Vaccines against drugs of abuse: where are we now?

Abstract

Drug addiction is a serious problem worldwide. One therapy being investigated is vaccines against drugs of abuse. The antibodies elicited against the drug can take up the drug and prevent it from reaching the reward centers in the brain. Few such vaccines have entered clinical trials, but research is going on apace. Many studies are very promising and more clinical trials should be coming out in the near future.

Introduction

Drug abuse is a serious problem in the USA and around the world. According to a study by the National Institute on Drug Abuse (NIDA) released in December 2012, illicit drug use in America went up 8.3% between 2002 and 2011 [NIDA, 2012]. In the New York Times in 1994, Dr Jack E. Henningfield of NIDA ranked the relative addictiveness of six substances ranging from least to most as cannabis (marijuana), caffeine, ethyl alcohol, cocaine, heroin and nicotine (tobacco) [Henningfield, 1994]. Other sources put methamphetamine between heroin and nicotine. The chemical structures of these drugs (except cannabis) are shown in Figure 1.

Figure 1.

Drugs of abuse.

The drug known as marijuana is found in the hemp plant in many molecular forms called cannabinoids. The plant is native to Central and South Asia and marijuana has been used medicinally worldwide at least since the fifth century BCE. Hemp plants are also cultivated for other useful products, such as fiber, oil and seeds. In the USA in 1970, the Controlled Substances Act classified marijuana as a drug with ‘no accepted medical use’. There has been much controversy over this definition, and as of August 2013, 20 states have legalized the medicinal use of marijuana [Procon, 2013].

Caffeine is famously found in drinks such as coffee and tea, and it acts as a fairly mild stimulant. These drinks have probably been consumed by humans since the Stone Age (60,000 BCE). There is controversy in the medical literature as to whether caffeine causes clinically significant dependence or addiction. Limited evidence even suggests that moderate consumption of caffeine has positive health effects [Nawrot et al. 2003], but high levels can have adverse effects, and may lead to withdrawal symptoms.

Ethyl alcohol has an extremely long history of consumption. It is easily produced by the fermentation of grain, fruit juices and honey. A study by the National Institute on Alcohol Abuse and Alcoholism found that 8.5 % of adult Americans met the criteria for an alcohol abuse disorder [NIAAA, 2004]. In 1920 a law was passed in the USA prohibiting the manufacture and sale of alcohol-containing liquors. A booming illegal trade in them ensued, and the law was cancelled in 1933. However, a variety of other laws seeking to limit the harm caused by overconsumption of alcohol have been put in place, such as those dealing with a minimum drinking age, the labeling of alcoholic beverages and drunk driving.

The leaves of the coca plant were chewed by the ancient Incans at least 5000 years ago to allow them to work at high altitudes. Cocaine was isolated from the leaves in 1859, was famously added to Coca Cola until 1903, and finally banned by the USA in 1922. The USA is the world’s biggest importer of illicit cocaine and it is the second most illegally trafficked drug in the world after marijuana.

The opium poppy has been cultivated in the Near East since the Neolithic Age. Opium, extracted from the latex of the seed pod of the plant, was smoked in the USA in the early 1800s and the pain-killer morphine was isolated from it in 1810. A more potent form of morphine, diacetylmorphine, known as heroin or diamorphine, was synthesized in the 1890s and its illegal use leads to a difficult addiction. The manufacture, possession or sale of heroin is now illegal without a license in almost every country in the world under Schedules I and IV of the Single Convention on Narcotic Drugs.

The stimulant amphetamine was first synthesized in Germany in 1887. Methamphetamine was developed in Japan in 1919, and was used in WWII to alleviate fatigue and increase alertness among soldiers and pilots [Drugfreeworld, 2013]. It was finally regulated in the USA in 1970 under the Controlled Substances Act. Many substances similar in chemical structure to methamphetamine such as adderall and benzidrine are sold legally in the USA but they have fewer pharmacological effects.

The smoking of tobacco leaves leading to nicotine addiction was introduced to the world from its native America in the sixteenth century, and now it is the most common form of drug addiction in the USA [American Society of Addiction Medicine, 2013]. The release of neurotransmitters and hormones is responsible for most of nicotine’s effects, as it acts as both a stimulant and a relaxant. Smokers link smoking to many social activities, making it a very difficult addiction to break [American Lung Association, 2013]. To quote from NIDA: ‘Tobacco use is the leading preventable cause of disease, disability, and death in the United States’ [NIDA, 2012].

