Vaccines in the Treatment of Substance Abuse

Although the rates of cigarette smoking in the United States have declined over the past several years, nicotine dependence continues to represent a significant cause of morbidity and mortality. The health consequences of smoking have been well defined, and greater than 400,000 people die annually from illness related to smoking (4, 5). Despite high reported rates of desire to quit smoking and numerous quit attempts by those who smoke, the majority of persons who use nicotine remain dependent (6). Smoking cessation programs and widely available pharmacotherapeutic treatment options offer some benefit; however, the ultimate success rate for quitting remains low (7).

There are three nicotine conjugate vaccines currently undergoing clinical trials: NicVax, NicQb, and TA-NIC. NicVax, a nicotine hapten conjugated to Pseudomonas exoprotein A, is undergoing its second of two phase III clinical trials (8). In previous studies, it was found to produce antibody titers in a linear dose-response fashion sufficient to reduce smoking among participants. Interestingly, there was no observed increase in compensatory smoking to overcome the effect of the vaccine. Further, in those receiving the highest dose (200 μg), significantly greater 30-day abstinence rates were observed (9).

NicVax demonstrated a favorable safety profile (9). Local reactions to the vaccine, ache and tenderness being most commonly reported, were mild to moderate in severity in almost all events (99.5%). Systemic reactions most commonly reported include malaise, headache, and myalgia. Of importance, there were no significant differences between experimental and placebo groups in terms of reported systemic adverse events. Of the 68 subjects enrolled, 56 successfully completed the study and received all scheduled vaccinations. Dropout was due to consent withdrawal (six participants), noncompliance with protocol (one participant), loss to follow-up (three participants), and development of medical problems (two participants). Of note, the two medically related, serious adverse events were unrelated to the study drug.

NicQb, composed of a nicotine hapten similar to that used in NicVax conjugated with a virus-like particle formed by bacteriophage Qb, is currently being tested in phase IIB/III clinical trials (10). In previous trials, NicQb demonstrated an ability to produce a nicotine-specific antibody response as well as a favorable safety profile (11). During phase I study of NicQb, recipients of the vaccine demonstrated an immunologic response with development of nicotine-specific IgM antibodies at day 7 and nicotine-specific IgG antibodies at day 14 (11). Adverse events were characterized as either mild (93%) or moderate (7%), with participants most commonly reporting an injection-site reaction. During the phase II trial of NicQb, most adverse events were deemed mild to moderate in scale (95.7%). Pain at the injection site was the most commonly reported local reaction, with relatively little reporting of swelling, erythema, and edema. The most prominent systemic adverse event was characterized as “flu-like symptoms,” reported by 69.4% of vaccine recipients compared with 12.5% of the placebo group. In general, the development of these symptoms occurred within 2–12 hours after receipt of the vaccine and resolved within 24 hours. Other commonly reported adverse events in the vaccine group compared with the placebo group included pyrexia (42% versus 8%), headache (40% versus 27%), nasopharyngitis (32% versus 26%), rigors (13.5% versus 0%), and myalgia (13.5% versus 5%). Nine serious adverse events were reported; however, only one event was deemed to be treatment-related (e.g., flu-like symptoms associated with chest pain).

TA-NIC, a nicotine hapten conjugated with inactivated cholera toxin B, also demonstrated encouraging results. Subjects received four doses of the vaccine over the first 8 weeks of the trial and an additional booster injection at week 32. At the 12-month follow-up, cessation rates were significantly higher among those receiving the highest dose of the vaccine comparison with rates in the placebo group (38% versus 8%) (12). Of importance, during a double-blind placebo-controlled dose-escalation study of TA-NIC, no serious safety issues were identified (13).

Taken together, these vaccines represent a powerfully important clinical advance in the treatment of nicotine dependence, particularly because high antibody titers resulting from their use correlate with increased rates of smoking cessation (3).

Cocaine abuse and dependence have consistently been demonstrated to be a source of significant morbidity and mortality worldwide and a continuing public health concern. The medical, psychological, and social consequences of cocaine abuse have been extensively studied in an effort to characterize its impact on the public. Chronic drug use has been demonstrated to be associated with increased utilization of health care services (14). In the United States, cocaine use is associated with increased numbers of emergency room visits (14, 15) as well as hospital admissions (16). Cocaine, because of its direct toxicity, has been associated with medical complications affecting numerous organ systems including cardiovascular (17), neurological (18), renal (19), respiratory (20), and immunological (21). At present, there are no U.S. Food and Drug Administration (FDA) approved pharmacotherapeutic options for treatment of this debilitating illness, and, unfortunately, behavioral therapies have demonstrated low success rates (22).

