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Vaccines for Drug Abuse

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Official websites use. Share sensitive information only on official, secure websites. Current medications for drug abuse have had only limited success. Anti-addiction vaccines to elicit antibodies that block the pharmacological effects of drugs have great potential for treating drug abuse. We review the status for two vaccines that are undergoing clinical trials cocaine and nicotine and two that are still in pre-clinical development methamphetamine and heroin. We also outline the challenges and ethical concerns for anti-addiction vaccine development and their use as future therapeutics. Drug dependence is a disease state in which physical dependence on a substance leads to compulsive and repetitive use despite negative consequences to the user's health, mental state or social life. Opioid dependence is considered to be a lifelong, chronic relapsing disorder and substantial therapeutic efforts are needed to keep people drug free. Methadone maintenance therapy MMT was introduced in s, and is currently recommended for opioid dependence because its outcomes are far superior to detoxification treatment. Naltrexone is a long acting opioid antagonist that does not produce euphoria and is not addicting. It is particularly suitable to prevent a relapse to opioid use after heroin detoxification for those with substantial contingencies that will enhance their compliance with treatment. High cost has made these opiate maintenance programs unfeasible in much of the world 7 and parts of the United States. Cocaine is the most problematic drug worldwide after the opiates, notably in the Americas. Government surveys indicate that 2. Methamphetamine use may constitute a threat to health that is similar to abuse of crack cocaine, and its abuse has grown at alarming rates in rural areas in the United States over the past two decades, as well as being widespread in Southeast and East Asia more recently. Tobacco addiction, the second-leading cause of death in the world is associated with approximately 5 million deaths each year, or 1 in 10 adult deaths. Currently, there are 1. In summary, we either lack treatments cocaine and methamphetamine or have had limited success with existing therapeutics heroin and nicotine. These limitations in treatment have opened the opportunity for developing alternatives such as vaccines for drug abuse. Anti-addiction vaccines have distinctly different mechanisms and therapeutic utility from small molecule approaches to treatment. They do not rely on inhibiting drug binding at specific receptors within the brain; rather the antibodies serve as pharmacokinetic antagonists, favorably altering the concentration-time course of drug distribution to multiple organ systems, especially reducing drug concentrations in the brain. Furthermore, vaccine production is less expensive, thus, they have great potential to become available for wider ranges of patients world-wide and for complementing the psychosocial tools needed for a transition to a medication-free and abstinent life. For example, the cocaine vaccine is comprised of succinylnorcocaine molecules covalently linked to a carrier protein derived from the cholera B toxin rCTB , which is suspended in an aluminum adjuvant. This vaccine can stimulate B-cell to produce antibodies to cocaine as well as rCTB. When cocaine is later introduced into bloodstream, cocaine antibodies can bind to the drug, and form the antibody-drug compound molecules in circulation Figure. These molecules are too large to cross the blood brain barrier, thereby reducing the rate and quantity of the drug entry into the brain. Individuals who use a drug without obtaining its reinforcing effects are expected sooner or later to shed the powerful mental associations between the drug and pleasure that underlie craving and relapse Figure. The cocaine vaccine is comprised of succinylnorcocaine molecules covalently linked to a carrier protein derived from the cholera B toxin rCTB , which is suspended in an aluminum adjuvant. When cocaine later enters the bloodstream, cocaine antibody can bind the drug, and form the antibody-drug compound molecules in circulation that are too large to cross the blood brain barrier. In the absence of cocaine vaccine, drug readily absorbs at the brain blood barrier and enters brain. Vaccine stimulates antibody production, sequesters drug in the blood circulation. This antibody-drug binding prevents the cocaine from rapidly leaving the blood vessels and entering the brain, reducing the drug's euphoric effects. The history of addiction vaccines starts nearly 40 years ago with vaccines for opiate addiction. As the spread of addiction to stimulants like cocaine and methamphetamine became epidemic, interest in addiction vaccines