Tobacco use is the leading preventable cause of death in the world. Currently, about 1 billion people smoke of which eventually half will die from smoking-related diseases . Worldwide, approximately 6 million people die from smoking each year, including more than 600,000 non-smokers who die from secondhand smoke . Although smokers are generally aware of the health consequences of smoking they have major difficulties to stop smoking . Without the use of effective therapies, less than 5% of the smokers are able to stay abstinent for one year after a quit attempt .
Nicotine is responsible for the addictive mechanism of tobacco use and the difficulties that smokers encounter when trying to quit smoking and remain abstinent. After inhalation of cigarette smoke, nicotine almost immediately travels to the blood stream and crosses the blood–brain barrier within 10 to 20 seconds . At this point the nicotine molecule acts on several neurotransmitter systems where it activates α4β2 nicotinic acetylcholine receptors and the dopamine reward system responsible for the reinforcing and addictive effects of nicotine .
Pharmacotherapy treatment for smoking cessation focuses on minimizing the nicotine withdrawal effects by substitution of the nicotine reward effects or by attenuating the reinforcing effects of tobacco [6, 7]. Currently available therapies such as nicotine replacement therapy (NRT), psychotropic drugs, and partial nicotine acetylcholine agonists, in combination with behavioral support, can increase abstinence rates to a maximum of 20 to 25% after one year [6, 8–10]. NRT reduces withdrawal by replacement of nicotine, which might result from abrupt cessation of nicotine use  while psychotropic drugs, such as bupropion and nortriptyline cause a blockade of neuronal re-uptake of several neurotransmitters like norepinephrine, serotonine, and dopamine . Blockage of this “biology of nicotine addiction” will reduce the reinforcing effect of nicotine and withdrawal symptoms . A more recent developed treatment strategy is the use of partial nicotine acetylcholine agonists like varenicline and cytisine, which stimulate the release of sufficient dopamine to reduce craving and withdrawal while simultaneously acting as a partial antagonist by blocking the binding and consequent reinforcing effects of inhaled nicotine [11, 12].
Since the majority of smokers who attempt to quit still fail to achieve long-term abstinence, and most smokers relapse in the first 8 days, the need for better cessation approaches is of major importance . A potential new treatment approach in smoking cessation and relapse prevention is nicotine vaccination, in which smokers who want to quit smoking receive multiple injections of a nicotine conjugate vaccine.
Nicotine vaccination: mechanism of action
Nicotine vaccination is a new therapy which is based on active immunization against the, otherwise, non-immunogenic, nicotine molecule. For this purpose, the small nicotine molecule is conjugated to a much larger carrier protein to induce and activate the immune system to produce highly specific nicotine antibodies . These antibodies sequester nicotine in the blood stream, after inhaling tobacco products, and the resulting antigen-antibody molecule becomes too large to cross the blood–brain barrier . By preventing large amounts of nicotine reaching the central nervous system, nicotine vaccination is believed to attenuate the rewarding effect of nicotine .
The nicotine conjugate vaccine NicVAX®, developed by Nabi Biopharmaceuticals, was initially developed as an aid in smoking cessation. For this purpose, multiple injections are administered prior to the planned quit date resulting in a gradual increase in anti-nicotine antibodies which helps smokers in gradually reducing the number of cigarettes and eventually achieve complete abstinence . Nicotine vaccines could also be used to prevent relapse. Hence, vaccinated ex-smokers who lapse (i.e., take a puff of a cigarette, have a positive smoking status for 1 week after a period of abstinence) are expected to experience diminished reward from nicotine inhalation which could prevent a full blown relapse (i.e., a positive smoking status for at least 2 weeks after a period of abstinence) . The effects of a brief exposure to a positive stimuli such as second hand smoke may also be blunted.
Nicotine vaccination: safety
Three phase I/II clinical trials with NicVAX® have been published so far. Two of these studies were designed to evaluate the immunogenicity and safety [18, 19], while another study was especially designed to demonstrate the proof of concept to determine the relationship between immunogenicity and smoking cessation outcomes . Regarding the reported safety data, participants commonly reported local reactions at the injection site like ‘ache’ and ‘tenderness’. The reported systemic reactions were mostly mild to moderate of intensity and included symptoms of general discomfort/malaise, myalgia, and headache . There was no significant difference in local and systemic reactions between the placebo group and the NicVAX® treatment group . Of all reported safety data, there was only one serious adverse event (anaphylactic reaction) in a subject with a history of allergic reactions that was considered by the investigator to be treatment-related .
