Anti-cocaine Vaccine Research Articles

Anti-cocaine Vaccine Development: Where Are We Now and Where Are We Going?

Cocaine is one of the oldest and most widely used illicit drugs in the world and is responsible for major worldwide medical and social problems. Drug addiction is a disease state where the body relies on a substance for normal functioning and develops a physical dependence leading to compulsive and repetitive use despite negative consequences to the user's health, mental state, or social life. The primary driver for the development of anti-cocaine vaccines has been the failure to develop effective pharmacological treatments to combat cocaine dependence. Despite several decades of research, no approved pharmacological treatments for cocaine dependence are available to assist addicts to overcome cocaine withdrawal or to prevent drug relapse. This Perspective highlights the challenges associated with anti-cocaine vaccines, including the current state of anti-cocaine vaccines and catalytic antibody research to aid in the fight against cocaine addiction.

Low doses of pharmaceutical formulations loaded with UFMG-V4N2 immunogen induce the production of IgG anti-cocaine antibodies and provide evidence of cerebral protection in the preclinical model

Anti-cocaine vaccines are a promising therapeutic strategy for treating cocaine use disorders. Here we hypothesize that nanoemulsions (NE) or suspensions (SS) loaded with the calix [4]arene-based immunogen UFMG-V4N2 can induce the production of anti-cocaine antibodies and decrease the passage of radiolabeled cocaine analog [99mTc]Trodat-1 through of the brain barrier. UFMG-V4N2 was characterized (solubility, morphology, DSC, XRD) and loaded into NEs and SSs using excipients approved for human use. Immunogenic efficacy was assessed by quantifying the titers and determining the specificity of anti-cocaine IgG antibodies, and by assessing the inhibition of [99mTc]Trodat-1 trafficking across the mice brain-barrier. UFMG-V4N2 is an amorphous, thermally stable molecule with very low hydrophilicity. The immunogenicity of NE or SS was similar, but aluminum phosphate and the lower dose of UFMG-V4N2 induced higher anti-cocaine IgG antibody titers, minimizing [99mTc]Trodat-1 uptake in the brain. Therefore, the UFMG-V4N2 may represent an alternative for the treatment of cocaine use disorder.

Safety and immunogenicity of the anti-cocaine vaccine UFMG-VAC-V4N2 in a non-human primate model.

A promising strategy for cocaine addiction treatment is the anti-drug vaccine. These vaccines induce the production of anticocaine antibodies, capable of linking to cocaine, and decrease the passage of cocaine throughout the blood-brain barrier, decreasing drug activity in the brain. Our research group developed a new vaccine candidate, the UFMG-V4N2, to treat cocaine use disorders (CUD) using an innovative carrier based on calixarenes. This study assessed the safety and immunogenicity of the anti-cocaine vaccine UFMG-VAC-V4N2 in a non-human primate toxicity study using single and multiple vaccine doses. The UFMG-VAC-V4N2 yielded only mild effects in the injection site and did not influence the general health, feeding behavior, or hematological, renal, hepatic, or metabolic parameters in the vaccinated marmosets. The anti-cocaine vaccine UFMG-VAC-V4N2 presented a favorable safety profile and induced the expected immune response in a non-human primate model of Callithrix penicillata. This preclinical UFMG-VAC-V4N2 study responds to the criteria required by international regulatory agencies contributing to future anticocaine clinical trials of this anti-cocaine vaccine.

Anti-Cocaine IgA Rather Than IgG Mediates Vaccine Protection from Cocaine Use.

