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Heroin is a highly abused opioid that has reached epidemic status within the United States. Yet, existing therapies to treat addiction are inadequate and frequently result into rates of high recidivism. Vaccination against heroin offers a promising alternative therapeutic option but requires further development to enhance the vaccine’s performance. Hsp70 is a conserved protein with known immunomodulatory properties and is considered an excellent immunodominant antigen. Within an antidrug vaccine context, we envisioned Hsp70 as a potential dual carrier-adjuvant, wherein immunogenicity would be increased by co-localization of adjuvant and antigenic drug hapten. Recombinant Mycobacterium tuberculosis Hsp70 was appended with heroin haptens and the resulting immunoconjugate granted anti-heroin antibody production and blunted heroin-induced antinociception. Moreover, Hsp70 as a carrier protein surpassed our benchmark Her-KLH cocktail through antibody-mediated blockade of 6-acetylmorphine, the main mediator of heroin’s psychoactivity. The work presents a new avenue for exploration in the use of hapten-Hsp70 conjugates to elicit anti-drug immune responses.

Fentanyl and its derivatives have become pervasive contaminants in the U.S. heroin supply. Previously, we reported a proof-of-concept vaccine designed to combat against heroin contaminated with fentanyl. Herein, we optimized the admixture vaccine and found that it surpassed the individual vaccines in every antinociceptive test, including a 10% fentanyl to heroin formulation. It is anticipated that other co-occurring drug abuse disorders may also be examined with admixture vaccines. © 2018 American Chemical Society.

Background: Increased death due to the opioid epidemic in the United States has necessitated the development of new strategies to treat addiction. Monoclonal antibodies and antidrug vaccines provide a tool that both aids addiction management and reduces the potential for overdose. Dual drug vaccines formulated by successive conjugation or by mixture have certain drawbacks. The current study examines an approach for combatting the dangers of fentanyl-laced heroin, by using a hapten with one epitope that has domains for both fentanyl and heroin. Results: We evaluated a series of nine vaccines developed from chemically contiguous haptens composed of both heroin- and fentanyl-like domains. Analysis of the results obtained by SPR and ELISA revealed trends in antibody affinity and titers for heroin and fentanyl based on epitope size and linker location. In antinociception studies, the best performing vaccines offered comparable protection against heroin as our benchmark heroin vaccine, but exhibited attenuated protection against fentanyl compared to our fentanyl vaccine. Conclusion: After thorough investigation of this strategy, we have identified key considerations for the development of a chemically contiguous heroin-fentanyl vaccine. Importantly, this is the first report of such a strategy in the opioid-drug-vaccine field.

Anti-drug vaccines have potential as new interventions against substance use disorder (SUD). However, given the challenges seen with inter-individual variability in SUD vaccine trials to date, new interventions should ensure a robust immune response and safety profile among a diverse population. This requires accounting for sex and heritable genetic differences in response to both abused substances as well as the vaccination itself. To test response variability to our heroin-tetanus toxoid (Her-TT) immunoconjugate vaccine, we vaccinated male and female mice from several mouse strains including Swiss Webster (SW), BALB/c, and Jackson diversity mice (J:DO). Previous studies with vaccinated male SW mice demonstrated a rare hypersensitivity resulting in mice rapidly expiring with exposure to a low dose of heroin. Our results indicate that this response is limited to only male SW mice, and not to any other strain or female SW mice. Our data suggest that this hypersensitivity is not the result of an overactive cytokine or IgE response. Vaccination was similarly effective among the sexes for each strain and against repeated heroin challenge. Inbred BALB/c and J:DO mice were found to have the best vaccine response against heroin in antinociception behavioral assay. These results highlight the importance of incorporating both male and female subjects, along with different strains to mimic diverse human populations, as new SUD vaccines are being tested.

