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New Vaccine Could Help Smokers Quit

Scripps researchers recognize importance of molecular ‘handed-ness’

According to a statement from the American Chemical Society, new research may help millions stick to a common resolution: quitting smoking. Researchers at the Scripps Institute in La Jolla, California, are working on a nicotine vaccine that could put an end to the addiction.

The approach of Kim Janda, PhD, and his colleagues is to get the body’s immune system to treat nicotine like a foreign invader. But getting the body to respond in the right way is a big challenge.

When a promising nicotine vaccine failed in clinical trials a few years ago, Janda and his team pressed on. Now they have designed a more effective nicotine vaccine and have proven that the structures of molecules used in vaccines is critical. Their findings were published in the Journal of Medicinal Chemistry.

According to the National Cancer Institute, smoking is the leading cause of eight types of cancer, including lung cancer and fast-moving pancreatic cancer.

Nicotine vaccines train the body to see nicotine as a foreign invader. To prompt this immune response, scientists have tried attaching nicotine derivatives, called haptens, to a larger carrier protein used in other approved vaccines.

The body reacts to the vaccine by creating antibodies to bind specifically to nicotine molecules. When a person later uses tobacco, the anti-nicotine antibodies stop the nicotine molecules from entering the central nervous system and reaching the brain.

Although a vaccine wouldn’t be a “silver bullet” — there would still be withdrawal symptoms — a person may be less motivated to relapse because the brain’s reward system could no longer react to nicotine, Janda said.

The problem with the previous nicotine vaccine, which worked in only 30% of subjects, was that it did not target the most common form of nicotine for attack. Nicotine has two forms that look like mirror images of each other; one is a “right-handed” version, and the other is a “left-handed” version. Even though 99% of the nicotine found in tobacco is the left-handed version, the previous vaccine elicited antibodies against both.

Janda believes that was a waste of the immune response. “This is a case where something very simple was overlooked,” he said.

In the new study, the researchers elicited a stronger antibody response by creating a vaccine from only left-handed nicotine haptens. To do this, they prepared haptens as a 50/50 mixture and as pure right-handed or pure left-handed versions of nicotine, so that they could use the two versions together or separately.

They tested both versions and the 50/50 mix in rats, injecting the animals three times over 42 days. This series of “booster” shots gave the animals’ immune systems a chance to create an effective number of antibodies to respond to nicotine.

The researchers analyzed blood from the three experimental groups and found that the left-handed hapten elicited a much more effective immune response. Compared with the right-handed hapten vaccine, the left-handed hapten vaccine prompted the body to create four times as many antibodies against left-handed nicotine molecules. The 50/50 mix was only 60% as effective as the pure left-handed version.

“This shows that future vaccines should target that left-handed version,” said Dr. Jonathan Lockner, the paper’s lead author. “There might even be more-effective haptens out there.”

The researchers believe that purifying nicotine hapten mixtures is an important and practical step in creating future nicotine vaccines. Janda said considering a molecule’s “handed-ness” is also critical for developing vaccines against other drugs of abuse, such as cocaine and heroin.

“This is just one area where we are looking outside the box to try to treat addiction,” Janda commented.

Sources: ACS; January 21, 2015; Scripps Research Institute; January 12, 2015; and Journal of Medicinal Chemistry; December 10, 2014.

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