Overcoming innate immune tolerance in the respiratory tract for optimal vaccine design
Led by Dr Rajko Reljic (SGUL) with Prof Tracy Hussell (University of Manchester) [originally awarded to and led by Dr Alastair Copland at SGUL]
Mucosal (i.e. non-injectable) administration is a preferred route of vaccine delivery against pathogens that infect mucosal tissues. Mycobacterium tuberculosis (Mtb) enters via the respiratory tract and infects lungs. Therefore, mucosal vaccination against tuberculosis would be highly desirable, for both practical reasons of the ease of vaccine delivery but also for enhanced protection, since the vaccine would engage the same immune tissues and mechanisms that the pathogen encounters itself. However, one significant roadblock in a mucosal vaccination strategy is the difficulty in inducing robust immune responses compared to systemic vaccination. This, we believe, is due to the high immune tolerance levels in mucosal tissues and the anti-inflammatory manner in which antigens are removed. For example, the phagocytic activity of lung alveolar macrophages may destroy the vaccine without effectively engaging the adaptive immune response. Another aspect is the removal or degradation of the vaccine by the mucosal fluids. To overcome these obstacles, we will study in detail the role of alveolar macrophages in mucosal vaccination. We will also attempt to bypass the macrophages by targeting novel vaccine constructs to the alveolar epithelium, leading to longer vaccine persistence and better access to the immune cells of the submucosa.
This project aimed to tackle the fundamental challenge of how to improve mucosal vaccine immunogenicity in the context of tuberculosis infection. We used a multi-pronged approach to tackle this challenge by focusing on some of the key steps and events during mucosal immunisation and vaccine interaction with the respiratory mucosa. We found that mucosal (intranasal) subunit vaccines that incorporate the HBHA antigen of M. tuberculosis confer better protection against infection then the same formulations without. We furthermore tested the role of alveolar macrophages in the priming of the immune response induced by a mucosal TB vaccine candidate. Depletion of alveolar macrophages by clodronate liposomes perturbed the composition of lung lavage cells so that macrophage population is largely diminished and there is an influx of a new, yet uncharacterised cell population. This is accompanied by an enhanced mucosal antibody (IgA and IgG) response to vaccine antigens and enhanced IFN-g production by spleen cells. The ongoing work is focused on determining if these immunological changes following depletion of alveolar macrophages could translate into better protection against M. tuberculosis infection in mice. Finally, we demonstrate that it is possible to downregulate lung macrophage function by pharmacological means by targeting CD200 receptor on their surface.
Copland A, Diogo GR, Hart P, Harris S, Tran AC, Paul MJ, Singh M, Cutting SM, Reljic R Mucosal delivery of fusion proteins with Bacillus subtilis spores enhances protection against tuberculosis by BCG. Front Immunol 2018 Mar 12;9:346