was rejuvenated, resulting in the development of cocaine conjugate vaccines, as well as vaccines for nicotine. Both of these vaccines have progressed to the point of successful clinical trials. The data from the cocaine and nicotine vaccine trials suggest that many patients may not produce a sufficient antibody response for clinical efficacy, but those patients who attain high levels of antibodies can have excellent abstinence rates. Indeed, anti-addiction vaccines are in various stages of development and being evaluated for quite a broad array of abused drugs, including cocaine, nicotine, methamphetamine, and heroin. Barbara Fox at Immulogic. Both the carrier protein and adjuvant used in this cocaine vaccine are different from what was used in the first animal morphine vaccine, although the proof of principle is the same. Along with other labs, these early studies showed that conjugate cocaine vaccines could elicit strong antibody responses that blocked the pharmacological effects of the cocaine in animal models. In those studies patients given relatively high vaccine doses for at least four vaccinations attained clinically relevant quantities of cocaine specific antibody, and the cocaine vaccine showed few side effects and no harmful interactions between the cocaine and anti-cocaine antibodies. Figure 3a left. Figure 3b right. The antibodies are produced to cocaine as well as cholera toxin b, since the polyclonal antibody response includes the cocaine chemically attached to the cholera toxin. This poor response is being actively investigated with a variety of very interesting leads related to human genetics and the production of immunological tolerance to cocaine. For example, this low level IgG response is associated in some patients with the presence of cocaine binding IgM antibodies which might reflect an immune response to adducts formed by the drug with native proteins in vivo. The high affinity IgG antibody levels decline substantially over about 3 months after the peak antibody response in the patients who produced sufficient cocaine antibody levels for therapeutic efficacy in the initial response. A booster vaccination is needed to re-stimulate a rise in the antibody levels to the peak. Rather than needing the full series of five vaccinations again, however, a single vaccination may be sufficient to elevate antibody levels back to their therapeutic levels for about 3 months. Thus, for a period of protection lasting two years, patients may need to get about six additional boosters given as one every 3 months. Exposure to cocaine alone will not provoke an increase in antibodies because the cocaine molecule is too small to activate memory B cells by cross linking the antibodies expressed on their surface. However, after boosting with the conjugate vaccine, sufficient quantities of newly produced antibodies will rapidly bind most of a usual dose of cocaine when it enters the bloodstream. This binding prevents the cocaine from rapidly leaving the blood vessels and entering the brain, heart or other organs, reducing the drug's euphoric effects. Figure 2 Because the antibody—cocaine complex is too large to pass thorough the normal blood brain barrier, the cocaine is then metabolized in the blood and liver to inactive metabolites by one of 3 mechanisms: spontaneous hydrolysis, tissue esterases especially in the liver , or butyryl cholinesterase in the bloodstream. Phase I and II studies with the cocaine vaccine were successful, in part, because of the combination of a good antibody response from conjugation with the cholera toxin carrier and the special advantage of the spontaneous and enzymatic hydrolysis of cocaine into inactive metabolites, as described above. When cocaine is bound by antibodies, the drug is slowly metabolized in the liver or other tissue sites, or excreted unchanged. The cocaine vaccine was conceived primarily as an agent for patients who could abstain from cocaine use for a limited period of time but needed help with maintaining that abstinence. This small exposure markedly intensifies craving, rather than reducing craving, and increases the risk for falling into a binge pattern of abuse and relapse. However, we also found that the vaccine could be useful beyond preventing this priming effect. In the Phase IIb cocaine trials some subjects who continued high level cocaine use did not appear to over-ride the antibody blockade of cocaine effects. The behavioral challenges for any successful vaccination program start with the need to have 2 to 3 months where the patient can be brought to a treatment site for five vaccinations. During these 2 to 3 months, the patients could be vulnerable to relapse if they have already discontinued drug use. While this drug abuse alone does not interfere with the vaccine's ability to induce the required antibody production, it is important that the