Novel Cocaine Vaccine Linked to a Disrupted Adenovirus Gene Transfer Vector Blocks Cocaine Psychostimulant and Reinforcing Effects

Abstract

Immunotherapy is a promising treatment for drug addiction. However, insufficient immune responses to vaccines in most subjects pose a challenge. In this study, we tested the efficacy of a new cocaine vaccine (dAd5GNE) in antagonizing cocaine addiction-related behaviors in rats. This vaccine used a disrupted serotype 5 adenovirus (Ad) gene transfer vector coupled to a third-generation cocaine hapten, termed GNE (6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid). Three groups of rats were immunized with dAd5GNE. One group was injected with 3 H-cocaine, and radioactivity in the blood and brain was determined. A second group was tested for cocaine-induced locomotor sensitization. A third group was examined for cocaine self-administration, extinction, and reinstatement of responding for cocaine. Antibody titers were determined at various time-points. In each experiment, we added a control group that was immunized with dAd5 without a hapten. The vaccination with dAd5GNE produced long-lasting high titers (410 5 ) of anti-cocaine antibodies in all of the rats. The vaccination inhibited cocaine-induced hyperlocomotor activity and sensitization. Vaccinated rats acquired cocaine self-administration, but they showed less motivation to self-administer cocaine under a progressive-ratio schedule than control rats. When cocaine was not available in a session, control rats exhibited 'extinction burst' responding, whereas vaccinated rats did not. Moreover, when primed with cocaine, vaccinated rats did not reinstate responding, suggesting a blockade of cocaine-seeking behavior. These data strongly suggest that our dAd5GNE vector-based vaccine may be effective in treating cocaine abuse and addiction.

Inmunoprotección activa contra cocaína

“…[36][37][38][39] Janda et al 20 desarrollaron el bacteriófago GNC92H2-p-VIII, al cual se le modificaron las proteínas de superficie pVIII, con el fin de generar una especie de malla esponjosa capaz de capturar las moléculas de cocaína dentro del SNC. La inmunización (dos veces diariamente) de ratas, vía intranasal con el bacteriófago, atenuó significativamente la actividad locomotora, pero sólo para dosis bajas o medias de cocaína.…”

“…La inmunización (dos veces diariamente) de ratas, vía intranasal con el bacteriófago, atenuó significativamente la actividad locomotora, pero sólo para dosis bajas o medias de cocaína. 36,37,39 Los estudios concluyeron que la eficacia del bacteriófago GNC92H2-p-VIII para capturar a la cocaína era dependiente del número de copias generadas.…”

“…39 En el intento número uno, el primer vector estuvo compuesto por un adenovirus-5 acoplado a la primera generación de hapteno GNC, el cual, al ser administrado, generó altos títulos de anticuerpos 38 capaces de atenuar los efectos estimulantes psicomotores de la cocaína en el ratón. Además, los títulos de anticuerpos permanecen en niveles altos hasta por tres meses después de la última administración.…”

Adenovirus Capsid-Based Anti-Cocaine Vaccine Prevents Cocaine from Binding to the Nonhuman Primate CNS Dopamine Transporter

“…À , and the E3 À serotype 5 Ad vector with b-galactosidase in the expression cassette Rosenfeld et al 1992;Wee et al 2012). The Ad5bgal vector was disrupted in 0.5% sodium dodecyl sulfate at 56 1C for 45 s. The cocaine hapten GNE (0.3 mg) was activated overnight at 4 1C after the addition of 7.2 ml charging solution (2.4 mg of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and 2 mg of N-hydroxysulfosuccinimide in 4 ml H 2 O and 40 ml dimethylformamide) Wee et al 2012).…”

“…With the goal of blocking access of cocaine to the CNS to prevent DAT occupancy levels that induce cocaine's psychotropic effects, we have developed an anti-cocaine vaccine (dAd5GNE) based on a cocaine analog covalently coupled to the capsid proteins of a disrupted serotype 5 human adenovirus Wee et al 2012). Studies in mice and rats have shown that dAd5GNE prevents cocaine-induced hyperactivity and addiction-related behavior in these species (Koob et al 2011;Hicks et al 2011;Wee et al 2012).…”