Active immunization against nicotine dependence

Tobacco smoking is the largest preventable cause of morbidity and premature mortality in the world. Although its medical consequences are well documented, 20-45% of the adult population in the European countries remains tobacco smokers. The drugs presently used in smoking cessation have limited efficiency and, therefore, there is a need for alternative and improved treatments. A novel type of drug in this regard may be provided by using active immunization against nicotine, i.e. nicotine vaccines. The rationale is to generate endogenous anti-nicotine antibodies that bind nicotine in the blood, thereby preventing it from reaching the brain where it exerts its reinforcing effects. Since nicotine is a small molecule, unable to elicit an immune response, it has to be coupled to a carrier protein via a linker.

In this thesis a series of novel nicotine immunogens, including structurally different linkers coupled to the 5- or 6-position of the nicotine molecule and conjugated to a carrier protein, were studied. The amounts of antibodies generated and their selectivity were assessed by ELISA techniques, and all immunogens generated anti-nicotine antibodies that recognized (S)-nicotine or nornicotine better than the other nicotine metabolites tested. In addition, no cross-reactivity to endogenous transmitters was detected. In vivo voltammetry was used to assess the nicotine-induced increase in dopamine release in the shell region of the nucleus accumbens, a neurochemical correlate to nicotine s rewarding properties, and our work revealed that this effect of nicotine was differentially affected depending on both the immunogen studied and the selectivity of the antibodies. The nicotine immunogen IP18-KLH, showing a favorable antibody selectivity profile, prevented the nicotine-induced dopamine release and, likewise, the reinstatement of nicotine-seeking behavior in previously self-administering rats. These effects of the immunization with IP18-KLH were found to be associated with an altered distribution of nicotine, resulting in elevated nicotine levels in serum, due to antibody binding, and consequently a retarded nicotine distribution to the brain.

Taken together our results provide substantial preclinical support for the potential utility of nicotine vaccines in the treatment of nicotine dependence, notably relapse prevention.

List of scientific papers

I. de Villiers SH, Lindblom N, Kalayanov G, Gordon S, Malmerfelt A, Johansson AM, Svensson TH (2002). Active immunization against nicotine suppresses nicotine-induced dopamine release in the rat nucleus accumbens shell. Respiration. 69(3): 247-53.
https://pubmed.ncbi.nlm.nih.gov/12097769

II. Lindblom N, de Villiers SH, Kalayanov G, Gordon S, Johansson AM, Svensson TH (2002). Active immunization against nicotine prevents reinstatement of nicotine-seeking behavior in rats. Respiration. 69(3): 254-60.
https://pubmed.ncbi.nlm.nih.gov/12097770

III. de Villiers SH, Lindblom N, Kalayanov G, Gordon S, Johansson AM, Svensson TH (2004). Active immunization against nicotine alters the distribution of nicotine but not the metabolism to cotinine in the rat. Naunyn Schmiedebergs Arch Pharmacol. 370(4): 299-304. Epub 2004 Sep 16.
https://pubmed.ncbi.nlm.nih.gov/15375641

IV. de Villiers SH, Lindblom N, Kalayanov G, Gordon S, Baraznenok I, Malmerfelt A, Marcus MM, Johansson AM, Svensson TH (2010). Nicotine hapten structure, antibody selectivity and effect relationships: results from a nicotine vaccine screening procedure. Vaccine. 28(10): 2161-8. Epub 2010 Jan 7.
https://pubmed.ncbi.nlm.nih.gov/20060511