patient get these vaccinations at appropriate times over the 3 months e. Thus, counseling or other treatment efforts will be critical to insure compliance with the schedule of vaccinations; such interventions could vary from residential substance abuse care to outpatient contingency management, in which patients are paid to come for the vaccinations with an escalating pay schedule for each vaccination obtained. The success of the first placebo controlled clinical trial of a cocaine vaccine, as well as the relative ease with which these vaccines can be manufactured, has encouraged a multisite Phase IIb clinical trial of the cocaine vaccine to move forward. This four-month, double-blind, randomized, placebo-controlled, study compares the effect of the cocaine vaccine to placebo in reducing cocaine use in treatment-seeking, cocaine-dependent individuals. Patients receive five vaccinations over a period of twelve weeks and some subjects will likely attain therapeutic antibody levels from the vaccine in weeks after the first three vaccinations. Based on the success of this vaccine in the earlier clinical trials, this cocaine vaccine may be one of the first anti-addiction vaccines to be approved by the FDA for human use. Nicotine does not have the advantage of a serum enzyme that breaks it down into an inactive metabolite in the bloodstream. Lacking such a serum enzyme makes a successful nicotine vaccine more difficult if the only goal is to prevent deliberate override of the antibody levels. However, nicotine vaccines may prove as effective as cocaine vaccines because those being vaccinated are typically very motivated to stop smoking and do not have the ambivalence about abstinence that is common among cocaine and other illicit drug users. This remarkably greater efficacy than binding capacity also is probably due to the rapid on and off binding rates for nicotine as a small molecule that is bound by a single antibody combining site. Nevertheless, having quantitatively high antibody responses to clinical vaccines is critical to success. Because of the substantial market for smoking cessation products, development of a vaccine against nicotine addiction has been of great interest to the pharmaceutical industry. As a result, three pharmaceutical companies have moved nicotine vaccines forward to human studies. Table 2. Phase II trials with NIC also known as Nicotine QB or CYTNicQB, a Virus like vaccine from Cytos Biotechnology were conducted in smokers, and the outcome data were available from study subjects who were divided into low, medium and high responders according to their nicotine antibody levels. The top third of the responders had higher abstinence rates at the 6 and 12 month follow ups, however, side-effects occurred in A new Phase II trial in cigarette smokers with a reformulated vaccine with fewer side effects was conducted in by Novartis. However, this trial also failed to achieve its primary endpoint continuous abstinence from smoking during weeks 8 to 12 after start of treatment , possibly due to the insufficient antibody titers produced by this vaccine. These trials demonstrated that NicVAX was well-tolerated, highly immunogenic, and gave a dose-dependent increase in antibody concentrations. In addition, these trials showed a correlation between antibody concentration and the ability of subjects to quit smoking and to remain abstinent up to 12 months. This trial enrolled a total of heavy smokers who smoked an average of 24 cigarettes per day prior to enrollment. Among those 61 who had this high antibody response, but failed to quit, the number of cigarettes smoked per day was reduced from 20 to Overall, these trials have not demonstrated nicotine vaccines to be superior to placebo when including all vaccinated subjects, because only a third of those vaccinated subjects developed sufficient levels of antibody to block the effects of nicotine. The primary endpoint of the study was the abstinence rate for 16 weeks ending at 12 months. Abstinence was evaluated by self-reported cigarette consumption and biologically verified by exhaled carbon monoxide. Unfortunately, the results from the first Phase III reported recently failed to meet its primary endpoint, namely the abstinence rate was not significantly greater in those vaccinated compared with the placebo group. Nabi is awaiting the results of a second Phase III trial, but that trial appears to suffer from similar design problems; that is, treatment efficacy is assessed after the active agent responsible for the therapeutic effect e. A successful nicotine vaccine could have an important advantage over pharmacological treatments in that they can have a prolonged effect for months after each booster dosing , thereby requiring limited patient cooperation to have adequate adherence, which could reduce relapse rates. Daily administration of a drug