At least four vaccines against nicotine are currently under clinical development,[ 74 ] but peer-reviewed reports have only been published for two of them:. This vaccine was developed by Nabi Pharmaceuticals and is currently being further evaluated for clinical use by GlaxoSmithKline. NIC synonym: NicotineQb[ 17 , 19 ] contains a nicotine derivative coupled to a virus-like particle formed by the coat protein of the bacteriophage Qb in Escherichia coli. This vaccine was developed by Cytos Biotechnology; further clinical evaluation is being carried out by Novartis.
All published clinical trials used alum as an adjuvant to boost immune responses. A summary of preliminary results published on company websites can be found elsewhere. In the following section, principal results regarding safety, immunogenicity and efficacy are reviewed. Three studies two using NicVAX[ 18 , 20 ] and one using NIC[ 19 ] were primarily designed to assess safety and immunogenicity and therefore included smaller groups of non-smokers or smokers not intending to quit; cessation counselling was not offered in these studies.
Two more recent trials also assessing efficacy included smokers willing to quit. The comparability of results is impaired by the fact that counselling was only provided in two out of five trials. Studies differed regarding vaccine doses used and vaccination schemes for details see table II. Mild to moderate local reactions at injection sites ache and tenderness were common in all studies.
Systemic reactions, which were also mild in most cases, included myalgia, malaise and headaches. The prevalence of these symptoms was similar in participants receiving a vaccine and those receiving adjuvant without the active vaccine, indicating that adverse events were not related to the vaccine itself. The immune response to nicotine vaccination was highly variable in all five trials.
As a common feature, higher vaccine doses elicited stronger responses, and antibody titres tended to peak following the final injection although this was not observed in all studies.
Data on antibody specificity following vaccination in humans have not been published. Three trials reported data on smoking status. At the same time, vaccination did not appear to induce withdrawal symptoms in smokers.
The first study formally assessing continuous abstinence rates was published in However, a per-protocol analysis excluding all subjects with concomitant use of nicotine replacement therapy revealed significantly higher abstinence rates in the upper third of responders i.
This difference was maintained until 12 months Based on these results, a subsequent trial was intended to further establish a relationship between antibody titres and smoking outcome. In addition, continuous abstinence was enhanced in subjects receiving the most intensive vaccination regimen.
However, in contrast to expectations from animal studies, vaccination failed to increase continuous abstinence rates over placebo. The basic idea of preventing nicotine from entering the brain, thereby blocking its rewarding effects in the mesolimbic system is attractive as antibodies are unlikely to elicit adverse effects within the brain[ 67 ] that have been described for other smoking-cessation medications.
A further advantage of this novel approach is that treatment adherence is likely to be favourable[ ] as vaccination requires only a limited number of injections and no daily dosing. Clinical trials have partially confirmed preclinical observations e. Knowledge of the reasons for this failure of the vaccination concept to successfully translate to the clinical setting is crucial for the future development of nicotine vaccines.
In addition, as nicotine-binding capacity is not only determined by antibody concentration, a more thorough investigation of antibody affinity and specificity in these trials would have been desirable. However, some issues going beyond these practical aspects need to be addressed in order to understand the obvious discrepancy between preclinical and clinical findings. Recent research into the pathophysiology of drug dependence indicates that viewing nicotine peaks and subsequent dopamine release in the NAcc as an indispensable element of tobacco addiction may be too simplistic.
Thus, dopaminergic VTA neurons have been found to increase their activity not only in response to nicotine but also in the presence of aversive stimuli,[ ] and animal studies suggest that hedonic responses can be elicited in the absence of dopamine. Finally, the whole concept of nicotine concentration peaks underlying the rewarding effects of smoking has been questioned by a positron emission tomography PET study suggesting a gradual increase in brain nicotine levels during smoking with no evidence of concentration peaks following each puff.
Until recently,[ ] the non-nicotinic components of tobacco addiction[ ] have received relatively little scientific attention. It is now recognized that tobacco addiction results from an interplay of pharmacological, psychological, genetic and environmental factors. Results of animal experiments indicate that nicotine and other agents might support early conditioning of the reward response triggered by smoking-related cues.
At a later stage, these conditioned stimuli might be sufficient to generate feelings of reward. At first glance, preclinical studies provide convincing evidence that a nicotine vaccine is likely to reduce nicotine self-administration[ 70 ] and possibly even attenuate withdrawal symptoms,[ 96 ] thus facilitating smoking cessation and preventing relapse. However, although great efforts were made to adjust nicotine concentrations in animals to those observed in smokers,[ ] the extent to which these findings can be applied to tobacco addiction in humans remains unclear.
