Both the active and placebo vaccine groups reduced their cocaine use during the first eight weeks probably due to reducing their illicit opiate use through methadone maintenance and CBT. The proportion of subjects having a 50% reduction in cocaine use was significantly greater in the high IgG than low IgG subjects (0.53 vs. 0.23) (P 0.04). The most common side effects were injection site induration and tenderness. There were no treatment related serious adverse events, withdrawals, or deaths. Conclusions Attaining high ( 43 g/mL) IgG anti-cocaine antibody levels was associated with significantly Derenofylline reduced cocaine use, but only 38% of the vaccinated attained these IgG levels and they had only 2 months of adequate cocaine blockade. Thus, we need improved vaccines and boosters. Introduction Cocaine dependence is common, involving one of every three drug related emergency department visits, and has substantial social and economic impacts on those afflicted 1, 2. In 2007 the United States had 2.5 million cocaine dependent people, and only 809,000 of them were treated 3. The FDA has not approved any pharmacotherapies for cocaine abuse, and behavioral therapies have had a wide range of efficacies with some promise for contingency management 4C10. Experimental animal studies, however, have suggested that high levels of anti-cocaine antibodies can sequester circulating cocaine 11C14 and facilitate inactivation of cocaine by naturally occurring plasma cholinesterases before the drug enters the brain 15. In both animals and humans, reducing cocaines entry into the brain by binding antibody reduces cocaine induced euphoria, without causing any direct psychoactive effects or drug-drug interactions associated with other pharmacotherapies 16C18 We tested a cocaine vaccine made by covalently linking succinylnorcocaine (SNC) to cholera B protein (rCTB), adsorbed onto aluminum hydroxide adjuvant. 19C21 The immunogenic carrier, rCTB, Derenofylline has a well established safety record worldwide when used to immunize against cholera 19, 22. In a randomized, double-blind placebo Derenofylline controlled trial involving 34 abstinent cocaine abusers engaged in out-patient treatment, we demonstrated that this vaccine was well tolerated and induced cocaine-specific IgG antibodies in a time Derenofylline and dose dependent manner 23. No serious adverse effects occurred during 12 months follow-up. We also showed a continued safety and immunogenicity profile in a second open-label dose escalation study involving both cocaine abstinent and active users 24. Subjective responses of the vaccinated subjects suggested that the vaccine exerted its expected reduction in euphoria during the time their antibody levels peaked, that is between weeks 12 and 16 after the first inoculation.23, 24 To influence drug seeking behavior, the concentration of anti-cocaine antibody in the blood must attain a target level. Early rat studies with cocaine-CTB vaccine showed that 0.7 mg/ml of high affinity IgG was sufficient to bind 8.7M of cocaine 11. Since cocaine users can experience pleasure at peak plasma cocaine concentrations as low as approximately 0.5 M, 25 we hypothesized that the antibody would need to bind and capture this Derenofylline amount of cocaine to slow delivery of typically abused amounts into the brain. Considering the two binding sites on each antibody, we calculated needing 0.28 M of moderate affinity anti-cocaine antibody in the blood, which equals our target of 43 ug/ml of specific IgG for sub-analyses of efficacy 11, 12, 26. We also hypothesized distinct patterns of cocaine usage based on subjects antibody Tmem33 levels. We have previously shown that 25C30% of vaccinated subjects produce relatively low antibody levels.23, 24 Furthermore, we knew that IgG antibody levels would reach a maximum between weeks 12 and 16, after which IgG antibody levels would begin to fall. Thus, we postulated that starting during week 9 immunized volunteers who made more than 43 ug/ml of anti-cocaine antibodies would use less cocaine than those immunized with the placebo or those who made less than 43 ug/ml following this series of vaccinations. METHODS SITE AND POPULATION Participants meeting DSM IV criteria 27 for cocaine and opioid dependence were enrolled in an out-patient methadone maintenance treatment program in West Haven, Connecticut. We studied methadone maintained subjects because retention in methadone maintenance programs is substantially better than in primary cocaine treatment programs 28 and we needed to retain these volunteers.