In developing a vaccine for fentanyl use disorder, we observed that IgA was the best correlate of vaccine-mediated protection from injected drug challenge, rather than IgG or binding affinity. Recent evidence shows that IgA secreting cells line the blood-brain barrier that capture pathogens and could prevent drug antigens from penetrating the brain. We assayed IgA and IgG antibodies from an anti-cocaine vaccine clinical trial and categorized each subject's antibody levels using half-log cut-points for IgA: <1000, <5000, <10,000 and >10,000; and for IgG: <10,000 to >100,000. We compared these antibody groups on urine toxicology in 130 subjects at week 9 after 3 booster vaccinations. We also provided relevant data on benzoylecgonine (BE, cocaine metabolite) from this study's placebo patients. BE urine levels were lowest for the highest IgA category; however, levels did not differ across IgG groups. Our findings linking IgA to protection from cocaine and fentanyl in mice, rats and humans are novel and suggest an increasingly recognized role of IgA in vaccine efficacy.

Calix[n]arene-based immunogens: A new non-proteic strategy for anti-cocaine vaccine

IntroductionCocaine use disorder is a significant public health issue without a current specific approved treatment. Among different approaches to this disorder, it is possible to highlight a promising immunologic strategy in which an immunogenic agent may reduce the reinforcing effects of the drug if they are able to yield sufficient specific antibodies capable to bind cocaine and/or its psychoactive metabolites before entering into the brain. Several carriers have been investigated in the anti-cocaine vaccine development; however, they generally present a very complex chemical structure, which potentially hampers the proper assessment of the coupling efficiency between the hapten units and the protein structure. ObjectivesThe present study reports the design, synthesis and preclinical evaluation of two novel calix[n]arene-based anti-cocaine immunogens (herein named as V4N2 and V8N2) by the tethering of the hydrolysis-tolerant hapten GNE (15) on calix[4]arene and calix[8]arene moieties. MethodsThe preclinical assessment corresponded to the immunogenicity and dose–response evaluation of V4N2 and V8N2. The potential of the produced antibodies to reduce the passage of cocaine analogue through the blood–brain-barrier (BBB), modifying its biodistribution was also investigated. ResultsBoth calix[n]arene-based immunogens elicited high titers of cocaine antibodies that modified the biodistribution of a cocaine radiolabeled analogue (99mTc-TRODAT-1) and decreased cocaine-induced behavior, according to an animal model. ConclusionThe present results demonstrate the potential of V4N2 and V8N2 as immunogens for the treatment of cocaine use disorder.

The GNE-KLH anti-cocaine vaccine protects dams and offspring from cocaine-induced effects during the prenatal and lactating periods.

Protecting children from prenatal cocaine exposure is a significant challenge for physicians and childbearing women with cocaine use disorder. Cocaine use is highly prevalent among reproductive-aged women and prenatal cocaine exposure produces obstetric, foetal neurodevelopmental and long-term behavioural impairments. Cocaine crosses the maternal and foetal blood-brain barrier and the placenta by diffusion. The best approach to prevent prenatal cocaine exposure is to stop cocaine use. However, only 25% of cocaine users can discontinue their use during pregnancy. Anti-cocaine vaccination decreases cocaine passage through the blood-brain barrier. This study describes an innovative approach for preventing prenatal cocaine exposure using the GNE-KLH anti-cocaine vaccine, a novel use for the named anti-drug vaccines. Here, we show that anti-cocaine vaccination with GNE-KLH produced and maintained anti-cocaine IgG antibody titres and avidity during pregnancy. These antibodies protected the pregnant rats and their pups against prenatal cocaine damage during pregnancy until weaning. The present work is the first preclinical evidence of the efficacy of an innovative mechanism to prevent prenatal cocaine exposure damage, a worldwide public health care issue. In the future, this mechanism may be useful in pregnant women with cocaine use disorder. Further studies to understand the mechanisms of how anti-cocaine antibodies exert their protective effects in pregnancy are warranted.

Cocaine vaccine dAd5GNE protects against moderate daily and high-dose "binge" cocaine use.