Russell Brand, British actor and former drug addict, is quoted as saying ‘The mentality and behavior of drug addicts and alcoholics is wholly irrational until you understand that they are completely powerless over their addiction and unless they have structured help, they have no hope’ [Brand, 2013]. This review discusses one intervention that is being studied to address the problem of drug addiction, namely vaccination against the addictive drug. NIDA has released a very apropos animation about this technique [NIDA, 2013].

The drug molecules discussed above are too small to attract the attention of the immune system by themselves, but if the drug is attached covalently to an immunogenic protein through a linker molecule, antibodies can be produced which bind the drug molecule and lead to its sequestration and elimination, ameliorating the effects of the drug on the central nervous system. Some of the addictive substances discussed above do not lend themselves to the development of a vaccine as the molecule is too small (ethyl alcohol), the molecular structures involved are too diverse and unstable (cannabinoids), or the drug may actually have positive health effects (caffeine). However, vaccines are in development against methamphetamine, and vaccines against morphine, nicotine and cocaine have advanced to clinical trials.

Morphine and heroin vaccines

In 1970, Spector and Parker reported the development of a vaccine against morphine [Spector and Parker, 1970]. The antibodies produced by vaccinated rabbits were used in a radioimmnoassay for morphine. In 1972, Ryan and colleagues reported that heroin users had antibodies against morphine in their blood [Ryan et al. 1972], and in 1975 Hill and colleagues successfully immunized rabbits against morphine by using a conjugate vaccine consisting of 6-succinylmorphine (6-SM) and bovine serum albumin (BSA) [Hill et al. 1975]. As heroin is very quickly hydrolyzed to 6-acetylmorphine in the serum of users, this vaccine would have been useful against both morphine and heroin. The next step would logically have been clinical trials of such a vaccine, but methadone, a synthetic opioid that blocks the euphoric effects of heroin, became available and it has been successfully used up until the present time to help relieve heroin addiction [Farrell et al. 1994]. In 1990, it was reported that workers in a narcotics manufacturing facility as well as heroin abusers had antibodies against morphine in their blood [Biagini et al. 1990]. However, interest in the development of antidrug vaccines in general was not renewed until later in the 1990s.

In 1999, a team of Iranian scientists followed up on the synthesis of the 6-SM-BSA conjugate vaccine [Akbarzadeh et al. 1999]. They subsequently claimed that in Iran in 2002, 4.5% out of a population of 6,700,000 were morphine abusers. In 2009 and 2012, they reported successful results in vaccine trials with 347 and 436 morphine addicts [Akbarzadeh et al. 2009; Farhangi et al. 2012]. However, a BSA vaccine would not seem to be desirable for worldwide use, as antibodies against beef products would also be elicited. In 2006, Anton and Leff at the National Institute of Psychiatry in Mexico treated the immunogenic protein tetanus toxoid (TT) with TFCS (6-(N-trifluoroacetyl)caproic acid succinimide) which reacts with the amino group of lysines to give a long spacer arm with a latent amino group. This TT derivative was reacted with 6-SM to give a conjugate vaccine that was used to vaccinate rats [Anton and Leff, 2006]. The rats produced a high level of antibodies that recognized both heroin and morphine and blocked the reinforcing effects of heroin. A conjugate vaccine consisting of a similar hapten, 6-glutarylmorphine bound to Keyhole Limpet Hemocyanin (KLH) was created by Chinese scientists at about the same time [Li et al. 2011], and was used to immunize rats. They observed that the antibodies produced were able to attenuate the behavioral and psychoactive effects of heroin in the animals. Also in 2011, Kim Janda and coworkers at The Scripps Research Institute in La Jolla, CA created what they termed a ‘dynamic’ vaccine by removing the N-methyl group from heroin and attaching a long linker containing an –SH group to that position to give a heroin-like hapten [Stowe et al. 2011]. When the acetyl groups were removed from that molecule, it gave a morphine-like hapten. These two haptens were reacted with maleimide-functionalized BSA and KLH. Although they did not test the heroin-like vaccine for hydrolysis of the 3-acetyl group, the antibodies it produced bound to 6-acetylmorphine with high affinity and to heroin and morphine with lesser affinity. The antibodies produced by the morphine-like vaccine bound to morphine and to a lesser extent to heroin, but did not bind to 6-acetyl morphine. More studies using the ‘dynamic’ heroin vaccine were reported by the Scripps group in 2013 [Schlosburg et al. 2013]. They made suggestions regarding attachment of the heroin hapten to other proteins approved for clinical use, such as TT and diphtheria toxoid. Also in 2013, the Kosten group at the VA Medical Center in Houston, TX published promising studies in rats using a 6-SM/KLH vaccine [Kosten et al. 2013]. They reported that morphine levels in the brains of the animals at 26 weeks were significantly lower in the vaccinated rats, and that behavioral studies also gave positive results showing that the vaccine elicited antimorphine antibodies.