First, much of this evidence relates to serum and brain nicotine concentrations measured shortly after the intravenous application of nicotine table I. Most animal models did not use nicotine inhalation as the primary route of drug administration. In addition, these experiments have not assessed temporal patterns of nicotine distribution to different organs including the brain[ ] and the lungs. Second, the immune response elicited by vaccination against nicotine may differ from species to species.
Yet, this difference might be attributable to the heterogeneous methodology in determining antibody levels. Third, as the rewarding properties of nicotine are limited,[ 51 ] preclinical research paradigms focusing on reinforcement[ ] may not be sufficient to model the complex pharmacological and behavioural aspects of smoking and cessation. In fact, animal studies have rarely used the cues and psychosocial processes associated with relapse.
As an introduction of nicotine vaccines to international markets will depend on the results of future trials, these studies need to be carefully designed. Despite the conclusion drawn from preclinical studies that a nicotine vaccine might be primarily useful in preventing relapse, published clinical trials were designed as smoking-cessation studies including target quit dates. They mainly assessed continuous abstinence rather than withdrawal severity, the incidence of lapses and their progression to full relapse.
In addition, antibody characteristics, including affinity and specificity, clearly have a huge impact on functionality[ 74 ] and thus require thorough evaluation in clinical trials. Careful selection of primary study endpoints and secondary measurements is therefore warranted for these trials, and study populations must be aligned to these endpoints.
Smokers who have already quit may represent an ideal target group for a relapse prevention study. However, the formation of sufficient amounts of antibodies takes at least 6 weeks, while most relapse occurs within the first 2 weeks of a quit attempt. Once these smokers feel prepared to quit, adequate antibody levels might be readily available. Finally, monotherapy with a nicotine vaccine does not appear to be a promising tool to overcome the complex physiological and psychosocial alterations observed in smokers.
Thus, a nicotine vaccine with sufficient efficacy could one day become part of a multifaceted intervention[ ] that includes behavioural as well as pharmacological approaches. Regarding the latter, varenicline might be used in combination with the vaccine as it produces high abstinence rates at the end of treatment,[ ] after which relapse needs to be prevented.
A 1-year study combining varenicline with placebo-controlled NicVAX focussing on relapse prevention in almost smokers is underway and may help to unravel a possible synergism between these drugs.
The utility of nicotine replacement therapy, bupropion and novel agents such as cytisine[ , ] in this setting also needs to be established. Finally, smokers who decide to quit spontaneously and seek immediate help might be offered passive immunization followed by pharmacotherapy to reduce craving and withdrawal symptoms while vaccination is started concomitantly in order to establish adequate antibody titres to prevent relapse at a later stage.
Vaccination against nicotine is an intriguing novel therapeutic approach to treating nicotine addiction. Animal studies indicate that antibodies profoundly change the pharmacokinetics of the drug and can interfere with nicotine self-administration.
In addition to assessing alternative routes of vaccine administration[ , ] and addressing ethical issues generally associated with vaccinations against drugs of abuse,[ , ] future studies will need to more clearly define the ideal indications and target populations for nicotine vaccines. Treatment of dependent smokers cannot be reduced to a course of vaccine injections but needs to acknowledge the complex pharmacological and behavioural aspects of smoking.
The authors declare that they did not receive any funding for the preparation of this review. He has been reimbursed for attendance and lecturing at several Pfizer symposia on smoking cessation from through He has also received travel expenses and honoraria from GlaxoSmithKline and Novartis.
None of these activities were related to this manuscript. Schayck received funding for research proposals from GlaxoSmithKline and Pfizer, as well as reimbursement for lecturing from Pfizer.
PHJ Hoogsteder has no conflicts of interest to declare. National Center for Biotechnology Information , U. Published online Nov Hoogsteder , and Constant P.
Onno van Schayck. Philippe H. Constant P. Author information Copyright and License information Disclaimer. Tobias Raupach, Email: ed. Corresponding author. This article has been cited by other articles in PMC. Abstract Tobacco smoking causes cardiovascular, respiratory and malignant disease, and stopping smoking is among the key medical interventions to lower the worldwide burden of these disorders.
Introduction There are currently 1 billion tobacco smokers in the world,[ 1 ] at least half of whom will eventually die from a smoking-related disease. Mechanisms of Nicotine Addiction 2. Vaccine Development: Rationale and Practical Aspects 3. Preclinical Studies 4. Open in a separate window. Table I.
