Mucosal delivery of antigen‐coated nanoparticles to lungs confers protective immunity against tuberculosis infection in mice

Abstract

Mucosal boosting of BCG-immunised individuals with a subunit tuberculosis (TB) vaccine would be highly desirable, considering that the lungs are the principal port of entry forMycobacterium tuberculosis (MTB) and the site of the primary infection and reactivation. However, the main roadblock for subunit TB vaccine development is the lack of suitable adjuvants that could induce robust local and systemic immune responses. Here, we describe a novel vaccine delivery system that was designed to mimic, in part, the MTB pathogen itself. The surface of yellow carnauba wax nanoparticles was coated with the highly immunogenic Ag85B Ag of MTB and they were directed to the alveolar epithelial surfaces by the incorporation of the heparin-binding hemagglutinin adhesion (HBHA) protein. Our results showed that the i.n. immunisation of BCG-primed BALB/c mice with nanoparticles adsorbed with Ag85B-HBHA (Nano-AH vaccine) induced robust humoral and cellular immune responses and IFN-γ production, and multifunctional CD4 + T cells expressing IFN-γ, IL-2 and TNF-α. Mice challenged with H37Rv MTB had a significantly reduced bacterial load in their lungs when compared with controls immunised with BCG alone. We therefore conclude that this immunisation approach is an effective means of boosting the BCG-induced anti-TB immunity.Keywords: Immunity r Mucosal r Nanoparticles r Tuberculosis r Vaccine Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionWith BCG considered an unsatisfactory vaccine and multi-drug resistant tuberculosis (TB) on the rise, there is an urgent need to Correspondence: Dr. Rajko Reljic e-mail: rreljic@sgul.ac.uk develop a more efficacious TB vaccine. Several new vaccine candidates are currently in clinical trials or have completed them, but none of them are able to induce sterilising immunity. Most disappointingly, a recently completed large phase-2b trial with the modified vaccinia Ankara-Ag85A-vectored vaccine in BCG-vaccinated children in South Africa failed to demonstrate any significantly added protection against TB compared with BCG alone [1]. However, many other vaccine candidates are still at the research and C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 440-449 Immunity to infection 441 development stage, and there is hope that some of them will enter the clinical trial pipeline in the near future. An alternative to either live (i.e. recombinant BCG) or the vector-based vaccines (i.e. replication deficient vaccinia virus or adenovirus) is immunisation with adjuvanted proteins, though the success of this approach has been somewhat limited because of the lack of safe and robust adjuvants. Adjuvant development has been hampered by a number of inherent difficulties, and only a few have so far been approved for human use. In particular, there is a dearth of adjuvants that are able to induce the Th1 immune responses required in TB. The only adjuvants that have been licensed for human use so ...

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“…An emerging approach involves the use of vaccines with adjuvanted proteins that are capable of inducing the T-helper 1 (Th1) immune response required for TB protection. [45] Despite these novel approaches, significant challenges still remain, which curtail the efficacy of present generation of TB vaccines. There remains a dearth of safe and robust adjuvants capable of stimulating the immune response needed for adequate TB protection; currently used adjuvants, e.g., aluminium hydroxide disappointingly suffers from limited efficacy, cytotoxicity, and instability during storage.…”

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