1. Nicotine Vaccines 6 Nicotine vaccines studied in animals 2 Nicotine vaccines in Phase I clinical trials Other vaccines –Cocaine: phase II clinical trial –Phencyclidine –Methamphetamine

2. Targeting the Drug Rather Than the Brain

3. + Blood Brain

4. Nicotine Immunogen Structure Carrier Protein Linker Nicotine

5. Nicotine Immunogen Structure Carrier Protein Linker Nicotine Smokers don’t have nicotine antibodies Smoking won’t boost or maintain antibody titers Boosting requires administration of immunogen

6. 1-2 months

7. + Blood Brain

8. Vaccine Effects on Nicotine Distribution 1 Minute after Nicotine 0.1 mg/kg i.v. Satoskar et al, CPDD 2000

9. Vaccine Effects on Nicotine Distribution 1 Minute after Nicotine 0.1 mg/kg i.v. Satoskar et al, CPDD 2000

10. * * Vaccine Effects on Nicotine Distribution Chronic Infusion 1 mg/kg/d + Acute Dose 0.03 mg/kg Hieda Y et al, Int J Immunopharmacol 2002;22:809

11. Effects of Antibody Titer on Brain Nicotine Concentration 1.5 1.0 50 150100 Brain Nicotine (ng/g) Serum Antibody Concentration (ELISA O.D.)

12. Vaccine Effects on Nicotine Elimination Serum Nicotine (ng/ml) 10 1 1000 100 012108264 Vaccine Control Hours Keyler D et al, Nicotine Tobacco Res 1999;1:241

13. Passive Immunization Blocks Nicotine-Induced Increases in Blood Pressure Pentel et al. Pharmacol Biochem Behav 2000;65:191

14. Passive Immunization Attenuates Nicotine Discrimination Malin et al. Life Sci 2002;70:2793

15. Malin DH et al. Pharmacol Biochem Behav 2001;68:87 Abstinence Signs (% of pre-treatment) 0 10 20 30 40 50 60 70 80 90 Control IgG Saline Control IgG Nicotine Nicotine IgG Nicotine * * Passive Immunization Attenuates Nicotine-Induced Relief of Nicotine Withdrawal

16. Vaccine Effects on the Acquisition of Nicotine Self-Administration 0.01 mg/kg/dose Mean Infusions

17. Vaccination Attenuates the Reinstatement of Nicotine Responding Lindblom et al. Resp 2002; 69:254 ControlVaccine

18. Antibody Response 10 ug Immunogen x 4 in Smokers Weeks Absorbance 0 24 681012 St. Clair Roberts et al. CPDD 2002

19. Lindmayer, K et al, European SRNT 2002 Antibody Titer after a Single Dose of Nicotine Conjugate Vaccine Days Reciprocal Endpoint Dilution

20. Cocaine Vaccine Persistence of Antibody Titers Kosten et al. Vaccine 2002;20:1196

21. Perspective Uses –Decrease reward: cessation, relapse (direct nicotine effects) –Not for craving or withdrawal (neuroadaptive processes)

22. Perspective Uses –Decrease reward: cessation, relapse (direct nicotine effects) –Not for craving or withdrawal (neuroadaptive processes) Attractive features –Infrequent dosing, long duration  compliance –Novel mechanism: combine with other medications –Safety/side effects

23. Perspective Uses –Decrease reward: cessation, relapse (direct nicotine effects) –Not for craving or withdrawal (neuroadaptive processes) Attractive features –Infrequent dosing, long duration  compliance –Novel mechanism: combine with other medications –Safety/side effects Limitations –Need high titers of antibody –Individual variability –Slow onset –Compensation

24. Perspective Uses –Decrease reward: cessation, relapse (direct nicotine effects) –Not for craving or withdrawal (neuroadaptive processes) Attractive features –Infrequent dosing, long duration  compliance –Novel mechanism: combine with other medications –Safety/side effects Limitations –Need high titers of antibody –Individual variability  Passive Immunization –Slow onset –Compensation

25. Future Directions Mechanisms –High drug:antibody ratio, role of  nicotine elimination Maximizing antibody titers –Carrier protein, adjuvants, schedules Vaccination v. passive immunization –Complementary roles Combinations of therapies –Medications, counseling Safety –Pregnancy

28. Passive Immunization Blocks Cocaine Self-Administration Fox BS et al. Nature Medicine 1996;2:1129 Infusions per hour

30. Vaccines Infectious Diseases v. Drug Dependence Infectious diseases –Bind pathogen  immune response  kill pathogen –Effects: often complete, long-lasting protection Drug dependence –Bind drug  alter pharmacokinetics  attenuate drug effect –Effects: dose-related, partial, selective, duration of months –Actions resemble a medication more than a vaccine

31. * * Abstinence Signs (% of pre-treatment) Malin DH et al. Pharmacol Biochem Behav 2001;68:87 PASSIVE IMMUNIZATION ATTENUATES NICOTINE-INDUCED RELIEF OF NICOTINE WITHDRAWAL

32. Effects of Antibody Titer on Brain Nicotine Concentration 1.5 1.0 50 150100 Brain Nicotine (ng/g) ELISA O.D.

33. Nicotine Vaccines Targeting the Drug Rather Than the Brain Rationale Mechanism of action Animal data Clinical trials Practical points Perspective Future directions

34. Comparison of Vaccination Regimens 0 24 68 10 12 Weeks Absorbance St. Clair Roberts et al. CPDD 2002

35. Passive Immunization Blocks Nicotine-Induced Increases in Locomotor Activity Pentel et al. Pharmacol Biochem Behav 2000;65:191

36. Malin DH et al. Pharmacol Biochem Behav 2001;68:87 Passive Immunization Attenuates Nicotine-Induced Relief of Nicotine Withdrawal Abstinence Signs (% of pre-treatment) 0 10 20 30 40 50 60 70 80 90 Control IgG Saline Control IgG Nicotine Nicotine IgG Nicotine * *