Testing a novel, self-adjuvanting mucosal vaccine candidate for TB in the mouse model of infection
Led by Dr Andy Tran (SGUL, UK), with Prof Andrea Cooper (University of Leicester, UK) and Prof Rajko Reljic (SGUL, UK)
Project Aims
Tuberculosis (TB) predominantly affects the lungs and is caused by Mycobacterium tuberculosis (Mtb). Despite being among the oldest known human pathogens and one of the first to be identified as a causative agent of an infectious human disease, there is currently only one licensed vaccine against TB, Bacillus Calmette Guerin (BCG), which offers highly variable levels of protection against pulmonary TB in adults. With the increasing burden of drug resistant TB, it is imperative that we continue to test and develop new and more effective vaccine strategies.
We propose that the "next generation" of TB vaccines should be focused on mucosal delivery to offer increased efficacy compared to BCG, in addition to a lower cost and ease of adminstration in low-middle income settings where TB is most prevalent. In this project, we will test a novel vaccine candidate, TB-PCF, based on our 'all-in-one' patented vaccine delivery system that does not require living organisms or chemical compounds (adjuvants) for it to induce a robust immune response after respiratory delivery. This can dramatically accelerate quality control and clinical development and testing, by reducing the number of discrete components required in a vaccine candidate, while inducing robust immunity. This project aims to test this novel vaccine candidate against TB in the mouse model of infection, using the mucosal route of vaccine delivery. Immune response to TB-PCF vaccination, with or without prior vaccination with systemic BCG, will be determined. Protective efficacy of the new vaccination regimen against pathogenic TB challenge will be also determined, and if successful, this will pave the way for further development of TB-PCF as a potential new BCG-boost TB vaccine candidate.
Project Outcomes
In this project, we tested a new tuberculosis vaccine candidate, termed TB-PCF, as a novel ‘all-in-one’ vaccine delivery system incorporating Fc portion of human IgG, molecular adjuvant CTB and ESAT6-CFP10 antigens of Mtb, within a single polymeric polypeptide. We have previously demonstrated promising immunogenicity and efficacy of the PCF platform against viral infections such as Dengue and SARS-CoV2, with this project being the first trial of the platform against a bacterial pathogen. Initially, we generated TB-PCF in the plant expression system and characterised the protein by size exclusion chromatography and dynamic light scattering, revealing the presence of polymeric structures which can aid antigen uptake and presentation. We then investigated the interaction of TB-PCF with antigen presenting cells in vitro, as well as the feasibility of aerosolisation, an important prerequisite for potential mucosal delivery. We then conducted an in vivo immunogenicity and an aerosol Mtb challenge study in the mouse model, following systemic priming and intranasal boosting with TB-PCF. Immunogenicity analysis revealed presence of systemic and mucosal antibodies, as well as CD4 and CD8 T effector memory cells (Th1 and Th17) which were able to partially restrict growth of Mtb in the in vitro MGIA assay. However, bacteriological plating of the infected lung tissue did not show reduction of bacterial burden in immunised mice. While the efficacy arm of the in vivo study did not show a protective effect, the promising immunogenicity results warrants further exploration of the PCF platform against other TB antigens.
Project Outputs - the project influenced the following manuscripts
García-Bengoa, M., et al. Immunogenicity of PE18, PE31, and PPE26 proteins from Mycobacterium tuberculosis in humans and mice. Front. Immunol. 14, 1307429-1307429, 2023