is not required; only bimonthly booster shots are needed to maintain an adequate antibody titer. However, there has been inconsistency in the degree of antibody response in large subject groups; some people do not achieve adequate antibody titers. Possible disadvantages of nicotine vaccines include the necessity for injections of the vaccine and the time delay before an effective immune response is achieved. Overall, nicotine vaccines could have significant success relatively soon, since they can be manufactured relatively inexpensively, the total smoking population worldwide is very large, motivation to quit smoking is generally high, and finally patients are quite unlikely to try to deliberately override the antibody capacity, unlike cocaine patients. By slowing methamphetamine's entry into the brain, antibodies may be effective in reducing the pharmacological effects of this drug on the brain, thereby reducing its behavioral reinforcement, although pharmacokinetic studies have shown that the half life of the drug in circulation is significantly prolonged when bound to the specific antibodies for methamphetamine. In vivo pharmacokinetics have shown that high concentrations of anti-methamphetamine monoclonal antibodies can produce a sustainable equilibrium shift of methamphetamine out of the brain and into the blood stream, as measured by substantial reductions in methamphetamine brain concentrations over time accompanied by substantial increases in methamphetamine serum concentrations. These antibody-induced reductions in methamphetamine volume of distribution, clearance from the blood stream, and substantially increased serum protein predominantly antibody binding are why antibody treatments are classified as pharmacokinetic antagonists; that is, they favorably change the concentration-time course of methamphetamine in brain and other organ systems. Even though the vaccines for methamphetamine abuse are still in preclinical development, this is a rapidly evolving field. A number of labs have been working on evaluating the best composition of a vaccine for methamphetamine by considering hapten design, selection of the carrier protein, the chemical positioning of a linker between the target antigen and the carrier protein, and choice of the best adjuvant. Behavioral effects included inhibition of methamphetamine-stimulated locomotor activity in the vaccinated animals Orson, unpublished. The passive administration of high affinity monoclonal antibodies have been shown to reduce methamphetamine self-administration in rats, 56 and to reduce locomotor activity in rats given high dose methamphetamine. The influence of average antibody binding affinity and kinetics from these new vaccines have not been adequately explored with traditional methods, and newer techniques will provide powerful analytical tools to evaluate these binding properties. These new techniques include surface plasmon resonance which measures real time purified antibody binding kinetics to immobilized targets on a gold foil surface , isothermal titration calorimetry which determines binding affinity by measuring heats of dilution with sequential addition of the unlabeled drug to purified antibody in solution , and microscale thermopheresis which measures antibody binding properties in biologically relevant solutions, e. The locomotor assay that is commonly used in behavioral testing for screening of cocaine vaccine candidates may have limitations for testing the actual efficacy of vaccines against methamphetamine. The history of anti-addiction vaccines starts nearly 40 years ago. The proof of principle for an anti-addiction vaccine was first demonstrated by two studies for morphine vaccines: In , Berkowitz and colleagues 26 published their creation of a morphine vaccine in animals. Using rats, they administered a morphine hapten linked to bovine serum albumin and created anti-morphine antibodies. These antibodies reduced the concentration of free morphine in the plasma of their vaccinated rats. In , Bonese created a similar vaccine in primates, and the vaccinated rhesus monkey primates decreased their self-administration of heroin. However, this vaccine required four boosts over 60 days, and biweekly boosts over the period of a year in order to keep adequate titers. Janda and his colleagues published their data recently and have found that the polyclonal antibodies produced by a vaccine with a heroin-like hapten linked to KLH had micromolar affinities to 6-acetyl morphine 6-AM , heroin and morphine, but were nonetheless able to prevent the acquisition of heroin self-administration and the antinociceptive effects of heroin in rodents. Conversely, antibodies generated by a morphine-like KLH-vaccine only had adequate affinity for morphine and reduced binding for heroin, but no affinity for 6-acetyl morphine; in addition, the morphine-like