BILLY wanted to be bad. He just never quite made it. Sure, he鈥檇 put in the
hours hanging out with the wrong crowd. He鈥檇 snorted what they snorted, injected
what they injected and smoked what they smoked. But while his friends found
bliss or oblivion, Billy was left to watch from the sidelines, untouched by the
drugs.
Billy鈥檚 parents couldn鈥檛 have been happier with the result. Years ago, they鈥檇
made the decision to vaccinate their son against addictive chemicals. Thanks to
a few simple injections, Billy鈥檚 blood was brimming with antibodies that bind to
these substances and stop them getting to his brain, like a thin red line of
defence against life鈥檚 vices.
Billy may be fictitious, but the prospect of an anti-drug vaccine isn鈥檛 just
a rebellious teenager鈥檚 nightmare. Academic labs and at least five companies are
in the advanced stages of animal testing for antibody therapies against cocaine,
phencyclidine (PCP), methamphetamine and even nicotine. One anti-cocaine vaccine
has already been tested for safety in drug abusers. By the end of the year, it
could be undergoing its first efficacy trials.
Advertisement
Treating drug abusers may be just the start. The idea that a jab in the arm
could take the kick out of cocaine and other drugs raises some thorny questions.
Should people be vaccinated, for example, simply because they belong to a group
thought to be particularly at risk of becoming addicted? Should parents be
allowed to make that decision for their children? Might companies screen job
applicants for traces of anti-drug antibodies, in the belief that this would
finger former users? It may be years before the first anti-vice vaccine goes on
the market. But the ethical debate has begun. 鈥淚 don鈥檛 think it鈥檚 too early to
start thinking about these things,鈥� says Frank Vocci, director of the drug
dependence research programme at the National Institute on Drug Abuse (NIDA) in
Washington DC.
For now, these therapies are being developed for addicts who want to kick the
habit or who overdose. The problem is particularly acute for cocaine鈥攁
drug for which there is currently no established medical treatment. In the US
alone, millions of people regularly snort, inject or smoke cocaine, and each
year, for 150 000 of them, the pleasure trip ends with a visit to the emergency
room. And cocaine is growing in popularity in Britain too.
Experiments with rats and monkeys have already shown that an injection of
antibodies can stop cocaine-addicted animals from seeking out the drug.
The hope now is that this will help people who want to quit. 鈥淭his isn鈥檛 a
cure, it鈥檚 like a safety belt,鈥� says Michael Owens of the University of
Arkansas for Medical Sciences in Little Rock. 鈥淔or people who use it
right, we think it will greatly reduce the chance they get hurt.鈥�
But potential misuse of the vaccine seems destined to trigger as much
interest as its benefits. Barbara Fox remembers about six years ago, when
her team at the Massachusetts-based company ImmuLogic presented their
grant request to the NIDA for the cocaine vaccine now in clinical trials,
it was turned down flat. It was considered too revolutionary, and there
were fears that it might be used on people who hadn鈥檛 given their consent.
鈥淭hey were worried it would be used coercively,鈥� says Fox, who is now at
Addiction Therapies in Wayland, Massachusetts.
Such fears don鈥檛 surprise Peter Cohen, a doctor and lawyer at Georgetown
University in Washington DC, who has written on the legal implications of
vaccines against addictive drugs (Drug and Alcohol Dependence, vol 48, p
167). He thinks that American law would allow parents to vaccinate
rebellious children like Billy against their will. 鈥淵ou don鈥檛 need a law
degree to see who is going to win that fight,鈥� he says. He is less
concerned about the spectre of job applicants being screened for
antibodies. 鈥淚 doubt that would stand up to legal challenge,鈥� he says. But
that doesn鈥檛 mean companies won鈥檛 try, he adds.
The idea of targeting 鈥渁t risk鈥� groups with an anti-addiction vaccine may
have been one reason why the NIDA panel initially took fright, according
to Charles Schuster, a former NIDA director now at Wayne State University
in Detroit, Michigan. 鈥淚 think someone called it a racist plot,鈥� he says.
