Multivalent Vaccine Strategies against Polydrug Use in Opioid Use Disorders.

The number of annual fatal drug overdoses reached more than 100,000 between April 2020 to 2021, of which the majority involved individual opioids or polydrug mixtures containing opioids. A series of conjugate vaccines targeting fentanyl, carfentanil, oxycodone, heroin, and their analogs or metabolites have shown preclinical proof of efficacy, selectivity, and safety. Individual vaccines consist of haptens, small molecules that mimic the structure of the targeted drug, conjugated to carrier proteins, such as detoxified diphtheria toxin (CRM) or keyhole limpet hemocyanin (KLH). These studies identified lead haptens based on fentanyl (Fen), carfentanil (Carf), oxycodone (Oxy), and heroin (Her). Preclinical studies showed the efficacy of each vaccine (Fen-CRM, Carf-CRM, Oxy-KLH, and Her-KLH) in blocking their respective target drug distribution to the brain and their behavioral effects in mice and rats. While multivalent vaccine formulations are commonly used as a safe and effective strategy against infectious diseases, multivalent vaccination strategies against polydrug use have not yet been fully explored at treating substance use disorders. In the current study, the balb/c mice were vaccinated with a combination of Fen-CRM, Carf-CRM, Oxy-KLH, and Her-KLH as a quadrivalent vaccine. ELISA showed that quadrivalent vaccine increased fentanyl-, carfentanil-, oxycodone-, and heroin-specific IgG titers in the immunized mice. Correspondingly, this simultaneous immunization prevented the distributions of fentanyl, carfentanil, oxycodone, and heroin to the brain when the mice were challenged by the mixture of these drugs. These data demonstrate that individual efficacy of monovalent vaccine was preserved in a multivalent formulation without interference. Amid opioid epidemics, multivalent vaccine strategies will provide a broad spectrum of protection against multiple opioids with a single vaccination.