The cocaine vaccine, TA-CD, is a cocaine hapten conjugated to inactivated cholera toxin B and is currently undergoing large-scale, multisite, phase IIb clinical testing. In the phase I trial to assess clinical safety and immunogenicity (N=34), the vaccine demonstrated an ability to elicit an immunological response in subjects (23). In those persons with an antibody response, there were noted reductions in the pleasurable effects from smoked cocaine (24, 25). Almost all recipients (33 of 34) reported local pain/tenderness after administration of the injection with no difference between groups (23). Treatment-related systemic adverse events occurring in all experimental groups and independent of vaccine dosage included tachycardia, elevated temperature (greatest mean increase of 1.9°F observed in the high-dose vaccine group), and hypertension.

In the phase IIa trial, the vaccine was well tolerated at two dose levels (100 μg×4 injections or 400 μg×5 injections), and subjects (N=18) developed cocaine-specific antibodies that persisted for at least 6 months (26). Of note, those receiving the higher dose of vaccine demonstrated a significantly higher mean antibody titer and were more likely to maintain abstinence compared with the low-dose group (24, 26). Sixteen of 18 subjects (89%) completed the vaccination series (24). There were no hospitalizations, deaths, or serious adverse events. No group differences were found for the most commonly reported adverse events (e.g., rhinitis, pharyngolaryngeal pain, nasal congestion, nausea, and vomiting) with the exception of headache, which was noted more frequently in the 400-μg group (nine of nine subjects) than in the 2000-μg group (one of seven subjects). The two subjects leaving the study received only one vaccination and did not complete the series; however, neither participant reported any adverse effects before discontinuation.

In the initial phase IIb trial of TA-CD in methadone-maintained individuals (N=115), the vaccine was found to produce substantial antibody response in one-third of the recipients. This high-antibody group demonstrated a higher percentage of cocaine-free urine samples (27). The safety profile of the vaccine also remained favorable. There were no differences between groups in regard to treatment-emergent adverse events or subject dropout (27). Of 115 subjects randomly assigned to receive either vaccine or placebo, 94 (82%) completed the study. Reasons cited for withdrawal from the study included incarceration and loss of housing due to cocaine use. All severe adverse effects were deemed to be unrelated to the vaccine but include various substance abuse-related consequences (i.e., cocaine-induced paranoia, alcoholic pancreatitis, and cellulitis from drug injection). Common adverse events reported among vaccine recipients compared with those receiving placebo included hot flashes (19% versus 12%), hyperhidrosis (15% versus 10%), nausea (14% versus 2%), and feeling cold (12% versus 7%).

Taken together, these findings suggest that not only are recipients of the vaccine able to mount an immunological response to the vaccine but also the antibodies created are sufficient to block the rewarding effects of cocaine that may lead to reduction in use of the substance. As with nicotine, the effects of the vaccine can be overcome by increasing the amount of cocaine used. Thus, it remains important to consider use of the vaccine in those persons who are motivated to abstain from drug use.

Although traditionally thought to be uncommon, phencyclidine (PCP) abuse represents a potential area of growing concern in the field of addiction. PCP, an arylcyclohexylamine, acts as an antagonist of the N-methyl-d-aspartate (NMDA) receptor. It has become increasingly more popular among select groups of substance abusers, as cigarettes or marijuana sticks are often laced with this drug (28). Although use of PCP in comparison with other substances like nicotine and cocaine is quite low, the medical and psychiatric impact of acute toxicity is considerable, and thus continued consideration should be given to this drug. Current treatment options for PCP abuse are limited to behavioral interventions, because there are no FDA-approved pharmacotherapy options available.

