Vice Vaccines
Scientists give a shot in the arm to the fight against smoking, drug abuse, and obesity
When Rachel Harrison was 16 years old, she took a drag from her first cigarette. She remembers loving it right away—the taste, the warmth, and especially the lightheaded rush that smoking gave her. Like a bad character in an after-school special, she chain-smoked an entire pack that first time while hanging out with other smokers from the popular crowd.
“I know it sounds cliché, but I started smoking because all the cool kids were doing it,” says Harrison, now 32.
From high school through college, and now in her job as a public relations professional in New York, Harrison has kept up the habit. Nowadays, she paces her smoking to three or four cigarettes each workday. The weekends are a “free-for-all,” she says, when she goes through often more than a pack a day.
But even though some part of her still loves each smoke as much as her first one, Harrison says, she longs to escape cigarettes’ fiery grip. In her quest to avoid the bad breath, wrinkles, and cancer that smoking can bring, she guesses that she’s tried to quit about 30 times in the past 15 years. But no matter which method she’s used—nicotine gum, the patch, or just quitting cold turkey—she’s never succeeded.
“I come back to it usually because a friend will be smoking and I’ll ask for a drag,” Harrison says. “That first drag will taste so disgusting, but for some reason, literally an hour later I’m asking for a full cigarette, then buying a new pack.”
Soon, Harrison and other people plagued by some of Western societies’ hardest-to-kick habits may literally get a shot in the arm: vaccines to help them quit. Vaccinations have long had a starring role in preventing a variety of diseases. But now, researchers are aiming the needle at a new set of targets—smoking, obesity, and illicit drugs. These vaccines, currently in development, could give people a novel way to boost their health and vanquish their vices.
Smoke out
Vaccines have been doing their part to eradicate disease since the 18th century, typically by jump-starting the immune system to fight infectious bacteria and viruses such as those that cause the flu, cholera, or tetanus. But in 1974, narcotics researcher C. Robert Schuster, then at the University of Chicago, and his colleagues published the first evidence that vaccines could rev up the immune system against a different type of target—heroin. In a twist on their typical preventive role, these vaccines stop substances from satisfying an already-addicted user’s cravings.
Normally, the immune system doesn’t recognize heroin and other drugs as foes worthy of attack. That’s because drug molecules are significantly smaller than the foreign proteins on bacteria and viruses that trigger the body to defend itself, says immunologist Michael Owens of the University of Arkansas for Medical Sciences in Little Rock.
“In general, the cutoff in size for the immune system to recognize something as foreign will be about 10,000 daltons in weight. Most drugs of abuse are less than 500 [daltons],” he says. One dalton is about the weight of a single hydrogen atom.
To get the immune system fired up to fight heroin, Schuster and his team decided to make a vaccine by attaching heroin molecules to something that reliably triggers a response in healthy people and other animals. They used a protein from cows’ blood. When the immune system senses the large, foreign protein with drug molecules piggybacked onto them, it pumps out a variety of antibodies, explains Owen. Some antibodies recognize pieces of the protein, but others home in on the drug.
“The small drug molecules are just along for the ride,” adds vaccine researcher Kim Janda of the Scripps Research Institute in La Jolla, Calif., but the immune system generates antibodies against them nonetheless.
After Schuster’s team gave the vaccine to heroin-addicted rhesus monkeys that could self-administer the drug by pushing a lever, the animals did so significantly less often than they had previously. The researchers hypothesized that the vaccine somehow prevented the monkeys from getting high, taking away their incentive to keep using the drug.
However, notes Owens, the idea of vaccinating against illegal drugs didn’t immediately catch on. Methadone, a drug that satisfies heroin’s cravings without causing a high, was already in use in the 1970s for treating heroin addiction, and Schuster’s team wasn’t seeing as strong an effect with its vaccine.
Over the next few decades, however, researchers began to see the value of Schuster’s approach for treating other types of addiction. For example, vaccines to help smokers such as Harrison quit are now advancing through clinical trials.
