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A Vision for Vaccines: Combating the Opioid Epidemic Candy S. Hwang and Kim D. Janda* Departments of Chemistry, Immunology, and Microbial Science, Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, United States
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reescalation of compulsive heroin self-administration following abstinence in dependent rats.3 Impressively, the vaccine significantly devalued the reinforcing and motivating properties of heroin, even in animal subjects with a history of dependence.3 Through the evolution of our drug-hapten conjugation strategy, we determined that amide-based coupling of drughapten to carrier protein was superior to our first-generation maleimide-based strategy, resulting in increased drug-hapten density and overall vaccine efficacy.4 Importantly, our secondgeneration heroin-hapten immunoconjugate was tested in a non-human primate model; this provided a crucial and translationally relevant platform for developing our vaccine for use in humans. The currently optimized vaccine formulation is capable of effective heroin blockade for several months, with roughly 10-fold shifts in antinociceptive potency in both rodents and monkeys. In our non-human primate study, the vaccine was shown to elicit anti-6-monoacetylmorphine (6AM) IgG antibodies in all subjects and could block the effects of heroin in a behavioral model with an efficacy similar to that of naltrexone.4 On the basis of our most recent comprehensive assessment, the vaccine comprised of adjuvants cytosinephosphodiester-guanine oligodeoxynucleotide (CpG ODN) 1826 (rodents) or 2006 (non-human primates) and alum with carrier protein tetanus toxoid (TT) elicits a strong humoral immune response and shows the most promise to move beyond preclinical development. Expanding our overall preclinical approach from heroin to the class of fentanyls was a logical extension considering the rise of opioid overdose from synthetic adulterants, along with their ease of synthesis and enhanced potency (Figure 2). However, there was considerable pessimism that a fentanyl vaccine might be forbidding because of high-affinity fentanyl μ-receptor binding (∼2 nM). Despite this undeniable challenge, success was seen with our report of a fentanyl vaccine that shifted the fentanyl dose−effect curve by >30-fold in behavioral assays for opioid-induced antinociception.5 Moreover, the vaccine could produce antibodies that recognized six fentanyl analogues with little cross-reactivity to oxycodone or methadone (Figure 3).5 This success has now led us to ask whether the most powerful heroin adulterant, carfentanil [10000 times more potent than morphine (Figure 2)], can be neutralized by an antibody. To probe the feasibility of this idea, we have taken recourse to prepare monoclonal antibodies. Happily, antibodies with singledigit nanomolar affinity for this incredibly dangerous synthetic opioid have now been isolated (unpublished data).
ubstance use disorder, especially in regard to use of opioids such as oxycodone, hydrocodone, heroin, and the fentanyls, has become a significant public health issue. According to the 2016 National Survey on Drug Use and Health, 11.8 million Americans misused opioids in the last year. Although the number of opioid abusers has remained relatively constant over the past decade, what is particularly troubling is the evolution of the heroin epidemic and the mounting number of overdose deaths. These incidents have been characterized by unintentional poisoning deaths involving synthetic designer drugs like fentanyl and have substantially increased from 2089 in 2002 to 13219 in 2016 (∼533% increase). The traditional mindset for treating an opioid use disorder has been to utilize pharmacotherapies such as naloxone and naltrexone that can displace the drug from the μ-opioid receptor, or buprenorphine and methadone, which mediate opioid signaling. As useful as these treatments are, we need to point out that such treatments suffer from side effects such as dysphoria and have a potential risk for abuse and overdose. Suffice it to say, treating an opioid use disorder has been a daunting challenge, and new therapeutics are needed not only for long-term opioid addiction treatment but also for overdose reversal. Indeed, most recently, a call has come from National Institutes of Health Director Collins and National Institute on Drug Abuse Director Volkow for the need to accelerate research with the goals of overdose reversal, addiction, treatment, and pain management. The research described herein is directed to that of vaccinology, which has had a profoundly positive impact on cancer and infectious diseases. We came to envision vaccines as a means of treating the opioid epidemic and providing long-term protection against opioids. A proof of concept for a drug abuse vaccine was first reported in the 1970s when non-human primates were immunized with a “morphine hapten” and then challenged with heroin.1 Unfortunately, heroin blockade was shown to be dosedependent and could be overcome by higher doses of the drug. This poor vaccine profile and methadone advancement were sound reasons to shelve further research on vaccines against drugs of abuse until we demonstrated efficacy with a cocaine vaccine.2 Our successful cocaine vaccine served to incite visions that vaccines could be readily created against any ̈ drug of abuse. However, this vision was naively simplistic as the pharmacokinetics and pharmacodynamics seen for each drug posed unique challenges in vaccine development. For example, the metabolic profile of heroin (Figure 1A) informed us that a new strategy would need to be developed for a successful heroin vaccine. As shown in Figure 1B, a “dynamic” heroin vaccine was evoked to counter heroin’s psychoactive metabolic profile. The importance of this strategy was seen in preventing various features of heroin abuse in rodents: including heroin reward, drug-induced reinstatement of drug seeking, and © XXXX American Chemical Society
Received: September 22, 2017
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DOI: 10.1021/acs.biochem.7b00948 Biochemistry XXXX, XXX, XXX−XXX
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Biochemistry
Figure 1. Vaccine strategy designed to target heroin. (A) Structure of heroin and its metabolites. (B) Dynamic heroin vaccine that elicits anti-heroin, anti-6-monoacetylmorphine, and anti-morphine IgG production. Structures highlighted in color represent the structure of opioids within the dynamic hapten.