Interestingly, PCP was the first drug of abuse to be examined in studies of passive immunity. Purified goat anti-PCP polyclonal antibodies were found to “substantially alter” the pharmacokinetics of PCP in dogs, resulting in redistribution of PCP from the systemic circulation and organ systems and back into plasma (29). In rat studies, passively administered monoclonal antibodies were found to result in similar findings, with reduction of PCP levels in brain as well as other organs (i.e., lung, heart, and testis), while renal elimination was increased (30, 31). In additional animal studies, monoclonal anti-PCP antibodies have demonstrated the ability to block locomotor activity and ataxia associated with PCP use and reverse acute toxicity from high-dose PCP administration (30, 31, 32).

The production of high-affinity monoclonal antibodies with affinity for PCP that can be safely used in humans has been a growing focus of research. The murine anti-PCP monoclonal antibody, mAb6B5, demonstrated long-term reductions in PCP brain concentration and locomotor activity. A murine/human chimera of mAb6B5 was also tested and found to have similar effects (33). Chimeric monoclonal antibodies represent another important option for treatment of SUDs, particularly because medications of this kind have already been approved by the FDA for treatment of other disorders, as in the case of rituximab treatment of lymphoma (34)

Methamphetamine (METH) use in the United States peaked in 2005, with an estimated 1.3 million users; however, more recent estimates suggest there are slightly more than 500,000 current users of METH (35). Despite this decrease in the overall number of users, the devastating impact to the individual as well as to the community cannot be underestimated. METH exerts its mechanism of action through the indirect agonism of monoamine transporters, as well as the vesicular monoamine transporter-2 (VMAT-2). Acute administration of METH results in the reversal of function of the VMAT-2, which effectively causes the release of monoamines from storage vesicles into the cytosol of neurons. In addition, METH reverses the function of the monoamine transporters, causing the release of dopamine, norepinephrine, and serotonin into the synaptic cleft. As a result, these monoamines are available to stimulate postsynaptic receptors (36). METH is highly addictive, due in large part to its active metabolite (amphetamine) and long half-life, which result in sustained action within the CNS. Currently, there are no medications approved for its treatment, and a vaccine that could address not only METH, but also demonstrate cross-reactivity for amphetamine, would be a formidable agent in the treatment of this particularly destructive SUD.

The preclinical development of METH immunotherapy is an area of active research and potential future targets of treatment include METH-induced acute overdose, relapse prevention, and use in at-risk populations using the drug but not yet dependent (37). Passive immunotherapy with monoclonal antibodies, which has been demonstrated in several animal studies, is likely to be beneficial in those with drug overdose. Monoclonal antibodies have demonstrated safety when administered to mice and an ability to block the hemodynamic and locomotor alterations typically induced by METH (38). Monoclonal antibodies have also been found to reduce brain concentrations of METH, shifting the drug into the circulation as evidenced by increasing serum concentration (39). Furthermore, METH self-administration in rats was reduced in those receiving monoclonal antibodies, possibly suggesting a use for passive immunotherapy in relapse prevention as well (40). In addition, the development of active vaccination is currently ongoing, with testing of several combinations of METH haptens and carrier protein conjugates (37).

In animal studies in the 1970s, administration of a morphine hapten conjugated with 6-hemisuccinyl-bovine serum albumin was found to result in the creation of anti-morphine antibodies, which reduced the concentration of the drug in plasma (in rats) and decreased self-administration of heroin (in rhesus monkey) (41, 42). However, the successful pharmacological management of opiate dependence with methadone and/or buprenorphine and its integration into the fabric of addiction treatment led to a slowing in the effort to create a vaccine for the treatment of heroin addiction. Years later, despite the availability of pharmacotherapy, opiate dependence remains a significant cause of morbidity and mortality in those with the illness. Increased rates of HIV and hepatitis C transmission, criminal involvement, and the general burden to governmental programs contribute to its societal consequences (43). Given the ongoing impact of opiate dependence, current consideration of immunotherapeutic approaches is warranted, because both active and passive immunization could be helpful in treatment of opiate overdose and relapse prevention.

In a recent study conducted in rats, a morphine/heroin vaccine created by conjugation of haptenized morphine to tetanus toxoid demonstrated significant immunogenicity with robust antibody production (44). Because the antibodies are unable to cross the blood-brain barrier, there is little chance for psychoactive effects or an impact on the endogenous opioidergic system. In this case, the creation of high-affinity antibodies with cross-reactivity for both morphine and heroin is also particularly important, because it will allow binding of both heroin and its metabolite (morphine). Ultimately, this novel vaccine may represent an exciting option for the treatment of opioid dependence.