Nicotine Conjugate Vaccine as a Novel Approach to Smoking Cessation

Anne R. Ottney, Pharm.D


Pharmacotherapy. 2011;31(7):703-713. 

In This Article


Nicotine is an alkaloid molecule (pKa 8.5), with a low molecular weight.[11] When inhaled through a cigarette, nicotine escapes first-pass metabolism in the liver and enter the lungs rapidly in smoke particles. Nicotine is absorbed in the pulmonary venous circulation and then enters the arterial circulation, where it is routed to the brain within a matter of seconds. Once across the blood-brain barrier, nicotine binds to nicotinic acetylcholinergic receptors in the central nervous system, with the highest affinity for the α4, β2 subunit. Repeated exposure to nicotine creates an upregulation of nicotinic receptors in the brain.

Due to its low molecular weight, nicotine does not have the potential to generate an immunogenic response on its own; however, attachment to a carrier protein renders a molecule large enough to be recognized by the body and ultimately elicit a reaction by the immune system. Although a variety of carrier proteins are available to attach to nicotine molecules, the 3′-AmNic-rEPA vaccine uses a bacterial toxin, Pseudomonas aeruginosa exoprotein A coupled with 3′-aminomethylnicotine, as a hapten to produce a functional unit. The Pseudomonas exoprotein used in the vaccine has been made nontoxic by an amino acid deletion. Vaccine administration produces nicotine-specific antibodies that are able to bind to nicotine from exogenous sources (e.g., cigarettes, nicotine replacement therapy) when introduced into the bloodstream. The coupling of the nicotine-specific antibodies with administered nicotine creates a large unit that is not able to cross the blood-brain barrier, limiting the rate and extent of nicotine absorption into the brain (Figure 1). The 3′-AmNic-rEPA vaccine has been shown to have a 2.7% cross-reactivity with cotinine, the major metabolite of nicotine.[12] Cotinine is a useful measure of nicotine exposure because of an extended half-life of 18–20 hours compared with the short half-life of nicotine (~2 hrs); however, cotinine does not cross the bloodbrain barrier and plays a minimal role in the development and maintenance of nicotine addiction.[5,13]

Figure 1.

Mechanism of action of the 3′-AmNic-rEPA vaccine. (A) Nicotine inhaled through smoke particles from cigarettes travels into the lungs where molecules are absorbed into the venous circulation, then routed to nicotinic cholinergic receptors in the brain, releasing dopamine among many other neurotransmitters. (B) In a subject immunized with the 3′-AmNic-rEPA vaccine, nicotine is bound to nicotine-specific antibodies present in the bloodstream after vaccination, minimizing nicotine distribution to the brain. Decreased nicotine distribution to the brain results in a decline in the reinforcing properties of nicotine.


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