Abuse of prescription opioids such as hydrocodone and oxycodone is a growing problem [Maxwell, 2011]. In 2012 the Pentel group at the Minneapolis Medical Research Foundation, Minneapolis, MN created a conjugate KLH vaccine using a tetraglycine linker attached to oxycodone that gave antibodies that recognized oxycodone [Pravetoni et al. 2012] and followed that up with a vaccine against both oxycodone and hydrocodone [Pravetoni et al. 2013]. They also reported that the efficacy of the vaccine when the hapten was attached using an amide linkage method was greater than when a maleimide-SH method was used. Unexpectedly, opioid vaccines do not recognize heroin or morphine and the heron/morphine vaccines do not recognize the prescription opiods. All of the studies discussed above would suggest that clinical trials in the USA using one or several of the vaccines under development may appear within the next few years.

Methamphetamine vaccines

The earliest vaccine against methamphetamine was created for use in a radioimmunoassay using N-(4-aminobutyl)methamphetamine as the hapten and BSA as the carrier protein [Cheng et al. 1973]. Several other papers were published later by a Korean group [Choi et al. 1994; Choi et al. 1997, 1998] utilizing the same hapten with BSA and various other carrier proteins, with the aim of detecting methamphetamine in urine samples. With an eye toward developing antidrug vaccines for human addicts, the Owens group at the University of Arkansas vaccinated rats using KLH as the carrier protein and a novel methamphetamine hapten with a 6-carbon spacer linked to the para position of the phenyl ring [Byrnes-Blake et al. 2001]. They showed that the generation of antibodies was not impeded if the rats were given methamphetamine during the active immunization. They next generated monoclonal antibodies against methamphetamine [McMillan et al. 2002, 2004; Byrnes-Blake et al. 2003] and tested them successfully in rats. Further, they refined the hapten structures so as to get monoclonal antibodies that recognized amphetamine and methylenedioxymethamphetamine (ecstasy) as well as methamphetamine [Peterson et al. 2007]. A French group also synthesized a variety of haptens and generated monoclonal antibodies against methamphetamine and its analogs [Danger et al. 2006]. The Owens group followed up with the synthesis of a hapten where the 10-carbon linker was attached through an oxygen atom to the meta position on the phenyl ring of the drug [Carroll et al. 2009]. This hapten (SMO9) was attached to carrier proteins and the resulting conjugates used to vaccinate mice. The antibodies produced recognized methamphetamine and the derivatives mentioned above. A relevant review about monoclonal antibody treatment for addiction was later published by the same group [Owens et al. 2011].

Subsequently, attention turned to the effects of active vaccination on the behavior of animals. Studies detailing that rats vaccinated with a SMO9-KLH conjugate vaccine were protected from methamphetamine-induced impairment of food responses were carried out by the Owens group [Rüedi-Bettschen et al. 2013]. The Scripps group showed that the thermoregulatory and locomotor effects produced by methamphetamine administration were particularly blocked in mice vaccinated with one of the vaccines developed by them (MH6) [Miller et al. 2013]. The Orson group at the VA Medical Center in Houston, TX reported a new vaccine consisting of N-succinylmethamphetamine conjugated to KLH (SMA-KLH) [Shen et al. 2013]. Previously this group had shown that low doses of methamphetamine caused hypolocomotion while high doses produced hyperlocomotion [Singh et al. 2012]. Both locomotion effects were reduced in the SMA-KLH vaccinated mice, and the ability of methamphetamine to support place conditioning was attenuated, also indicating that the antibodies produced were effective. All three research groups suggested that antimethamphetamine vaccination would be helpful to human addicts. Because of the promising animal studies discussed here, clinical trials of one or more of these vaccines may be undertaken in the near future.

