May 21, 2003 Scientists at The Scripps Research Institute (TSRI) have designed a new way to make vaccines against drugs of abuse that could become a valuable tool for treating addiction by helping the body clear the drug from the bloodstream. The latest vaccine they created using this approach induces the body to clear nicotine.
"These new vaccines greatly suppress the reinforcing aspects of the drug," says principal investigator Kim D. Janda, Ph.D. "Blocking it before it gets to the brain--that's the key."
The structure and design of the nicotine vaccine are described in an article that will be published in an upcoming issue of the Journal of the American Chemical Society. Research Associate Michael M. Meijler, Ph.D., who is the article's lead author, synthesized this vaccine under the guidance of Janda, who holds the Ely R. Callaway, Jr. Chair in Chemistry and is an investigator in The Skaggs Institute for Chemical Biology at TSRI.
Having shown the vaccine's effectiveness in laboratory models, Meijler and Janda have now reformulated the vaccine for investigation for use in human trials. Eventually, this sort of vaccine would be given to people undergoing smoking cessation programs to aid in their recovery.
Many believe that people continue to smoke because tobacco contains nicotine, which is an addictive chemical. Many smoking cessation strategies, in fact, provide cigarette addicts with nicotine from sources other than tobacco--such as patches or gum.
Janda and his laboratory, however, have taken an "immunopharmacotherapy" approach. That is, they have designed a drug that stimulates the immune system to clear the nicotine from the system. They based this work on previous successes Janda had in developing a vaccine for another addictive drug--cocaine--which is currently in clinical trials.
The new idea that they have developed is to take a chemical that resembles nicotine and use it to induce an active immune response. In this immune response, the body produces antibodies against nicotine that can neutralize it in the bloodstream. If a smoker later smokes a cigarette, the antibodies will clear the nicotine from the system before it reaches the brain.
Developing a nicotine vaccine proved difficult. At first, Janda and his colleagues were not able to induce an effective immune response as they had previously with cocaine. Then Janda and Meijler realized that the difference could be that cocaine is a relatively inflexible molecule where nicotine has a flexible axis that allows it to adopt multiple shapes.
Janda and Meijler had been designing a vaccine that was equally flexible, and so they decided to make one that was rigid and resembled only one form of nicotine.
"These [induced] antibodies make a much more focused immune response," says Meijler. In fact, he adds, the vaccine is better because it induced a larger antibody response and the antibodies themselves bound more tightly (with higher affinity) to the nicotine.
Furthermore, adds Janda, "This could be a general method for vaccine development for drugs of abuse--period."
The research article "A New Strategy for Improved Vaccines Using Conformationally Constrained Haptens" is authored by Michael M. Meijler, Masayuki Matsushita, Lawrence J. Altobell, III, Peter Wirsching, and Kim D. Janda and will appear in the June 18, 2003 issue of the Journal of the American Chemical Society. The research was funded by The Skaggs Institute for Research.
Supporting Material: Statistics on Smoking and Public Health Smoking is a major health problem in the United States, and hundreds of thousands of Americans die each year from smoking-related lung cancer, ischemic heart disease, and chronic airway obstruction.
Although the percentage of U.S. residents who smoke has declined steadily in the United States since the mid-1960s, about 22.8 percent of the total adult population still smokes, according to the U.S. Centers for Disease Control and Prevention (CDC). San Diego and Orange County are two of the five metropolitan areas with the nation's lowest smoking rates. The San Diego regional rate was 15.2 percent.
Nevertheless, smoking-related cancer is still a great cause for concern in Southern California and in the rest of the nation. In a 2002 report, the CDC estimated that from 1995 to 1999, smoking killed more than 440,000 people in the United States each year and caused more than $150 billion in annual health-related economic losses.
### For supporting statistics on tobacco use and related mortality, please see: A 2001 report from the CDC: "Cigarette Smoking in 99 Metropolitan Areas--United States, 2000," MMWR 50(49); December 14, 2001. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5049a3.htm.
A 2002 report from the CDC: "Annual Smoking-Attributable Mortality, Years of Potential Life Lost, and Economic Costs--United States, 19951999," MMWR 51(14) April 12, 2002. http://www.cdc.gov/tobacco/research_data/economics/mmwr5114.highlights.htm.
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