Nicotine Vaccines

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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

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Targeting the Drug Rather Than the Brain
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Blood
Brain

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Nicotine Immunogen Structure
Linker
Carrier Protein
Nicotine
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Nicotine Immunogen Structure
Linker
Carrier Protein
Nicotine

• Smokers dont have nicotine antibodies
• Smoking wont boost or maintain antibody titers
• Boosting requires administration of immunogen

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1-2 months
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Blood
Brain

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Vaccine Effects on Nicotine Distribution 1
Minute after Nicotine 0.1 mg/kg i.v.
Satoskar et al, CPDD 2000
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Vaccine Effects on Nicotine Distribution 1
Minute after Nicotine 0.1 mg/kg i.v.
Satoskar et al, CPDD 2000
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Vaccine Effects on Nicotine Distribution
Chronic Infusion 1 mg/kg/d Acute Dose 0.03 mg/kg


Hieda Y et al, Int J Immunopharmacol 200222809
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Effects of Antibody Titer onBrain Nicotine
Concentration
1.5
Serum Antibody Concentration (ELISA O.D.)
1.0
150
100
50
Brain Nicotine (ng/g)
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Vaccine Effects on Nicotine Elimination
Keyler D et al, Nicotine Tobacco Res 19991241
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Passive Immunization Blocks
Nicotine-Induced Increases in Blood Pressure
Pentel et al. Pharmacol Biochem Behav 200065191
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Passive Immunization Attenuates Nicotine
Discrimination
Malin et al. Life Sci 2002702793
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Passive Immunization Attenuates
Nicotine-Induced Relief of Nicotine Withdrawal
Malin DH et al. Pharmacol Biochem Behav 20016887
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Vaccine Effects on the Acquisition of Nicotine
Self-Administration0.01 mg/kg/dose
Mean Infusions
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Vaccination Attenuates the Reinstatement of
Nicotine Responding
Control
Vaccine
Lindblom et al. Resp 2002 69254
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Antibody Response10 ug Immunogen x 4 in Smokers
Absorbance
0
2
4
6
8
10
12
Weeks
St. Clair Roberts et al. CPDD 2002
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Antibody Titer after a Single Dose of Nicotine
Conjugate Vaccine
Reciprocal Endpoint Dilution
Days
Lindmayer, K et al, European SRNT 2002
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Cocaine Vaccine Persistence of Antibody Titers
Kosten et al. Vaccine 2002201196
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Perspective

• Uses
• Decrease reward cessation, relapse (direct
  nicotine effects)
• Not for craving or withdrawal (neuroadaptive
  processes)

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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

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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

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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

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Future Directions

• Mechanisms
• High drugantibody 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

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Passive Immunization Blocks Cocaine
Self-Administration
Infusions per hour
Fox BS et al. Nature Medicine 199621129
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VaccinesInfectious 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

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PASSIVE IMMUNIZATION ATTENUATES
NICOTINE-INDUCED RELIEF OF NICOTINE
WITHDRAWAL


Abstinence Signs ( of pre-treatment)
Malin DH et al. Pharmacol Biochem Behav 20016887
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Effects of Antibody Titer onBrain Nicotine
Concentration
1.5
ELISA O.D.
1.0
150
100
50
Brain Nicotine (ng/g)
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Nicotine VaccinesTargeting the Drug Rather Than
the Brain

• Rationale
• Mechanism of action
• Animal data
• Clinical trials
• Practical points
• Perspective
• Future directions

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Comparison of Vaccination Regimens
Absorbance
0
2
4
6
8
12
10
Weeks
St. Clair Roberts et al. CPDD 2002
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Passive Immunization Blocks
Nicotine-Induced Increases in Locomotor Activity
Pentel et al. Pharmacol Biochem Behav 200065191
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Passive Immunization Attenuates
Nicotine-Induced Relief of Nicotine Withdrawal
Malin DH et al. Pharmacol Biochem Behav 20016887