Elsevier

Vaccine

Volume 20, Issues 7–8, 15 January 2002, Pages 1196-1204
Vaccine

Human therapeutic cocaine vaccine: safety and immunogenicity

https://doi.org/10.1016/S0264-410X(01)00425-XGet rights and content

Abstract

This randomized, double blind, placebo controlled, phase I clinical trial assessed the safety and immunogenicity of a therapeutic cocaine vaccine TA-CD in 34 former cocaine abusers: 8 at 13 μg active vaccine, 10 at 82 μg and 10 at 709 μg, with two additional subjects getting placebo in each cohort. All got intra-muscular injections at 0–2 months and were monitored for safety and antibody production for 3 months. Of the 34 subjects 27 completed the full course of three injections, of these, only 24 returned for the final scheduled visit at day 84. The vaccine was well-tolerated and had no serious drug-related adverse events, although three subjects at the highest dose experienced brief post injection twitching. Fifteen subjects on TA-CD therapeutic vaccine were followed for 1 year. Antibody levels were correlated with vaccine dose and number of injections. Anti-cocaine antibodies were detected after the second injection, peaked at 3 months and declined to baseline by 1 year. Thus, the therapeutic vaccine was well tolerated with dose related increases in antibody levels, and a high proportion of patients recruited into the study were retained.

Introduction

The search for a pharmacotherapeutic agent to treat cocaine dependence began in the early 1980s as clinicians and researchers realized that standard drug counseling alone had little impact on the addiction for many cocaine abusers [1]. The National Institute on Drug Abuse estimates that, in the US, at least 2 million persons are cocaine abusers and that 1–3 million persons are in need of treatment [2], [3]. While cocaine abusers have no severe life-threatening symptoms when stopping cocaine, the psychological addiction in subjects with cocaine use disorders can be disabling and lead to relapse [4], [5], [6].

A therapeutic vaccine provides a unique approach to the pharmacotherapy of cocaine addiction and may be more successful than agents tested up to now [5]. As a unique approach, this therapeutic vaccine is not like the agonist substitution approach of methadone for opioid dependence or nicotine replacement therapy for tobacco dependence. This vaccine more closely resembles an antagonist such as naltrexone for opioid dependence, but the vaccine will not have the potency of naltrexone for opioids. Direct dopamine antagonist (e.g. haloperidol) as well as agonist approaches (e.g. bromocriptine) to stimulant use have, thus, far failed. The dopaminergic medications were examined based on two concepts. The first concept for antagonists is that blocking the effects of high dopamine levels that are produced by cocaine use might directly reduce reinforcement and euphoria from cocaine use. The second concept for agonists to increase dopamine neuronal stimulation is that dopamine is relatively depleted because of down-regulation of the dopamine system after chronic overstimulation by cocaine abuse and that relapse during protracted withdrawal from cocaine would be less likely if this relative depletion was addressed. Other pharmacotherapies that have failed to show efficacy are antidepressants and anti-seizure medications, but most recently disulfiram, which produces an aversive reaction to alcohol, has shown some promise and may complement a therapeutic vaccine approach. Antidepressants were tried because the cocaine withdrawal syndrome resembles depression, and depressive disorders in cocaine abusers are much more common than expected from community samples. Anti-seizure medications were examined because of the clinical similarities of drug craving to stimulant sensitized responses in animals, and anti-seizure medications block these sensitized responses (e.g. excess locomotor activity) in animals. Finally, disulfiram has been studied because of its actions on dopamine beta hydroxylase and the activity of this enzyme to increase dopamine levels by blocking the conversion of dopamine to norepinephrine. This increase in dopamine might be helpful for reversing the relative depletion of dopamine after chronic cocaine abuse, but using cocaine while taking disulfiram also appears to trigger paranoia and aversive responses to the cocaine, thereby, reducing cocaine use by a second mechanism. Thus, disulfiram may produce aversive reactions to cocaine as well as alcohol, but by different mechanisms. Three clinical trials have supported this use of disulfiram for cocaine dependence, and disulfiram may ultimately be an excellent adjunctive treatment with a vaccine approach.

The idea behind a therapeutic vaccine is that if an addict takes cocaine after being immunized, the cocaine will encounter and bind to antibodies on entering the bloodstream, preventing uptake of cocaine across the blood–brain barrier, dulling or even obliterating the euphoric rush. Because this type of antagonism is likely to be weak and partial, the vaccine will not deter use by those cocaine abusers who are not engaged in a therapeutic relapse prevention program and are not motivated to stop using cocaine. However, a therapeutic vaccine based on active-immunization has the potential to provide long lasting clinical efficacy for relapse prevention after administration and to have minimal problems with compliance in humans who are motivated to stop using cocaine. Overdosing with cocaine in an attempt to overcome this weak antagonism is, therefore, unlikely.