vaccine was not effective for prevention of heroin administration acquisition. Heroin is a prodrug, rapidly converted to the pharmacologically active opiate 6-acetylmorphine and to morphine by esterases in both the periphery and the central nervous system CNS. A vaccine that produces antibodies which bind to morphineglucuronide is desirable, though likely less important quantitatively, as the penetration of morphineglucuronide into the CNS is slow and it contributes substantially less than the other metabolites to the reinforcing effects of opiates. Earlier study using a morphinesuccinyl-BSA conjugate produced antisera that bound to heroin, morphine, as well as other active morphine derivatives. Our recent studies have demonstrated that moderate to high levels of anti-morphine antibodies are elicited by 6-succinylmorphine conjugated to KLH together with either alum or monophosphoryl lipid A MPL in rodents 69 , 70 In agreement with previous studies 61 , we showed that polyclonal antibodies generated by morphine vaccines were able to bind to morphine and its metabolites 6-acetyl morphine, 3-glucuronide morphine, and 6-glucuronide morphine with nanomolar affinity. These behavioral changes in the vaccinated rats were at least in part due to sequestration of the drug in the blood and reduction of the drug levels in the brain by antibodies. A significant challenge to this approach has been the wide range of abused prescription opioids. Although morphine and heroin can both be blocked by antibodies from a single type of vaccine, at least five different vaccine types may be needed to block all the types of synthetic opiates that have now been manufactured as alternatives to morphine due to their widely varying chemical structures. Because prescription opiate abuse has overtaken heroin as the major opiate abuse problem here, a vaccine approach to blocking heroin abuse will be less urgent for clinical use in the USA. However, in the developing world, such as Southeast Asia, the Middle East Iran and Mexico, where morphine and heroin are the opiates most commonly abused, an effective vaccine would be life-saving and very cost effective. By building on previous research, designing methodologically sound studies and systematically assessing patient outcomes during the clinical trial and at 6 to 12 month follow-ups, such vaccines can hopefully win FDA approval and then assist in combating this serious public health issue. Clinical trials of cocaine and nicotine vaccines have so far reported modest efficacy. The abstinence rates among those vaccinated against nicotine have been no better than placebo overall, but the rates have been superior to placebo in the third of patients who achieved therapeutic antibody levels, demonstrating that the principle of antibody blockade is valid, and that an adequate antibody response is a primary requirement for efficacy. Thus, enhancing the proportion of responders and the magnitude of antibody responses will be critical for achieving broad utility of this approach. These changes could potentially also increase adverse effects so that the safety and efficacy of the revised dosage schedules will need to be established. Adequate use of adjuvants with a highly immunogenic carrier protein is critical for development of an efficacious conjugate vaccine. The innovative design of the conjugate vaccines using highly immunogenic foreign carrier proteins can dramatically improve the quantity and quality of immune responses. The OMPC carrier has had extraordinary success as the protein conjugate partner for Haemophilus influenza type b polysaccharide vaccine. Our preliminary data unpublished indicates that OMPC is particularly attractive as a carrier for the anti-addition conjugate vaccines, since it elicits early, high level antibody responses to the drug. KLH vaccines for nicotine 72 and cocaine 73 , 74 have shown excellent results in animals to reduce the free drug level in plasma. Other KLH conjugates are in active clinical evaluation for cancer bladder, breast myeloma, prostate, ovarian, lymphoma 75 and hypertension. The responses to proteins with alum tend to be a mix of Th2 and Th1 cells, 80 in humans, and it is used primarily to enhance antibody production. It stimulates stronger antibody responses, permits fewer antigen doses, and generates marked memory responses with a mixed Th1-Th2 cell phenotype. High immunogenicity of the vaccine can also help confer greater antibody specificity to reduce competition for binding to other compounds such as endogenous molecules or inactive metabolites. This improves safety and reduces the likelihood of adverse side effects. Proper use of carrier proteins as well as adjuvants may contribute to development of an efficacious vaccine for drug abuse. Apart from the technical and biological development hurdles discussed above, ethical and legal