Growing nonmedical use of prescription opioids is a global problem, motivating research on ways to reduce use and combat addiction. Medical cannabis (“medical marijuana”) legalization has been associated epidemiologically with reduced opioid harms and cannabinoids have been shown to modulate effects of opioids in animal models. This study was conducted to determine if Δ 9 -tetrahydrocannabinol (THC) enhances the behavioral effects of oxycodone. Male rats were trained to intravenously self-administer (IVSA) oxycodone (0.15 mg/kg/infusion) during 1 h, 4 h or 8 h sessions. Following acquisition rats were exposed to THC by vapor inhalation (1 h and 8 h groups) or injection (0–10 mg/kg, i.p.; all groups) prior to IVSA sessions. Fewer oxycodone infusions were obtained by rats following vaporized or injected THC compared with vehicle treatment prior to the session. Follow-up studies demonstrated parallel dose-dependent effects of THC, i.p., on self-administration of different per-infusion doses of oxycodone and a preserved loading dose early in the session. These patterns are inconsistent with behavioral suppression. Additional groups of male and female Wistar rats were assessed for nociception following inhalation of vaporized THC (50 mg/mL), oxycodone (100 mg/mL) or the combination. Tail withdrawal latency was increased more by the THC/oxycodone combination compared to either drug alone. Similar additive antinociceptive effects were produced by injection of THC (5.0 mg/kg, i.p.) and oxycodone (2.0 mg/kg, s.c.). Together these data demonstrate additive effects of THC and oxycodone and suggest the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids. © 2019 Elsevier Ltd

One proposed factor contributing to the increased frequency of opioid overdose deaths is the emergence of novel synthetic opioids, including illicit fentanyl and fentanyl analogues. A treatment strategy currently under development to address the ongoing opioid crisis is immunopharmacotherapies or opioid-targeted vaccines. The present study determined the effectiveness and selectivity of a fentanyl-tetanus toxoid conjugate vaccine to alter the behavioral effects of fentanyl and a structurally dissimilar mu-opioid agonist oxycodone in male rhesus monkeys (n = 3-4). Fentanyl and oxycodone produced dose-dependent suppression of behavior in an assay of schedule-controlled responding and antinociception in an assay of thermal nociception (50 degrees C). Acute naltrexone (0.032 mg/kg) produced an approximate 10-fold potency shift for fentanyl to decrease operant responding. The fentanyl vaccine was administered at weeks 0, 2, 4, 9, 19, and 44 and fentanyl or oxycodone potencies in both behavioral assays were redetermined over the course of 49 weeks. The vaccine significantly and selectively shifted fentanyl potency at least 10-fold in both assays at several time points over the entire experimental period. Mid-point titer levels correlated with fentanyl antinociceptive potency shifts. Antibody affinity for fentanyl as measured by a competitive binding assay improved over time to approximately 3-4 nM. The fentanyl vaccine also increased fentanyl plasma levels approximately 6-fold consistent with the hypothesis that the vaccine sequesters fentanyl in the blood. Overall, these results support the continued development and evaluation of this fentanyl vaccine in humans to address the ongoing opioid crisis.

Growing nonmedical use of prescription opioids is a global problem, motivating research on ways to reduce use and combat addiction. Medical cannabis ("medical marijuana") legalization has been associated epidemiologically with reduced opioid harms and cannabinoids have been shown to modulate effects of opioids in animal models. This study was conducted to determine if DELTA9-tetrahydrocannabinol (THC) enhances the behavioral effects of oxycodone. Male rats were trained to intravenously self-administer (IVSA) oxycodone (0.15mg/kg/infusion) during 1h, 4h or 8h sessions. Following acquisition rats were exposed to THC by vapor inhalation (1h and 8h groups) or injection (0-10mg/kg, i.p.; all groups) prior to IVSA sessions. Fewer oxycodone infusions were obtained by rats following vaporized or injected THC compared with vehicle treatment prior to the session. Follow-up studies demonstrated parallel dose-dependent effects of THC, i.p., on self-administration of different per-infusion doses of oxycodone and a preserved loading dose early in the session. These patterns are inconsistent with behavioral suppression. Additional groups of male and female Wistar rats were assessed for nociception following inhalation of vaporized THC (50mg/mL), oxycodone (100mg/mL) or the combination. Tail withdrawal latency was increased more by the THC/oxycodone combination compared to either drug alone. Similar additive antinociceptive effects were produced by injection of THC (5.0mg/kg, i.p.) and oxycodone (2.0mg/kg, s.c.). Together these data demonstrate additive effects of THC and oxycodone and suggest the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids. Copyright © 2019 Elsevier Ltd. All rights reserved.

