A Vaccine against Nicotine for Smoking Cessation: A Randomized Controlled Trial

Background:  A portion of the whole world smokes tobacco because of their addiction to nicotine. Tobacco is harmful to one’s body.  If there is an effective, easy way to quit smoking, such as a vaccination against nicotine, then less tobacco would be smoked and overall health status of individuals would improve.

Objective:  To assess the immunogenicity, efficacy, safety and tolerability of Nicotine-QB vaccine ( a vaccine against nicotine).

Methods:  The study was a parallel, double blinded, placebo-controlled experiment conducted between December 2003 and September 2004 at 3 centers in Switzerland.  Inclusion criteria included patients between 18 and 70 years of age who smoked 10 to 40 cigarettes per day for more than 3 years, a baseline Fagerstrom Score of at least 5 and are willing to quit smoking.  Women of childbearing age had to agree to use an effective form of contraception during treatment and one year after.  Exclusion criteria included:  cardiovascular, renal, pulmonary, endocrine, or neurological disorders, ulcers, skin disorders, autoimmune diseases or severe allergies; a current diagnosis or a history of major depressive episodes, panic attacks, psychosis, bipolar or eating disorders.  Also included in the exclusion criteria were use of other smoking cessation treatments within 6 months of study enrollment, pregnancy or lactation, abuse of alcohol or other recreational drugs, use of a psychoactive drug except for sleeping pills within one month of enrollment and regular use of a non-cigarette tobacco product.  Outcome measures included abstinence from smoking, immunogenicity, and safety and tolerability.  Abstinence from smoking was self-reported and confirmed by a carbon monoxide concentration in expired air of less than 10 ppm.  Immunogenicity was accessed by antibody response measured by ELISA titers.  Safety and tolerability was measured by vital signs, examinations, patient reported symptoms, Questionnaire on Smoking Urges and the Wisconsin Withdrawal Scale.  There were 341 patients enrolled and randomized into two groups.  A total of 229 patients received the Nicotine-QB vaccination and 112 patients received the placebo vaccination in the safety population.  The study consisted of 1 injection given once a month at months 0,1,2,3,4 and follow-up lasted 6 months.  Based on continuous abstinence rates, a sample size of 300 was sufficient to detect a difference of at least 15% with an alpha error of 5% or less and a power of 90% or more was calculated.  Pearson Chi-Square test without correction was used to determine the statistical significance of the effect of the vaccination.  Continuous data was analyzed using two-sample t-test or the Mann-Whitney test for two groups and data with more than three groups was analyzed with Kruskal-Wallis test.

Results:  Data was reported using the intention-to-treat population consisting of 229 patients receiving the experimental drug and 111 patients receiving placebo. The primary endpoints were immunogenicity, abstinence rates and safety and tolerability.  With regards to immunogenicity, patients receiving the vaccination had a 100% antibody response.  Abstinence rates were statistically significant at month 2 between the vaccinated (47.2%) and placebo (35.1%) groups P=0.036.  Abstinence rates after month 2 were not statistically significant.  Continuous abstinence rates between month 3 and month 6 were 30.1% in the vaccine group and 26.1% in the placebo group P=0.44.  “Flu-like” symptoms was the most common reported symptom associated with the vaccination 69.4% in the vaccinated group compared to 1.5% in the placebo group OR=15.9 (95%CI (8.5-29.8)).  Subgroup analysis was done to investigate the association of antibody levels with abstinence from smoking.  Subgroup analysis was done using per protocol population which consisted of 159 patients receiving the vaccine and 80 patients receiving placebo.  The subgroup analysis concluded that between months 2 and 6 there was a statistically significant difference in continuous abstinence rates between placebo and the 3 subgroups (low, medium and high) (P=0.012).  The difference in abstinence rates between high antibody responders (56.6%) and placebo (31.3%) at months 2 through 6 were both clinically relevant and statistically significant (P=0.004).  The author’s concluded the vaccination did not significantly increase continuous abstinence rates in intention-to-treat population.  However, subgroup analysis showed that patients generating a higher antibody response achieved a higher abstinence rate compared to placebo.  They also concluded that the vaccine was safe and generally well tolerated.

Strengths:  The study was a randomized, double-blind, placebo controlled design, which is the gold standard for a drug efficacy study (Phase II).  The background information provided an appropriate rationale for conducting the study.  The study’s blinding, power, sample size, and outcome measures were appropriate.

Weaknesses:  Since flu-like symptoms were significantly higher in the vaccination group, unblinding could have occurred.  Extensive exclusion criteria makes it unlikely to be able to extrapolate the study’s results to the general population.  The study’s authors received compensation from Cytos Biotechnology, the manufacturer of the vaccine, which creates a potential conflict of interest. 

Conclusions:    The study showed promising results with abstinence when a high antibody titer was achieved; however, I would not recommend the vaccination until further research is completed on its dose and dosage frequency.  For example, a higher dose should be studied to observe if more patients receive a high titer response and or increased adverse events.  Only short term safety and efficacy was studied therefore long term studies need to be done.  A study should also be done comparing the vaccination to other methods of smoking cessation (ie. Chantix®).  In conclusion, the study has stringent exclusion criteria making it almost impossible to extrapolate this study to the general population.

Reference:  Cornuz J, Zwahlen S, Jungi WF,Osterwalder, J, Klingler K, et al. (2008) A Vaccine against Nicotine for Smoking Cessation:  A Randomized Controlled Trial.  PLoS ONE 3 (6): e 2547. Doi:10.1371/journal.pone.0002547           

Ashley Corcoran, PharmD candidate