nicotine vaccines 6 nicotine vaccines studied in animals 2 nicotine vaccines in phase i clinical...
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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
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.
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 onBrain Nicotine Concentration
1.5
1.0
50 150100
Brain Nicotine (ng/g)
Se
rum
An
tibo
dy
Co
nce
ntr
atio
n(E
LIS
A O
.D.)
Vaccine Effects on Nicotine Elimination
Ser
um N
icot
ine
(ng/
ml)
10
1
1000
100
0 121082 64
VaccineControl
Hours
Keyler D et al, Nicotine Tobacco Res 1999;1:241
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
Malin DH et al. Pharmacol Biochem Behav 2001;68:87
Ab
stin
en
ce S
ign
s (%
of p
re-t
reat
me
nt)
0
10
20
30
40
50
60
70
80
90
Control IgGSaline
Control IgGNicotine
Nicotine IgGNicotine
* *
Passive Immunization Attenuates Nicotine-Induced Relief of Nicotine Withdrawal
Vaccine Effects on the Acquisition of Nicotine Self-Administration
0.01 mg/kg/dose
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
0
25
50
75
Control
Immunized
FR 1 FR 2 FR 3
*
Session
Mea
n In
fusi
ons
Vaccination Attenuates the Reinstatement of Nicotine Responding
Lindblom et al. Resp 2002; 69:254
Control Vaccine
Antibody Response10 ug Immunogen x 4 in Smokers
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
2.2
2.4
2.6
2.8
3
0 2 4 6 8 10 12
Time (Weeks)
Ab
so
rban
ce a
t 492n
m o
f 1 in
270 d
ilu
tio
n
Weeks
Abs
orba
nce
0 2 4 6 8 10 12
St. Clair Roberts et al. CPDD 2002
Anti-Nicotine Antibody Level
0
100
200
300
400
500
600
700
800
900
1000
Injection 7 14 21 28 35 49 63
Days
Rec
ipro
cal E
nd
po
int
Dilu
tio
n
Lindmayer, K et al, European SRNT 2002
Antibody Titer after a Single Dose of Nicotine Conjugate Vaccine
Days
Rec
ipro
cal
En
dp
oi n
t D
ilu
t io
n
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
Control
0
2
4
10
8
6
baselin e 1 2 3 4 5
Day
Saline
Antibody
Passive Immunization Blocks Cocaine Self-Administration
Fox BS et al. Nature Medicine 1996;2:1129
Infu
sio
ns
per
hou
r
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
0
10
20
30
40
50
60
70
80
90
Control IgGSaline
Control IgGNicotine
Nicotine IgGNicotine
* *
Ab
sti
ne
nc
e S
ign
s (
% o
f p
re-t
rea
tmen
t)
Malin DH et al. Pharmacol Biochem Behav 2001;68:87
PASSIVE IMMUNIZATION ATTENUATES NICOTINE-INDUCED RELIEF
OF NICOTINE WITHDRAWAL
Effects of Antibody Titer onBrain Nicotine Concentration
1.5
1.0
50 150100
Brain Nicotine (ng/g)
EL
ISA
O.D
.
Nicotine VaccinesTargeting the Drug Rather Than the Brain
• Rationale• Mechanism of action• Animal data• Clinical trials• Practical points• Perspective• Future directions
Comparison of Vaccination Regimens
0.000
0.200
0.400
0.600
0.800
1.000
0 2 4 6 8 10 12
Time (Weeks)
Ab
so
rban
ce a
t 492n
m o
f 1 i
n 2
70 d
ilu
tio
n
4 x 10ug
4 x 50ug
4 x 50ug NS
4 x 50ug
5 x 50ug
4 x 50ug
0 2 4 6 8 10 12
Weeks
Abs
orba
nce
St. Clair Roberts et al. CPDD 2002
Passive Immunization Blocks Nicotine-Induced Increases in Locomotor Activity
Pentel et al. Pharmacol Biochem Behav 2000;65:191
Malin DH et al. Pharmacol Biochem Behav 2001;68:87
Passive Immunization Attenuates Nicotine-Induced Relief of Nicotine Withdrawal
Ab
sti
ne
nc
e S
ign
s (
% o
f p
re-t
rea
tmen
t)
0
10
20
30
40
50
60
70
80
90
Control IgGSaline
Control IgGNicotine
Nicotine IgGNicotine
* *