Nicotine vaccines

The first nicotine vaccine was reported in 1973 by Langone at Brandeis University in Waltham, MA [Langone et al. 1973]. He created the hapten trans-3’-succinylmethylnicotine, conjugated it to KLH and used this vaccine to immunize rabbits. The serum obtained was used for the immunoassay of nicotine in the sera and urine of human smokers. At about the same time, a Japanese group [Matsushita et al. 1974] and Castro and Prieto at the University of Miami Medical School, Miami, FL also developed antinicotine vaccines [Castro and Prieto, 1975]. These were BSA conjugates using haptens with linkers attached to the 6 position of the pyridine ring of nicotine. The serum from the vaccinated animals was also used for radioimmunoassays of nicotine in the blood of smokers [Matsukura, 1975; Castro et al. 1980].

In 1997, Pentel at the Minneapolis Medical Research Foundation in Minneapolis, MN took up the gauntlet and immunized rats with a conjugate vaccine consisting of a 6-linked hapten and KLH dubbed 6-CMUNic-KLH [Heida et al. 1997]. Subsequent papers showed that this vaccine and one in which a 3’ linked hapten conjugated to Pseudomonas aeruginosa exoprotein A and dubbed 3’-AmNic-rEPA reduced the level of nicotine in the brain of rats and also attenuated behavioral and cardiovascular effects in the animals [Keyler et al. 1999; Heida et al. 1999, 2000; Pentel et al. 2000; Satoskar et al. 2003]. Pentel later reported on the enhanced immunogenicity that occurred when the two vaccines 6-CMUNic-KLH and 3’-AmNic-rEPA were delivered together [Keyler et al. 2008]. He then created a new hapten, 1’-SNic, which has a linker with an –SH group for attachment to a maleimide-activated carrier protein. The three haptens thus had linkers attached to different positions on the nicotine molecule and then each was attached to a different carrier protein by different chemistries [Pravetoni et al. 2012]. Notably, the antibodies elicited by the three vaccines had nonoverlapping specificities. Pentel then showed that intradermal delivery of antinicotine vaccines in combination with noninflammatory adjuvants gave improved immunogenicity [Chen et al. 2012] and further showed that when the three vaccines were delivered together with alum it was even more efficacious than if one of them was delivered alone [de Villiers et al. 2013].

The Scripps group took an interest in antinicotine vaccines and in 2001 they synthesized a hapten which had a carboxylic acid ended linker attached to the pyrrolidine nitrogen of nor-nicotine which was dubbed NIC [Isomura et al. 2001]. Rats vaccinated with NIC-KLH had a decrease in locomotor activity after being given a dose of nicotine, and also had less nicotine in the brain [Carrera et al. 2004]. The group also created two conformationally constrained haptens, CNI and CNA, whose conjugates with KLH elicited greatly increased Ab titers over NIC-KLH [Meijler et al. 2003]. Finally, they synthesized a unique hapten where there was an ether group at the 3’ position of the molecule (AM1). This prevented the possible hydrolysis of an ester group at that position (as might be the case with Langone’s vaccine) as well as the unwanted development of antibodies that would recognize the amide group of Pentel’s 3’-AnNic-rEPA vaccine. AM1 was conjugated to three highly immunogenic proteins, KLH, TT and diphtheria toxin cross-reactive mutant 197 (CRM). The three conjugates were used to immunize mice in combination with the adjuvant AS-03, a GlaxoSmithKline squalene-based adjuvant system currently approved for use in pandemic influenza vaccines in the European Union and some countries in Asia. The TT vaccine proved to be the most promising and was used successfully in behavioral studies in rats [Moreno et al. 2010]. The Scripps group is now exploring the use of liposomes to enhance the immunogenicity of the AM1-KH vaccine [Lockner et al. 2013].

A group from Independent Pharmaceutica AB, Stockholm, Sweden studied the effect that linkers had on the immunogenicity of a their vaccines, and determined that the 6 position was better than the 5, and the flexibility of the linker close to the pyridine ring was important [de Villiers et al. 2010]. Very recently, a novel construct was developed at Virginia Tech which involved using a nano-lipoplex to deliver the vaccine [Hu et al. 2014] and a group at Cornell Medical College, NY developed a promising vaccine using an adenovirus hexon protein [Rosenberg et al. 2013]. They reported that the AM1 hapten conjugated to the capsid proteins of disrupted adenovirus elicited antinicotine antibodies even when the mice had been preimmunized against the virus [De et al. 2013]. Further, a group at Pfizer Vaccines Research in Ottowa, Canada showed that the use of an adjuvant consisting of CpG and Alum increased the affinity and titer of antibodies in mice and nonhuman primates given a 3’AmNic-Diphtheria toxoid vaccine [McCluskie et al. 2013].

