Joe Clarke* has lived a tough life. Almost 50 years old, he’s used cocaine for more than half his life, and his habit has brought with it the ills that plague many drug addicts: depression, recurrent pneumonias, family disruption, unemployment, and repeated arrest and imprisonment as a result of illegal behavior. As soon as Joe made money—usually from selling drugs, robbery, shoplifting, or pimping out his various girlfriends—his addiction would rob him of it. He would sometimes spend several hundred dollars a day on cocaine. His life was a constant hustle of getting together enough money to support his addiction, while trying to avoid arrest for his illegal activities.
About 20 years ago, Joe switched from snorting coke to smoking crack and was shortly thereafter sentenced to several years in prison for a drug-related felony. It was his longest break from cocaine, but he relapsed into regular use just three months after being released. He had tried a number of times to kick his habit.
Then last year he heard about a new cocaine vaccine being tested in clinical trials. Joe sought treatment, because he felt “too old to still be using cocaine,” and the trial seemed “like a medical cure” that would help him “get my life back.”
The vaccine consists of molecules of cocaine covalently bonded to a large carrier protein, namely a recombinant cholera toxin B subunit (which is harmless in isolation from the natural molecule’s toxic A subunit). The carrier choice was dictated by the knowledge that a cholera vaccine made from this subunit has been administered to millions of people without any adverse effects, and by the fact that Americans are rarely exposed to or vaccinated against cholera, so most would likely mount a new and robust immune response to this protein and the attached cocaine molecule.
After intramuscular injection, the vaccine enters the bloodstream and triggers plasma cells to produce antibodies to the cocaine molecule as a component of the immunogenic cholera protein. This creates an army of antibodies that can latch onto free cocaine molecules in the bloodstream and, because they are too bulky to fit through tight junctions in blood vessels, prevent the drug from leaving the circulatory system and entering tissues and organs.
Most importantly, tiny cocaine molecules bound to big antibodies can no longer cross the blood-brain barrier into the brain, where they would ordinarily block dopamine-transport receptors and cause the buildup of dopamine that users perceive as a “high.” Cocaine that is kept from reaching its “target” in the brain is prevented from triggering reward sensations. With continued, regular booster vaccinations, necessary because the antibody titer declines steeply about 3 months after reaching peak levels, the bonds of addiction may be loosened, giving addicts a stab at kicking their habit altogether.
Last November Joe enrolled in a double-blind, randomized, placebo-controlled cocaine vaccine trial that is in one of the final stages of testing before receiving US Food and Drug Administration approval.
His life was a constant hustle of getting together enough money to support his addiction, while trying to avoid arrest for his illegal activities.
Cocaine dependence has no FDA-approved pharmacotherapies, in contrast to heroin addiction, which is treated with synthetic opiates like methadone or buprenorphine. For cocaine addicts the standard of care is outpatient behavior-modification treatment, but unfortunately such programs do not have a good track record of establishing long-term abstinence. The elusive key to helping coke addicts stamp out their dependency is finding a way to make short-term abstinence stick. For many suffering from debilitating cocaine addictions, a vaccine may be Joe’s last hope for weaning himself off the drug for good.
The road to an addiction vaccine
The idea of using vaccines to fight drug addiction traces its origins back nearly 40 years: Albany Medical College’s Bernard Berkowitz tested whether mice would form antibodies in response to a morphine vaccine,[1. B. Berkowitz, S. Spector, “Evidence for active immunity to morphine in mice,” Science, 178:1290-92, 1972.] and University of Chicago psychiatrist K.F. Bonese studied the effects of a similar morphine vaccine on heroin self-administration in rhesus macaques.[2. K.F. Bonese et al., “Changes in heroin self administration by a rhesus monkey after morphine immunisation,” Nature, 252:708-10, 1974.] Both teams used an immunogenic protein carrier, bovine serum albumin, as the carrier protein, combined with considerably stronger adjuvants than the alum that is now permitted for use in humans. Berkowitz found that mice produced antibodies that bound morphine and reduced its analgesic efficacy, and Bonese’s vaccine significantly reduced the self-administration of heroin by his primate model organism.
