Opioid Vaccines Research Articles

A two-dose regimen of Qβ virus-like particle-based vaccines elicit protective antibodies against heroin and fentanyl.

Opioid overdoses and the growing rate of opioid use disorder (OUD) are major public health concerns, particularly in the United States. Current treatment approaches for OUD have failed to slow the growth of the opioid crisis. Opioid vaccines have shown pre-clinical success in targeting multiple different opioid drugs. However, the need for many immunizations can limit their clinical implementation. In this study, we investigate the development of novel opioid vaccines by independently targeting fentanyl and the active metabolites of heroin using a bacteriophage virus-like particle (VLP) vaccine platform. We establish the successful conjugation of haptens to bacteriophage Qβ VLPs and demonstrate immunogenicity of Qβ-fentanyl, Qβ-morphine, and Qβ-6-acetylmorphine in animal models after one or two immunizations. We show that in independently or in combination, these vaccines elicit high-titer, high-avidity, and durable antibody responses. Moreover, we reveal their protective capacities against heroin or fentanyl challenge after two immunizations. Overall, these findings establish Qβ-VLP conjugated vaccines for heroin and fentanyl as very promising opioid vaccine candidates.

Opioid vaccine clinical testing: lessons learned.

Opioid use disorder (OUD) presents a serious public health concern, with dramatic increases in opioid-overdose mortality in recent years and a small percentage of those with OUD accessing or remaining engaged with available treatments. Efforts are currently underway to identify vaccines targeting opioids, which could provide a novel and complimentary approach. The current review provides an overview of existing literature, practical considerations for designing and conducting clinical trials with vaccines for opioids, and future directions. This review covers the following themes: clinical trial design and selection of endpoints, timepoint selection, practical considerations and lessons learned from the first (ongoing) trial of a vaccine targeting opioids, and future directions. Efforts to develop and test vaccines targeting OUD are based on a foundation of preclinical work and close collaboration between preclinical and clinical researchers. Efforts to learn from shortcomings of prior clinical trials of vaccines for other substances are essential in designing and testing effective vaccines for OUD. Design and implementation of clinical trials for a vaccine for OUD requires careful balance of participant safety and strategies for retention and efforts to gather viable data to inform future work.

A bacteriophage virus-like particle vaccine against oxycodone elicits high-titer and long-lasting antibodies that sequester drug in the blood

Opioid use disorder (OUD) and opioid overdoses are public health emergencies. In 2021, 80,000 opioid overdose associated deaths were reported in the United States. Despite the availability of treatment strategies, including medications for opioid use disorder (MOUD) and naloxone, opioid overdoses continue to increase at an alarming rate. Opioid vaccines are a novel approach to combat the growing crisis with several candidates recently entering human clinical trials. In this study, we investigated Qβ bacteriophage virus-like particles (VLPs) as a vaccine platform for immunogenic display of oxycodone. A derivative of oxycodone was conjugated to pre-formed Qβ VLPs using a sulfhydryl-amine reactive heterobifunctional crosslinker with high loading of oxycodone. In mice, intramuscular immunization with Qβ-oxycodone elicited high-titer, high-avidity and long-lasting antibody responses. Qβ-oxycodone was also immunogenic after storage at ambient room temperature for over two weeks, demonstrating that the vaccine is highly thermostable. In mice, immunization with Qβ-oxycodone elicited antibodies that sequester oxycodone in the serum, an important mechanism for preventing the adverse effects of opioid activity. Finally, Qβ-oxycodone is immunogenic in nonhuman primates, eliciting serum oxycodone antibodies after intramuscular immunization of rhesus macaques. These data establish Qβ-oxycodone as a promising opioid vaccine candidate.

Immuno-profiling of Individuals with Opioid Use Disorder : Insights for antibody development and immunological efficacy

