A novel TLR adjuvant increases the efficacy of vaccines against fentanyl-induced toxicity and overdose

Abstract

Abstract The widespread illicit use of fentanyl and its analogs is associated with the increased incidence of fatal drug overdoses in the United States in recent years. Pre-clinical studies with vaccines targeting opioids show selectivity and efficacy but clinical data suggests vaccine efficacy against drugs of abuse may be limited by individual variability and a requirement for high and sustained antibody levels. New strategies are needed to enhance vaccine efficacy and increase the quantity and quality of the anti-drug antibody response. We investigated the ability of novel synthetic TLR adjuvants to increase anti-fentanyl antibody titers and protect from fentanyl challenge in mice. Fentanyl-based haptens were conjugated to CRM and combined with alum, novel synthetic TLR adjuvants, or combinations thereof. The most promising TLR adjuvants and combination adjuvants increased anti-fentanyl hapten total IgG, IgG1, and IgG2a antibody concentrations. Splenocyte restimulation with CRM protein showed adjuvant combinations significantly increased secretion of Th1-type cytokines compared to antigen only or single adjuvants alone. Likewise, in a fentanyl challenge model, combination adjuvanted vaccines increased protection from respiratory depression compared to mice vaccinated with antigen alone or single adjuvant controls. These data demonstrate that TLR adjuvants improve the anti-fentanyl adaptive immune response and increase protection against fentanyl challenge in mice, and may enhance vaccine-induced protection against fentanyl overdose in humans.