Opioid abuse in the United States has been declared a national crisis and is exacerbated by an inexpensive, readily available, and illicit supply of synthetic opioids. Specifically, fentanyl and related analogues such as carfentanil pose a significant danger to opioid users due to their high potency and rapid acting depression of respiration. In recent years these synthetic opioids have become the number one cause of drug-related deaths. In our research efforts to combat the public health threat posed by synthetic opioids, we have developed monoclonal antibodies (mAbs) against the fentanyl class of drugs. The mAbs were generated in hybridomas derived from mice vaccinated with a fentanyl conjugate vaccine. Guided by a surface plasmon resonance (SPR) binding assay, we selected six hybridomas that produced mAbs with 10-11 M binding affinity for fentanyl, yet broad cross-reactivity with related fentanyl analogues. In mouse antinociception models, our lead mAb (6A4) could blunt the effects of both fentanyl and carfentanil in a dose-responsive manner. Additionally, mice pretreated with 6A4 displayed enhanced survival when subjected to fentanyl above LD50 doses. Pharmacokinetic analysis revealed that the antibody sequesters large amounts of these drugs in the blood, thus reducing drug biodistribution to the brain and other tissue. Lastly, the 6A4 mAb could effectively reverse fentanyl/carfentanil-induced antinociception comparable to the opioid antagonist naloxone, the standard of care drug for treating opioid overdose. While naloxone is known for its short half-life, we found the half-life of 6A4 to be approximately 6 days in mice, thus monoclonal antibodies could theoretically be useful in preventing renarcotization events in which opioid intoxication recurs following quick metabolism of naloxone. Our results as a whole demonstrate that monoclonal antibodies could be a desirable treatment modality for synthetic opioid overdose and possibly opioid use disorder.

The current opioid crisis remains a significant public health issue and there is a critical need for biomedical research to develop effective and easily deployable candidate treatments. One emerging treatment strategy for opioid use disorder includes immunopharmacotherapies or opioid-targeted vaccines. The present study determined the effectiveness of a fentanyl-tetanus toxoid conjugate vaccine to alter fentanyl self-administration using a fentanyl-vs.-food choice procedure in male and female rats under three experimental conditions. For comparison, continuous 7-day naltrexone (0.01-0.1 mg/kg/h) and 7-day clonidine (3.2-10 mug/kg/h) treatment effects were also determined on fentanyl-vs.-food choice. Male and female rats responded for concurrently available 18% diluted Ensure R (liquid food) and fentanyl (0-10 mug/kg/infusion) infusions during daily sessions. Under baseline and saline treatment conditions, fentanyl maintained a dose-dependent increase in fentanyl-vs.-food choice. First, fentanyl vaccine administration significantly blunted fentanyl reinforcement and increased food reinforcement for 15 weeks in non-opioid dependent rats. Second, surmountability experiments by increasing the unit fentanyl dose available during the self-administration session 10-fold empirically determined that the fentanyl vaccine produced an approximate 22-fold potency shift in fentanyl-vs.-food choice that was as effective as the clinically approved treatment naltrexone. Clonidine treatment significantly increased fentanyl-vs.-food choice. Lastly, fentanyl vaccine administration prevented the expression of withdrawal-associated increases in fentanyl-vs.-food choice following introduction of extended 12 h fentanyl access sessions. Overall, these results support the potential and further consideration of immunopharmacotherapies as candidate treatments to address the current opioid crisis.