challenges are also barriers to implementation of these innovative treatments. Commercially, vaccines themselves are generally considered high risk with a low profit margin, in large part because of the extended liability that a company can incur with the prolonged legal exposure produced through vaccination. The fundamental stigma of substance abuse, often viewed as a moral failure rather than a brain disease, pervades many aspects of treatment for substance abuse. When addiction is considered a failure of will power or as willful misconduct, then treatment is generally directed toward the behavioral disorder, with little consideration given to direct medical intervention, so that even the addict may not recognize the potential benefit of therapeutic vaccination. The economic correlate of this perception within the pharmaceutical industry is that these patients would provide a poor return on investment for the costs and risks of developing an immunological intervention. This perception has been countered to a significant extent for tobacco smoking, possibly because of its legality and high worldwide prevalence, and as a result, nicotine vaccines have been in clinical trials by three companies. Vaccines may have potential use as preventive agents in high risk populations; however, certain ethical concerns need to be considered carefully before implementation in that context. If the adolescents then subsequently smoked ten times more cigarettes in order to overcome the nicotine blockade, the result of such high levels of smoking for prolonged periods would be a massive increase of ingested carcinogens, on which the vaccine would have no effect. It may also be feasible to use the vaccines in drug-abusing pregnant women to protect the fetus and mother from drug exposure and its complications. Finally, parents might request that their children be vaccinated to prevent future drug abuse, even though the risks of future drug abuse for them as individuals might not be well defined. The ethical and legal challenges have made FDA approval for an anti-addiction vaccine extremely complicated, and the precise requirements for FDA approval are not clear because no such vaccine has yet been approved. The preventive use of a vaccine in healthy young people would require stronger evidence of safety and efficacy than shorter-term use to reduce relapse in adults who are drug dependent. Obtaining evidence to meet regulatory requirements for such use would likely be even more expensive to accomplish. Current medications for drug abuse have only had limited success for drugs such as cocaine, nicotine, methamphetamine, and heroin. Therapeutic vaccines are very attractive because they sequester the drug in the blood, and have no direct effects on the brain, endocrine system or any other organs. A primary goal for anti-addiction vaccines is to help addicts stay off the abused substance by inhibiting the dramatic reinforcement of drug seeking behavior that can occur from social stresses leading to single or brief drug exposures, especially in the early critical months after withdrawal. Ideally, however, it would be useful to have the capacity to block multiple doses at high concentrations. The results from human studies of the first cocaine vaccine and three nicotine vaccines are promising, and preclinical development of efficacious methamphetamine and opiate vaccines is rapidly progressing. Higher average antibody titers than those yet produced seem likely to be required if vaccines are to become a feasible alternative to the available active compounds. Advances in vaccine conjugate design, carrier protein use, and especially adjuvant optimization should significantly enhance the quantity and quality of the antibodies produced, allowing drug vaccines to become useful clinical tools for the treatment of substance abuse. However, current treatments for opiates in particular may have limited needs for alternatives, since they have a track record of success in maintaining abstinence and preventing complications of abused drugs. Furthermore, concern has been raised regarding the ethical, legal, and regulatory barriers to implementation of anti-addition vaccines. As a library, NLM provides access to scientific literature. Clin Pharmacol Ther. Published in final edited form as: Clin Pharmacol Ther. Find articles by Xiaoyun Shen. Find articles by Frank M Orson. Find articles by Thomas R Kosten. Kosten kosten bcm. Issue date Jan. PMC Copyright notice. The publisher's version of this article is available at Clin Pharmacol Ther. Illicit drug use at the global level among people aged 15—64 years in Drug problem Number of people million persons Percentage of the population total 4, million persons Used drugs at least once during to 3. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

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