But many people are untroubled by such worries, says Schuster, and he
suspects that a vaccine would have wide appeal. In the 1970s, when he was
director of the drug abuse centre at the University of Chicago, Schuster
was the first to show that anti-drug antibodies, in this case anti-heroin,
could work in animals. 鈥淲hen I published, I got calls and letters from
parents all over the world saying would you please, please immunise my
child,鈥� he says.
And it鈥檚 not just parents who think vaccines might be a good idea. Ali
Fattom, a vaccine specialist at the Florida-based company Nabi, thinks
that many kids would volunteer. Fattom recently asked the classmates of
his 16-year-old son about their feelings towards an anti-nicotine vaccine.
鈥淢ost of these guys say I鈥檒l take it first thing, because that would
relieve the risk of experimenting with cigarettes and getting addicted,鈥�
he says.
But the ethical issues surrounding these vaccines run deep. 鈥淪hould we be
taking away people鈥檚 pleasures?鈥� asks John St Clair Roberts, medical
director at the British company Cantab Pharmaceuticals, based in
Cambridge, which took over Fox鈥檚 vaccine programme from ImmuLogic and now
runs the clinical trials. 鈥淎 person who gives up today might change their
mind tomorrow,鈥� he points out. 鈥淏ut you can鈥檛 turn off the immune system
with a switch.鈥�
None of this will matter, however, unless the successes of the animal
studies can be translated to humans. And this is far from certain鈥攏ot
least because researchers don鈥檛 yet understand exactly how these vaccines
work.
Indeed, the approach was all but abandoned shortly after Schuster鈥檚
pioneering work in Chicago. The work began when a colleague pointed out a
newly developed antibody treatment for accidental overdoses of the heart
medicine digitalis, which worked by binding the drug safely in the blood.
Schuster and his team began to wonder whether it might be possible to
treat heroin addiction in the same way.
Constant cravings
The idea seemed straightforward enough. A major problem for recovering
addicts is relapse. After a period of abstinence, they succumb to a
craving for their drug and take a hit. But that taste only reinforces a
greater hankering, and starts an ugly cycle of treatment and relapse.
Schuster reasoned that because antibodies are too big to cross the
blood-brain barrier, any drug they grabbed would be kept safely away from
the brain.
To test the idea, Schuster and his team created a vaccine by chemically
joining a heroin-like molecule to a protein that they knew would be
detected by the immune system and stimulate antibody-producing cells.
Next, they inoculated heroin-addicted rhesus monkeys that had been trained
to self-administer by hitting a lever which injected heroin straight into
their blood. Their results were dramatic.
At the peak of the vaccine鈥檚 effectiveness, immunised monkeys found heroin
no more alluring than a salty water control (Nature, vol 252, p 708). But
despite this success, there were major drawbacks. In particular, the
animals had to undergo a brutal inoculation regime several times a day for
weeks for the vaccine to be effective, which caused ulcers to form at the
site of the injection. The researchers were also disappointed that the
monkeys鈥� antibody levels seemed to drop within a few weeks, and that as
the drug dose was raised, the antibodies became saturated, and the animals
resumed their heroin habit.
The approach was all but abandoned shortly afterwards because, on top of
these problems, it faced competition from other methods of treating heroin
addiction. It was around this time that other groups were reporting
excellent results using chemicals such as methadone and naltrexone, which
block the action of heroin by competing with the drug for special receptor
sites in the brain. Everyone became convinced that the true salvation for
addicts everywhere lay in this 鈥渟mall chemical鈥� therapy. One reason they
seemed a better bet was that their molecules are similar in size to the
drug they are countering, so they could be given in doses equal to or
greater than the drug, while antibodies, being large molecules, seemed
easier to outnumber.
