Stimulation of Nucleotide Oligomerization Domain and Toll-Like Receptors 2 to Enhance the Effect of Bacillus Calmette Guerin Immunization for Prevention of Mycobacterium Tuberculosis Infection: Protocol for a Series of Preclinical Randomized Controlled Trials

Eisenhut, Michael

doi:10.2196/13045

Cited by 2 publications

(3 citation statements)

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“…Data presented above indicated that Inarigivir and its isomers are potent adjuvants enhancing both the in vitro function of APCs and in vivo efficacy of the BCG vaccine in mice. The mycobacterial NOD2 ligand, muramyl-dipeptide (MDP) has been extensively tested as an adjuvant inducing IL-1β from MΦs, but moderately increasing the efficacy of the BCG vaccine in mice ( 53 ). Therefore, we sought to compare the activity of Inarigivir isomers with MDP to determine if they are more potent.…”

Section: Resultsmentioning

confidence: 99%

“…These data are also consistent with the finding that, a combination of TLR-2 and MDP dual adjuvant combination with BCG reduced the lung MTB burden by < 0. 5-log10 ( 53 ). Increased efficacy of Rp -Inarigivir isomer adjuvant was also reflected by a better induction of Th1 cytokine positive CD4 and CD8 T cells in the spleens ( Figure 6B ), though the difference was not found statistically significant when measured specifically for MTB antigen specific CD8 T cells.…”

Section: Resultsmentioning

confidence: 99%

“…Since MDP is also a well-known NOD2 agonist, both Rp -Inarigivir and Sp -Inarigivir combinations with BCG were compared with MDP and BCG combination. In a recent study, BCG vaccine combination with MDP showed < 0.5 log10 reduction of MTB burden in the lungs of mice ( 53 ). In contrast, both Rp -Inarigivir and Sp -Inarigivir were superior to MDP in decreasing the lung burden of MTB by ~1-log10 ( Figure 6 ).…”

Section: Discussionmentioning

confidence: 99%

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NOD2/RIG-I Activating Inarigivir Adjuvant Enhances the Efficacy of BCG Vaccine Against Tuberculosis in Mice

et al. 2020

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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