Ron Zimmerman
October 17, 2011 — Up to now, vaccines have been used effectively against a variety of infectious diseases, but what if they could be developed to treat and/or prevent addiction?
Take smoking, for example. Someone who wanted to quit would go through their usual lighting up routine, but when nicotine does not arrive in the brain, they would probably extinguish the cigarette and not light another. Without feeling nicotine's effects, it is likely they would view smoking as a waste of money.
Or consider a vaccine against methamphetamine: Snorted or injected, the drug would not give the user a high, so what would be the point of going to the trouble of scoring this illegal drug in the first place?
Now both vaccines, for nicotine and for methamphetamine, have gone beyond the dreaming stage. Recently, the National Institute on Drug Abuse (NIDA) awarded "visionary" grants to 2 scientists who believe that in the not-too-distant future, vaccines will be available not just for smallpox and whooping cough but also for substance abuse.
Two scientists proposing to develop vaccines against methamphetamine and nicotine have been selected to receive NIDA's second Avant-Garde Awards for Innovative Medication Development Research.
The scientists, Thomas Kosten, MD, from Baylor College of Medicine, Houston, Texas, and Peter Burkhard, PhD, from the University of Connecticut, Storrs, will each receive $500,000 per year for 5 years from NIDA to support their research.
Addiction vaccines could be life-changing for the estimated 22 million drug abusers in the United States. NIDA estimates that every year, addiction costs the country $84 billion in direct healthcare costs, lost earnings, crime, and accidents. The cost trend is rising, and researchers hope that addiction vaccines may reverse it, not only by treating addicts but also by immunizing young people before they become addicted.
Just like regular vaccines, substance abuse vaccines work by provoking the immune system to produce antibodies, which then causes the body to suspend and reject the drug before it reaches the brain. That is the goal, but thus far, success in humans has been elusive.
Dr. Thomas Kosten
Dr. Kosten is working on a novel human methamphetamine vaccine, and since at this time there is no US Food and Drug Administration (FDA)–approved medication for methamphetamine addiction, his research could have substantial effect.
Dr. Burkhard's peptide nanoparticle antinicotine vaccine would be administered intranasally, which would be easier and less painful than an injection. He believes his de novo peptide design, coupled with nicotine, will induce a strong immune response against nicotine without the need for other chemicals to enhance it, leading to fewer adverse effects and a less expensive vaccine.
Addiction Interrupted
Both vaccines are expected to enter initial clinical trials within 5 years. They both work essentially in the same way: They induce a patient's immune system to generate antibodies that then bind to the target drug, forming compound molecules that are too large to move from the bloodstream to the brain.
Once the drug is denied access to the patient's brain, it cannot produce the reinforcement or "high" that is the major component of the motivation to continue using it. In short, the familiar addiction cycle — drug use, resultant brain stimulation, and then a subsequent desire for continued drug use — is interrupted.
Once the drug is denied access to the patient's brain, it cannot produce the reinforcement or "high" that is the major component of the motivation to continue using it. In short, the familiar addiction cycle — drug use, resultant brain stimulation, and then a subsequent desire for continued drug use — is interrupted.
The science behind vaccines for addiction goes back to the 1950s, when researchers developed a vaccine against fatal overdoses of the heart drug digitalis.
Then, in the 1970s, at the University of Chicago, researchers working with monkey models were successful in creating antibodies to heroin in their subjects by attaching molecules of heroin to a protein from cow's blood. This is the model on which Dr. Kosten has based his research.
Another major precedent for these 2 new addiction vaccines is the work of California researcher Kim D. Janda, PhD, from Scripps Research Institute in La Jolla, who made headlines in July when his team announced it had produced a vaccine against heroin's effects in rats. His laboratory's rodents stopped helping themselves to the drug after they received a vaccine, and it is thought they did so because the heroin stopped having any effect.
However, that success followed a serious setback in Dr. Janda's work on another vaccine: A phase 2 clinical trial for a nicotine vaccine based on his work had disappointing results. Patients receiving the vaccine only quit smoking at the same rate as those receiving placebo, so the trial was halted.