The cocaine vaccine dAd5GNE is comprised of a disrupted serotype 5 adenovirus gene therapy vector covalently conjugated to the cocaine analog GNE. The vaccine evokes a high titer of circulating anti-cocaine antibodies that prevent cocaine from reaching its cognate receptors in the central nervous system. Prior studies have demonstrated the efficacy of dAd5GNE in models of occasional, moderate cocaine use. However, previous studies have not sufficiently evaluated the efficacy of dAd5GNE in models of the repetitive and high-dose “binge” use patterns common in human addicts. In the present study, we evaluated the capacity of dAd5GNE vaccination to protect against “binge” cocaine use and circumstances where vaccinated addicts attempt to override the vaccine. We modeled repetitive daily cocaine use in vaccinated Balb/c mice and African green monkeys, and evaluated high-dose “binge” scenarios in Balb/c mice. In each model of daily use the dAd5GNE vaccine prevented cocaine from reaching the central nervous system. In the high-dose “binge” model, vaccination decreased cocaine-induced hyperactivity and reduced the number of cocaine-induced seizures. Based on this data and our prior data in rodents and nonhuman primates, we have initiated a clinical trial evaluating the dAd5GNE anti-cocaine vaccine as a potential therapy for cocaine addicts who wish to stop cocaine use. If dAd5GNE vaccination is safe and produces high anti-cocaine antibody titers in the clinic, we hypothesize that the vaccine will restrict the access of cocaine to the central nervous system and inhibit cocaine-induced “highs” even in the context of moderate daily and high-dose “binge” use that might otherwise cause a drug-induced overdose.

Efficient Syntheses of Cocaine Vaccines and Their in Vivo Evaluation.

Though cocaine abuse and addiction continue to have serious implications for health and society, no FDA-approved interventions have been developed. Anticocaine conjugate vaccines offer an attractive opportunity for addiction treatment; however, vaccines have thus far failed in clinical trials. As a result, anticocaine vaccines must be further optimized to achieve clinical translation. Herein, we report a study on the relationship between vaccine efficacy and hapten stability toward hydrolysis. Two haptens developed by our laboratory, GND and GNE, were conjugated to tetanus toxoid (TT) and formulated with alum and cytosine-guanine oligodeoxynucleotide 1826 (CpG ODN 1826) adjuvants, the optimal formulation in anticocaine vaccine design. GND, a diamide, is more hydrolytically stable than GNE, a monoamide, toward butyrylcholinesterases. Ultimately, both vaccines induced antibodies with high affinity for cocaine. In hyperlocomotion testing, GND-TT and GNE-TT vaccinated mice exhibited a robust blockade of cocaine’s stimulatory effects at all tested doses. Overall, antibodies raised against both haptens were highly effective in protecting mice from cocaine-induced psychostimulation.

Cocaine Vaccine Development: Evaluation of Carrier and Adjuvant Combinations That Activate Multiple Toll-Like Receptors.

Although cocaine abuse and addiction continue to cause serious health and societal problems, an FDA-approved medication to treat cocaine addiction has yet to be developed. Employing a pharmacokinetic strategy, an anticocaine vaccine provides an attractive avenue to address these issues; however, current vaccines have shown varying degrees of efficacy, indicating that further formulation is necessary. As a means to improve vaccine efficacy, we examined the effects of varying anticocaine vaccine formulations by combining a Toll-like receptor 9 (TLR9) agonist with a TLR5 agonist in the presence of alum. The TLR9 agonist used was cytosine-guanine oligodeoxynucleotide 1826 (CpG 1826), while the TLR5 agonist was flagellin (FliC). Formulations with the TLR9 agonist elicited superior anticocaine antibody titers and blockade of hyperlocomotor effects compared to vaccines without CpG 1826. This improvement was seen regardless of whether the TLR5 agonist, FliC, or the nonadjuvanting Tetanus Toxoid (TT) was used as the carrier protein. Additional insights into the value of FliC as a carrier versus adjuvant was also investigated by generating two unique formats of the protein, wild-type and mutated flagellin (mFliC). While the mFliC conjugate retained its ability to stimulate mTLR5, it yielded reduced cocaine sequestration and functional blockade relative to FliC and TT. Overall, this work indicates that activation of TLR9 can improve the function of cocaine vaccines in the presence of TLR5 activation by FliC, with any potential additive effects limited by the inefficiency of FliC as a carrier protein as compared to TT.