It was nearly 20 years before researchers seriously reconsidered the
vaccine idea, and for a simple reason: desperation. No drug had emerged to
treat cocaine and its use was reaching new heights. Then a pharmaceuticals
company asked Kim Janda at the Scripps Research Institute in La Jolla,
California to develop a vaccine that would stimulate animals to produce
antibodies which could be used in a cocaine screening test.
To Janda鈥檚 surprise, the vaccine his team created dramatically blunted
the psychoactive effects of cocaine in rats, halting the hyperactivity and
sniffing that the drug usually inspired (Nature, vol 378, p 727). As it
turned out, Fox and her colleagues at ImmuLogic were right on Janda鈥檚
heels, having decided to take a gamble on a cocaine vaccine of their own.
They soon reported that immunised rats would stop self-dosing cocaine,
much as Schuster鈥檚 monkeys resisted heroin (Nature Medicine, vol 2, p
1129).
Advances in vaccine design meant that the treatment worked after just a
small number of injections, and caused no ill effects. So ImmuLogic pushed
ahead with clinical safety trials, ultimately selling the rights to
Cantab. The British company recently reported that there were no adverse
reactions among the 34 recovering cocaine users who participated in the
study. All produced substantial levels of antibodies to cocaine, and in
three of the participants, antibodies could be detected a year later.
With the prospects for Cantab鈥檚 cocaine vaccine looking promising, other
labs have gone on to investigate the effects of vaccines on other
addictive drugs. For sheer numbers, the most impressive must be the study
reported this February at the Sixth Annual Meeting of the Society for
Research on Nicotine and Tobacco in Arlington, Virginia, by Fattom and his
colleagues.
Over one week, they infused rats with a dose of nicotine equivalent to
1400 cigarettes, together with antibodies against nicotine. They then
stopped the nicotine infusion and looked for the characteristic signs of
nicotine withdrawal, such as chattering teeth, gasps and tremors. Even
after this enormous dose, the symptoms were reduced by half relative to
unimmunised controls. At a more realistic nicotine intake rate, the
antibody was completely protective. This is encouraging evidence that the
vaccine might not only help people give up cigarettes, but could stop
others from becoming addicted, says Fattom.
Other researchers have shown that vaccines are effective at blocking the
effects of PCP and methamphetamine. The success of these animal
experiments might suggest that the ability of antibodies to mop up the
drug is now beyond doubt. But things are not that simple. Fox鈥檚 group, for
instance, showed early on that 30 seconds after a dose of cocaine, the
brain concentration of the drug in immunised rats is reduced by only 30 to
63 per cent. So it is still at a level that would have given an
unimmunised animal a rush. 鈥淭he paper calculation tells you it shouldn鈥檛
work,鈥� says Fox. 鈥淏ut the animal behaviour data tell you it does. So the
question is why.鈥�
There are at least two ideas in circulation. One is linked to the notion
that a drug鈥檚 addictive effect is related to the speed at which it enters
the brain. Cocaine is more addictive when smoked as crack than when
snorted because the lungs have a larger surface area than the nose. So for
the antibody to work, it might not need to hang on to the drug, just slow
its progress to the brain. By contrast, the negative or 鈥渄ysphoric鈥�
effects of cocaine such as anxiety and nausea seem to come from its final
concentration in the brain. So antibodies might take away all the good
effects of cocaine and leave only the bad.
Owens has other data suggesting that antibody therapy ends up targeting
the brain selectively. His lab has done extensive work on the kinetics of
PCP interactions in the brains of rats. When the researchers infuse the
animals with extremely high doses of purified anti-PCP antibodies, the
brain concentration of the drug drops to zero, even though levels remains
high in other parts of the body (The Journal of Pharmacology and
Experimental Therapeutics, vol 292, p 831).
