# Presentation: 687381

## 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

## Targeting the Drug Rather Than the Brain

## Blood

- +

- Brain

## Nicotine Immunogen Structure

**Carrier Protein**

**Linker**

**Nicotine**

## 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

## 1-2 months

## Blood

- +

- Brain

## Vaccine Effects on Nicotine Distribution    1 Minute after Nicotine 0.1 mg/kg i.v.

- Satoskar et al, CPDD 2000

## Vaccine Effects on Nicotine Distribution    1 Minute after Nicotine 0.1 mg/kg i.v.

- Vaccine Effects on Nicotine Distribution    1 Minute after Nicotine 0.1 mg/kg i.v.

- Satoskar et al, CPDD 2000

## *

*****

*****

- 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

## Effects of Antibody Titer onBrain Nicotine Concentration

**1.5**

**1.0**

**50**

**150**

**100**

- Brain Nicotine (ng/g)

- Serum Antibody Concentration
- (ELISA O.D.)

## Vaccine Effects on Nicotine Elimination

- Keyler D et al, Nicotine Tobacco Res 1999;1:241

##    Passive Immunization Blocks                      Nicotine-Induced Increases in Blood Pressure  

**   **Passive Immunization Blocks                      Nicotine-Induced Increases in Blood Pressure**  **

- Pentel et al. Pharmacol Biochem Behav 2000;65:191

##    Passive Immunization Attenuates Nicotine Discrimination  

- Malin et al. Life Sci 2002;70:2793

##    Passive Immunization Attenuates Nicotine-Induced Relief of Nicotine Withdrawal

**   **Passive Immunization Attenuates Nicotine-Induced Relief of Nicotine Withdrawal

## Vaccine Effects on the Acquisition of Nicotine Self-Administration0.01 mg/kg/dose

- Mean Infusions

##    Vaccination Attenuates the Reinstatement of Nicotine Responding  

**   **Vaccination Attenuates the Reinstatement of Nicotine Responding**  **

- Lindblom et al. Resp 2002; 69:254

** **Control

- Vaccine

## Antibody Response10 ug Immunogen x 4 in Smokers 

- Weeks

**    **Absorbance

**0**

**2**

**4**

**     ****6**

**8**

**10**

**12**

- St. Clair Roberts et al. CPDD 2002

## Antibody Titer after a Single Dose of Nicotine Conjugate Vaccine

- Lindmayer, K et al, European SRNT 2002

**Days**

**Reciprocal Endpoint Dilution**

##    Cocaine Vaccine Persistence of Antibody Titers

**   **Cocaine Vaccine Persistence of Antibody Titers

- Kosten et al. Vaccine 2002;20:1196

## Perspective

-   Uses
- Decrease reward: cessation, _relapse_ (direct nicotine effects)
- Not for craving or withdrawal (neuroadaptive processes)

## 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

## 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

## 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

## 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

## Slide 26

## Slide 27

## Passive Immunization Blocks Cocaine Self-Administration

- Fox BS et al.  Nature Medicine 1996;2:1129

- Infusions per hour

## Slide 29

## 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

## *

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**Abstinence Signs (% of pre-treatment)**

- Malin DH et al. Pharmacol Biochem Behav 2001;68:87

**   ****PASSIVE IMMUNIZATION ATTENUATES                     NICOTINE-INDUCED RELIEF OF NICOTINE WITHDRAWAL  **

## Effects of Antibody Titer onBrain Nicotine Concentration

**1.5**

**1.0**

**50**

**150**

**100**

- Brain Nicotine (ng/g)

- ELISA O.D.

## Nicotine VaccinesTargeting the Drug Rather Than the Brain

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

## Comparison of Vaccination Regimens

**0**

**2**

**4**

**      ****6**

**8**

**10**

**12**

- Weeks

**    **Absorbance

- St. Clair Roberts et al. CPDD 2002

##    Passive Immunization Blocks                    Nicotine-Induced Increases in Locomotor Activity  

**   **Passive Immunization Blocks                    Nicotine-Induced Increases in Locomotor Activity**  **

- Pentel et al. Pharmacol Biochem Behav 2000;65:191

##    Passive Immunization Attenuates Nicotine-Induced Relief of Nicotine Withdrawal

**   **Passive Immunization Attenuates Nicotine-Induced Relief of Nicotine Withdrawal