Abstract Opioid use disorders (OUD) and overdose are a public health emergency in the United States and worldwide. Immunotherapeutics such as vaccines and monoclonal antibodies (mAbs) offer potential solutions in treatment and prevention of OUD and overdose. To accelerate their translation, our work focuses on immunoprofiling of opioid-specific antibodies and B cell repertoires in drug-naive individuals and those with OUD. Using antigen-based enrichment paired with flow cytometry, we found that individuals with OUD display increased frequency of opioid-specific B cells. When the individuals with OUD are compared to the drug-naive individuals, the increased opioid-induced B cell population was not paired with increased opioid-specific IgG polyclonal antibodies, changes in the B cell repertoires were associated with cytokine patterns. Sequencing of the B cell receptor (BCR) revealed that opioids affect the V(D)J rearrangement in B cells, as shown by isolation of a human mid-affinity monoclonal antibody against oxycodone and morphine. Results indicate that immunoprofiling could corroborate diagnosis of OUD, and could provide biomarkers to support testing of novel immunotherapeutics in individuals with OUD. Supported by grants from NIH U01 DA051658 Antibody-based countermeasures against fentanyl and its analogs and UG3 DA 0477117 Phase 1a/1b clinical trials of multivalent opioid vaccine components.

Immunoprofiling of Individuals With Opioid Use Disorder (OUD) Identifies Potential Biomarkers for Opioid Vaccine Efficacy

Immunoprofiling of Individuals With Opioid Use Disorder (OUD) Identifies Potential Biomarkers for Opioid Vaccine Efficacy

Immunotherapies for the Treatment of Drug Addiction.

Substance use disorders (SUD) are a serious public health concern globally. Existing treatment platforms suffer from a lack of effectiveness. The development of immunotherapies against these substances of abuse for both prophylactic and therapeutic use has gained tremendous importance as an alternative and/or supplementary to existing therapies. Significant development has been made in this area over the last few decades. Herein, we highlight the vaccine and other biologics development strategies, preclinical, clinical updates along with challenges and future directions. Articles were searched in PubMed, ClinicalTrial.gov, and google electronic databases relevant to development, preclinical, clinical trials of nicotine, cocaine, methamphetamine, and opioid vaccines. Various new emerging vaccine development strategies for SUD were also identified through this search and discussed. A good number of vaccine candidates demonstrated promising results in preclinical and clinical phases and support the concept of developing a vaccine for SUD. However, there have been no ultimate success as yet, and there remain some challenges with a massive push to take more candidates to clinical trials for further evaluation to break the bottleneck.

Lessons from COVID-19 to increase opioid vaccine acceptance

COVID-19 has put vaccine efficacy in the spotlight. The reluctancy of people towards vaccination though, have prevented the end of the pandemic. Currently opioid vaccines are being developed, which could help prevent opioid addiction, overdoses, or relapse in combination with medication assisted therapy.

Effect of Preexisting Immunity to Tetanus Toxoid on the Efficacy of Tetanus Toxoid-Conjugated Heroin Vaccine in Mice

Opioid use disorder (OUD) is a serious health problem that has dramatically increased over the last decade. Although current therapies for the management of OUD can be effective, they have limitations. The complementary strategy to combat the opioid crisis is the development of a conjugate vaccine to generate high affinity antibodies in order to neutralize opioids in circulation before reaching the brain. The components of an opioid vaccine include an opioid hapten (6-AmHap) that is conjugated to a carrier protein (tetanus toxoid) with the addition of adjuvants (Army Liposome Formulation adsorbed to aluminum hydroxide-ALFA). There is no consensus in the literature as to whether preexisting immunity to the carrier protein may impact the immunogenicity of the conjugate vaccine by inducing an enhanced or suppressed immune response to the hapten. Here, we investigated whether pre-exposure to tetanus toxoid would affect the immunogenicity and efficacy of the heroin vaccine, TT-6-AmHap. Mice were primed with diphtheria, tetanus, and acellular pertussis (DTaP) vaccine at weeks -4 and -2, then immunized with TT-6-AmHap vaccine at weeks 0, 3, and 6. Using ELISA and behavioral assays, we found that preexisting immunity to tetanus toxoid had no influence on the immunogenicity and efficacy of the TT-6-AmHap vaccine.

A Highly Efficacious Carfentanil Vaccine That Blunts Opioid-Induced Antinociception and Respiratory Depression

The opioid epidemic remains a dire public health crisis with millions of people currently suffering from opioid use disorder (OUD) and tens of thousands dying each year. Synthetic opioids are most responsible for the crisis because of their extreme potency and ease of manufacture. Carfentanil for example has an estimated potency 10,000 times greater than morphine and thus is highly dangerous for human use. Herein, we report two synthetic opioid vaccines that elicited high-affinity antibodies against carfentanil and fentanyl with cross-reactivity to other synthetic opioids in mice and offered protection against opioid-induced respiratory depression, the primary cause of overdose deaths. These vaccines also successfully diminished drug biodistribution to the brain and shielded against opioid analgesic effects. Collectively, these findings provide new insights into the development of immunotherapeutic strategies aimed at opioid abuse and overdose.