To date, none of Dr. Janda's vaccines has received FDA approval, and despite successes in animal models in his laboratory, they have not yet produced consistent results in humans.
As Dr. Janda recently told the New York Times: "The big problem plaguing these vaccines right now is difficulty predicting in humans how well it's going to work."
That difficulty was revealed in widely anticipated cocaine vaccine studies, in which a bacterial protein plus a molecule that is a cocaine look-alike trained the immune system to produce antibodies that bind to any cocaine in the bloodstream.
"Like Wiping Out Switzerland"
In a 2010 vaccine study at Columbia University, New York City, conducted by Margaret Haney, PhD, with crack cocaine addicts, the level of antibodies in the volunteers varied widely. Only 38% of the cocaine users produced enough antibodies to quell the drug's effects, and of those, only half stayed off the drug more than half the time.
In a 2008 analysis of 34 behavioral studies in cocaine, methamphetamine, and marijuana addictions, improvement was seen in 67% of the addicts. "You can't expect a medication or vaccine alone to take care of addiction," said Dr. Haney."I am entirely humble about that."
Dr. Nora Volkow
NIDA Director Nora D. Volkow, MD, said Dr. Kosten and Dr. Burkhard were awarded the grants because they have already demonstrated proficiency in the laboratory with vaccines.
"They also have clear plans for initiating clinical trials within an accelerated period of time," said Dr Volkow. And that's the goal of NIDA's Avant-Garde Grant Program: "[T]o support investigators of exceptional creativity who propose bold and highly innovative new research approaches that have the potential to produce a major impact on the treatment of drug abuse."
Seven million people die from smoking addiction every year. That's like wiping out Switzerland. It's a tremendous step forward to have a vaccine to prevent smoking, not only for these 7 million who die but also for the other countless millions who are living with their smoking addiction.
"Seven million people die from smoking addiction every year," Dr. Burkhard told Medscape Medical News, "that's like wiping out Switzerland. It's a tremendous step forward to have a vaccine to prevent smoking, not only for these 7 million who die but also for the other countless millions who are living with their smoking addiction."
Nicotine presents a particular challenge in developing a vaccine against it, as on its own it is completely nonimmunogenic. "So you have to couple it to a carrier to induce an immune response," he added.
Dr. Peter Burkhard
Dr. Burkhard heads the Burkhard Protein Design Group at the University of Connecticut, which has developed proprietary methods to synthetically produce nanosize protein particles.
"Our greatest challenge is generating as strong an immune response as possible to induce the effect we're looking for," he said. "The idea has been around for awhile, and other companies have brought it into clinical trials, where they have shown that it works, but it only works if you have really high levels of antibodies. Most of the clinical trials have failed for this reason, because they were only able to induce antibodies in about 30% of the population. And that's simply not good enough."
Dr. Burkhard's 18-nm particles are produced in his group's laboratory after first being designed on a computer.
"We predict a peptide sequence that is then able to self-assemble into a particle with icosahedral symmetry," he said. "Then we go into the lab to synthesize this peptide by biotech procedures, expressing it in [Escherichia coli], purifying it, and then refolding it. With those nanoparticles, the next step is coupling the nicotine molecule to the nanoparticle."
No Guarantees
Under the NIDA grant timeline, Dr. Burkhard plans to spend the first year and a half developing an effective nanoparticle vaccine, "so that we can be sure that we do get enough antibodies."
It will then take a year to manufacture enough vaccine for his 2-year phase 1 clinical trial. "That's our expertise, developing these nanoparticles that have been shown to be very immunogenic, and we have some 'tricks of the trade' to really tweak the immune system to give us a very strong antibody response. There's no guarantee that it will work, but we have confidence that we can achieve that," said Dr. Burkhard.
In addition to his grant to develop a methamphetamine vaccine, Dr. Kosten already has a cocaine vaccine under development.
Known as TA-CD, for Therapy Addiction–Cocaine Addiction, this vaccine uses an inactivated cholera protein to bind to cocaine in the user's bloodstream. The approach is to prevent the addictive substance from ever reaching the brain, and thereby prevent the chemical cascade that results in a euphoric "high."
