Wednesday, April 30, 2014

xBio 2014 ASPET Blogging: Vaccines for Smoking Cessation and/or Prevention

Figure 1: Quitting smoking is rarely easy. (Source)
Trying to quit smoking is hard. I think I quit at least a dozen times before it finally stuck. Even now, 12 years later, I still occasionally pick up a dream cigarette when I'm asleep. Dream smoking: the healthy way to smoke. When quitting, I went the cold turkey route even though there were options available for nicotine replacement. Today, there are even more options, both pharmacological and behavioral. Dr. Rajeev Desai, at McLean Hospital and Harvard Medical School, is examining the possibility of using an alternative pharmacological approach or a vaccination to help people quit smoking.
Vaccinations work by taking advantage of the body’s natural response to foreign particles, called antigens. Antigens can be a virus, a specific piece of a virus, or even a tiny spot on a pollen grain. The body has or makes antibodies that fit to the antigen like a lock around a key. In the case of viruses, the cells that make antibodies have memory so the next time the same type of antigen appears in the body, the immune system attacks it again, usually destroying it before it can make you sick again. That’s why if you’ve had the chicken pox, for example, you don’t usually get them again if you’re exposed a second time.

Figure 2: katiesci's depiction of a
nanoparticle nicotine vaccine. The
antibodies will stick to the nicotine
and keep it from entering the brain.

The idea behind a nicotine vaccine is a little different. Rather than attacking nicotine, which is just a chemical, a vaccine would keep it from getting into the brain where it exerts most of its effects (Figure 2). Nicotine is a small molecule which can easily cross into the blood brain barrier, a barrier formed by close-fitting cells that make up the vessels leading into the brain. Bound to an antibody, nicotine would be too large to cross the barrier. 

Making vaccines for a chemical such as nicotine, which is not normally antigenic (doesn’t provoke an immune response), can be tricky though. Dr. Desai’s lab uses a nanoparticle-based vaccine. Nicotine is stuck onto the outer shell of the nanoparticle so that it’s “visible” to the immune system when it enters the body (Figure 2). The body will recognize the nanoparticle as foreign and create antibodies to capture it. Without a way to get into the brain, the physiological response to nicotine would be lessened which could reduce interest in smoking.

In order to test how well the nicotine vaccine works, Dr. Desai's lab uses a drug discrimination assay. In humans, this would be really easy: just ask if they feel like they've been injected with nicotine or saline. Animals can't answer, of course, but we can get an idea of their ability to discriminate between the presence of a particular dose of a substance and its absence, which we can track. Dr. Desai's lab does this using squirrel monkeys and a lever pressing operant chamber. In a recent study, one group of animals received nicotine before being placed in the chamber and were trained to turn off stimulus lights associated with the delivery of a reward when they pressed, for example, the right lever. This group was called "nicotine-experienced" and is analogous to people who already use nicotine. After being trained to recognize that they'd been given nicotine these animals received the vaccine. Another group of animals received the vaccine before exposure to nicotine and the discrimination test. They were trained to press, for example, the left lever for a reward. This group was called "nicotine-naïve", and was similar to people who have never used nicotine. The dosing schedule for the vaccine, whether received before or after nicotine exposure, was one dose per month for five months.

The nicotine-naïve group of animals, which had the vaccine prior to nicotine exposure, was unable to distinguish between saline and nicotine! This suggests they did not experience the subjective effects of nicotine, which is great! Subjective in this case means they didn't feel like they had received nicotine even though they had. The nicotine-experienced group, which received the vaccine after being trained to recognize nicotine were unable to identify the previously recognizable dose of nicotine. However, in test sessions with higher doses of nicotine they could detect the presence of nicotine. In humans, this would translate to: "Hey, I'm not getting the same feeling I used to get from this. I think I'll try taking more." Although it's important to note that they weren't self-administering higher doses but rather reporting that they had been given a higher dose.

The results suggest people who have never smoked would benefit most from this type of vaccine. It seems almost counterintuitive because helping people who already smoke to quit is generally the goal in smoking-related research. There would be barriers to implement full scale use of a vaccine that needs to be given to prior to someone starting smoking. However, this is how vaccines work: they're given before exposure to the illness so that the body can respond when they do encounter it. 

Because smokers are 13-23 times more likely to develop lung cancer it makes sense to try to prevent them from ever starting to smoke (American Lung Association). Widespread use of a nicotine vaccine could be controversial, but identifying and vaccinating people from high risk groups could be more acceptable. 

In addition, the vaccine could also be effective for people who already use nicotine if it were combined with a pharmacological approach. The vaccine could prevent some of the nicotine from getting into the brain. The nicotine still sneaking into the brain, and the addiction-related effects it would have, could be treated with a lower dose of a drug designed to help people quit smoking, like Chantix. Research is ongoing to identify other potential drugs that may keep nicotine from exerting its effects on the brain. Using a lower dose of either current or future therapeutics would help avoid side effects. Both anti-nicotine vaccines and pharmacological approaches could also be combined with a behavioral treatment strategy, such as counseling, incentive programs, and cognitive behavioral therapy to counter the other aspects tobacco addiction. 

The promising research presented at this symposium suggest nicotine use could be dramatically decreased and that quitting would be easier than trying to go cold turkey and dealing with the full effects of nicotine and tobacco withdrawal. 

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