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A vaccine for modern living
30 July 2008
From New Scientist Print Edition.
Jim Giles

Four years ago, a group of drug users turned up at the Yale School of Medicine. Most were hooked on crack cocaine, a highly addictive form of the drug. All of them wanted to quit. "They came to us because their lives had gotten screwed up by the drug," says Thomas Kosten, an expert in drug addiction who worked with the addicts.

The odds were not in their favour. More than 2 million Americans take some form of cocaine regularly, and most find it extremely hard to kick the habit. Even if an addict stays off the drug for months, a single "hit" in a weak moment causes the cravings to surge, and the addiction can take over their lives again.

The cocaine users who enrolled in Kosten's trial also had weak moments. For a few of them, though, something extraordinary happened when they snorted or injected the drug: it had no effect. Kosten had vaccinated them against cocaine, and antibodies to the drug were circulating around the addicts' bloodstreams, ready to neutralise cocaine molecules. The addicts were protected against cocaine in the same way that childhood vaccinations protect much of the world from polio and measles. And with the help of the vaccine, several of the addicts were drug-free by the end of Kosten's study.

Vaccines are one of the most successful medical inventions. Without them, you might not have been around to read this - your ancestors could have been killed by plagues such as smallpox. Now the hope is that this technology can also treat modern health scourges, and not just addictive drugs. Obesity and high blood pressure are some of the other conditions that vaccines might help us deal with. If advocates of this approach are right, the work in Kosten's lab is just one example of what will be the second vaccine revolution.

It's a revolution that can't come quickly enough. In the case of addiction, treatments such as behavioural therapy are expensive and often don't make much of a difference. Smoking is one of the world's biggest killers. Meanwhile, obesity has reached epidemic proportions in the US and is rising elsewhere.

Vaccines would offer a completely different approach to these problems. The idea is to get the body to produce antibodies that bind to and neutralise specific substances such as cocaine. Almost all drugs consist of molecules too small to trigger an immune reaction, however, so some trickery is required.

To make a molecule big enough for the immune system to respond to, Kosten, who is now at Baylor College of Medicine in Houston, Texas, attached 10 molecules of cocaine to the surface of a cholera protein. Vaccination with this "mega-cocaine" molecule stimulates the production of antibodies that latch onto normal cocaine molecules as well as the large synthetic molecule.

When bound to an antibody, cocaine molecules cannot pass through the blood-brain barrier. So if people produce high enough levels of antibodies, cocaine does not produce its usual pleasurable effect. For those trying to beat addiction, this means that instead of a moment of weakness leading straight back to regular drug use, the lapse will just be a discouraging waste of money.

That's the idea anyway, but does it actually work? The idea of vaccinating against addictive drugs was first explored in the 1970s. Tests on monkeys showed it worked - except that it took several vaccinations per day to generate antibody levels high enough to stop the animals self-administering heroin. The approach was abandoned but as technology improved, researchers returned to the idea. After promising results in animal studies, the first vaccines are now being tested on people.

The trial of Korsten's cocaine vaccine involved more than 100 addicts and ran for 24 weeks. Around a third of the 55 people given the shots rather than a placebo reduced their cocaine use, and of the 21 who produced above-average levels of antibodies, 10 stopped using the drug altogether. Users who produce high levels of antibody say they get no effect from their usual drug dose. Korsten is now experimenting with different forms of the vaccine to find one that provides a consistently high antibody response.

Despite these impressive results, a one-off vaccine shot is not a long-term solution. The immune system has evolved to fight pathogens, which enter the body in low numbers and so require only low levels of circulating antibodies to counter. Cocaine enters the body in one big hit, a flood by comparison, so booster shots are needed to keep antibody levels high enough to cope. In Korsten's study, addicts received five injections over a 12-week period. "If you don't have motivation, the odds of sticking around for 12 weeks are small," he says.

For those with enough desire to quit, however, the vaccine looks as if it could make a difference. In fact, after the study had ended, those addicts who had remained drug-free asked if they could continue to receive the vaccine. Unfortunately, Korsten did not have approval to extend the trial, so could do nothing when the ex-addicts' antibody levels dwindled. Even after months off a drug, addicts often relapse. After the protection faded, those slips led to further use. "It took a lot of willpower after the vaccine had worn off," says Korsten. "After a year, I don't know that anyone wasn't back to using some cocaine."

Development of the cocaine vaccine is now in the hands of Celtic Pharma, based in Hamilton, Bermuda. If further trials are successful, the firm plans to submit the vaccine for approval in 2010. That could turn out to be the first of many - a similar vaccine for methamphetamine developed by Kosten's team is already showing promising results in animal studies. Meanwhile, another drug-use danger, the risk of overdose, looks as if it could be tackled using a related approach (see "Anti-angel dust").

However, even if these anti-addiction vaccines work, who is going to pay for them? Many governments are already reluctant to fund treatments such as behavioural counselling, so why would they fund vaccines?

Taxpayers are already paying the costs of addiction, responds Michael Owens of the University of Arkansas for Medical Sciences in Little Rock, whose team is developing the methamphetamine vaccine. The total cost of drug abuse in the US alone, from drug-related crime and locking up offenders to treating the health problems caused by drugs, is around $200 billion annually. Refusing to pay for vaccines, or any other proven treatment, is a false economy, Owens says.

