An Immunconjugate Vaccine Alters Distribution and Reduces the Antinociceptive, Behavioral and Physiological Effects of Fentanyl in Male and Female Rats

Fentanyl (FEN) is a potent synthetic opioid associated with increasing incidence of opioid use disorder (OUD) and fatal opioid overdose. Vaccine immunotherapy for FEN-associated disorders may be a viable therapeutic strategy. Here, we expand and confirm our previous study in mice showing immunological and antinociception efficacy of our FEN vaccine administered with the adjuvant dmLT. In this study, immunized male and female rats produced significant levels of anti-FEN antibodies that were highly effective at neutralizing FEN-induced antinociception in the tail flick assay and hot plate assays. The vaccine also decreased FEN brain levels following drug administration. Immunization blocked FEN-induced, but not morphine-induced, rate-disrupting effects on schedule-controlled responding. Vaccination prevented decreases on physiological measures (oxygen saturation, heart rate) and reduction in overall activity following FEN administration in male rats. The impact of FEN on these measures was greater in unvaccinated male rats compared to unvaccinated female rats. Cross-reactivity assays showed anti-FEN antibodies bound to FEN and sufentanil but not to morphine, methadone, buprenorphine, or oxycodone. These data support further clinical development of this vaccine to address OUD in humans.

Automated summary

The study demonstrates that a Fentanyl vaccine, administered with the adjuvant dmLT, produces significant levels of anti-Fentanyl antibodies in rats and effectively neutralizes Fentanyl-induced antinociception. The vaccine also reduces Fentanyl levels in the brain and blocks Fentanyl-induced disruption of scheduled behavior. Furthermore, the vaccination prevents physiological changes and overall activity reduction caused by Fentanyl administration in male rats. These findings support the development of the vaccine for addressing Opioid Use Disorder in humans.