Efficacy of an adenovirus-based anti-cocaine vaccine to reduce cocaine self-administration and reacqusition using a choice procedure in rhesus macaques

Immunopharmacotherapy offers an approach for treating cocaine abuse by specifically targeting the cocaine molecule and preventing its access to the CNS. dAd5GNE is a novel cocaine vaccine that attenuates the stimulant and the reinforcing effects of cocaine in rats. The goal of this study was to extend and validate dAd5GNE vaccine efficacy in non-human primates. Six experimentally naïve adult female rhesus monkeys (Macaca mulatta) were trained to self-administer 0.1mg/kg/injection intravenous (i.v.) cocaine or receive candy; then 4 monkeys were administered the vaccine and 2 monkeys were administered vehicle intramuscularly, with additional vaccine boosts throughout the study. The reinforcing effects of cocaine were measured during self-administration, extinction, and reacquisition (relapse) phases. Serum antibody titers in the vaccinated monkeys remained high throughout the study. There was no change in the preference for cocaine over candy over a 20-week period in 5 of the 6 monkeys; only one of the 4 (25%) vaccinated monkeys showed a decrease in cocaine choice. All 6 monkeys extinguished responding for cocaine during saline extinction testing; vaccinated monkeys tended to take longer to extinguish responding than control monkeys (17.5 vs. 7.0 sessions). Vaccination substantially retarded reacquisition of cocaine self-administration; control monkeys resumed cocaine self-administration within 6–41 sessions and 1 vaccinated monkey resumed cocaine self-administration in 19 sessions. The other 3 vaccinated monkeys required between 57 and 94 sessions to resume cocaine self-administration even in the context of employing several manipulations to encourage cocaine reacquisition. These data suggest that the dAdGNE vaccine may have therapeutic potential for humans who achieve cocaine abstinence as part of a relapse prevention strategy.

36. Translation of an Adenovirus-Based Cocaine Vaccine dAd5GNE to a Clinical Trial

dAd5GNE, an anti-cocaine vaccine based on a disrupted serotype 5 adenovirus gene transfer vector covalently conjugated to the cocaine analog GNE, evokes high titers of high affinity anti-cocaine antibodies that prevent cocaine from reaching its cognate receptor in the CNS. dAd5GNE has been shown to be effective in preclinical efficacy studies in mice, rats and nonhuman primates. In order to translate dAd5GNE to the clinic, this study focused on optimizing the choice of adjuvant, timing of vaccination regimen and dose. Adjuvant. To evaluate vaccine formulation, the adjuvants Adjuplex and Alum were assessed at a fixed dose to identify the formulation that evoked the fastest and highest titer response. BALB/c mice vaccinated with dAd5GNE/Adjuplex demonstrated high serum anti-cocaine antibody titers (>5×105) after a single administration while animals vaccinated with dAd5GNE/Alum required multiple injections to achieve high titers, and mice vaccinated with dAd5GNE/PBS plateaued at a lower titer. Therefore, a formulation based on the Adjuplex adjuvant was chosen for the clinical protocol. Timing. The measurement of titer half-life in nonhuman primates following individual vaccinations at variable intervals was used to inform the timing between vaccine boosts. The anti-cocaine antibody titer half-life in 8 dAd5GNE/Adjuplex vaccinated nonhuman primates was assayed regularly over the course of 1 yr and the titer half-life was calculated following each administration. The average half-life for all animals was 4.0 ± 0.2 wk. Continued cocaine use did not impact the titer half-life. These results indicate that a 4 wk interval for vaccinations is necessary to maintain the high titer anti-cocaine antibody levels. Dose. We measured the dose response in mice to provide the baseline for a phase I/II clinical trial and identified the range of doses that bracket the anticipated minimum effective dose and maximum tolerated dose. Doses from 0.04-40 μg of the vaccine were evaluated in BALB/c for the capacity to evoke antibody titers and to minimize access of radiolabelled cocaine to the CNS. Doses at and above 4 µg produced high anti-cocaine antibody titers above the threshold for efficacy (>5×105) which substantially reduced cocaine levels in the brain (p<0.0001 vs PBS). Using a modified weight adjusted dose from these results, the vaccine doses to be evaluated in the clinical trial were determined to be 100 to 1000 µg. The results of these studies combine to provide the specifications for critical vaccine design parameters required to translate the anti-cocaine vaccine to evaluation in a clinical trial. Based on these specifications the FDA has allowed the Adjuplex-formulated dAd5GNE vaccine to proceed to clinical study with a monthly vaccination regimen in recovering cocaine addicts.