Governments and health insurers may have fewer worries about paying for the next-generation vaccine that is furthest along in development. It tackles the addictive drug that does the most damage to people's health: nicotine. More than a billion people worldwide are hooked on the evil weed, a habit that claims more than 5 million lives a year, roughly one every 6 seconds. Most smokers in rich countries want to quit, but this doesn't make quitting any easier. In the US, around 40 per cent of smokers try to quit every year, but six months on, 19 out of 20 are smoking again. As any smoker will tell you, quitting is easy. Staying quit is the hard part.

Initial results suggest a vaccine could help. Last November, for example, Nabi Biopharmaceuticals of Rockville, Maryland, announced that in a trial involving 300 smokers, 15 per cent of those given the vaccine had quit after a year compared with 6 per cent of those given a placebo. Another vaccine, created by Cytos Biotechnology of Zurich, Switzerland, has also produced promising results, and the project has now been taken over by pharmaceutical giant Novartis.

The nicotine vaccine works like the cocaine vaccine, protecting ex-smokers against lapses - those who succumb to temptation find smoking a cigarette does not satisfy their cravings. You might think that this approach could backfire, as some smokers might keep puffing until their nicotine levels are high enough to overwhelm the neutralising antibodies. Surprisingly, though, Nabi found that those smokers who produced high levels of nicotine antibodies yet did not quit still smoked fewer cigarettes.

Addicts are not the only people who suffer when willpower wanes. High blood pressure can be controlled using conventional drugs, but for some patients this means taking up to 10 expensive pills a day. And when the pills are working, people start thinking they do not need to take them any more. Up to a third of patients fail to take their drugs as prescribed. Even if people do take them as recommended, the pills cannot prevent the surges in blood pressure that normally happen during the early morning.

An injection delivered every few months would make life much simpler. In this case, the vaccine target is not a virus or other invader, but a hormone that helps to control the width of blood vessels. Reducing the levels of this hormone, called angiotensin, relaxes blood vessels and lowers blood pressure.

To spur the immune system into action, angiotensin is attached to larger, virus-like particles. The first human trial, involving 72 patients, suggests that the resulting vaccine is safe, a team in Switzerland reported earlier this year (The Lancet, vol 371, p 821). While the doses tested produced only a modest blood pressure reduction, higher doses and more frequent injections should in theory produce higher antibody levels and a greater effect.

The company behind the vaccine, Cytos, is now planning bigger trials. Meanwhile, at the Scripps Research Institute in La Jolla, California, researchers are carrying out animal trials of a hormone that regulates appetite - ghrelin - in the hope of producing an immunological therapy for obesity.

The effects of these vaccines are not permanent: because the hormones ghrelin and angiotensin are too small to stimulate the immune system, antibody levels will slowly fall without booster shots. Nevertheless, both projects have led to a few raised eyebrows. Hormones are often part of a complex web of signals, and no one can be sure of what will happen if the molecules are targeted by the body's immune system.

Angiotensin, for example, also helps regulate salt and water levels. Knocking out a few molecules would not normally cause a problem, but if a patient becomes dehydrated, perhaps by developing diarrhoea, they need angiotensin to be doing its job. If not, the systems that should kick in to conserve salt and water might not work well enough, resulting in kidney failure or even death.

People on regular blood pressure drugs can simply stop taking their medication if they become dehydrated. By contrast, it takes months for the effects of a vaccine to wear off. The dehydration issue needs to be studied carefully, and researchers should ensure that people are aware that there could be problems with their water and salt level controls, says Hans Herlitz, who treats blood pressure patients at Sahlgrenska University Hospital in Gothenburg, Sweden.

Nevertheless, the vaccine could prove useful, says Herlitz. His cautious optimism sums up the attitude of those familiar with the next-generation vaccines. They are not a magic bullet that will instantly end drug addiction or obesity, let alone prevent these problems. Yet given that current treatments for these conditions have only a limited effect, new approaches are desperately needed. The second vaccine revolution will not eradicate killer diseases. It might, however, cut the death toll from problems that, if untreated, will become some of the biggest killers of the 21st century.

From issue 2667 of New Scientist magazine, 30 July 2008, page 42-45

Anti-angel dust Addiction is not the only danger from drug use. The problems with angel dust, or phencyclidine (PCP), come from the drug's immediate effects. PCP makes people feel dissociated from their body, and they sometimes become violent as well. Because it's also an anaesthetic, the overall feeling can be one of power and invulnerability. This makes it difficult and often dangerous for medics to deal with the people high on PCP whom they encounter. Yet what if a single injection could restore normal consciousness? This is the goal of Michael Owens of the University of Arkansas for Medical Sciences in Little Rock. He is developing an antibody that binds to PCP, blocking its effects. In rats, the antibodies counter the effects of PCP to such an extent that the animals survive doses that are usually lethal. In fact, the antibody is mysteriously strong. "We've never seen an antibody work this well," Owens says. An antibody dose equivalent to 100th of the number of PCP molecules in the animals is enough to have dramatic effects. Since such a low dose should mop up only a tiny proportion of PCP molecules, leaving most floating freely in the bloodstream, it's not clear why the animals' behaviour should change. Whatever the answer, the finding is good news. One fear about vaccines designed to trigger the production of antibodies that mop up drugs is that addicts may boost the amount of drug they take until the antibodies are overwhelmed. That remains a possibility, but Owens's work suggests that, even when outnumbered, antibodies can still protect the brain.

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