ASPET 2014: Vaccinating against the effects of nicotine
April 27, 2014
This platform presentation was in symposium 166. New Preclinical and Clinical Perspectives for Smoking Cessation on Sun, Apr 27, 3:00 – 5:30 PM at the 2014 Experimental Biology meeting.
R. I. Desai (University website, PubMed) presented new results from a study of a vaccine designed to attenuate the effects of nicotine.
I previously discussed the principles involved in anti-cocaine vaccination, and NIDA has generated this handy video explainer on the basic principle of vaccination against drugs of abuse
Desai noted at the outset that there have been four anti-nicotine vaccines developed by drug companies with some of them advancing to Phase II or even Phase III trials. As he remarked, they have all been viewed as failures. Nevertheless it is the case that some of the failures have been due to insufficient antibody titer having been produced in a relatively large proportion of the subjects. Thus, it may be that the principle is still sound but that the vaccines need to be improved in terms of generating more consistent, high antibody titers.
This study used the SEL-068 nano particle vaccine described here in abstract form. Although Desai did not hammer home the point in his presentation, one presumes that this new nanoparticle vaccine is hypothesized to generate higher antibody levels in animals.
This particular study used the drug discrimination procedure (see here for description) to evaluate the interoceptive stimulus or subjective properties of nicotine in squirrel monkeys. The animals were trained to discriminate nicotine from saline pretreatment with a stimulus-termination procedure; one lever was correct when nicotine had been administered and the other lever was correct when saline had been administered. Control animals learned the discrimination well within 30 sessions and some evidence of learning could be observed as early as 3-4 sessions of training.
The control animals received vaccination only after the nicotine/saline discrimination had been learned. The training drug was changed to epibatidine ( a nicotine acetylcholine receptor agonist, i.e., similar to nicotine in pharmacological action) during the vaccination to avoid complicating interpretation of the discrimination behavior. After a few weeks of the vaccination treatment, discrimination for epibatidine was high, however the animals were now unable to discriminate the original training dose of nicotine. A follow-up nicotine dose-substitution challenge showed that only a minor rightward shift of the dose-response function had been produced. A slightly higher dose of nicotine engendered over 80% responding on the lever associated with epibatidine (and previously nicotine).
The effect of vaccination could be overcome by slight increases in the dose, at least in animals previously experienced with nicotine.
Interestingly, the animals that were vaccinated prior to the start of any discrimination training did not learn the nicotine discrimination. Over about 30 training sessions, there was no selective responding on the nicotine paired lever when nicotine had been administered. This indicates that the subjective feeling of the training dose of nicotine had been attenuated to the point where it wasn’t reliably different from vehicle exposure.
The research team then went on to train the vaccinated group to discriminate epibatidine from saline. In this case, the discrimination was established with about the same time course as was seen for nicotine in the non-vaccinated group. It is structurally different, thus antibodies specific to nicotine that were generated by the vaccine would not be expected to recognize epibatidine. This part of the study shows that the vaccinated animals would still be able to form a discriminative set based on the activity of receptors through which a major part of nicotine’s action is conferred.
One of the most interesting outcomes of this study was that the learning of a discrimination based on nicotine could be blocked by vaccination. This tends to suggest that the most effective clinical target will be to vaccinate children before they have any experience with nicotine.
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also see Would you vaccinate against drug abuse?
DrugMonkey 
April 28, 2014 at 11:16 am
I work in the traditional infectious disease vaccine space. Here we try to elicit antibodies or T cells to foreign antigens. Once the infection is cured, there is nothing left for the immune system to interact with and it winds down until the next encounter with the same pathogen. Making vaccines against self-antigens seems counter-intuitive in that the antigen is never cleared so the immune system either causes chronic inflammation in the brain or simply becomes tolerant. A neurobiologist I am not, but presumably nicotine receptors have a day job which would also be disrupted by blocking antibodies?
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April 28, 2014 at 12:46 pm
@bacillus
The endogenous agonist for nicotinic receptors is the neurotransmitter acetylcholine. Since it does not have the same molecular structure as nicotine, it should not be blocked by the antibodies.
The antibodies would not cross the blood-brain barrier so brain inflammation would not be a problem. The NIDA video above did not mention any type of other inflammatory side effects, but it did say that a new dose would need to be given pretty frequently (every few days or weeks)–so presumably the antibody titer does not stay chronically elevated.
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April 28, 2014 at 1:32 pm
It is definitely a challenge to maintain antibody titer….this area of research is on the weeks to months scale of success at the moment, from what I’ve seen. not on the years scale. and obviously for functional efficacy you want to maintain high circulating antibodies…rapid scale up one re-exposed, a la pathogen response, isn’t going to do the trick
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April 28, 2014 at 3:04 pm
If my understanding of the abstract is correct, the antibodies will recognize the nicotine compound, not the receptors. Though, if it worked, would a cigarette would cause a several-day long bout of flu like symptoms … that would seriously suck. Would there be other issues wrt clearance, eg, people with IgA nephropathy or colitis. Interesting.
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April 28, 2014 at 4:15 pm
Why flu-like?
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April 29, 2014 at 8:00 am
Thanks to all for the education.
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