Preclinical Development of a Vaccine ‘Against Smoking’

Abstract

Background: Nicotine is the main culprit for dependence on tobacco-containing products, which in turn are a major etiologic factor for cardiovascular diseases and cancer. This publication describes a vaccine, which elicits antibodies against nicotine. The antibodies in the blood stream intercept the nicotine molecule on its way to its receptors and greatly diminish the nicotine influx to the brain shortly after smoking. Methods: The nicotine molecule is chemically linked to cholera toxin B as a carrier protein in order to induce antibodies. The potential to elicit antibodies after subcutaneous as well as intranasal immunization is evaluated. In order to simulate realistic conditions, nicotine pumps delivering the nicotine equivalent of 5 packages of cigarettes for 4 weeks are implanted into the mice 1 week prior to vaccination. The protective effect of the vaccine is measured 5 weeks after vaccination by comparing the influx of radiolabeled nicotine in the brains of vaccinated and non-vaccinated animals 5 min after challenge with the nicotine equivalent of 2 cigarettes. Results: The polyclonal antibodies induced by the vaccine show a mean avidity of 1.8 × 10⁷ l/Mol. Subcutaneous immunization elicits high antibody levels of the IgG class, and significant IgA antibody levels in the saliva of vaccinated mice can be found after intranasal vaccination. The protective effect also in the animals with implanted nicotine pumps is significant: less than 10% of radiolabeled nicotine found in the brains of non-vaccinated animals can be found in the brains of vaccinated animals. Conclusions: These data provide credible evidence that a vaccine can break the vicious circle between smoking and instant gratification by intercepting the nicotine molecule. Astonishingly, there is no sign of exhaustion of specific antibodies even under extreme conditions, which makes it highly unlikely that a smoker can overcome the protective effect of the vaccine by smoking more. Finally, the high titers of specific antibodies after 1 year let us hope that booster vaccinations are probably only necessary in intervals of years.

A therapeutic vaccine for nicotine dependence: preclinical efficacy, and phase I safety and immunogenicity

“…Maximum titers were measured at about day 21 from which point antinicotine antibody levels slowly declined with a half-life of approximately 60 days. Addition of Alum increased the titers in mice about 6-fold and maximum titers after one boost (at day 14) were reached between day 40 and day 60. Analyses of the subclasses revealed high IgG2a titers which is indicative for a Th1-type immune response.…”

“…The inhibition of nicotine entry into brain was analyzed by intravenous injection of tritium-labeled (-)-nicotine (Amersham) (739 ng or 1875 ng) in the tail vein and collection of blood and brain after five minutes. This time-point was selected because nicotine concentrations in the brain of mice decline with a half-life of about 6.5 min [14,31,32]. Nicotine concentrations in serum and brain were calculated from the radioactivity present.…”

“…Coupling haptens to protein carriers typically enhances their immunogenicity. Nicotine conjugates have been successfully used to vaccinate against nicotine [11][12][13][14][15]. Vaccine efficacy in animal models was demonstrated in several different ways.…”

“…After administration of nicotine, concentrations in serum were found to be higher in immunized rats compared with unvaccinated animals, as nicotine was bound to the antibodies. Correspondingly, nicotine concentrations in the brain were lower [11,12,14,15]. The effect on the reward system in brain was demonstrated by suppression of nicotine-induced dopamine release in brains of vaccinated rats [13].…”

Vaccines against nicotine

“…Our group has shown in a mouse model that intranasal immunization is able to elicit significant levels of antibodies and we would expect some of the future application schedules to use intranasal application forms of the vaccine. 36 None of the vaccine studies carried out so far has reported major side effects. Some of the studies report on minor side effects, limited in most cases to the site of injection and which are of short duration.…”