Nicotine Vaccine: A Promising Treatment for Nicotine Addiction

Director
Transdisciplinary Tobacco Use Research Center
University of Minnesota
Minneapolis, MN

Lung cancer remains the leading cause of cancer-related death in the US, a total greater than for the other five leading cancers combined. Most lung cancer cases are smoking related, and while the numbers of smokers in the US are declining, approximately 45 million Americans continue to smoke.

Although efforts to increase the success of smoking cessation initiatives continue, it remains difficult for many individuals to relinquish their dependence on nicotine products. With this in mind, researchers are turning to novel approaches to aid smokers in their attempts to quit. One intriguing avenue of exploration is the development of a nicotine vaccine.

Nicotine immunization is a novel treatment that targets the drug rather than the brain. The nicotine vaccine stimulates the immune system to develop antibodies that bind with the nicotine molecule, forming a complex that is too large to pass through the blood-brain barrier. It is thought that the vaccine is successful because of the reduced amount of nicotine entering the brain as well as its slow delivery to the brain. Vaccinated smokers do not experience the sudden "rush" of nicotine associated with pleasurable effects. This process potentially reduces the addiction to nicotine. The vaccine under study has few side effects on the central nervous system because the antibody itself is targeted specifically for nicotine and does not alter any functions of the brain.

Animal studies have demonstrated that these vaccines reduce nicotine brain distribution in clinically relevant acute and chronic nicotine doses. They also have shown a slowing and attenuation of early nicotine distribution to the brain as well as a slowing of nicotine elimination. These effects lead to less reinforcement from smoking. Nicotine vaccination in rats (or passive immunization with nicotine-specific antibody to simulate vaccination) results in decreased nicotine discrimination, development of nicotine dependence, reversal of nicotine abstinence signs by nicotine, reinstatement of nicotine responding, and acquisition of nicotine self-administration. All of these findings form the basis for the hypothesis that immunization can impact nicotine drug effects, including those responsible for maintaining nicotine addiction.

In recent years, preliminary human studies have been conducted to determine the safety of the nicotine vaccine, the vaccine dose necessary to yield sufficient antibody titers, and the scheduling of doses to yield maximum boost in antibody titers. Our multisite (University of Minnesota, University of Nebraska, and University of Wisconsin) clinical trial randomly assigned smokers who were not necessarily interested in quitting to receive either 50, 100, or 200 µg of vaccine or placebo and "booster shots" one, two, and six months later. After 38 weeks of follow-up, the vaccine was found to be well-tolerated. Although almost all of the participants reported at least one reaction, these were minor and consisted mainly of headache, malaise, or myalgia. These resolved within a few days, and none required medical intervention. The most commonly reported side effect was ache and tenderness near the injection site. Antibody levels were found to be low after the first dose, and increased after subsequent doses. Maximum levels were reached at 8--16 weeks and thereafter declined when no further injections were given. The rate of 30-day abstinence was significantly different across 4 doses and the 200-µg dose was associated with the highest rate of abstinence. An intriguing finding was that although this study was not designed to test the treatment effect, 38% of the participants in the high-dose vaccine group were able to quit smoking for at least 30 days. This was an impressive and completely unexpected finding because helping smokers to quit was not an aim of this study. In fact, in order to participate, smokers had to attest that they did not have a planned quit date for the next 30 days.

No differences were noted in withdrawal symptoms between participants who received the vaccine and those who got the placebo and no precipitation of withdrawal was observed. No compensatory smoking behavior was noted; i.e., vaccinated participants did not puff harder on cigarettes or smoked more cigarettes to make up for the lower levels of nicotine delivered to the brain.

Two additional phase I/II clinical studies have been conducted by others using similar vaccines that showed comparable safety profiles and high abstinence rates in the highest nicotine dose or antibody level groups. Because the vaccine targets nicotine itself and doesn't affect brain function, there are fewer side effects, and because of the way it is delivered, compliance may be better than current nicotine patches or chewing gums. Rather than daily medication, a periodic booster would be all that is necessary to help smokers quit their nicotine addiction. Although not a miracle drug, it does have potential to help decrease some smokers' dependence on nicotine. This type of vaccine will not address all the features of tobacco addiction; it is best suited to reducing the immediate effects of nicotine, but will not reduce withdrawal or craving, and other measures or medications may be needed to take full advantage of the vaccine. If successful, a vaccine would be just one tool among many available to smokers who wish to quit. Smoking is more than a response to nicotine--there are also behavioral components, and there must be behavioral components to any treatment.

In summary, the nicotine vaccine appears to be a promising intervention for tobacco dependence, as a complement to other treatments or as a relapse prevention aid. More research is required because other questions about the vaccine need to be answered, such as whether higher antibody levels can be sustained for longer periods, how long the effectiveness of the vaccine will last for a smoker, and whether the vaccine can be used to successfully prevent people who quit smoking from relapsing and starting to smoke again.

References

1. Hatsukami D, Rennard S, Jorenby D, et al. Safety and immunogenicity of a nicotine conjugate vaccine in current smokers. Clinical Pharmacology and Therapeutics. 2005;78: 456-467.
2. Keyler D, Hieda Y, St. Peter J, et al. Altered disposition of repeated nicotine doses in rats immunized against nicotine. Nicotine & Tobacco Research. 1999;1:241-249.
3. Lesage MG, Keyler DE, Hieda Y, et al. Effects of a nicotine conjugate vaccine on the acquisition and maintenance of nicotine self-administration in rats. Psychopharmacology (Berl). 2002;184:409-416.
4. Lindblom N, de Villiers SH, Kalayanov G, et al. Active immunization against nicotine prevents reinstatement of nicotine-seeking behavior in rats. Respiration. 2002;69:254-260.
5. Malin D. Passive immunization against nicotine attenuates dependence as measured by mecamylamine-precipitated withdrawal. Society for Research on Nicotine and Tobacco 8th Annual Meeting. Savannah, Georgia, February 20-23, 2002.
6. Malin D, Alvarado CL, Woodhouse KS, et al. Passive immunization against nicotine attenuates nicotine discrimination. Life Sciences. 2002;70:2793-2798.
7. Malin D, Lake J, Lin A, et al Passive immunization against nicotine prevents nicotine alleviation of nicotine abstinence syndrome. Pharmacology Biochemistry & Behavior. 2001;68:87-92.
8. Pentel PR, Keyler DE. Vaccines to treat drug addiction. In M. M. Levine (Ed.), New Generation Vaccines (pp. 1057-1066). New York: Dekker. 2004.
9. Satoskar SD, Keyler DE, Le Sage MG, et al. Tissue-dependent effects of immunization with a nicotine conjugate vaccine on the distribution of nicotine in rats. International Immunopharmacology. 2003;3:957-970.