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

Abstract

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.

Anti-Cocaine IgA Rather Than IgG Mediates Vaccine Protection from Cocaine Use

“…Perhaps more importantly, we observed that immunoglobulin A (IgA) was the best correlate of vaccine-mediated protection from an injected drug challenge, rather than IgG, IgG1, IgG2a or binding affinity [8]. We recently replicated this IgA association with blocking analgesia and reducing brain levels of FEN in rats [19]. IgA is typically thought to prevent mucosal microbial or drug exposures, and our findings about IgA for blocking injected drugs is a critical discovery.…”

Vaccines to Treat Substance Use Disorders: Current Status and Future Directions

“…In a preclinical animal study, FEN-CRM + dmLT (a fentanyl-like hapten was combined with the carrier protein CRM197 and an adjuvant derived from heat-labile enterotoxins from E. coli (LT) named dmLT) generated significant amounts of anti-fentanyl antibodies that were associated with a significant blockade of fentanyl’s analgesic effects in mice. In the meantime, cross-reactivity assays demonstrated that anti-fentanyl antibodies exhibit binding affinity to fentanyl and sufentanil, while displaying no binding interaction with morphine, methadone, buprenorphine, or oxycodone [ 15 ]. In another study, Carfen-ester-TT (the methyl ester functional group of carfentanil as the point of linker attachment) and Carfen-p-phenyl-TT (positions the linker at the para position of the phenethyl ring) can effectively target fentanyl and carfentanil, eliciting high-affinity antibodies against both drugs in mice [ 58 ].…”

Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs—Lessons from Animal Studies

“…In the rat, dose–response curves of respiratory effects were shifted to the right with the vaccine, without affecting the ability of naloxone to reverse the respiratory depression [ 81 ]. Vaccinated rats showed improved physiological parameters including oxygen saturation and heart rate after exposure to fentanyl compared to unvaccinated rats [ 82 ]. In comparison to the controls, decreased post-exposure drug levels in the brain were observed in rats vaccinated with F1-CRM, a supported candidate vaccine against fentanyl and selected analogues.…”