Table II. Strengths and Limitations; Suggestions for Future Research The basic idea of preventing nicotine from entering the brain, thereby blocking its rewarding effects in the mesolimbic system is attractive as antibodies are unlikely to elicit adverse effects within the brain[ 67 ] that have been described for other smoking-cessation medications.
Conclusions Vaccination against nicotine is an intriguing novel therapeutic approach to treating nicotine addiction. Acknowledgements The authors declare that they did not receive any funding for the preparation of this review. References 1. WHO report on the global tobacco epidemic, warning about the dangers of tobacco.
Geneva: WHO, [online]. Mathers CD, Loncar D. Projections of global mortality and burden of disease from to PLoS Med. Benowitz NL. Nicotine addiction. Results from past, current and future research should be reported in full. Adverse events and serious adverse events should continue to be carefully monitored and thoroughly reported. By reducing the amount of nicotine that reaches the brain when a person smokes a cigarette, nicotine vaccines may help people to stop smoking or to prevent recent quitters from relapsing.
The aims of this review are to assess the efficacy of nicotine vaccines for smoking cessation and for relapse prevention, and to assess the frequency and type of adverse events associated with the use of nicotine vaccines. We searched the Cochrane Tobacco Addiction Review Group specialised register for trials, using the term 'vaccine' in the title or abstract, or in a keyword date of most recent search April We searched the Annual Meeting abstracts of the Society for Research on Nicotine and Tobacco up to , using the search string 'vaccin'.
We searched Google Scholar for 'nicotine vaccine'. We also searched company websites and Google for information related to specific vaccines. We searched clinicaltrials. We included randomized controlled trials of nicotine vaccines, at Phase II and Phase III trial stage and beyond, in adult smokers or recent ex-smokers.
We included studies of nicotine vaccines used as part of smoking cessation or relapse prevention interventions. We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, blinding of participants and personnel, reporting of outcomes, and completeness of follow-up. Our primary outcome measure was a minimum of six months abstinence from smoking.
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On May 11, , the U. You do not have to be a Michigan Medicine patient to schedule an appointment, but you do need a Michigan Medicine medical record number MRN. You can establish an MRN if you do not have one. All Michigan residents age 16 and older are eligible to receive the COVID vaccine, by appointment as supply allows.
The Pfizer-BioNTech vaccine is authorized for persons age 12 and up previously age 16 and up. Last Update Posted : January 12, Study Description. The purpose of this study is to determine whether vaccination with NicVAX will result in a higher continuous abstinence rate than vaccination with placebo in smokers who want to quit smoking.
In addition, two different formulations and dosing schedules will be studied, to select the dose and dosing schedule which generates the highest level of anti-nicotine antibodies. The primary study period is 12 months, which was extended by amendment to include up to 2 years of observations.
Detailed Description:. FDA Resources. Arms and Interventions. Other Name: 3'-aminomethylnicotine-rEPA conjugate vaccine. Outcome Measures. Primary Outcome Measures : Continuous smoking abstinence [ Time Frame: 8 week interval Weeks 19 to 26, inclusive, following the first vaccination ].
Secondary Outcome Measures : Point prevalence abstinence [ Time Frame: at 12 months, and other time points; extended up to 24 months ] Duration of smoking abstinence [ Time Frame: at 6 and 12 months ] Safety [ Time Frame: months, and extended up to 24 months ] Numbers of cigarettes per day [ Time Frame: Target quit day to 12 months ] Cumulative number of cigarettes smoked [ Time Frame: during weeks ] Exhaled CO [ Time Frame: at clinic visits ] Urine cotinine [ Time Frame: at clinic visits ] Modified Minnesota Nicotine Withdrawal Questionnaire [ Time Frame: weekly for 6 months, daily for 14 days after quit attempt ] Cigarette Evaluation Questionnaire a.
Nabi Questionnaire [ Time Frame: weekly for 6 motnhs ] Fagerstrom Test for Nicotine Dependence [ Time Frame: baseline, weeks 26 and 52 ] serum anti-nicotine antibody concentrations by Elisa [ Time Frame: periodic from baseline to month 12, extended to month 24 ]. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision.
Inclusion Criteria: Smokes at least 15 cigarettes per day Wants to quit smoking Good general health Negative pregnancy test prior to study entry Carbon monoxide level greater than 10 ppm Exclusion Criteria: Prior exposure to NicVAX or any other nicotine vaccine Known allergic reaction to alum or any of the components of the vaccine Use of steroids, immunosuppressive agents or other medication that might interfere with an immune response.
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