Developing Translational Vaccines against Heroin and Fentanyl through Investigation of Adjuvants and Stability.

The nearly insurmountable adversity that accompanies opioid use disorder (OUD) creates life-altering complications for opioid users. To worsen matters, existing small-molecule drugs continue to inadequately address OUD due to their engagement of the opioid receptor, which can leave the user to deal with side effects and financial hardships from their repeated use. An alternative therapeutic approach utilizes endogenously generated antibodies through active vaccination to reduce the effect of opioids without modulating the opioid receptor. Here, we explore different adjuvants and storage conditions to improve opioid vaccine efficacy and shelf life. Our results revealed that inulin-based formulations (Advax) containing a CpG oligodeoxynucleotide (ODN) acted as effective adjuvants when combined with a heroin conjugate: immunized mice showed excellent recovery from heroin-induced antinociception accompanied by high titer, high opioid affinity serum antibodies similar to the immunopotentiating properties of traditional alum-based adjuvants. Moreover, nonhuman primates vaccinated with a heroin/fentanyl combination vaccine demonstrated potent antibody responses against opioids when formulated with both inulin and alum adjuvants. Finally, storing a freeze-dried opioid vaccine formulation maintained efficacy for up 1 year at room temperature. The results from our studies represent an advance toward a clinically feasible opioid vaccine.

A synthetic opioid vaccine attenuates fentanyl-vs-food choice in male and female rhesus monkeys

AimOpioid-targeted vaccines are under consideration as candidate Opioid Use Disorder medications. We recently reported that a fentanyl-targeted vaccine produced a robust and long-lasting attenuation of fentanyl-vs-food choice in rats. In the current study, we evaluated an optimized fentanyl-targeted vaccine in rhesus monkeys to determine whether vaccine effectiveness to attenuate fentanyl choice translated to a species with greater phylogenetic similarity to humans. MethodsAdult male (2) and female (3) rhesus monkeys were trained to respond under a concurrent schedule of food (1 g pellets) and intravenous fentanyl (0, 0.032−1 μg/kg/injection) reinforcement during daily 2 h sessions. Fentanyl choice dose-effect functions were determined daily and 7-day buprenorphine treatments (0.0032−0.032 mg/kg/h IV; n = 4–5) were determined for comparison to vaccine effects. Subsequently, a fentanyl-CRM197 conjugate vaccine was administered at week 0, 3, 8, 15 over a 29-week experimental period during which fentanyl choice dose-effect functions continued to be determined daily. ResultsBuprenorphine significantly decreased fentanyl choice and reciprocally increased food choice. Vaccination eliminated fentanyl choice and increased food choice in four-of-the-five monkeys. A transient and less robust vaccine effect was observed in the fifth monkey. Fentanyl-specific antibody concentrations peaked after the third vaccination to approximately 50 μg/mL while anti-fentanyl antibody affinity increased to a sustained low nanomolar level. ConclusionThese results translate fentanyl vaccine effectiveness from rats to rhesus monkeys to decrease fentanyl-vs-food choice, albeit with greater individual differences observed in monkeys. These results support the potential and further clinical evaluation of this fentanyl-targeted vaccine as a candidate Opioid Use Disorder medication.

Assessing Biological, Structural, and Ethical Barriers to Implementation of Opioid Vaccination

