Preclinical Evaluation of Vaccines to Treat Opioid Use Disorders: How Close are We to a Clinically Viable Therapeutic?

Abstract

The ongoing opioid crisis, now into its second decade, represents a global public health challenge. Moreover, the opioid crisis has manifested despite clinical access to three approved opioid use disorder medications: the full opioid agonist methadone, the partial opioid agonist buprenorphine, and the opioid antagonist naltrexone. Although current opioid use disorder medications are underutilized, the ongoing opioid crisis has also identified the need for basic research to develop both safer and more effective opioid use disorder medications. Emerging preclinical evidence suggests that opioid-targeted vaccines or immunopharmacotherapies may be promising opioid use disorder therapeutics. One premise for this article is to critically examine whether vaccine effectiveness evaluated using preclinical antinociceptive endpoints is predictive of vaccine effectiveness on abuse-related endpoints such as drug self-administration, drug discrimination, and conditioned place preference. A second premise is to apply decades of knowledge in the preclinical evaluation of candidate small-molecule therapeutics for opioid use disorder to the preclinical evaluation of candidate opioid use disorder immunopharmacotherapies. We conclude with preclinical experimental design attributes to enhance preclinical-to-clinical translatability and potential future directions for immunopharmacotherapies to address the dynamic illicit opioid environment. Key Points Vaccine effectiveness should be assessed in terms of opioid agonist potency shifts. Vaccine effectiveness on a preclinical endpoint should be directly compared to effectiveness with naltrexone or buprenorphine treatment. Vaccine effectiveness should be evaluated on preclinical endpoints that are analogous to clinical opioid use disorder endpoints to enhance translational concordance.

Preclinical Efficacy and Selectivity of Vaccines Targeting Fentanyl, Alfentanil, Sufentanil, and Acetylfentanyl in Rats

“… 8 , 9 Vaccines against fentanyl or other opioids, a proposed alternative or adjunct therapy for OUD, operate through production of target-specific polyclonal antibodies, which sequester drug in the serum and reduce brain exposure to the compound of interest. Such vaccines, which consist of an opioid-based hapten conjugated to an immunogenic carrier protein, have shown substantial preclinical efficacy as a strategy to combat OUD and drug-related overdose (reviewed in refs ( 10 and 11 )). A vaccine targeting oxycodone is currently being investigated in subjects with OUD in Phase I clinical trials.…”

Synthesis and immunological effects of C14-linked 4,5-epoxymorphinan analogues as novel heroin vaccine haptens

“…Kirby and co-workers have observed similar ring opened side-products when attempting hydrogenation of 4 . 25 This issue was circumvented by first protecting the C6 position as the ketal followed by cleavage of the N–O bond and removal of the Troc group with zinc dust. Hydrolysis of the ketal group after reduction was accomplished utilizing concentrated HCl, affording 7 in 47% over three steps.…”

“…3,11,18 More recent works have shown that linker sites at C3 and C6 also yield antibodies selective to target drugs that translate to protection against heroin-induced physiological effects. 3,8,17 With a few on-going efforts to translate experimental opioid vaccines to humans, 25 there is a need to study many variants of a given hapten to fully understand how the molecular scaffold ultimately impacts the selectivity of the induced antibodies, which in turn dictate the vaccine efficacy in vivo.…”

Emerging Concepts and Technologies in Vaccine Development

“…It should be noted that clinical trial results have only been reported for vaccines against nicotine and cocaine addictions, with the vaccines demonstrating efficacy only in a subset of patients that were able to achieve high neutralizing antibody titers ( 153 , 183 – 186 ). The recent vaccine developments to ameliorate drug abuse have been reviewed more extensively elsewhere ( 153 , 160 , 187 ).…”