B, and HBHA. Mucosal immunization of BCG-primed mice with Nano-FP1 significantly enhanced protection in animals challenged with low dose, aerosolized Mtb. Bacterial control by Nano-FP1 was associated with dramatically enhanced cellular immunity compared to BCG, including superior CD4(+) and CD8(+) T cell proliferation, tissue-resident memory T cell (Trm) seeding in the lungs, and cytokine polyfunctionality. Alongside these effects, we also observed potent humoral responses, such as the generation of Ag85B-specific serum IgG and respiratory IgA. Finally, we found that YC-NPs were able to activate antigen-presenting cells via an unconventional IRF-3-associated activation signature, without the production of potentially harmful inflammatory mediators, providing a mechanistic framework for vaccine efficacy and future development.

• 出版日期2018-3-7