Abstract
Tuberculosis (TB) is the most deadly infectious disease in existence, and the only available vaccine, Bacillus Calmette-Guérin (BCG), is almost a century old and poorly protective. The immunological complexity of TB, coupled with rising resistance to antimicrobial therapies, necessitates a pipeline of diverse novel vaccines. Here, we show that Bacillus subtilis spores can be coated with a fusion protein 1 (“FP1”) consisting of Mycobacterium tuberculosis (Mtb) antigens Ag85B, ACR, and HBHA. The resultant vaccine, Spore-FP1, was tested in a murine low-dose Mtb aerosol challenge model. Mice were primed with subcutaneous BCG, followed by mucosal booster immunizations with Spore-FP1. We show that Spore-FP1 enhanced pulmonary control of Mtb, as evidenced by reduced bacterial burdens in the lungs. This was associated with elevated antigen-specific IgG and IgA titers in the serum and lung mucosal surface, respectively. Spore-FP1 immunization generated superior antigen-specific memory T-cell proliferation in both CD4+ and CD8+ compartments, alongside bolstered Th1-, Th17-, and Treg-type cytokine production, compared to BCG immunization alone. CD69+CD103+ tissue resident memory T-cells (Trm) were found within the lung parenchyma after mucosal immunization with Spore-FP1, confirming the advantages of mucosal delivery. Our data show that Spore-FP1 is a promising new TB vaccine that can successfully augment protection and immunogenicity in BCG-primed animals.
Highlights
In 2015, tuberculosis (TB) overtook HIV/AIDS as the leading cause of death due to infection [1]
Spores were incubated with FP-1 prior to centrifugation to quantity the amount of free fusion protein 1 (FP1) present in the supernatant after adsorption
Tuberculosis is a disease defined by an immunological complexity that has hindered efforts toward vaccine development and allowed Mycobacterium tuberculosis (Mtb) to persist perniciously across the globe
Summary
In 2015, tuberculosis (TB) overtook HIV/AIDS as the leading cause of death due to infection [1]. The proposed reasons for the failure of BCG to adequately protect against TB are many and varied They include (i) BCG sub-strain heterogeneity [3], (ii) pre-exposure of the host to environmental non-tubercle mycobacteria [4], (iii) a failure to prevent pulmonary infection [5], and (iv) limited protection in adults compared to children [6]. A novel TB vaccine is likely to supplement, rather than replace, BCG
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