Enhancement of a Heroin Vaccine through Hapten Deuteration

Abstract

The United States is in the midst of an unprecedented epidemic of opioid substance use disorder, and while pharmacotherapies including opioid agonists and antagonists have shown success, they can be inadequate and frequently result in high recidivism. With these challenges facing opioid use disorder treatments immunopharmacotherapy is being explored as an alternative therapy option and is based upon antibody−opioid sequestering to block brain entry. Development of a heroin vaccine has become a major research focal point; however, producing an efficient vaccine against heroin has been particularly challenging because of the need to generate not only a potent immune response but one against heroin and its multiple psychoactive molecules. In this study, we explored the consequence of regioselective deuteration of a heroin hapten and its impact upon the immune response against heroin and its psychoactive metabolites. Deuterium (H dAc ) and cognate protium heroin (H Ac ) haptens were compared head to head in an inclusive vaccine study. Strikingly the H dAc vaccine granted greater efficacy in blunting heroin analgesia in murine behavioral models compared to the H Ac vaccine. Binding studies confirmed that the H dAc vaccine elicited both greater quantities and equivalent or higher affinity antibodies toward heroin and 6-AM. Blood−brain biodistribution experiments corroborated these affinity tests. These findings suggest that regioselective hapten deuteration could be useful for the resurrection of previous drug of abuse vaccines that have met limited success in the past.

Therapeutic and Prophylactic Vaccines to Counteract Fentanyl Use Disorders and Toxicity

“…Similarly, the binding of nicotine to a nicotine-specific Fab was largely driven by hydrophobic contact with the nicotine rings including the charged pyrrolidine nitrogen . In support of this hypothesis, minimal modifications of hapten structures such as fluorination or deuteration , seem to impact vaccine efficacy against their respective drug targets. It has been consistently shown that oxycodone is a more immunogenic hapten core than hydrocodone, despite a minor structural difference consisting of a -OH vs -H at the C14 position on the morphinan structure. , Differences between the original pharmacophore and the cognate hapten structure may alter their ability to engage the BCR of hapten-specific B cells, as supported by evidence that a higher frequency of B cells specific for oxycodone-based haptens is found in the murine preimmunization repertoire compared to hydrocodone-based haptens .…”

“…64 Similarly, the binding of nicotine to a nicotine-specific Fab was largely driven by hydrophobic contact with the nicotine rings including the charged pyrrolidine nitrogen. 65 In support of this hypothesis, minimal modifications of hapten structures such as fluorination or deuteration 66,67 seem to impact vaccine efficacy against their respective drug targets. It has been consistently shown that oxycodone is a more immunogenic hapten core than hydrocodone, despite a minor structural difference consisting of a -OH vs -H at the C14 position on the morphinan structure.…”

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

“…To prepare the vaccine, they used a heroin-mimicking molecule in which they replaced several hydrogen atoms with deuterium and found that the new vaccine was significantly improved as shown from titer, affinity, specificity, and behavioral models including antinociception and drug biodistribution (Figure 9). 413…”

A Vaccine against Benzimidazole-Derived New Psychoactive Substances That Are More Potent Than Fentanyl

“…Activation was monitored by LC–MS, and the activated hapten was subsequently coupled to an immunogenic carrier protein. We implemented keyhole limpet hemocyanin (KLH) as the carrier protein, because it has been used in prior clinical trials and has been successfully utilized in other immunopharmacotherapeutic vaccines. ,− Application of KLH was cost-effective and convenient, but future studies geared for clinical application will require a more suitable carrier protein …”