Targeting nicotine addiction: the possibility of a therapeutic vaccine

Figures & data

Figure 1 Chemical structure of nicotine (with permission Bentham Science Publishers^©).⁶⁵

Table 1 Nicotine replacement therapies and their combinations

Formulation	Population	Comments	Refs.
Nicotine nasal spray	∼36% nonwhite smokers (Hispanic)	The proportion of patients who achieved smoking cessation was significantly greater with nicotine nasal spray compared with the nicotine transdermal patch. May cause nose and eye irritation or cough. Higher potential for addiction compared with other nicotine replacement therapies.	^Citation62^–^Citation65
Transdermal nicotine patches	British, native Alaskans and American Indians	No significant findings favoring the use of nicotine transdermal patches were noted between the intervention and control groups. Emotional symptomatology appeared in patients: affective blunting; anhedonia with tiredness and lack of energy; anxiety; hypersensitivity; and tension. Less potential for addiction compared with gum.	^Citation63,Citation66,Citation67
Nicotine lozenge	American, British (UK)	Similar results among smokers regardless of success or failure of previous pharmacologic therapy. May cause mouth soreness or dyspepsia.	^Citation68,Citation69
Nicotine inhaler	British, American	Flexible dosing; mimics hand-to-mouth action of smoking; few side effects. Frequent dosing necessary. May cause mouth and throat Irritation. It is contraindicated for pregnancy category D, cardiovascular precautions.	^Citation63,Citation70
Nicotine gum	British, American	Quit rates were higher in specialized cessation clinics than in primary care settings; higher potential for addiction than the patch. Avoid in patients with dental problems or temporomandibular joint syndrome. Cardiovascular precautions.	^Citation63,Citation71,Citation72
Transdermal nicotine patch and nicotine gum	Belgian	Combination more effective than either agent alone.	^Citation73
Transdermal nicotine patch and nicotine spray	Icelander	Combination more effective than either agent alone.	^Citation74
Transdermal nicotine patch and nicotine inhaler	French	Combination more effective than either agent alone.	^Citation75
Group-based cognitive–behavioral therapy and transdermal nicotine patches	African-American, American	The results show that 7-day point prevalence abstinence was significantly greater in the group-based cognitive–behavioral therapy than the group general health education at the end of counseling (51% versus 27%), at 3 months (34% versus 20%), and at 6 months (31% versus 14%). Long-term quit rates could be improved by education programs.	^Citation76,Citation77