Mind-altering
Owens suspects that PCP wouldn鈥檛 have the psychoactive effects it did if
it wasn鈥檛 able to penetrate the blood-brain barrier rapidly. This may
explain why a little bit of antibody works far better than expected鈥攊t
mops up the drug in the blood vessels and the resulting drug diffusion
gradient causes the drug to leak rapidly back from the brain into the
blood vessels. 鈥淚f one organ is preferentially protected, isn鈥檛 it
wonderful that it鈥檚 the brain?鈥� says Owens.
But even given immunotherapy鈥檚 mysterious success, researchers are eager
to improve on it further by changing the method of immunisation.
Inoculation with a vaccine, made from a drug linked to a protein, causes
active immunity, a natural antibody response which triggers the body to
produce a wide array of molecules with varying abilities to grab the drug.
It鈥檚 a method that can remain effective for a few months to a couple of
years. By contrast, the animal can also be given passive immunity by
infusing it with monoclonal antibodies, a single species of molecule
produced from an antibody-producing cell cultured in the laboratory.
Monoclonals can be selected to have very specific properties, such as very
tight binding of the drug, but they are short-lived, lasting just a few
weeks.
In a paper just published (Proceedings of the National Academy of
Sciences vol 97, p 6202), Janda describes how he has combined the active
and passive approaches to deliver what he calls a 鈥渙ne-two punch鈥�. The
vaccine alone is able to stop rodents from self-administering the drug
until high doses are available. But with monoclonals included, even doses
equivalent to three hits of cocaine are blunted and the animals stop
pushing the lever after a few tries. Janda compares the natural antibody
response to a group of workers of varying strengths trying to capture the
drug. But the monoclonal antibody is in a different league: 鈥淚t鈥檚 like
sending in Superman to help,鈥� he says.
At Columbia University in New York City, Donald Landry and his
colleagues have even found that some monoclonals can destroy cocaine
molecules. His team developed these 鈥渃atalytic鈥� antibodies by creating a
vaccine that mimics cocaine鈥檚 鈥渢ransition state鈥�, a fragile form of the
molecule which breaks down into fragments鈥攅cgonine methyl ester, or EME,
and benzoic acid鈥攚hich aren鈥檛 toxic or psychoactive. They used the vaccine
to isolate monoclonal antibodies that bind to the cocaine and twist it
into its fragile state, making it more likely to snap apart
(see Diagram).
This ability to break down cocaine seems to give the antibody extra
potency. For one thing, the broken fragments just slip away, leaving the
antibody free to work again. At concentrations at which a comparable
cocaine-binding antibody had no effect in rats, Landry鈥檚 catalytic
antibodies increased the lethal threshold for cocaine threefold and also
dramatically blunted self-dosing of cocaine by addicted animals
(Proceedings of the National Academy of Sciences, vol 95, p 10 176).
The vaccines are at last looking as though they might be a more promising
treatment than the small chemicals. Antibodies don鈥檛 mess with brain
chemistry the way blocking drugs do, so there should be fewer side
effects. And antibodies are expected to be long-lived鈥攆rom weeks to
years鈥攃ompared with a single day for a dose of naltrexone. 鈥淩ight now, an
addicted patient has to ask themselves every day if they should take their
medicine or get high,鈥� says Colin Brewer of the Stapleford Clinic in
London. 鈥淚f they only have to make that decision every few weeks, it would
be a great relief.鈥� He thinks antibodies would be a big help to recovering
addicts who have trouble sticking with their therapy.
Researchers are confident they can push the vaccine technology even
further. And they have another reason to be optimistic. It鈥檚 only
anecdotal, but the story is often told of two men from the Cantab trial
who started doing hits of cocaine after their treatment鈥攖o no avail. One
experienced nothing from the drug, the other felt his heart race, but
didn鈥檛 achieve a high.
Tom Kosten, a psychiatrist at Yale University who conducted the trial,
says that if this anecdote foretells that effective immunotherapy is
possible, then he, for one, will gladly confront the moral and medical
morass that will follow. 鈥淚n my thinking,鈥� he says, 鈥渋f we have a real
vaccine to argue about, we would be very lucky.鈥