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.

Fig 1. Vaccination inhibits oxycodone-induced antinociception, respiratory depression, and bradycardia.

Oxycodone was administered s.c. every 15 min at increasing doses and the doses listed are the cumulative dose received. A) Vaccine effects on oxycodone-induced antinociception. Latency to respond is capped at 60 seconds. Naloxone was administered 15 min after the final oxycodone dose. B) Vaccine effects on oxycodone-induced respiratory depression measured as SaO₂. C) Vaccine effects on oxycodone-induced decreases in heart rate. * p < 0.05, ** p < 0.01, *** p < 0.001 for the difference between OXY-dKLH and control groups. ## p < 0.01 for the difference (within a single group) between values measured after the 9.0 mg/kg oxycodone dose and after naloxone. There were no differences between groups in latency to respond, SaO₂, or heart rate following naloxone treatment. Mean ± SEM; n = 15 for KLH and n = 16 for OXY-KLH.

Fig 2. Naloxone reverses oxycodone-induced respiratory depression in vaccinated animals.

Naloxone 0.1 mg/kg s.c. was administered to mice 30 minutes after oxycodone 9.0 mg/kg s.c. SaO₂ recovered promptly in both OXY-dKLH and control groups. SaO₂ did not differ between OXY-dKLH and control groups at any time after naloxone treatment (p = 0.65). Mean ± SEM; n = 11 for KLH and n = 12 for OXY-KLH.

Fig 3. Concurrent morphine administration does not interfere with oxycodone vaccine immunogenicity.

A) Prior to vaccination, mice receiving s.c. morphine infusion (8 mg/kg/day) showed a significant increase in latency to respond in the hotplate antinociception test (mean ± SEM, *p <0.05). This confirms that mice received a behaviorally active dose of morphine for the following experiment: B) After initiation of vaccination, oxycodone-specific antibody titers in serum did not differ between mice receiving morphine infusion (8 mg/kg/day) and those receiving saline (mean ± SD, p = 0.51). For both figures, n = 13 for saline-treated group and n = 12 for morphine-treated group.

Fig 4. Concurrent administration of extended-release naltrexone does not interfere with oxycodone vaccine immunogenicity.

Mice received 50 mg/kg naltrexone i.m. on day -1 and then vaccinated with OXY-KLH on days 0, 14 and 28. Serum oxycodone-specific antibody titers did not differ between groups at any time after completion of vaccination (p = 0.21). Mean ± SEM, n = 4–7/group.

Fig 5. Oxycodone-specific monoclonal antibody prevents oxycodone-induced activation of opioid receptors.

OXY-specific mAb blocked OXY-stimulated calcium mobilization but did not block morphine-stimulated calcium mobilization. ***P < 0.001 compared to OXY. Bars represent the % EC₅₀ compared to oxycodone alone (left) or morphine alone (right). Mean ± SEM, n = 3/group.