Improving the protective characteristics of a promising tuberculosis vaccine candidate

Tuberculosis (TB) remains the leading cause of death from a single infectious agent, particularly in low- and middle-income countries where the burden of disease and drug resistance is greatest. The only licensed TB vaccine, Bacillus Calmette–Guérin (BCG), offers limited and inconsistent protection against adult pulmonary disease, necessitating the development of more effective vaccination strategies. This thesis explores subunit vaccine strategies aimed at improving the efficacy of BCG, by utilising the mycobacterial antigen PPE15 (Rv1039c) as a model antigen. PPE15 was delivered via protein-adjuvant and RNA platforms, both as homologous and heterologous prime-boost regimens in combination with a chimpanzee adenoviral vector, ChAdOx1.PPE15. Among the formulations tested, PPE15 protein combined with the liposome-based adjuvant LMQ, was particularly promising, inducing robust CD4+ T cell responses and protection against M.tb challenge. Novel RNA-based approaches, mRNA and self-amplifying RNA (saRNA), induced potent CD8+ T cell and antibody responses but did not provide protection. Immunogenicity analyses suggest that the absence of antigen-specific lung resident memory T cells (TRM) following RNA vaccination might underlie the lack of protection. Supporting this hypothesis, heterologous prime-boost regimens combining both RNA.PPE15 or PPE15-LMQ with intranasal ChAdOx1.PPE15 increased the frequency of lung TRM and improved protection, these findings also highlight the importance of prime-pull approaches as a strategy to improve lung immunity and highlight an important role of TRM in TB protection. Overall, the findings support the inclusion of PPE15 in next-generation TB vaccine regimens and demonstrate that optimising vaccine platform and delivery routes can significantly enhance immune protection against M.tb. These insights contribute to the rational design of TB vaccines and the broader goal of identifying immune correlates of protection, ultimately advancing the global effort to eliminate TB.