It is hoped that without that high, the user's addictive cycle will be broken. In fact, a blinded, placebo-controlled study of 114 participants conducted by Dr. Kosten and his wife, neuroscientist Therese Kosten, PhD, showed that individuals who received the vaccine were twice as likely to reduce their cocaine use by at least 50% compared with those who received placebo. The study is now under review, and the Kostens are seeking FDA approval for a larger, 300-person, multicenter trial.
What is the scientific principle behind the vaccine? Dr. Kosten explained that although most foreign substances in the body trigger an immune-system response, drugs like cocaine fail to do so because their molecules are too small. They slip across the blood–brain barrier precisely because the molecules are so tiny.
When cocaine is bound to a much larger protein...the immune system creates antibodies to both the larger protein and the drug that it carries. Then, the next time the user administers the drug, the body's immune defenses attach onto the cocaine and break it down with enzymes.
However, when cocaine is bound to a much larger protein, such as the inactivated cholera protein that has been widely tested and found to be without adverse effects, the immune system creates antibodies to both the larger protein and the drug it carries. Then, the next time the user administers the drug, the body's immune defenses attach onto the cocaine and break it down with enzymes.
"It's like a big sponge for cocaine," Dr. Kosten told Medscape Medical News. "The drug remains trapped in the blood until it's metabolized and made inactive by the liver and secreted in the kidneys."
Users can thwart the vaccine and their fortified immune system responses by taking more cocaine than their immune system can handle, so the user has to want to slow or stop their cocaine use for the vaccine to be effective in curbing their addiction. And that is why TA-CD is currently thought of as a therapeutic drug, not a preventative, said Dr. Kosten.
Made in China
Other researchers have run into a wall in trying to find a substance that will bind to materials such as tetrahydrocannabinol, or THC, in marijuana, so the body can see that substance.
Dr. Janda has tried to make vaccines against alcohol and marijuana use, but so far the effort has failed. He said that in the case of alcohol, its ethanol molecules have proven to be too small to attach a protein to them, and in the case of marijuana, its main ingredient, THC, hides too well for the immune system to react to it.
Using cholera bacterium as a vector was an essential part of Dr. Kosten's new cocaine vaccine, he said, because it allows the vaccine to avoid potential viral syndromes associated with other vaccines. In addition, most people in Western countries where cocaine abuse is most severe do not have natural immunity to cholera.
In Dr. Kosten's methamphetamine vaccine, he is using a Neisseria meningitis protein as a vector.
Dr. Volkow believes the field of drug abuse treatment is on the cusp of a large paradigm shift.
A successful vaccine will make it easier for addicted individuals to establish and maintain abstinence. It will reduce the chances that isolated lapses into drug taking escalate into protracted relapses. Ideally, a single dose will remain effective for months or longer.
"Vaccines have a unique role to play in a comprehensive strategy to help people overcome addictions. A successful vaccine will make it easier for addicted individuals to establish and maintain abstinence. It will reduce the chances that isolated lapses into drug taking escalate into protracted relapses. Ideally, a single dose will remain effective for months or longer," she said.
Although NIDA views vaccines as a potentially powerful tool to aid addicts from their illegal drugs, pharmaceutical companies are not lining up with research grants, say these researchers.
They believe the pharmaceutical companies do not see much money to be made in a shot that is given once every 6 months, and also perhaps because the companies are not anxious to associate their companies with drug addicts.
"Pharma does not see a profit in these vaccines, and only sees great risk in this population due to their lifestyle and [potential for] overdoses," said Dr. Kosten.
Dr. Kosten is taking his methamphetamine vaccine manufacturing and clinical trial to China, as his greatest challenge has been in finding a domestic manufacturer.
"We've had no success doing this in the United States, but we have had success in China. We will manufacture the vaccine in China and do clinical trials there after getting Chinese FDA approval about 3 years from now. A placebo-controlled study will compare vaccinated [groups] to placebo groups during a 6-month outpatient clinical trial. We'll have the vaccine in humans in 4 years and have a commercial product in 10 years," he said.
From :
Medscape