Given the diverse public health challenges facing the United States today, the opioid overdose epidemic is among the most pressing. Nearly 50,000 individuals died in the past year due to opioid overdose, and around 500,000 individuals have died due to opioid overdose overall. These staggering numbers of deaths have unfortunately occurred despite the availability of effective treatments for both overdose reversal and opioid use disorder. Unfortunately, less than 20% of individuals who may qualify for such treatments actually access them. Given the clear ongoing need for new solutions, vaccination against both prescription and illicit opioids has been proposed as an alternative method to address this crisis. Indeed, following on from promising pre‐clinical work in both rodents and non‐human primates, the first clinical trials to test opioid vaccines have now been registered. Considering that previous vaccines directed against small molecules such as nicotine ultimately failed to reach the market, and that even approved treatments for opioid use disorder face barriers to dissemination and widespread use, we undertook a concerted, human subject investigation into three separate domains of translational barriers that could impact the ultimate success of the opioid vaccine approach. We first investigated biological barriers to success, specifically using ELISA to assess the blood of individuals who were either chronic opioid users or matched controls to look for development of endogenous anti‐opioid antibodies that could ultimately suppress immune responses to vaccination. We next assessed structural barriers to implementation, surveying current and future healthcare providers about present use and perceived structural challenges to the use of interventions for opioid use disorder. Finally, we assessed ethical barriers to implementation of vaccine‐based therapeutics for substance use disorders, also using a targeted survey approach. Overall, this investigation identified limited evidence of endogenous antibody formation in chronic prescription opioid users, identified some structural difficulties arising from injectable formulations and cost concerns, and identified ethical concerns regarding compulsory use of vaccination, as well as potential use in protected classes of individuals. Nevertheless, opioid vaccination was reported to be a helpful potential addition for the treatment of opioid use disorder and overdose.Support or Funding InformationThis work was generously supported by the ALSAM foundation (5‐77693), the UW‐Madison School of Pharmacy, and Office of the Vice Chancellor for Research and Graduate Education. Furthermore, this study was conducted in collaboration with the Pharmacy Practice Enhancement and Action Research Link (PearlRx) of Wisconsin, a statewide pharmacist practice‐based research network which is in part supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR002373 and the Pharmacy Society of Wisconsin. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.Competitive ELISA with Oxycodone demonstrates little difference in serum binding to OXY‐BSA, between chronically opioid exposed and opioid naive subjects with lower‐back pain, indicating that endogenous anti‐opioid antibodies may not be a biological barrier to vaccine success in this population. MEan +/− SEM.Figure 1Currentlly practicing healthcare providers surveyed through PearlRx indicate that affordability is the greatest structural barrier to implementation of anti‐opioid vaccination, while lack of time is the lowest structural barrier. Provider availability, patient refusal, and access to the medication were of intermediate concern. Mean +/− SEM.Figure 2

Current status of immunotherapies for addiction.

The treatment of substance use disorders has always been challenging because multiple neurotransmitters mediate addiction. However, with smoking being the leading cause of preventable death and the recent opioid epidemic in the United States, the search for novel solutions becomes more imperative. In this review, we discuss the use of antibodies to treat addictions and highlight areas of success and areas that require improvement, using examples from cocaine, nicotine, and opioid vaccines. Through each example, we examine creative problem-solving strategies for developing future vaccines, such as using an adenovirus vector as a carrier, designing bivalent vaccines, stimulating Toll-like receptors for adjuvant effects, and altering the route of administration. Our review also covers passive immunization alone to override or prevent drug toxicity as well as in combination with vaccines for more rapid and potentially greater efficacy.

Effectiveness and selectivity of a heroin conjugate vaccine to attenuate heroin, 6-acetylmorphine, and morphine antinociception in rats: Comparison with naltrexone

BackgroundOne emerging strategy to address the opioid crisis includes opioid-targeted immunopharmacotherapies. This study compared effectiveness of a heroin-tetanus toxoid (TT) conjugate vaccine to antagonize heroin, 6-acetylmorphine (6-AM), morphine, and fentanyl antinociception in rats. MethodsAdult male and female Sprague Dawley rats received three doses of active or control vaccine at weeks 0, 2, and 4. Vaccine pharmacological selectivity was assessed by comparing opioid dose-effect curves in 50 °C warm-water tail-withdrawal procedure before and after active or control heroin-TT vaccine. Route of heroin administration [subcutaneous (SC) vs. intravenous [IV)] was also examined as a determinant of vaccine effectiveness. Continuous naltrexone treatment (0.0032-0.032 mg/kg/h) effects on heroin, 6-AM, and morphine antinociceptive potency were also determined as a benchmark for minimal vaccine effectiveness. ResultsThe heroin-TT vaccine decreased potency of SC heroin (5-fold), IV heroin (3-fold), and IV 6-AM (3-fold) for several weeks without affecting IV morphine or SC and IV fentanyl potency. The control vaccine did not alter potency of any opioid. Naltrexone dose-dependently decreased antinociceptive potency of SC heroin, and treatment with 0.01 mg/kg/h naltrexone produced similar, approximate 8-fold decreases in potencies of SC and IV heroin, IV 6-AM, and IV morphine. The combination of naltrexone and active vaccine was more effective than naltrexone alone to antagonize SC heroin but not IV heroin. ConclusionsThe heroin-TT vaccine formulation examined is less effective, but more selective, than chronic naltrexone to attenuate heroin antinociception in rats. Furthermore, these results provide an empirical framework for future preclinical opioid vaccine research to benchmark effectiveness against naltrexone.

