Smoking has many serious adverse effects on health and with many government initiatives to reduce or prevent smoking, it has become less socially acceptable. Consequently, many smokers wish to quit the habit, and while many make attempts each year, only a small minority of those who manage to quit do not relapse. The very high failure rate is the result of the addictive nature of nicotine plus the easy availability of cigarettes.
With smoking, or use of nicotine in other forms (e.g., sinus, patches, gum), nicotine enters the bloodstream and rapidly thereafter enters the brain, where it stimulates nicotinic acetylcholine receptors, causing release of dopamine, which in turn activates reward centres. With a smoking quit attempt, there is a loss of the reward response, as well as withdrawal symptoms including a decline in cognitive function. The main reason for relapse is that the loss of reward and the unpleasant withdrawal symptoms can immediately be relieved by smoking.
There are various non-vaccine therapies for smoking cessation. Nicotine replacement therapy, such as nicotine containing chewing gum or skin patches, may help wean smokers off cigarettes but they do not break the addiction cycle that nicotine causes. Another approach is the use of drugs that target nicotinic acetylcholine receptors, such as varenicline. Such drugs, which reduce the rewards normally encountered by smoking, have been relatively successful in aiding smoking cessation, however relapse rates are high after drug treatment ends since a lapse (e.g., smoking a single cigarette) can easily turn into a full relapse with reactivation of reward centres.
More recent nicotine cessation strategies have focused on vaccines that stimulate the immune system to produce anti-nicotine antibodies that bind to nicotine in the bloodstream, thus reducing the amount and rate that nicotine can enter the brain. This in turns prevents reward centres from being activated and helps break the addiction cycle. Since antibodies induced by vaccines can be long-living, anti-nicotine vaccines are useful both to assist in smoking cessation as well as prevention of relapse. Additionally, since the antibodies act in the periphery, there is no risk of central nervous system (CNS) adverse effects. Examples of such vaccines are described in WO 00/32239, WO 02/49667, WO 03/82329 and US 2006/111271. Nicotine derivatives are described in EP-A-421762, WO 01/70730, WO 01/80844 and US 2005/119480. Further nicotine derivatives have been identified under registry numbers 136400-02-7, 250683-10-4, 861023-80-5 and 861025-04-9. Nicotine haptens are described in WO 99/61054, WO 02/58635, WO 03/82329, WO 2005/40338 and EP-A-1849780.