Such a therapeutic vaccine has been developed: TA-CD vaccine comprises a protein conjugate in which succinylnorcocaine (SNC) is coupled to the carrier protein, recombinant cholera toxin B (rCTB), and uses aluminum hydroxide as an adjuvant. The cholera toxin was selected because it has been widely tested for other purposes and has an established safety record in humans. Furthermore, it has several chemical sites at exposed lysine residues that allowed relatively efficient succinyl conjugation with three to six norcocaine molecules. TA-CD has been shown to produce antibodies to cocaine in animals [7]. These vaccine-generated antibodies bound only modest amounts of injected cocaine, but nevertheless decreased self-administration of cocaine in immunized rodents [8]. The objectives of that study were to determine, first, whether changes in self-administration behavior would be systematically related to antibody level and, second, how the antibody affected the self-administration of different doses of cocaine after active-immunization. The cocaine vaccine induced average serum antibody levels of 0.08 mg/ml and reduced the reacquisition of self-administration behavior by 1 mg/kg cocaine when serum antibody levels exceeded 0.05 mg/ml using either active or passive immunization. Furthermore, there was no evidence that the antagonism was surmountable within the cocaine dose range examined (up to 5.6 mg/kg).

Prior to initiating the trial, this therapeutic vaccine was tested in animals and showed no toxicity at several times proposed doses in humans. The animal toxicity testing included four animal studies—1 week long multiple dose rat study, and three special toxicity studies in mice. The rat study included histopathological examinations of organs, blood cells and serum protein (e.g. antibody level) determinations. There were no signs of systemic toxicity, but there were local reactions at the injection sites due to the mechanical process of injection on a daily basis. The mouse studies examined any toxicity from administering cocaine to immunized animals and found lower levels of cocaine induced mortality in the immunized compared to non-immunized animals, as expected. A second study showed that the vaccine did not produce toxic reactions greater than those produced by cocaine itself. Thus, animal studies showed no limiting toxicity. Nevertheless, expected adverse events may be similar to those observed with other subunit vaccines containing aluminum hydroxide as an adjuvant. Adverse events associated with aluminum adjuvants include erythema and subcutaneous nodules at the injection site [9]. Previous studies with the rCTB carrier had not produced significant systemic adverse events [10], [11]. However, both early (1–3 days) and late (4–10 days) local reactions were reported by about half the subjects in the Svennerholm study after immunization. Systemic gastrointestinal symptoms occurred in less than a quarter of the subjects.

The therapeutic vaccine itself was not expected to have any cocaine-like side effects that might produce psychoactive effects such as mania, because no free psychoactive drug components from cocaine or active derivatives should be found in the circulation after administering TA-CD for several reasons. First, the rCTB is covalently linked to the SNC by a stable, amide linkage. Second, the amount of SNC contained in the vaccine, even if released by breaking the covalent bond, is about 1000 times lower than the typical human doses of cocaine (e.g. 30 mg) [12], [13]. Finally, no benzoylecgonine, the cocaine metabolite at highest concentration in urine where it can be detected at levels down to 50 μg/ml, was detected in urine samples.

Section snippets

Protocol outline

This phase I study was conducted to evaluate the safety and immunogenicity of TA-CD cocaine therapeutic vaccine in humans in a group of abstinent cocaine abusers who were confined in a residential drug treatment program and then followed for 1 year after initial vaccination by which time most subjects had left the residential facility. In this study we evaluated local and systemic adverse events.

Therapeutic vaccine formulation

The active component of the cocaine therapeutic vaccine TA-CD was SNC linked to a carrier protein

Demographics and screening results

We screened 50 subjects for this study and 16 failed to pass the screening. Nine subjects were not included due to medical reasons: unstable diabetes, liver function test elevations more than three times the upper limit of normal, HIV infection, eye infection and one subject who was taking systemic steroids for asthma. Three subjects left treatment during the screening and three others had an insufficient history of cocaine use. One was incarcerated during the screening process. The 34 subjects

Discussion

The cocaine therapeutic vaccine TA-CD was well tolerated when administered as a course of three injections of 13, 82 or 709 μg given at monthly intervals to abstinent cocaine abusers residing within a drug-free residential setting. No serious vaccine-related adverse events were reported during the 3 months study period or during the 12 months follow-up when most subjects had left the drug-free residence.

Minor adverse events included small temperature elevations in about one-third of the

Acknowledgements

This research was supported by NIDA SPIRCAP 1U19DA10946 and Veterans Administration Mental Illness Research, Education and Clinical Center (New England MIRECC).

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Present address: VA Connecticut Healthcare System, Psychiatry 151D, 950 Campbell Avenue, West Haven, CT 06516, USA.

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