and potentially preventing overdose. Also not lost upon us is the idea of a combination therapy of methadone or buprenorphine with our vaccine, which could enhance therapeutic efficacy by alleviating opioid cravings. As described above, the major benefits to vaccination over current pharmacological antagonists are a potential for an increased duration of action and decreased side effects. We anticipate future studies will involve more advanced non-human primate models, which will elucidate the true potential of these opioid vaccines to move beyond the preclinical space.
Figure 2. Relative potency of select opioids and the μ-opioid receptor.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Candy S. Hwang: 0000-0003-2826-4078 Kim D. Janda: 0000-0001-6759-4227 Funding
This work was supported by National Institutes of Health Grants UH3 DA041146 (K.D.J.) and F32 AI126628 (C.S.H.). Notes
The authors declare no competing financial interest.
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Figure 3. Structural similarities between the 4-anilidopiperidine opioids. (A) Overlay of fentanyl and derivatives (lines). (B) Markush structures of fentanyl hapten and derivatives. Structures were energy minimized and aligned. This figure was generated in PyMol.
ACKNOWLEDGMENTS We thank Lucy Lin for assistance in preparing the manuscript. This is manuscript #29523 from The Scripps Research Institute.
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The recent increase in the frequency of contamination of heroin with fentanyl and its congeners, brought on by a need to increase potency and increase the cost efficiency of the preparation, has substantially increased the rate of casualties from heroin overdose. Because of this ongoing trend, new therapies for treating opioid substance use disorder are urgently needed. Considering the studies presented here, and the promising results observed, opioid vaccines have the potential to be clinically useful, both serving as a safety net for preventing relapse episodes in heroin users undergoing cessation therapy
REFERENCES
(1) Bonese, K. F., Wainer, B. H., Fitch, F. W., Rothberg, R. M., and Schuster, C. R. (1974) Changes in heroin self-administration by a rhesus monkey after morphine immunisation. Nature 252, 708−710. (2) Carrera, M. R. A., Ashley, J. A., Parsons, L. H., Wirsching, P., Koob, G. F., and Janda, K. D. (1995) Suppression of psychoactive effects of cocaine by active immunization. Nature 378, 727−730. (3) Schlosburg, J. E., Vendruscolo, L. F., Bremer, P. T., Lockner, J. W., Wade, C. L., Nunes, A. A. K., Stowe, G. N., Edwards, S., Janda, K. D., and Koob, G. F. (2013) Dynamic vaccine blocks relapse to
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DOI: 10.1021/acs.biochem.7b00948 Biochemistry XXXX, XXX, XXX−XXX
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Biochemistry compulsive intake of heroin. Proc. Natl. Acad. Sci. U. S. A. 110, 9036− 9041. (4) Bremer, P. T., Schlosburg, J. E., Banks, M. L., Steele, F. F., Zhou, B., Poklis, J. L., and Janda, K. D. (2017) Development of a Clinically Viable Heroin Vaccine. J. Am. Chem. Soc. 139, 8601−8611. (5) Bremer, P. T., Kimishima, A., Schlosburg, J. E., Zhou, B., Collins, K. C., and Janda, K. D. (2016) Combatting Synthetic Designer Opioids: A Conjugate Vaccine Ablates Lethal Doses of Fentanyl Class Drugs. Angew. Chem., Int. Ed. 55, 3772−3775.
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DOI: 10.1021/acs.biochem.7b00948 Biochemistry XXXX, XXX, XXX−XXX