One of these vaccines, called NicVax and manufactured by Nabi Biopharmaceuticals in Boca Raton, Fla., works by attaching multiple nicotine molecules to a protein taken from Pseudomonas aeruginosa, a species of bacteria that occasionally infects people.
When a smoker lights up and draws the addictive drug into his or her bloodstream, antibodies glom on to individual nicotine molecules, explains Nabi scientist Henrik Rasmussen. As a result, the formerly tiny molecules morph into clumps made of nicotine and antibodies. Those clusters are far too big to cross the blood-brain barrier and stimulate the brain’s feel-good centers, an action that normally cements nicotine’s addictive power.
Smokers still experience the typical array of withdrawal symptoms, including cravings for cigarettes. But after learning that cigarettes are no longer satisfying, Rasmussen notes, people find that their cravings quickly decline.
“People can still smoke, but they don’t get the rush, they don’t feel good, and they don’t keep the addiction. You take away the reason they smoke,” he says.
After the promising results in animals, Nabi scientists began a series of clinical trials 4 years ago to test whether NicVax is safe and effective in people. In 2005, the company released its latest results. Sixty-four smokers who were all interested in quitting participated in that trial. Some of them received various doses of the vaccine, delivered in a series of injections over 6 weeks. Others got a series of placebo shots.
Only 9 percent of the placebo group successfully laid off cigarettes for 30 days—a standard criterion that the U. S. Food and Drug Administration uses to define smoking cessation. However, of those smokers who got the highest vaccine dose, 33 percent passed the 30-day test of success. Moreover, even smokers who got the vaccine but didn’t quit smoking, lit up significantly fewer cigarettes after the trial than smokers who got the placebo did.
Nabi is currently performing a similar trial with 300 smokers at nine sites across the country. The company expects to announce the results of this larger study in April or May, says spokesperson Tom Rathjen.
With the market hot for new smoking-cessation products, Nabi has some competition. Two other companies—Cytos Biotechnology of Zurich and Celtic Pharma of Hamilton, Bermuda—are developing their own versions of nicotine vaccines. Celtic is also working toward a vaccine based on similar technology to fight cocaine addiction. All these vaccines are currently going through clinical trials.
Weighing in
If these vaccines eventually head to the market, they’ll be welcomed by addicted people, who currently have few effective treatment options, says vaccine researcher Janda. He and his team saw a similar possibility for people struggling against obesity.
“Success has been limited with obesity, [the] same as with treating addiction to drugs of abuse. We thought we could take a similar tack” by developing an antiobesity vaccine, Janda says. In the Aug. 29, 2006 Proceedings of the National Academy of Sciences, Janda and his colleagues published a proof-of-principle study showing that a vaccine they’d developed can prevent weight gain in rats.
To produce their antiobesity vaccine, the researchers needed a molecule on which to focus the immune system’s antibodies, like the nicotine or cocaine molecules targeted by vaccines against those addictions. But obesity is a complex phenomenon spurred by hundreds of different molecules in the body. Eventually, Janda’s team settled on ghrelin, a hormone that spikes hunger, slows metabolism, encourages fat storage, and shifts food preferences toward diets rich in fat.
The scientists created molecules that mimic the structure of different forms of ghrelin. By attaching each one to a larger carrier protein, the team created three different vaccines. The researchers then vaccinated groups of rats with one of the vaccines or a placebo.
Janda’s group found that rats vaccinated against either of two forms of the hormone called ghrelin 1 and ghrelin 3 gained significantly less weight and had less body fat over the next several months than did rats vaccinated with the placebo, even though all the animals ate the same amount of chow.
Nevertheless, the vaccine has far to go before it is shown to be effective in people, Janda says. For example, lab rats that received the vaccine ate healthy, low-fat diets. Now, Janda and his team plan on testing whether immunizing against ghrelin is still effective for animals that eat high-fat food more typical of a Western diet.
“I’m not saying this is a magic bullet, but this could eventually be used as a crutch” to help people lose weight, says Janda. He notes that a combination of vaccines against ghrelin and other weight-loss drugs currently on the market might someday be used to boost people’s chances of success.
