Conjugate vaccine produces long-lasting attenuation of fentanyl vs. food choice and blocks expression of opioid withdrawal-induced increases in fentanyl choice in rats

Abstract

The current opioid crisis remains a significant public health issue and there is a critical need for biomedical research to develop effective and easily deployable candidate treatments. One emerging treatment strategy for opioid use disorder includes immunopharmacotherapies or opioid-targeted vaccines. The present study determined the effectiveness of a fentanyl-tetanus toxoid conjugate vaccine to alter fentanyl self-administration using a fentanyl-vs.-food choice procedure in male and female rats under three experimental conditions. For comparison, continuous 7-day naltrexone (0.01-0.1 mg/kg/h) and 7-day clonidine (3.2-10 μg/kg/h) treatment effects were also determined on fentanyl-vs.-food choice. Male and female rats responded for concurrently available 18% diluted Ensure® (liquid food) and fentanyl (0-10 μg/kg/infusion) infusions during daily sessions. Under baseline and saline treatment conditions, fentanyl maintained a dose-dependent increase in fentanyl-vs.-food choice. First, fentanyl vaccine administration significantly blunted fentanyl reinforcement and increased food reinforcement for 15 weeks in non-opioid dependent rats. Second, surmountability experiments by increasing the unit fentanyl dose available during the self-administration session 10-fold empirically determined that the fentanyl vaccine produced an approximate 22-fold potency shift in fentanyl-vs.food choice that was as effective as the clinically approved treatment naltrexone. Clonidine treatment significantly increased fentanyl-vs.-food choice. Lastly, fentanyl vaccine administration prevented the expression of withdrawal-associated increases in fentanyl-vs.-food choice following introduction of extended 12 h fentanyl access sessions. Overall, these results support the potential and further consideration of immunopharmacotherapies as candidate treatments to address the current opioid crisis.

Preclinical Evaluation of Vaccines to Treat Opioid Use Disorders: How Close are We to a Clinically Viable Therapeutic?

“…However, the vaccinated rats exhibited an extinction-like pattern of behavior across the nine experimental sessions, suggesting that rates of self-administration in the first cohort of vaccinated rats were maintained, at least in part, by the visual discriminative stimuli. Furthermore, this pattern of extinction-like responding was also observed in a recent rat study following fentanyl-TT vaccine administration [47]. Although these results provide evidence that opioid vaccines can block escalation of opioid self-administration, the magnitude of vaccine-induced potency shifts on this endpoint remains to be empirically determined.…”

“…Concurrent schedules are routinely used in human laboratory drug self-administration studies [45,46] evaluating candidate small-molecule medications for substance use disorder. In a recent study by our group [47], fentanyl-TT vaccine administration promoted behavioral reallocation away from fentanyl self-administration and towards food (i.e., diluted vanilla-flavored Ensure ® ) by week 4 and vaccine effectiveness was sustained for at least 16 weeks. Furthermore, vaccine effectiveness was similar to continuous naltrexone treatment.…”

“…In summary, opioid vaccines attenuate ongoing opioid self-administration in both non-human primates and rats, providing proof-of-principle empirical validation and support for progression to human laboratory/clinical trials. Strengths of evaluating vaccine effectiveness on maintenance of opioid self-administration include (1) repeated testing within the same animal allowing for the within-subject evaluation of vaccine effectiveness time course [26,47], (2) within-subject behavioral selectivity of vaccine effectiveness [25,26], and (3) within-subject comparison with positive control and clinically used medications [26,47]. Because many of these studies have only examined a single-unit dose of the targeted opioid (but see [25,34,47]), quantifying potency shifts in the opioid self-administration dose-effect function and comparisons of vaccine effectiveness across different laboratories are complicated.…”

Utility of fentanyl vaccines: unique challenges posed by preventing opioid overdose and treating opioid use disorder

“…In summary, Townsend et al [1] provide evidence of a highly effective fentanyl vaccine. Such a vaccine strategy has great potential as an adjunct for preventing fentanyl-induced overdoses.…”

“…In the current issue of Neuropsychopharmacology, Townsend et al [1] reported a time course of efficacy for a fentanyl-tetanus toxoid conjugate vaccine designed to induce the production of peripherally circulating antibodies against fentanyl in rats, thus preventing fentanyl from reaching the brain. Following vaccine treatment at weeks 0 and 3, the authors observed maximal antibody titers in week 5, with a slow decay of titers across subsequent weeks until week 17, at which point a "booster" vaccine treatment was given.…”