Table 2 Non-nicotine replacement therapies and their combinations

Formulation	Population	Comments	Refs.
Varenicline	Asian	Helps patients achieve smoking cessation by reducing cravings/withdrawal symptoms and smoking satisfaction. The most commonly reported adverse effects for varenicline, bupropion sustained release, and placebo in the pooled analysis were nausea (28.8%, 9.9%, and 9.1%, respectively), insomnia (14.2%, 21.5%, and 12.6%), and headache (14.2%, 11.1%, and 12.4%). Particular attention with patients with comorbid conditions such as those with psychiatric disorders and cardiovascular disease. There is no consistent evidence that varenicline reduces weight gain compared with placebo.	^Citation78^–^Citation85
Bupropion sustained release	African-American	Smokers abstain at a significantly greater rate (P < 0.05) when using bupropion sustained release versus placebo.	^Citation86
Bupropion sustained release	American	The efficacy of bupropion has been confirmed in several large studies. Its most common side effects (occurrence >1:100) are dry mouth, headache, nausea and insomnia and its most rare side effects (occurrence > 1:10,000 and <1:1000) are seizure, severe hypersensitivity reaction. Moreover, bupropion has been reported more effective than the nicotine patch. Bupropion advantage is that it reduces post-cessation weight gain (0.8 kg), compared with nicotine replacement therapies by 0.5 kg.	^Citation87^–^Citation91
Nortriptyline	American, Brazilian	In controlled clinical trials nortriptyline alone has shown to be effective with odds ratios ranging from 1.2 to 5.5, for smoking cessation in four studies, with only one study lacking a statistically significant benefit. The smoking cessation rates achieved with nortriptyline appear to be comparable to those achieved with bupropion. Common side effects reported are dry mouth, light-headedness, shakiness, and blurred vision, although urinary retention, constipation, sexual difficulties, and risk of seizures.	^Citation92^–^Citation96
Clonidine (can be taken orally or through a transdermal patch)	American, Chinese, French	Placebo-controlled clinical trials indicate that clonidine is superior to placebo (2.4 and 2.0 ratios). This is comparable with the efficacy of nicotine replacement therapies and bupropion. It may be beneficial in female smokers. Significant side effects, such as dry mouth, dizziness and postural hypotension make its use less desirable. Patients with a history of depression or occlusive peripheral vascular disease should avoid using clonidine.	^Citation97^–^Citation99
Endogenous Opioids (EOPs) – naltrexone	American	There is conflicting evidence for the effectiveness of naltrexone monotherapy for smoking cessation.	^Citation100
Naltrexone and Transdermal nicotine patch	84.3% of white American	Treatment with low-dose naltrexone does not significantly reduce weight gain or improve smoking cessation in highly weight-concerned smokers. Given that this population gained relatively little weight even on placebo, cognitive interventions to reduce weight concerns in combination with approved smoking cessation pharmacotherapy are preferable. Nevertheless, there may be other sub-populations of smokers at risk of substantial weight gain following smoking cessation for whom the weight suppressing effects of naltrexone might be of benefit.	^Citation101
Naltrexone and bupropion	White American, American, non-obese adults, overweight and obese adults	Smoking cessation rates are similar to bupropion, but there was a significant trend for less weight gain with the combination than with placebo and monotherapy.	^Citation102,Citation103
Naltrexone and bupropion both sustained release formulations, plus behavioral counseling	93.3% white American with overweight or obese adults	Combination decreased nicotine use, limited nicotine withdrawal symptoms, and no significant weight gain. The most common adverse events were nausea, insomnia, and constipation.	^Citation104
Selective serotonin reuptake inhibitors (SSRIs)	British, American	Significant short-term effect (6 months). None demonstrated any long-term benefit.	^Citation105,Citation106
– fluoxetine and paroxetine		An analysis of fluoxetine trials with negative results indicated some benefit in the subgroup of smokers who had a history of major depression.
Selective serotonin reuptake inhibitors (SSRIs) Anxiolytics: – buspirone – diazepam – meprobamate – propanolol – metoprolol – oxprenolol – ondansetron	American, British	Buspirone does not cause physical dependence. However, a placebo-controlled trial failed to support its efficacy in smoking cessation. Anxiolytics have been examined to aid smoking cessation, finding no or unclear effects on abstinence or withdrawal symptoms.	^Citation107,Citation108
Mecamylamine	American and Canadian	Mecamylamine reduces cholinergic activity, so it was hypothesized that it may reduce urges to smoke by blocking the rewarding effect of nicotine, and be most effective when combined with nicotine replacement therapies. Mecamylamine, compared to placebo, increased the number of cigarettes smoked and plasma nicotine levels. Moreover, it increased smoking intensity and resulted in greater plasma nicotine levels in smokers with schizophrenia compared to controls.	^Citation109^–^Citation111
Monoamine oxidase (MAO) inhibitors: – moclobemide – selegiline hydrochloride	American and Canadian	In one long term trial, moclobemide was found to have a significant effect on smoking cessation at 6 months, but not at 1 year, compared with placebo. Selegiline hydrochloride was safe and well-tolerated by adult cigarette smokers, but did not improve smoking abstinence rates compared to placebo. A common adverse effect reported for selegiline hydrochloride was dry mouth.	^Citation112,Citation113

Table 3 Companies and countries involved in the design and development of vaccines for smoking cessation

	Country
Main companies
Cytos AGN	Switzerland
Nabi, Inc	United States
Celtic Pharma	United Kingdom
Other companies
Chilka Ltd	British Virgin Islands
Scripps	San Diego, USA
Pharmaceutica AB	Stockholm, Sweden
University of Nebraska	USA

Table 4 Inclusion and exclusion criteria for the clinical trials of main companies involved in the development of smoking cessation vaccine

Company	Inclusion criteria	Exclusion criteria
Cytos AGN	Participants between 18 and 70 years, to have been smoking at least 10 but no more than 40 cigarettes/day for more than 3 years, and willing to quit smoking. Women of childbearing age had to agree to use an effective form of contraception during treatment and up to 12 months after the last dose of the vaccine.	Cardiovascular, renal, pulmonary, endocrine, or neurological disorders, ulcers, skin disorders, autoimmune diseases or severe allergies; behavior likely to promote HIV acquisition; an active liver infectious disease; a current diagnosis or a history of major depressive episodes, of panic attacks, psychosis, bipolar or eating disorders; use of other smoking-cessation treatments, like bupropion or nicotine replacement therapy within 6 months before study enrollment or at the time of screening; pregnancy or lactation; abuse of alcohol or other recreational drugs; use of a psychoactive drug (excluding sleeping pills) within one month before enrollment; and regular use of any non-cigarette tobacco product.
Nabi, Inc	Participants between 20 and 65 years, willing to quit smoking.	Cardiovascular, renal, pulmonary, endocrine, or neurological disorders, not using other smoking cessation therapies for at least six months before the study.
Celtic Pharma	Participants between 18 and 70 years, willing to quit smoking.	Cardiovascular, renal, pulmonary, hepatic, endocrine, or neurological disorders, ulcers, and autoimmune diseases

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