Nicotine vaccination: immunogenicity
Immunogenicity has been shown to be dose-related. Additional injections and higher vaccine doses have been shown to be related to stronger immune responses and higher antibody titers . These antibody titers typically peak following the final injection when 4 or 5 vaccinations are administered .The peak geometric mean antibody concentration reported in response to the nicotine conjugate vaccine NicVAX® was 45 μg/ml in the subgroup who received 5 injections with 400 μg of NicVAX®. Previous data reported no difference in antibody response between smokers and non-smokers .
Nicotine vaccination: efficacy
Currently, only one study has been published to evaluate the relationship between smoking cessation outcomes and immunogenicity in smokers treated with 4 or 5 injections of NicVAX® in different dose schedules . A subgroup of the top 30% antibody responders were significantly more likely than the placebo group to achieve 8 weeks of continuous abstinence from weeks 19 through 26 (24.5% vs. 12.0%, odds ratio (OR) = 2.69, 95% confidence interval (CI) = 1.14–6.37) and weeks 19 through 52 (19.7% vs. 10.0%, OR = 2.64, 95%CI = 1.03–6.79). The target quit day was dependent on the dose regimen, which was either week 5 (for 5 injections schedule) or week 7 (for 4 injections schedule). Smokers who received the 5 injection schedule with 400 μg NicVAX® dose elicited the highest antibody response, which resulted in significantly higher abstinence rates than placebo . In vaccinated smokers who failed to quit smoking, the authors observed a statistically significant reduction in daily cigarette consumption between the top 30% antibody responders and the placebo group in weeks 19–52; the median reduction in cigarette consumption between both groups was 4.6 cigarettes a day . There were no differences in withdrawal symptoms and no evidence for compensatory smoking in those smokers who received injections with NicVAX®.
During the conduct of the current study, Nabi Biopharmaceuticals announced negative results of two phase III, randomized, placebo controlled trials on the efficacy of NicVAX®. Both trials were designed identically and included approximately 1,000 smokers who received a set of 6 injections of 400 μg NicVAX® or placebo. The preliminary results of the trials showed that the primary endpoint of 16 weeks abstinence measured at 12 months was not met; there was no statistically difference between the NicVAX® and placebo group .
Nicotine vaccination: rationale for combination with varenicline
The purpose and rationale of the proposed study is to evaluate the efficacy of NicVAX® co-administered with varenicline as an aid to smoking cessation, long-term abstinence, and relapse prevention. Preliminary data on NicVAX® suggest that antibody levels peak after the last injection, and it is therefore likely that smokers who quit smoking have less difficulty to remain abstinent.
In the proposed study we combine NicVAX® with a 12-week treatment of varenicline to stimulate participants to stop smoking before week 12. Varenicline is used for immediate smoking cessation by reducing withdrawal and craving during the first 12 weeks of treatment. Varenicline has proven to be superior to placebo for smoking cessation at one year of follow-up . Therefore, this phase IIb study design will be ideal to evaluate relapse, especially because end of treatment abstinence with varenicline is about 45% from weeks 9 to 12 . The current trial is designed so that the anti-nicotine antibody concentration at the end of the varenicline therapy (week 12) would be high enough to decrease the chance of relapse, occurring 2 weeks after the 4th vaccination. It is worth noting that anti-nicotine antibodies in response to NicVAX® do not cross react with varenicline.[Nabi unpublished data]
The primary objective of our trial is to evaluate the efficacy of 6 injections with 400 μg of the nicotine conjugate vaccine NicVAX® or placebo co-administered with varenicline for smoking cessation and relapse prevention, by comparing biochemically validated prolonged abstinence from week 9 to 52 in smokers who want to quit.
There are several secondary objectives which aim to understand the benefit of NicVAX® vaccination co-administered with varenicline for smoking cessation. The most important secondary objectives will be described in detail in this article (an overview of all other secondary objectives is listed in Appendix A).
To evaluate the safety and immunogenicity of NicVAX®.
To evaluate abstinence rates from week 37–52
To evaluate abstinence rates from week 9–24
Abstinence from week 9–52, week 9–24 and 37–52 in the subset of NicVAX subjects with the high antibody responses.
To evaluate lapse and relapse rates from week 12–52.
To evaluate withdrawal symptoms using the Minnesota Nicotine Withdrawal Scale (MNWS).
To evaluate nicotine dependency measured by the Fagerström Test for Nicotine Dependence (FTND).
To evaluate cigarette consumption.
The Dutch Central Committee on Research Involving Human Participants approved the study protocol (NL25046.000.08).
This trial is registered at ClinicalTrials.gov (NCT00995033).