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( ) is the causative agent of tuberculosis (TB), a disease with a severe global burden. The intractability of has prevented the identification of clear correlates of protection against TB and hindered the development of novel TB vaccines that are urgently required. Lipid nanoparticle (LNP)-formulated mRNA is a highly promising vaccine platform that has yet to be thoroughly applied to TB. We selected five antigens (PPE15, ESAT6, EspC, EsxI, MetE) and evaluated their potential as LNP-formulated mRNA vaccines, both when each antigen was delivered individually, and when all five antigens were combined in a mix regimen (m-Mix). Each mRNA construct demonstrated unique cellular and humoral immunogenicity, and both m-Mix, as well as the single antigen EsxI, conferred significant protection in a murine challenge model. Whilst the potent immune responses of each mRNA were maintained when applied as a boost to BCG, there was no additional increase to the efficacy of BCG. Combination of m-Mix with a recombinant, replication-deficient chimpanzee adenovirus (ChAdOx1), in a heterologous prime-boost delivery (C-m-Mix), appeared to result in increased protection upon murine infection, than either regimen alone. This work warrants further investigation of LNP-formulated mRNA vaccines for TB, whilst indicating the potential of m-Mix and C-m-Mix to progress to further stages of vaccine development.

BCG remains the only licensed vaccine for tuberculosis (TB), but its efficacy wanes over time. Subunit vaccines, aim to improve BCG immunity and protection, by inducing responses to a few mycobacterial antigens delivered with a specific platform. Since the platform shapes the immune response induced, selecting the right platform has been challenging due to the lack of immune correlates of protection. Recently, the protein-adjuvated subunit vaccine. M72/AS01E, demonstrated 49.7% efficacy in preventing active TB in latently infected adults, indicating that protective immunity through subunit vaccines is possible. In this study we evaluated the immunogenicity and efficacy of the promising mycobacterial antigen PPE15, formulated with five adjuvants developed by the Vaccine Formulation Institute. While all adjuvants were immunogenic, PPE15 with LMQ protected vaccinated mice against an in vivo Mycobacterium tuberculosis challenge, both as a standalone vaccine and as a boost to BCG. Vaccinated mice had enriched lung parenchymal antigen-specific CD4 + CXCR3 + KLRG1− T cells previously associated with TB protection. Heterologous vaccination strategies were also explored by combining intranasal ChAdOx1.PPE15 viral vector, with intramuscular PPE15-LMQ resulting in improved protection compared to individual vaccines. These findings support the progression of this vaccine candidate to the next stages of development.

The development of tuberculosis (TB) vaccines has been hindered by the complex nature of Mycobacterium tuberculosis ( M.tb ) and the absence of clearly defined immune markers of protection. While Bacillus Calmette-Guerin (BCG) is currently the only licensed TB vaccine, its effectiveness diminishes in adulthood. In our previous research, we identified that boosting BCG with an intranasally administered chimpanzee adenovirus expressing the PPE15 antigen of M.tb (ChAdOx1.PPE15) improved its protection. To enhance the vaccine’s efficacy, we combined PPE15 with the other three members of the Esx-5a secretion system and Ag85A into a multi-antigen construct (5Ag). Leveraging the mucosal administration safety of ChAdOx1, we targeted the site of M.tb infection to induce localized mucosal responses, while employing modified vaccinia virus (MVA) to boost systemic immune responses. The combination of these antigens resulted in enhanced BCG protection in both the lungs and spleens of vaccinated mice. These findings provide support for advancing ChAdOx1.5Ag and MVA.5Ag to the next stages of vaccine development.

Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide, and Bacillus Calmette-Guérin (BCG) offers inconsistent protection against adult pulmonary TB. We previously showed that homologous mRNA vaccination encoding the mycobacterial antigen PPE15 (mRNA.PPE15) enhanced immunogenicity but did not improve protection over BCG alone. We hypothesised that a heterologous \"prime-pull\" strategy, systemic mRNA priming followed by mucosal adenoviral boosting, would enrich lung-resident memory T cells (TRM) and improve efficacy. Female C57BL/6 mice received BCG prime followed by subunit regimens combining intramuscular mRNA.PPE15 and intranasal ChAdOx1.PPE15 in different administration orders, alongside homologous controls. Cellular responses in spleen and lung were quantified by intracellular cytokine staining after PPE15 peptides stimulation. Intravascular staining was used to distinguish parenchymal (IV-) from vascular (IV+) cells and combined with tetramer staining to identify PPE15-specific CD4+ and CD8+ TRM-phenotype in the lung parenchymal following vaccination. PPE15-specific serum antibodies were measured by ELISA. Protective efficacy was assessed four weeks after aerosol ( ) challenge by lung and spleen CFU enumeration. Heterologous vaccination induced robust spleen CD4+ and CD8+ responses and PPE15-specific IgG. In the lung, mRNA.PPE15-ChAdOx1.PPE15 induced IFN-γ+ CD4+ and CD8+ T cells in the parenchyma and PPE15-specific TRM-like cells. Following challenge, both heterologous regimens reduced lung CFU compared to naïve controls, but only mRNA.PPE15-ChAdOx1.PPE15 significantly decreased CFU in both lungs and spleen. When used to boost BCG, BCG-mRNA.PPE15-ChAdOx1.PPE15 achieved 0.8 log10 CFU reductions in lungs and spleen compared to BCG control group and induced the greatest numbers of lung TRM-phenotype cells. A heterologous prime-pull strategy that combines intramuscular mRNA.PPE15 priming with intranasal ChAdOx1.PPE15 boosting effectively directs PPE15-specific T cells to the lung parenchyma, enriches TRM-like populations, and improves protection over homologous regimens. There was a trend for the mRNA.PPE15-ChAdOx1.PPE15 regimen to outperform the reverse order, particularly as a BCG booster. These data support heterologous platform vaccination and prime-pull strategy as a novel strategy for TB vaccines and indicate potential to progress to the next stages of vaccine development.

Tuberculosis (TB), caused by (MTB), remains a significant global health concern. The existing vaccine, Bacillus Calmette-Guérin (BCG), provides inconsistent protection, highlighting the pressing need for a more effective vaccine. We aimed to identify novel antigens and assess their protective efficacy as TB vaccine candidates. Using immunopeptidomics, we identified 64 and 80 unique mycobacterial antigens derived from BCG and MTB, respectively. We prioritised antigens based on HLA allele coverage through an immunoinformatics approach. The candidates, , , and , delivered as DNA vaccines, were evaluated for efficacy in mice using the ex vivo Mycobacterial Growth Inhibition Assay (MGIA) and was identified as a promising candidate. In vivo murine challenge experiments confirmed the protective efficacy conferred by when formulated as recombinant protein with AS01™ or AddaS03™ adjuvants, compared to the naïve group. The immunogenic profiles of formulated in the two different adjuvants differed, with -AS01™ inducing antigen-specific IFN-γ, TNF-α, IL-2, IL-17, IgG1 and IgG2a-c, while -AddaS03™ induced TNF-α, IL-2, IL-17, IL-4, IgM, IgG1, IgG2b. Our findings highlight as a promising protective antigen for future TB vaccine development.