Psychopharmacology: neuroimmune signaling in psychiatric disease-developing vaccines against abused drugs using toll-like receptor agonists.

RATIONALE: Since substance use disorders have few or no effective pharmacotherapies, researchers have developed vaccines as immune-therapies against nicotine, cocaine, methamphetamine, and opioids including fentanyl.

OBJECTIVES

We focus on enhancing antibody (AB) production through stimulation of toll-like receptor-5 (TLR5) during active vaccination. The stimulating adjuvant is Entolimod, a novel protein derivative of flagellin. We review the molecular and cellular mechanisms underlying Entolimod's actions on TLR5.

RESULTS

Entolimod shows excellent efficacy for increasing AB levels to levels well beyond those produced by anti-addiction vaccines alone in animal models and humans. These ABs also significantly block the behavioral effects of the targeted drug of abuse. The TLR5 stimulation involves a wide range of immune cell types such as dendritic, antigen presenting, T and B cells. Entolimod binding to TLR5 initiates an intracellular signaling cascade that stimulates cytokine production of tumor necrosis factor and two interleukins (IL-6 and IL-12). While cytokine release can be catastrophic in cytokine storm, Entolimod produces a modulated release with few side effects even at doses 30 times greater than doses needed in these vaccine studies. Entolimod has markedly increased AB responses to all of our anti-addiction vaccines in rodent models, and in normal humans.

CONCLUSIONS

Entolimod and TLR5 stimulation has broad application to vaccines and potentially to other psychiatric disorders like depression, which has critical inflammatory contributions that Entolimod could reduce.