Development of vaccines for treatment of opioid abuse using carrier proteins suitable for pharmaceutical manufacturing

Abstract In 2016, over 50,000 people died in the US from heroin and prescription opioid related overdoses. Current standard of care is not sufficient. Therapeutic vaccines against opioids are safe, long-lasting, and cost-effective alternatives to opioid-based pharmacotherapy. Opioid vaccines elicit opioid-specific antibodies that prevent opioid distribution to the brain and opioid-induced behavior and toxicity. To ensure translation, we have developed candidate vaccines that include components suitable for good manufacturing practices and have the ability to be characterized according to FDA guidelines. In this study, we synthesized three oxycodone-based (OXY) haptens to assess linker and bioconjugation chemistry in vaccine efficacy against oxycodone in mice. Then, we tested efficacy of lead OXY haptens conjugated to novel carrier proteins consisting of E. coli-expressed diphtheria cross-reactive material (EcoCRM™) and nontoxic tetanus toxin fragment (rTTHc). Haptens using tetraglycine linkers coupled with carbodiimide chemistry elicited the greatest oxycodone specific serum IgG antibody titers and significantly reduced oxycodone distribution to the brain. Oxycodone vaccines containing EcoCRM™ and rTTHc, adsorbed on alum adjuvant, were effective in inducing expansion of oxycodone-specific plasma and germinal center B cells, blocking oxycodone distribution to the brain, and were easily characterized by mass spectrometry. The OXY-EcoCRM™ and OXY-rTTHc were equivalent, or superior, to vaccines containing keyhole limpet hemocyanin protein, tetanus toxoid and CRM197, making them candidate immunogens for further development.

Blocking interleukin-4 enhances efficacy of vaccines for treatment of opioid abuse and prevention of opioid overdose

Vaccines offer an option to treat heroin and prescription opioid abuse and prevent fatal overdoses. Opioid vaccines elicit antibodies that block opioid distribution to the brain and reduce opioid-induced behavioral effects and toxicity. The major limitation to the translation of addiction vaccines is that efficacy is observed only in subjects achieving optimal drug-specific serum antibody levels. This study tested whether efficacy of a vaccine against oxycodone is increased by immunomodulators targeting key cytokine signaling pathways involved in B and T cell lymphocyte activation. Blockage of IL-4 signaling increased vaccine efficacy in blocking oxycodone distribution to the brain and protection against opioid-induced behavior and toxicity in mice. This strategy generalized to a peptide-protein conjugate immunogen, and a tetanus-diphtheria-pertussis vaccine. These data demonstrate that cytokine-based immunomodulators increase efficacy of vaccines against small molecules, peptides and proteins, and identify IL-4 as a pharmacological target for improving efficacy of next-generation vaccines.

Opioid Dose- and Route-Dependent Efficacy of Oxycodone and Heroin Vaccines in Rats.

Heroin and oxycodone abuse occurs over a wide range of drug doses and by various routes of administration characterized by differing rates of drug absorption. The current study addressed the efficacy of a heroin vaccine [morphine hapten conjugated to keyhole limpet hemocyanin (M-KLH)] or oxycodone vaccine [oxycodone hapten conjugated to keyhole limpet hemocyanin (OXY-KLH)] for reducing drug distribution to brain after intravenous heroin or oxycodone, or subcutaneous oxycodone. Rats immunized with M-KLH or keyhole limpet hemocyanin (KLH) control received an intravenous bolus dose of 0.26 or 2.6 mg/kg heroin. Vaccination with M-KLH increased retention of heroin and its active metabolites 6-acetylmorphine (6-AM) and morphine in plasma compared with KLH controls, and reduced total opioid (heroin + 6-AM + morphine) distribution to brain but only at the lower heroin dose. Immunization also protected against respiratory depression at the lower heroin dose. Rats immunized with OXY-KLH or KLH control received 0.22 or 2.2 mg/kg oxycodone intravenously, the molar equivalent of the heroin doses. Immunization with OXY-KLH significantly reduced oxycodone distribution to brain after either oxycodone dose, although the magnitude of effect of immunization at the higher oxycodone dose was small (12%). By contrast, vaccination with OXY-KLH was more effective when oxycodone was administered subcutaneously rather than intravenously, reducing oxycodone distribution to brain by 44% after an oxycodone dose of 2.3 mg/kg. Vaccination also reduced oxycodone-induced antinociception. These data suggest that the efficacy of OXY-KLH and M-KLH opioid vaccines is highly dependent upon opioid dose and route of administration.

