A remarkable individual, who completely kicked nicotine addiction, smugly cites data from the Centers for Disease Control and Prevention: Of the 48 million adult U.S. smokers, about 70 percent - 34 million people - have made at least one attempt to shake their addiction, yet only 1.2 million quit permanently.

And according to the World Health Organization, at least 1.1 billion people worldwide - a third of the global adult population - use tobacco products, which cause 4 million premature deaths annually. In the U.S., nicotine use is the leading preventable cause of mortality, inflicting more than 430,000 deaths each year, at an estimated $97 billion in direct and indirect medical costs.

"The reason it's so difficult to quit smoking is because nicotine is highly addictive," pointed out Robert Naso, senior vice president of product development at Nabi Biopharmaceuticals in Boca Raton, Fla. "When a person smokes," Naso continued, "nicotine enters his or her body and goes straight to the brain. There it generates positive sensations, such as pleasure and relaxation. However, the body does not develop antibodies to immunize against nicotine."

On June 12, Nabi announced that it had begun Phase I human trials of NicVAX, a proprietary vaccine to help the body develop antibodies that bind to nicotine and block it from reaching the brain. "The trial is taking place at a clinic in Pittsburgh that specializes in clinical trials," observed behavioral pharmacologist David Malin, a research grantee of NIDA, the National Institute of Drug Abuse, coordinated by Nabi. "But the great bulk of the Phase I and Phase II testing is intended for the University of Minnesota department of psychiatry."

Malin, a professor of psychology and neuroscience at the University of Houston-Clear Lake in Texas, is lead author of a paper in the biweekly Life Sciences, an Elsevier Sciences journal formally dated April 26, 2002. In fact, it reached readers only late last week. The article is titled: "Passive immunization against nicotine attenuates nicotine discrimination." Its senior author is Ali Fattom, Nabi's vice president of research.

"The paper's finding," Malin summed up," is that immunization of 10 rats against nicotine interferes with their recognition of nicotine injection. And over several months of training, the animals learned to press one lever for food reward, after they've been given an injection of saline, and to press the other lever after an injection of nicotine. Those rats were performing with perfect accuracy. Essentially," Malin continued, "the rodent was telling me either, Yes, you've just injected me with nicotine; it feels like nicotine.' Or, No, it doesn't feel like nicotine, but something else.'

"The rats were passively immunized with Immunoglobulin G Ig (IgG) from the antiserum of rabbits immunized with NicVAX, the anti-nicotine vaccine developed by Nabi. We isolated IgG containing their nicotine antibodies from these rabbits. And the dummy control vaccine was IgG from non-immunized rabbits."

Vaccine Robs Relapsed Smoker Of Comfort

"NicVAX vaccine raises a possibility," Malin suggested, "for a smoker who is trying to quit, and who has been immunized with NicVAX but has relapsed - as usually happens. This person sneaks a cigarette despite his best intentions, and expects to feel a certain satisfaction from smoking that cigarette. This suggests that that smoker is going to be disappointed. The smoke may not feel the way the relapsing smoker expects to feel, because the nicotine in that cigarette will be impeded in reaching the brain. This raises several possibilities," Malin went on. "One is that immunization might help extinguish the smoking habit, by interfering with the rewarding effects of nicotine."

Malin described how Nabi constructed its NicVAX vaccine: "Nicotine is a small molecule," he recounted, "and therefore it's not immunogenic. So to get antibodies against it, the scientists conjugated the nicotine molecule to a much larger protein that can provoke immune responses. This is the exoprotein of the bacterium Pseudomonas aeruginosa," he explained. "What they used is a linker, held at a distance from the protein, so that part of the molecule is exposed to the outside. They finally came up with an optimal way of conjugating the small molecule to the large immunogenic protein, to get antibodies against nicotine itself. Most people have antibodies against Pseudomonas, which might even aid the immunization in the human being - by priming as it were.

"Before receiving the antibodies," Malin went on, "those 10 rats were reliably performing after injection with nicotine or saline. They made over 90 percent of their bar-presses on the correct lever - that is, on the nicotine-associated lever - on a day when they were injected with nicotine; and pressed the saline-linked lever after being injected with saline. Then, on the days following the passive immunization when they were injected with saline, they still responded on the saline lever. Their ability to recognize saline was certainly not impaired. But when injected with the dose of nicotine, the majority of their responses were on the saline lever, not on the nicotine lever - even though they'd been injected with nicotine.

"It was as though the rat were telling us," Malin observed: I don't know what you've injected me with, but if I have to guess, I guess it's saline.' This even though they had been injected with nicotine. As a result of immunization, there was no change for saline, but it really brought down the responding after two different doses of nicotine by 61 percent."

Next Target: Keeping Youngsters From Smoking

Malin's journal papers demonstrated several effects of passive immunization - meaning antibodies from external sources rather than generated by one's own immune system.

"We showed it interfered with locomotor effects of nicotine," Malin said. "Also, dose-related increase in blood pressure, blocked by IgG antiserum. Most significantly, we showed that nicotine relieves the nicotine withdrawal syndrome very promptly - no big surprise. But in passively immunized rats, nicotine no longer relieved that withdrawal syndrome to the same extent. It's greatly impaired. So that's where we are in passive immunization.

"We would now like to do a lot of work on active immunization. Our next big focus is giving the vaccine to young people at high risk of becoming nicotine dependent and developing a serious smoking habit, and keeping them from developing it in the first place. That," Malin concluded, "is what we're writing up now."