Passive aggression
Vaccines such as those in the works for nicotine and obesity take advantage of a natural tendency of the immune system: the antibodies that it pumps out when stimulated can linger in the body and work a long time.
However, these vaccines also have their disadvantages, says Owens. It can take weeks or months for an antibody to reach an effective concentration in the blood, so a patient’s response to these treatments would be delayed. Furthermore, long-lasting antibodies aren’t always desirable. For example, in the case of the antiobesity vaccine, doctors would need to end patients’ treatments once they reached their target weight, rather than have patients continue to drop pounds.
With that in mind, Owens, Janda, and other researchers are crafting vaccines that work in a different way. Rather than prompting the body to create its own antibodies, these passive vaccines consist of custom-made antibodies to be pumped directly into a patient’s bloodstream. They’d go to work right away against a habit-driving substance but then degrade and be cleared from the circulation in a few weeks, says Owens.
Janda’s team is planning to develop a passive version of its antighrelin vaccine, while Owens and his colleagues have such vaccines in the works against a variety of addictive drugs, such as phencyclidine (PCP), methamphetamine, and cocaine. Each of these vaccines has had some success in limiting the amounts of drugs that addicted lab animals choose to self-administer.
Such vaccines could be expensive in quantities suited to people, notes Janda. The versions being tested are monoclonal antibodies, which are crafted to recognize a single target, such as one type of drug molecule. Until recently, researchers assumed that at least one antibody molecule was needed to neutralize each drug molecule. With some drug addicts using many grams of a drug at a time, Owens estimates that such an approach could cost tens of thousands of dollars for a month of treatment.
In 2003, however, he and his team discovered that a heavy dose isn’t always necessary. After tweaking the molecular structure of a PCP vaccine that they’d developed, the researchers reported success with an amount of antibodies less than 1/100th the molecular equivalent of the amount of PCP that rats were receiving. The animals given that vaccine dose avoided the extreme weight loss and death that befell about 25 percent of rats given sham vaccines, the researchers reported.
“We don’t need huge amounts to offer a tremendous effect,” says Owens. “If cost is on the left hand and effectiveness is on the right hand, we’re finally moving those to the point of merging.”
Owens and his colleagues are currently planning a clinical trial of their PCP vaccine, which they hope to start this year.
The old standby
Although vaccines against smoking, obesity, and drugs would offer new ways of fighting these conditions, Frank Vocci, director of the division of treatment and research at the National Institute on Drug Abuse in Baltimore, says that such vaccines probably wouldn’t be foolproof. Theoretically, smokers and drug addicts could override the vaccines by taking an amount of nicotine or another drug that overwhelms their capacities. And none of the vaccines addresses the behavioral components of addiction that often lead people to relapse. Those include being around the people and places that lead smokers to light up or food addicts to overeat.
“This isn’t something you can give to someone who doesn’t want to have treatment,” says Vocci. “They’re going to have to want to stop their addictive behaviors.”
Thomas Kosten, of the Yale University School of Medicine, who is developing both active and passive vaccines against cocaine, proposes that the vaccines’ best use would be in combination with other treatments or as supports to get people through times when they’re likely to relapse. For example, although cocaine addicts on the vaccine might still get high by taking four to five times the normal amount of drug, “if nothing else, that’s expensive,” says Kosten. Inability to buy the massive amounts of a drug needed to get high after getting a vaccine may be just the trick to help addicts overcome the urge to use, he speculates.
Even though vaccines might be something an addict could lean on, says Nabi Biopharmaceuticals spokesperson Rathjen, people will still need to rely on an old standby for quitting any addictive behavior: willpower.
Harrison, the reluctant smoker, says that she “would love to get on the [nicotine] vaccine.” But since she’s not in any nicotine vaccine clinical trial, she’s still relying on simple willpower. With a New Year’s resolution to quit smoking, she’s now halved the number of cigarettes that she was smoking last year.
