Abstract
Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) kills about 1.5 million people each year and the widely used Bacille Calmette-Guérin (BCG) vaccine provides a partial protection against TB in children and adults. Because BCG vaccine evades lysosomal fusion in antigen presenting cells (APCs), leading to an inefficient production of peptides and antigen presentation required to activate CD4 T cells, we sought to boost its efficacy using novel agonists of RIG-I and NOD2 as adjuvants. We recently reported that the dinucleotide SB 9200 (Inarigivir) derived from our small molecule nucleic acid hybrid (SMNH)® platform, activated RIG-I and NOD2 receptors and exhibited a broad-spectrum antiviral activity against hepatitis B and C, Norovirus, RSV, influenza and parainfluenza. Inarigivir increased the ability of BCG-infected mouse APCs to secrete elevated levels of IL-12, TNF-α, and IFN-β, and Caspase-1 dependent IL-1β cytokine. Inarigivir also increased the ability of macrophages to kill MTB in a Caspase-1-, and autophagy-dependent manner. Furthermore, Inarigivir led to a Capsase-1 and NOD2- dependent increase in the ability of BCG-infected APCs to present an Ag85B-p25 epitope to CD4 T cells in vitro. Consistent with an increase in immunogenicity of adjuvant treated APCs, the Inarigivir-BCG vaccine combination induced robust protection against tuberculosis in a mouse model of MTB infection, decreasing the lung burden of MTB by 1-log10 more than that afforded by BCG vaccine alone. The Inarigivir-BCG combination was also more efficacious than a muramyl-dipeptide-BCG vaccine combination against tuberculosis in mice, generating better memory T cell responses supporting its novel adjuvant potential for the BCG vaccine.
Highlights
Mycobacterium tuberculosis (MTB) kills more than 1.5 million people each year and is the leading cause of death due to infections [1]
Because Bacille Calmette-Guérin (BCG) vaccine phagosomes evade lysosomal degradation, we have investigated the hypothesis that agonists of the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and Retinoic acid-inducible gene-I (RIG-I) can act as adjuvants for BCG
We further demonstrate that Inarigivir boosts the efficacy of the BCG vaccine against tuberculosis in mice and represents a new generation of adjuvants that target NOD2/RIG-I signaling and perhaps they can be safely combined with other vaccines
Summary
Mycobacterium tuberculosis (MTB) kills more than 1.5 million people each year and is the leading cause of death due to infections [1]. BCG, an attenuated strain of Mycobacterium bovis has been used as a vaccine against tuberculosis since 1921, and nearly a billion doses have been given to infants so far with remarkably fewer side effects. BCG is known to effectively protect infants against disseminated forms of TB, it provides a variable (0–80%) protection against pulmonary tuberculosis and appears to be ineffective in protecting against adult tuberculosis [5, 6]. BCG is known to induce “trained immunity” which protects against unrelated bacterial and viral infections of children and even against an experimental yellow fever virus infection of adults [9, 10]. BCG vaccine is being repurposed for protection against SARS-CoV-2 infections [12, 13]
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