Twenty years after Berkowitz’s and Bonese’s groundbreaking research, an emerging epidemic of cocaine addiction led the National Institute on Drug Abuse to support Barbara Fox at the pharmaceutical company ImmuLogic, which was developing a cocaine vaccine for humans. She devised a process for chemically linking cocaine to bovine serum albumin, and oversaw the toxicology and animal studies required by the FDA to get the treatment ready for clinical testing.[3. B.S. Fox et al., “Efficacy of a therapeutic cocaine vaccine in rodent models,” Nat Med, 2:1129-32, 1996.] She also conducted studies in collaboration with Boston University behavioral pharmacologist Kathy Kantak showing that the antibodies produced by a similar vaccine, now using inactive cholera toxin B as the carrier protein, could block or reduce cocaine self-administration in rats.[4. K.M. Kantak et al., “Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administration model,” Psychopharmacology, 148:251-62, 2000.]
By 1996 the vaccine was approved for human use, and our Yale University group was the first to test it in humans. In a Phase I study that examined the safety of three dosages of active vaccine (13, 82, and 709 µg) given once a month over three months to 27 cocaine addicts, we found that the formulation was free of side effects (except for brief muscle twitching at the injection site at the highest dose).[5. T.R. Kosten et al., “Human therapeutic cocaine vaccine: safety and immunogenicity,” Vaccine, 20:1196-204, 2002.] The trial also showed a clear dose response: subjects receiving the 709-µg dose produced nearly two and a half times the antibodies generated by the 82-µg and 13-µg groups. But the peak antibody levels at the 709-µg dose were still lower than what we calculated as necessary to reduce cocaine abuse relapse in humans, based on both the rodent self-administration studies and theoretical calculations of needed binding capacity.
We therefore undertook two new Phase II studies in outpatients, one designed to trigger a more robust immune response and another to study the relationship between antibody titer and subjective drug response. In the first, patients received vaccine doses either four or five times during the 3-month vaccination window, instead of the three doses given in the Phase I study. Eight subjects who received five 400-µg doses at 0, 2, 4, 8 and 12 weeks produced the optimal peak antibody response. Ten addicts in the study who received only four 100-µg injections over the course of eight weeks developed only half that level of antibodies. They were also twice as likely to relapse into cocaine abuse within six months, though subjects from both groups did relapse.[6. B.A. Martell et al., “Vaccine pharmacotherapy for the treatment of cocaine dependence,” Biol Psychiatry, 58:158-64, 2005.]
In the second study, cocaine was directly administered to subjects (as smoked doses of crack) over the same study period, during which they received five vaccine doses of either 82 µg or 360 µg, and their antibody levels were monitored. The results clearly showed that subjects with low (less than 10 µg/ml) peak antibody levels did not experience any significant decrease in reward sensations, while those with high antibody levels (10–22 µg/ml) reported an 80% attenuation of the high from a 25-mg cocaine dose and 50% attenuation at 50 mg of cocaine.[7. M. Haney et al., “Cocaine-specific antibodies blunt the subjective effects of smoked cocaine in humans,” Biol Psychiatry, 67:59-65, 2010.]
The current work
In a Phase IIb trial, which ran from 2003 to 2005, we administered the cocaine vaccine to addicted outpatients in five shots over a period of 12 weeks.[8. B.A. Martell et al., “Cocaine vaccine for the treatment of cocaine dependence: A randomized double-blinded placebo-controlled efficacy trial,” Arch Gen Psychiatry, 66:1116-23, 2009.] About 40% of the patients attained antibody levels at or above our target of 43 µg/ml, which we found was high enough to make it very difficult or impossible to ingest enough cocaine to overwhelm the vaccine’s blockade of the drug. In previous trials, we’d seen patients try to beat the vaccine by snorting or smoking large amounts of cocaine that could swamp the available antibody population. But we hadn’t expected the vaccine to be so powerful that it completely blocked the effects of such cocaine binges.
