The aim of this proposal is to study mechanism-based strategies for enhancing the efficacy of vaccination for the treatment of nicotine dependence in rats. Vaccination of rats against nicotine binds and sequesters nicotine in serum, reduces nicotine distribution to brain, and blocks or attenuates a variety of nicotine-induced behaviors that are relevant to nicotine dependence. These results suggest that vaccination may be useful in the treatment or prevention of nicotine dependence, and a phase I clinical trial has been initiated. However, there are potential limitations to vaccine efficacy, and some effects of vaccination are incomplete. This may be due to the finite amount of antibody that can be elicited by vaccination (and the variability in response among subjects), inability to control the affinity of antibodies elicited by vaccination, or the spectrum of action of vaccination which may target some aspects of nicotine dependence (e.g. reinforcement) better than others (e.g. ongoing withdrawal). This study will examine two general approaches to enhancing the efficacy of immunization; (a) the use of passive immunization with monoclonal nicotine-specific antibodies to investigate the relationship of affinity and dose to efficacy, and to determine whether passive immunization (administration of exogenous antibody) may have therapeutic application of its own as an alternative or supplement to vaccination, and (b) combining vaccination with other interventions that act via complementary mechanisms. Specific hypotheses to be tested are that 1) The efficacy of immunization can be enhanced by optimizing antibody affinity for nicotine, 2) Efficacy can be enhanced by using passive immunization to provide higher doses of antibody than can be achieved with vaccination, 3) Passive immunization with therapeutically effective antibody doses is well tolerated, 4) Vaccine efficacy can be enhanced by combining it with the nicotinic receptor antagonist mecamylamine, or nicotine infusion (simulating nicotine replacement therapy), and 5) Efficacy can be enhanced by combining vaccination with passive immunization, a strategy that could exploit the potential clinical advantages of each. These questions will be studied using a variety of pharmacokinetic and behavioral models including nicotine distribution to brain after acute and chronic nicotine dosing, nicotine self-administration, reinstatement of nicotine responding, nicotine abstinence, and relief of nicotine abstinence by nicotine. These data will expand our understanding of the mechanisms, limitations and clinical potential of both vaccination and passive immunization for the treatment or prevention of nicotine dependence.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Patel, Amrat
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Minneapolis Medical Research Fdn, Inc.
United States
Zip Code
De Biasi, M; McLaughlin, I; Perez, E E et al. (2014) Scientific overview: 2013 BBC plenary symposium on tobacco addiction. Drug Alcohol Depend 141:107-17
Pentel, Paul R; LeSage, Mark G (2014) New directions in nicotine vaccine design and use. Adv Pharmacol 69:553-80
Cornish, Katherine E; de Villiers, Sabina H L; Pravetoni, Marco et al. (2013) Immunogenicity of individual vaccine components in a bivalent nicotine vaccine differ according to vaccine formulation and administration conditions. PLoS One 8:e82557
de Villiers, Sabina H L; Cornish, Katherine E; Troska, Andrew J et al. (2013) Increased efficacy of a trivalent nicotine vaccine compared to a dose-matched monovalent vaccine when formulated with alum. Vaccine 31:6185-93
Chen, Xinyuan; Pravetoni, Marco; Bhayana, Brijesh et al. (2012) High immunogenicity of nicotine vaccines obtained by intradermal delivery with safe adjuvants. Vaccine 31:159-64
LeSage, Mark G; Shelley, David; Pravetoni, Marco et al. (2012) Enhanced attenuation of nicotine discrimination in rats by combining nicotine-specific antibodies with a nicotinic receptor antagonist. Pharmacol Biochem Behav 102:157-62
Pravetoni, M; Keyler, D E; Pidaparthi, R R et al. (2012) Structurally distinct nicotine immunogens elicit antibodies with non-overlapping specificities. Biochem Pharmacol 83:543-50
Pravetoni, M; Keyler, D E; Raleigh, M D et al. (2011) Vaccination against nicotine alters the distribution of nicotine delivered via cigarette smoke inhalation to rats. Biochem Pharmacol 81:1164-70
Cornish, Katherine E; Harris, Andrew C; LeSage, Mark G et al. (2011) Combined active and passive immunization against nicotine: minimizing monoclonal antibody requirements using a target antibody concentration strategy. Int Immunopharmacol 11:1809-15
Harris, Andrew C; Mattson, Christina; Lesage, Mark G et al. (2010) Comparison of the behavioral effects of cigarette smoke and pure nicotine in rats. Pharmacol Biochem Behav 96:217-27

Showing the most recent 10 out of 33 publications