Suppression of Cocaine-Evoked Hyperactivity by Self-Adjuvanting and Multivalent Peptide Nanofiber Vaccines.

The development of anti-cocaine vaccines that counteract the rewarding effects of the drug are currently being investigated as adjunct therapies for prevention of relapse in abstinent users. However, cocaine is weakly immunogenic and requires conjugation to carrier proteins and coadministration with strong adjuvants, which carry the risk of local reactogenicity and systemic toxicity. Here we report synthetic and multivalent self-assembling peptide nanofibers as adjuvant-free carriers for cocaine vaccines. A novel cocaine hapten modified at the P3 site was conjugated to the N-terminus of an amphipathic self-assembling domain KFE8. In aqueous buffers the cocaine-KFE8 conjugate assembled into β-sheet rich nanofibers, which raised anti-cocaine antibodies without the need for added adjuvants in mice. Vaccinated mice were treated with cocaine and a significant negative correlation was observed between antibody levels and cocaine-evoked hyperactivity. These totally synthetic and multivalent nanofibers with well-defined chemical composition represent the first generation of adjuvant-free cocaine vaccines.

Inmunoprotección activa contra cocaína

Resumen Introducción. La farmacopea clásica, empleada para atenuar la dependencia a ciertas drogas de abuso ilegal, como la cocaína, ha demostrado una pobre eficacia terapéutica. Basado en este desalentador panorama clínico-terapéutico, desde hace más de una década diversos investigadores han desarrollado nuevas estrategias terapéuticas contra la adicción a la cocaína. Estas nuevas estrategias experimentales están basadas en el diseño y la síntesis de formulaciones estructurales de vacunas terapéuticas contra la adicción a la cocaína. Objetivo. Realizar una descripción del desarrollo y la validación terapéutica de la inmunización activa contra la cocaína. Método. Se realizó una búsqueda bibliográfica con el uso del PubMed, usando como descriptores las palabras “Cocaine” y “Vaccine”. Se obtuvieron 155 artículos, de los cuales se usaron 46 para esta revisión. Resultados. A nivel preclínico, la vacunación activa genera altos niveles de anticuerpos capaces de reconocer con alta especificidad a la cocaína dentro del torrente sanguíneo, atenuando las alteraciones conductuales inducidas por diversas dosis de cocaína. Discusión y conclusión. Los resultados preclínicos y clínicos han reforzado “la prueba de concepto” terapéutica de la vacunación activa para el control farmacológico de la recaída al consumo adictivo de la cocaína en el humano, sin embargo, dieron pauta a la postulación y a la justificación de sintetizar nuevos modelos de uso humano de vacunas anticocaína.