About a quarter of the subjects in these trials did not produce high levels of anti-cocaine antibodies, and we’re currently investigating this nonresponse issue, which is turning up a variety of interesting leads related to human genetics and the production of immunological tolerance for particular substances.
Among those patients who produced cocaine antibodies at sufficient levels for therapeutic efficacy, the high antibody levels persisted for about 2 to 3 months. Beyond that period, a single booster vaccination was needed to again stimulate the production of more antibodies.
Joe’s tentative success
Joe is one of the trial subjects who seem to be benefiting from participation in the cocaine vaccine study. Though we cannot be sure that Joe received the vaccine, because the trial is double-blind and some participants received placebo, cocaine addiction appears to be loosening its grip on Joe’s life. But any success he’s experienced has been hard-won. Joe used cocaine on 19 days in the month leading up to the trial, and his desire to continue using was relatively high throughout the first five weeks of the study. Every four or five days, he reported that his “craving” returned, and he would “test out the vaccine” by ingesting more cocaine. But when he smoked crack during week 6, which was after the third vaccine injection, he reported a dramatic “decrease of high” for the first time. This absence of euphoria occurred despite smoking an additional $40 worth of crack.
Even though he could no longer get high, Joe continued to experience aversive effects such as irritability and anxiety after ingesting cocaine. He also still had physiological effects such as numbing sensations, glazed-over eyes, and rapid respiration and heart rate when he used cocaine. His desire to use cocaine decreased slightly after the fourth injection in week 9. During the final two weeks of the study, Joe used cocaine only once and reported increased motivation to abstain, find steady employment, and rebuild and maintain healthy relationships with family members.
While taking part in the vaccine trial, Joe also participated in an intervention that included cognitive-behavioral therapy (CBT), which taught him behavioral and cognitive skills to recognize and avoid high-risk situations associated with drug use. He was also concurrently enrolled in a contingency-management program, which rewarded him with gift vouchers for attending the weekly CBT sessions.
Not by vaccine alone
Though the early results of the cocaine vaccine trials are promising, there are significant roadblocks to its commercialization and widespread use. The first of these is psychosocial. In large part, society still views substance abuse as a moral failure rather than a brain disease. When addiction is considered a failure of will power and an act of willful misconduct, it becomes harder for the general public and their political representatives to accept that a physiological intervention can lead to a cure.
These perception problems breed economic hurdles to making a commercial cocaine vaccine. Within the pharmaceutical industry, cocaine addicts are considered poor investments for developing medications of any type. This misperception has been countered to a significant extent for tobacco smoking, and nicotine vaccines are under development by several major pharmaceutical companies worldwide. But for stimulants such as cocaine and methamphetamine, these misperceptions persist, and the size of the potential market for vaccines against these drugs is likely more than 3 million customers, according to US Substance Abuse and Mental Health Services Administration statistics.
In addition to these economic and social impediments to the development of a cocaine vaccine, there are thorny ethical, legal, regulatory, scientific, and behavioral challenges that complicate the issue. From a behavioral standpoint, requiring drug-addicted patients to report to treatment sites at regular intervals over 8 to 12 weeks is problematic. For the vaccine to trigger an effective antibody response during these 2 to 3 months, the patient must get the vaccine shots at specific times (at 2, 4, 8 and 12 weeks after the initial vaccination)—a feat of scheduling that requires significant behavioral intervention for most cocaine addicts. Therapeutic interventions that may be needed to insure compliance include residential care or outpatient contingency management, in which patients are paid to show up for the vaccinations on a pay schedule that escalates for each vaccination obtained.
The elusive key to helping coke addicts stamp out their dependency is finding a way to make short-term abstinence stick.
