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

Abstract

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.