Safety and efficacy of an oxycodone vaccine: Addressing some of the unique considerations posed by opioid abuse

Abstract

Among vaccines aimed at treating substance use disorders, those targeting opioids present several unique medication development challenges. 1) Opioid overdose is a common complication of abuse, so it is desirable for an opioid vaccine to block the toxic as well as the addictive effects of opioids. 2) It is important that an opioid vaccine not interfere with the action of opioid antagonists used to reverse opioid overdose or treat addiction. 3) Some opioids are immunosuppressive and chronic ongoing opioid use could interfere with vaccine immunogenicity. 4) Although antibody-bound oxycodone is unable to enter the brain because of its size, it might still be able to activate peripheral opioid receptors. To assess vaccine impact on opioid toxicity, rats vaccinated with oxycodone conjugated to keyhole limpet hemocyanin subunit dimer (OXY-dKLH) adsorbed to alum or controls vaccinated with dKLH were compared with regard to oxycodone-induced hotplate analgesia and oxycodone-induced respiratory depression and bradycardia. Vaccination shifted the dose-response curves to the right, representing protection, for each of these endpoints. Naloxone was equally effective in both OXY-dKLH and control groups, providing complete and rapid reversal of respiratory depression. The administration of a long-acting naltrexone formulation during vaccination did not impair vaccine immunogenicity in mice. Similarly, serum anti-oxycodone antibody titers were not altered by continuous morphine infusion during vaccination compared to opioid-naïve controls. Competitive ELISA assay showed negligible or low affinity of immune antiserum for endogenous opioids or opioid antagonists. In vitro receptor binding assays showed that antibody-bound oxycodone does not activate mu opioid receptors. These data support further study of OXY-dKLH as a potential treatment for oxycodone abuse and suggest that vaccination might also reduce the severity of oxycodone overdose.

Opioid Dose- and Route-Dependent Efficacy of Oxycodone and Heroin Vaccines in Rats

“…To measure drug-specific serum IgG antibody titers, morphine or oxycodone haptens conjugated to bovine serum albumin were coated on enzyme-linked immunosorbent assay plates at 5 ng/well in carbonate buffer (pH 9.6) and blocked with 1% gelatin (Pravetoni et al, 2012c;Raleigh et al, 2013Raleigh et al, , 2017. Goat anti-rat IgG conjugated to horseradish peroxidase was used as secondary antibodies (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA).…”

“…M-KLH effects on respiratory depression were not studied in the highdose heroin group because they had received naloxone to prevent respiratory arrest and OXY-KLH effects were not reported for the low-dose oxycodone group because controls did not show significant respiratory depression. However, OXY-KLH has been shown to reduce oxycodone-induced respiratory depression following a cumulative subcutaneous oxycodone dose of 9 mg/kg (Raleigh et al, 2017). Protection against opioid-induced respiratory depression is of note because respiratory depression is the principal mechanism of death from opioid overdose.…”

A Fentanyl Vaccine Alters Fentanyl Distribution and Protects against Fentanyl-Induced Effects in Mice and Rats

“…The fentanyl vaccine was developed using a fentanylbased hapten (F) conjugated to either the native decamer keyhole limpet hemocyanin (KLH) carrier protein or the GMPgrade subunit KLH (sKLH) by means of a tetraglycine linker using carbodiimide chemistry to create F-KLH and F-sKLH, respectively. This vaccine design is analogous to other opioid vaccines that are being prepared for clinical use (Raleigh et al, 2017(Raleigh et al, , 2018. Mice and rats immunized with F-KLH had lower fentanyl-induced antinociception compared with controls.…”

“…Opioid vaccines have been explored preclinically as a treatment of OUD and have been effective in rodent and nonhuman primate models (Stowe et al, 2011;Bremer and Janda, 2012;Pravetoni et al, 2012b;Matyas et al, 2013;Raleigh et al, 2013Raleigh et al, , 2014Raleigh et al, , 2017Schlosburg et al, 2013;Bremer et al, 2014Bremer et al, , 2017. Opioid vaccines elicit opioid-specific antibodies that bind to the targeted opioids in the blood and reduce their distribution to the brain, reducing their behavioral and toxic effects.…”

Alum adjuvant is more effective than MF59 at prompting early germinal center formation in response to peptide-protein conjugates and enhancing efficacy of a vaccine against opioid use disorders

“…We have previously shown that active immunization with the oxycodone vaccine OXY-KLH reduced oxycodone distribution to the brain in mice and rats, 2,3 and prevented oxycodone-induced behavior and toxicity associated with overdose. 31 However, this is a first report of using oxycodone-induced motor activity to select a lead vaccine formulation. To date, OXY-KLH has been formulated in alum, Freund's, MPLA, and alum mixed with MPLA.…”