Probing the protective effects of a conformationally constrained nicotine vaccine.

ABSTRACT

Despite being consistently ranked as the leading cause of preventable death in the United States, about 20% of the population continues to smoke. Current smoking cessation therapies offer limited success, show high rates of relapse, and have potentially dangerous side effects, consequently emphasizing the need for alternative therapies. Immunopharmacotherapy aims to use highly specific antibodies to sequester nicotine in the bloodstream thus blunting passage into the brain and minimizing positive reinforcing effects. A successful vaccination strategy is dependent upon the appropriate hapten design, carrier protein and adjuvant which affect both the magnitude and affinity of the immune response elicited. Our laboratory previously demonstrated the use of molecular constraint as a means to increase the intrinsic immunogenicity and antigenicity of a nicotine vaccine. The present study expands upon those initial results and explores the protective effects of vaccination with both constrained hapten CNI and its unconstrained counterpart NIC. Our results demonstrate how immunization with CNI-KLH produces large amounts of moderate affinity anti-nicotine antibodies even when formulated with ALUM adjuvant, making it particularly relevant for human use. In contrast, vaccination with NIC-KLH produced moderate amounts of high affinity anti-nicotine antibodies. These differential responses proved critical in offering protecting effects. Vaccination with CNI, but not NIC, resulted in an increase of self-administration responding on a progressive ratio schedule using a high nicotine dose (0.03 mg/kg/infusion; ≈ 2 cigarettes in human) as compared to KLH-controls. Furthermore, vaccination with CNI was able to antagonize the analgesic effects of a heavy bolus dose of nicotine (0.35 mg/kg). These results support our hypothesis that molecular constraint can be advantageously utilized to increase the immunogenicity of a nicotine vaccine. Furthermore in correlating the behavioral effects with the differential responses elicited, we shed light on the distinct roles of antibody concentration and affinity.