Selected Toll‐like receptor agonists increase the efficacy of vaccines against fentanyl use disorder and overdose.

R3584 --> In the United States, the majority of drug fatal overdoses are attributed to synthetic opioids such as fentanyl and its analogs. The opioid receptor antagonist naloxone is the leading treatment for opioid overdose, but it is limited in its ability to reverse overdoses of long‐acting, highly potent opioids, and can only be administered post‐exposure. Vaccines consisting of fentanyl‐based haptens conjugated to immunogenic carrier proteins offer a novel strategy to combat fentanyl use disorder and overdose as they can be administered both prophylactically and therapeutically, and have the potential to offer long‐lasting protection against fentanyl's pharmacological effects and overdose in pre‐clinical models. Anti‐fentanyl vaccines stimulate the immune system to produce fentanyl‐specific antibodies which sequester the drug in serum and prevent fentanyl distribution to the brain. Vaccination selectively reduces fentanyl‐induced bradycardia, respiratory depression, antinociception, and fentanyl self‐administration. To improve the clinical potential of anti‐drug vaccines, adjuvants can be added to stimulate the immune system to increase the quality and quantity of the antibody response against the target drug. In this study, mice (n=6/group) and rats (n=6/group) were vaccinated with a lead anti‐fentanyl vaccine (F‐CRM) formulated in a series of Toll‐like receptor (TLR) agonists. After immunization, mice and rats were challenged with fentanyl (0.05‐0.45 mg/kg). Antinociception, bradycardia, respiratory depression, and distribution of fentanyl in the blood and brain were measured post‐challenge. Selected TLR agonists increased the vaccine's ability to induce fentanyl‐specific antibodies in both mice and rats, and increased its efficacy in reducing fentanyl‐induced effects. Co‐administration of F‐CRM formulated in selected TLR adjuvants also offered greater protection against fentanyl‐induced respiratory arrest induced by overdose. These data support further development of anti‐fentanyl vaccines formulated in novel TLR adjuvants and warrant future studies exploring their applicability to other vaccine formulations against substance use disorders. [ABSTRACT FROM AUTHOR]