455. Safety of Vaccination to Treat Cocaine Addiction with Capsid Proteins from a Disrupted Adenovirus Conjugated to a Cocaine Analog

Cocaine is a highly addictive drug with significant social, societal, economic and medical impact, yet there are no effective therapies for cocaine addiction. An anti-cocaine vaccine that could evoke antibodies to bind the drug and prevent its transfer across the blood-brain barrier to its cognate CNS receptors is a promising strategy for treatment of cocaine addiction. In preclinical studies, an anti-cocaine vaccine (dAd5GNE) consisting of a disrupted E1- E3- serotype 5 adenovirus covalently conjugated to the cocaine analog GNE evoked high-titers of anti-cocaine antibodies that blocked cocaine from reaching the central nervous system of mice, rats and monkeys, abrogating cocaine-induced behaviors. The objective of this study was to ascertain if vaccination of a clinical grade dAd5GNE formulated in Adjuplex™ adjuvant administered to mice and non-human primates (NHPs) could be achieved with a safety profile acceptable to move this therapy to humans. Age-matched Balb/c mice (n=48 male, n=48 female for each group) were vaccinated monthly with a vehicle control, Adjuplex™ alone or dAd5GNE, (0.4 or 4 mg) + Adjuplex™. At 1, 5, 13 and 26 wk, evaluation of gross and histopathology, complete blood count, and serum chemistry were performed in a blinded fashion. No significant differences between Adjuplex™ control- and vaccine-treated groups were observed and no adverse effects could be attributed to the vaccine. Some histiocytic inflammatory infiltrates at the site of injection were observed in mice for which doses of Adjuplex™ were >150-fold the weight-adjusted human dose. African green monkeys vaccinated monthly with Adjuplex™ formulated dAd5GNE (50 mg, 100 mg or 200 mg), or adjuvant control (n=2 male, n=2 female for each group) were evaluated for standard general safety parameters plus heart rate, respiratory rate, and body temperature over the course of 6 months. To reflect the use of the vaccine in cocaine addict populations, all NHPs were challenged with cocaine (1 mg/kg, intravenous) on each of the 3 days leading up to sacrifice with vital signs monitored for 30 min following each challenge. Examination of the brain, thyroid, parathyroid, pituitary, mediastinal lymph node, mesenteric lymph node, popliteal lymph nodes, inguinal lymph node, pericardium, aorta, thymus, diaphragm, salivary gland, gall bladder, stomach, mesenteric adipose tissue, adrenals, trachea, esophagus, urinary bladder, sternum, eye, cervical spinal cord, pituitary, sciatic nerve, skin, quadriceps revealed no adverse effects related to the intramuscular administration of dAd5GNE in mice or NHPs. Unlike the murine study, no untoward effects associated with the adjuvant were observed at the site of injection. This safety profile suggests that vaccination with dAd5GNE meets the criteria to proceed to clinical trial.

Attenuation of cocaine-induced locomotor activity in male and female mice by active immunization.

Immunotherapy for drug addiction is being investigated in several laboratories but most studies are conducted in animals of one sex. Yet, women show heightened immune responses and are more likely to develop autoimmune diseases than men. The purpose of this study was to compare the effects of an active anti-cocaine vaccine, succinyl-norcocaine conjugated to keyhole limpet hemocyanin, for its ability to elicit antibodies and alter cocaine-induced ambulatory activity in male versus female mice. Male and female BALB/c mice were vaccinated (n = 44) or served as non-vaccinated controls (n = 34). Three weeks after initial vaccination, a booster was given. Ambulatory activity induced by cocaine (20 mg/kg) was assessed at 7 weeks and plasma obtained at 8 weeks to assess antibody levels. High antibody titers were produced in mice of both sexes. The vaccine reduced ambulatory activity cocaine-induced but this effect was greater in female compared to male mice. The efficacy of this anti-cocaine vaccine is demonstrated in mice of both sexes but its functional consequences are greater in females than males. Results point to the importance of testing animals of both sexes in studies of immunotherapies for addiction.