The vaccine works best for patients who desire and can attain short-term abstinence from cocaine, but need help with maintaining that abstinence. Because the vaccine doesn’t alleviate their cue-induced psychological craving, but only dampens the drug’s pleasurable effect, it is likely to be effective only in patients who are determined and supported in their commitment to quitting. However, vaccine treatment may help users overcome a critical obstacle that occurs across all addictions and is known as the “priming effect”.[9. H. de Wit, “Priming effects with drugs and other reinforcers,” Exp & Clin Psychopharm, 4:5-10, 1996.] After they attain abstinence, many cocaine abusers will try taking a small amount of cocaine to relieve craving induced by cues and psychological factors such as sadness or emotional responses to stressful events. Instead of fixing their emotional distress, that lapse into cocaine use markedly intensifies their physiological craving, and they risk falling into a binge pattern of abuse.
The cocaine vaccine is designed to block the priming effect, but it is vulnerable to deliberate attempts to override the antibody blockade with more cocaine than the patients would typically use. We considered this impulse to override the vaccine nearly impossible to prevent, based on the amount of antibody that we could realistically expect to develop from our vaccines. Even though one study showed that doubling the antibody levels from 22 µg/ml to 43 µg/ml made the antibody blockade effectively unbreakable, patients still upped the amount of money they were spending on cocaine as they attempted to recapture the euphoric feeling of which the vaccine had deprived them. Hence there is a need for strong and concurrent behavior treatments, and potentially for other medications such as indirect dopamine agonists and serotonin enhancers. These medications can renormalize the deficits in these neurotransmitter systems that are induced by cocaine dependence.
Remaining scientific challenges overlap with the regulatory uncertainties surrounding the cocaine vaccine’s bid for FDA approval, which is coupled with the huge cost of thoroughly demonstrating clinical efficacy and medical safety. Since there is no FDA-approved cocaine pharmacotherapy, the precise pathway to approval is unclear—a great concern to those companies that might otherwise manufacture, license, and sell these vaccines.
The ethical issues for any long-acting medication are also complex, but particularly important for addiction vaccines is the potential for unintended adverse consequences of administering the treatment. For example, a patient vaccinated against nicotine might responds by smoking ten times more cigarettes in order to overcome the nicotine blockade, and would experience a massive increase in inhaled carcinogens. People vaccinated against cocaine may try to override the treatment in a similar fashion, taking far more of the drug than they otherwise would and suffering the side effects of that increased use. Also, with commercially available addiction vaccines, a risk exists for potential coercion in the vaccination of prisoners, adolescents, pregnant drug-abusing women, or any group that may not have the full capacity for informed consent.
A way forward?
Even with these challenges, the success of recent clinical trials and the simplicity of the vaccine’s manufacture and mechanism of action make producing the therapy on a commercial scale relatively inexpensive. This could make the cocaine vaccine available to a wide range of disadvantaged populations both in the developed world and in developing nations, where addictions have had devastating consequences for national economies and health-care systems.
Care providers interested in using the cocaine vaccine to help addicts kick their habits will have to recognize the need for sustained and perhaps open-ended therapy, including required revaccination several times over a treatment course that may last as long as ten years. A single booster vaccination should produce a further two to three months of blockade from relapse, whether the initial vaccinations occurred three months, three years, or three decades in the past. That is the great advantage and utility of this very cost-effective and potentially lifelong protection from relapse and re-addiction.
The vaccine combined with cognitive-behavioral therapy seemed to spark a significant change in Joe’s behavior. But cocaine addiction is a chronic, relapsing disorder, and even with the help of the cocaine vaccine, Joe’s full recovery will likely take at least two years. Joe was able to curb his drug use, but that is unlikely to be sustained after the antibody levels drop in a month or so. I’ve seen addicts enrolled in our previous randomized clinical trial relapse into rampant cocaine use when antibody levels fell after the study was completed. Joe’s experience and those of the many other patients who have been vaccinated suggests that recovery using a blocking therapy is a long and slow process that unfolds over a number of years, and will succeed only with vigilance on the part of the patient as well as the care provider.
Thomas Kosten MD, is Jay H. Waggoner Chair at Baylor College of Medicine and research director of the VA National Substance Use Disorders Quality Enhancement Research Initiative at the Houston VA.
This article is adapted from an upcoming review in F1000 Medicine Reports.It will be available for citation at f1000.com/reports (open access).