| Tobacco addiction is the leading cause of preventable death worldwide. Many people continue to smoke cigarettes despite clear detrimental health effects. Available smoking cessation therapies are only partially effective, making new treatment approaches necessary to increase smoking cessation rates. Immunization against nicotine features a different mechanism of action than currently available medications. As a pharmacokinetic antagonist, immunization against nicotine alters distribution, metabolism, and clearance of nicotine to attenuate nicotine-induced behavior in animal models. Nicotine vaccines in clinical trials show efficacy but are limited by the modest and highly variable nicotine-specific antibody (NicAb) concentrations produced. This thesis focuses on ways to improve efficacy of a nicotine vaccine by combining it with additional forms of immunotherapy.;The first aim of this thesis examined the effects of supplementing vaccination against nicotine with individualized doses of Nic311, a nicotine-specific monoclonal antibody. Compared to either immunotherapy alone, combining active and passive immunization produced greater alterations in nicotine pharmacokinetics and nicotine-induced behavior using a locomotor activity model. Only small doses of Nic311 were necessary to supplement vaccine-generated NicAb concentrations to a previously effective threshold. This decreased cost and use of typically expensive monoclonal antibodies, potentially increasing viability of this approach in a clinical setting.;The second aim of this thesis examined the effects of concurrent administration of two immunologically distinct nicotine immunogens in a bivalent vaccine over a range of vaccine formulations and immunization conditions. Immunogens were co-administered in a bivalent vaccine without compromising immunogenicity of either immunogen when delivered subcutaneously in alum, but not when delivered intraperitoneally in Freund's adjuvant. When combined in alum, immune responses elicited by the two immunogens were largely independent of one another. This suggests that subjects who responded poorly to one immunogen may have responded better to the second, immunologically distinct immunogen in the bivalent vaccine. These results indicate that the bivalent vaccine strategy is a feasible way to increase antibody concentrations above what can be achieved using one immunogen alone, but integrity of the response is highly dependent on vaccine formulation and administration conditions. |