Vaccines to combat the opioid crisis: Vaccines that prevent opioids and other substances of abuse from entering the brain could effectively treat addiction and abuse.

In August 2017, US President Donald Trump declared the abuse of opioids by millions of Americans a national state of emergency and highlighted the staggering statistics associated with substance use disorder (SUD), which are at record highs. The NIH reported that in 2015, 2.6 million Americans suffered from opioid use disorder (OUD), which caused US$78.5 billion in healthcare, law enforcement, and lost productivity costs for prescription opioids alone [1]. A 2016 National Survey on Drug Use and Health reported that approximately 13 million Americans had misused opioids, including heroin, oxycodone, hydrocodone, and fentanyl, one or more times in the preceding year [2]. Most strikingly, the incidence of opioid‐related overdose deaths has quadrupled since 1999, with no signs of slowing. Currently, more than 90 Americans die each day from opioid overdose [3]. While the statistics are grim, an increasing commitment and more resources to develop new and efficient therapies for OUD gives hope for effectively combating the drug crisis. Earlier this year, the NIH launched a scientific initiative to combat OUD emphasizing three research areas: improvement of overdose‐reversal interventions; new treatments for opioid addiction; and alternative strategies to safely manage chronic pain [1]. A promising approach for treating addiction is immunopharmacotherapy: vaccination against a drug of abuse to induce a tailored antibody response, which prevents the drug from entering the brain and eliciting its psychoactive effects. Vaccines against heroin, oxycodone, hydrocodone, and fentanyl addiction have already shown great success in preclinical evaluation, but have yet to enter clinical trials. This commentary discusses the clinical potential for opioid vaccines along with the experimental and societal aspects that have so far prevented the development of this approach. Ultimately, the field is on the verge of delivering a vaccine with clinical utility. Currently, only four FDA‐approved …

Safety and efficacy of an oxycodone vaccine: Addressing some of the unique considerations posed by opioid abuse.

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.

Co-administration of morphine and oxycodone vaccines reduces the distribution of 6-monoacetylmorphine and oxycodone to brain in rats

Opioid conjugate vaccines have shown promise in animal models as a potential treatment for opioid addiction. Individual vaccines are quite specific and each targets only a limited number of structurally similar opioids. Since opioid users can switch or transition between opioids, we studied a bivalent immunization strategy of combining 2 vaccines that could target several of the most commonly abused opioids; heroin, oxycodone and their active metabolites. Morphine (M) and oxycodone (OXY) haptens were conjugated to keyhole limpet hemocyanin (KLH) through tetraglycine (Gly)4 linkers at the C6 position. Immunization of rats with M-KLH alone produced high titers of antibodies directed against heroin, 6-monoacetylmorphine (6-MAM) and morphine. Immunization with OXY-KLH produced high titers of antibodies against oxycodone and oxymorphone. Immunization with the bivalent vaccine produced consistently high antibody titers against both immunogens. Bivalent vaccine antibody titers against the individual immunogens were higher than with the monovalent vaccines alone owing, at least in part, to cross-reactivity of the antibodies. Administration of a single concurrent intravenous dose of 6-MAM and oxycodone to rats immunized with the bivalent vaccine increased 6-MAM, morphine and oxycodone retention in serum and reduced the distribution of 6-MAM and oxycodone to brain. Vaccine efficacy correlated with serum antibody titers for both monovalent vaccines, alone or in combination. Efficacy of the individual vaccines was not compromised by their combined use. Consistent with the enhanced titers in the bivalent group, a trend toward enhanced pharmacokinetic efficacy with the bivalent vaccine was observed. These data support the possibility of co-administering two or more opioid vaccines concurrently to target multiple abusable opioids without compromising the immunogenicity or efficacy of the individual components.