Several companies have carried out clinical trials of antinicotine vaccines. Nabi (now Biota Pharmaceuticals, Rockville, MD) carried out a trial of the 3’-AmNic-rEPA, but only 11% of the people given the vaccine quit smoking, almost the same percentage as those given placebo [Nabi, 2011]. Recently the Swedish vaccine Niccine investigated by Independent Pharmaceutica AB was reported as having poor efficacy [Tonstad et al. 2013]. Other companies, such as Cytos (Switzerland) and Celtic Pharma (Bermuda) have also carried out clinical trials with similar results. In the developmental stage are vaccines from Chilka Ltd, the University of Nebraska, and Scripps of San Diego. However, in a review from the Department of Primary Care Health Sciences, University of Oxford, UK, the authors boldly state ‘There is currently no evidence that nicotine vaccines enhance long-term smoking cessation’ [Hartmann-Boyce et al. 2012]. This would suggest that more research is needed in order to develop better vaccine formulations and immunization conditions [Raupach et al. 2012]. Recent publications show that research is proceeding productively along those lines. Furthermore, it is generally agreed that antinicotine vaccination will be best used in combination with other treatment modalities, such as psychotherapy.

Cocaine vaccines

The cocaine molecule has several positions where linkers may be conveniently attached: the nitrogen, the methyl ester, and the benzoic acid ester. In the 1990s, there was interest in generating catalytic antibodies against cocaine which would hydrolyze the benzoic acid moiety of cocaine to give the inactive metabolite ecgonine methyl ester [Landry et al. 1993; Chandrakumar et al. 1993; Basmadjian et al. 1995; Yang et al. 1996; Berkman et al. 1996]. Landry and coworkers showed that such catalytic antibodies were effective against cocaine’s effects in rats [Mets et al. 1998; Deng et al. 2002]. A group at the Human BioMolecular Research Institute, San Diego, CA also developed catalytic antibodies [Cashman et al. 2000]. The Scripps group investigated single-chain catalytic antibodies [McKenzie et al. 2007] and later compared catalytic and conventional cocaine vaccines, deciding that noncatalytic hapten designs were more satisfactory [Cai et al. 2013b]. It is doubtful that clinical trials of catalytic cocaine vaccines will be undertaken, but perhaps monoclonal catalytic antibodies will have some usefulness.

In the later 1990s, many research groups became interested in anticocaine vaccines. The Scripps group announced the development of a stable anticocaine vaccine [Carrera et al. 1995]. The hapten consisted of a linker attached by an ester group to benzoyl ecgonine which was conjugated to KLH to give a vaccine dubbed GNC-KLH. Locomotor activity was suppressed in the vaccinated rats, and the level of cocaine in brain tissue was lowered. The Scripps group next synthesized a cocaine diamide hapten (GND) which they said was more effective than GNC [Sakurai et al. 1996]. Ettinger created a cocaine-KLH vaccine by a photoactivation technique which gave positive behavioral effects [Ettinger et al. 1997]. In 1996, workers at the ImmunoLogic Pharmaceutical Corp. reported on the efficacy of a new vaccine consisting of the hapten succinylnorcocaine (SNC) conjugated to BSA. High-titer antibodies were elicited in rats and the levels of cocaine in their brains was decreased after only 30 s [Fox et al. 1996; Fox, 1997]. Studies in rats were continued successfully with a vaccine consisting of SNC conjugated to cholera toxin B, designated TA-CD [Kantak et al. 2000, 2001]. In 2002, a clinical trial of the safety and immunogenicity of the vaccine was initiated by Kosten of Yale University, New Haven, CT, which proved promising [Kosten et al. 2002]. The results of a follow-up trial were reported in 2005 [Martell et al. 2005]. The vaccine was well tolerated and the subjects who had a more intense vaccination schedule were more likely to decrease their cocaine use and reported that the cocaine they did take was less euphoric. However, only 38% of the vaccinated subjects had antibody levels high enough to sustain less cocaine use [Martell et al. 2009]. Another report about the results of the use of the TA-CD vaccine in smokers was perhaps somewhat more optimistic, but there was still a wide range of antibody levels among the subjects [Haney et al. 2010].