Humanized mouse models to study effects of anti-cocaine vaccine

Los Institutos de Medicina Legal (IML) en España tienen como misión principal auxiliar a la administración de justicia. La presente revisión analiza la potencialidad de la información de los IML centrada en el campo de la patología forense. Se destaca la importancia de dicha información para mejorar la validez de las estadísticas de mortalidad en las defunciones con intervención judicial, especialmente la persistencia de la escasa validez de estas, ya detectada hace más de una década. Se describe también el documento estadístico y el sistema de declaración de las defunciones con intervención judicial introducidos en 2009 por el Instituto Nacional de Estadística. Se profundiza en el papel de los IML en el conocimiento de la mortalidad y algunos determinantes de ciertas causas de muerte: las debidas a lesiones por tráfico, suicidio, por reacción aguda a drogas de abuso, así como las muertes infantiles y la muerte súbita. Se concluye que la relevancia social y sanitaria de los IML se proyecta más allá de su valioso auxilio a la justicia, ya que brinda un gran servicio a la sociedad y aporta información indispensable para el conocimiento y abordaje de problemas de salud pública relativos a cuestiones de gran impacto social y sanitario.The main mission of Spanish Institutes of Legal Medicine (ILMs) is to serve the justice system. We review the potential broader role of the work done by ILMs, with an emphasis on forensic pathology. The relevance of forensic information to increase the quality of mortality statistics is highlighted, taking into account the persistence of the low validity of the external causes of death in the Mortality Register that was already detected more than a decade ago. The new statistical form and reporting system for the deaths under ILMs jurisdiction, as introduced by the Spanish Instituto Nacional de Estadística in 2009, are also described. The IMLs role in the investigation of the following mortality causes and of their determinants is reviewed in detail: traffic accidents, suicide, drugs of abuse, child deaths and sudden deaths. We conclude that an important public role of IMLs is emerging beyond their valuable service to the justice system, mainly through the gathering of data critical to assess and prevent several medical and public health and safety issues of great social impact and through their participation in epidemiologic research and surveillance.

222. Fate of Systemically Administered Cocaine in Nonhuman Primates Treated with the dAd5GNE Anti-Cocaine Vaccine

222. Fate of Systemically Administered Cocaine in Nonhuman Primates Treated with the dAd5GNE Anti-Cocaine Vaccine

782. Efficacy of the dAd5GNE Anti-Cocaine Vaccine in Models of “Binge” Cocaine Use

782. Efficacy of the dAd5GNE Anti-Cocaine Vaccine in Models of “Binge” Cocaine Use

Fate of Systemically Administered Cocaine in Nonhuman Primates Treated with the dAd5GNE Anticocaine Vaccine

Cocaine use disorders are mediated by the cocaine blockade of the dopamine transporter in the central nervous system (CNS). On the basis of the concept that these effects could be obviated if cocaine were prevented from reaching its cognate receptors in the CNS, we have developed an anticocaine vaccine, dAd5GNE, based on a cocaine analog covalently linked to capsid proteins of an E1(-)E3(-) serotype 5 adenovirus. While the vaccine effectively blocks systemically administered cocaine from reaching the brain by mediating sequestration of the cocaine in the blood, the fact that cocaine also has significant peripheral effects raises concerns that vaccination-mediated redistribution could lead to adverse effects in the visceral organs. The distribution of systemically administered cocaine at a weight-adjusted typical human dose was evaluated along with cocaine metabolites in both dAd5GNE-vaccinated and control nonhuman primates. dAd5GNE sequestration of cocaine to the blood not only prevented cocaine access to the CNS, but also limited access of both the drug and its metabolites to other cocaine-sensitive organs. The levels of cocaine in the blood of vaccinated animals rapidly decreased, suggesting that while the antibody limits access of the drug and its active metabolites to the brain and sensitive organs of the periphery, it does not prolong drug levels in the blood compartment. Gross and histopathology of major organs found no vaccine-mediated untoward effects. These results build on our earlier measures of efficacy and demonstrate that the dAd5GNE vaccine-mediated redistribution of administered cocaine is not likely to impact the vaccine safety profile.

Fate of Systemically Administered Cocaine in Nonhuman Primates Treated with the dAd5GNE Anti-cocaine Vaccine

Fate of Systemically Administered Cocaine in Nonhuman Primates Treated with the dAd5GNE Anti-cocaine Vaccine