The Scripps group has continued to study anticocaine vaccines. Use of their GNC-KLH vaccine protected rats against drug relapse [Carrera et al. 2000], and their GND vaccination successfully prevented hyperlocomotion in rats given a dose of cocaine [Carrera et al. 2001]. Synthesis of a novel hapten where the linker was attached to the C-7 carbon on the opposite side of the molecule from the methyl ester and the benzoate group was carried out and this hapten was attached to KLH and used for vaccinations. Unfortunately, this idea did not play out and the antibodies produced bound cocaine poorly [Ino et al. 2007]. The Scripps group and collaborators next conjugated the GNC hapten to a disrupted adenovirus. This construct was used to vaccinate mice who showed hyperlocomotion after a cocaine dose [Hicks et al. 2011]. A similar vaccine which used the GNE hapten where the linker was attached to BE through an amide link (dAdSGNE] had blunted psychostimulant and reinforcing effects [Wee et al. 2012; Koob et al. 2011]. As with the nicotine vaccine which used the same carrier protein, there was no adverse effect if the animals were prevaccinated with the disrupted adenovirus alone [De et al. 2013]. Recently, the dADSGNE vaccine was given to Rhesus monkeys and positron emission tomography studies were carried out showing that the antibodies produced reduced the binding of cocaine to the dopamine transporter in the brains of the monkeys [Maoz et al. 2013]. The Scripps group and collaborators also tweaked the SNC hapten by adding fluorine to the 4’ position of the benzoic acid moiety of the molecule [Cai et al. 2013a] and reported that the KLH conjugate vaccine gave higher antibody concentrations than the SNC-KLH vaccine. Some of the Scripps group’s anticocaine vaccines look very promising in animal studies and clinical trials should follow in the near future. This group also created a useful monoclonal antibody which prevented death by cocaine overdose in a mouse model (Carrera et al. 2005)

Brimijoin at the Mayo Clinic, Rochester, MN has developed a method based on viral gene transfer to deliver a cocaine hydrolase derived from human butyrylcholinesterase [Gao and Brimijoin, 2009]. Combining this treatment with an anticocaine vaccine should lead to a much improved intervention for cocaine use [Gao et al. 2010]. Such studies were successfully carried out in mice by the Orson group and showed that there was a synergistic effect on behavior and cocaine toxicity with the use of both modalities at the same time [Carroll et al. 2012; Gao et al. 2013; Brimijoin et al. 2013a,b]. As has been pointed out for other therapies for drug abuse, this treatment will require extensive studies regarding its safety and efficacy, but it is probably the most promising treatment for cocaine addiction in sight.

Conclusion

The development of vaccines against drugs of abuse is proceeding apace [Kosten, 2013], but there are issues that need to be examined before this treatment can realize its full potential. The areas for revisitation are as follows: hapten structure, linkage chemistry, immunogenic proteins, and adjuvants. Much has been tweaked in the structure of each of the drugs discussed above in order to attach a suitable linker with varying degrees of success. Any hapten used should generate antibodies that bind to the free drug in serum with good affinity and specificity, a goal that has not always been achieved. The linkage methods used to create the conjugate vaccine should be simple and robust to allow for the commercial production of the vaccine by good manufacturing practices, and the linker should not lend itself or its attached drug to hydrolysis. It has been known for some time that the more haptens attached to a protein, the better the antibody response. However, the number of haptens attached per mole of protein has seldom been reported and it is an important consideration. Many different immunogenic proteins have been used in the creation of antidrug vaccines, ranging from relatively simple ones such as BSA through cholera toxin, tetanus toxoid, KLH and adenovirus hexon protein. Eventually the most promising immunogenic protein will come forward so that it can be approved by the US Food and Drug Administration and clinical trials using such a conjugate vaccine can be initiated. The question of adjuvants is an important one, and studies are being carried out in animals by many groups in order to determine which adjuvant or which combination of adjuvants is the best stimulant for the immune system. Recently, clinical trials of the nicotine and cocaine vaccines have been disappointing, in that the level of antibodies in the blood of a majority of the patients has been low, and these patients tended not to be successful in giving up their addiction. Hopefully study of the areas mentioned above will bring forth vaccines that produce higher levels of antibodies so that in combination with therapy and rehab, drug addiction will become a treatable problem.