Therapeutic Vaccines for Treating Nicotine Addiction

Abstract

Cigarette smoking is responsible for nearly one-half million deaths per year in the United States (USHHS, The Health Consequences of Smoking—50 years of progress. A report of the Surgeon General, 2014). The Centers for Disease Control estimates that the direct healthcare costs attributable to treating smoking and smoking-attributable illness exceed $170 billion per year (CDC, Smoking & Tobacco Use: Fast Facts, 2015). Only one in five smokers achieves long-term abstinence using standard of care pharmacotherapies (Cahill et al. Cochrane Database Syst Rev 4:CD006103, 2012), leaving the majority still smoking and seeking alternatives. New effective medications to treat nicotine addiction are urgently needed. Therapeutic nicotine vaccines target nicotine in the circulation rather than the nicotinic acetylcholine receptors in the brain. Nicotine-specific antibodies elicited by vaccination alter the pharmacokinetics (PK) of nicotine, slowing and reducing its entry into the brain and attenuating its reinforcing effects by binding nicotine in the blood (Gorelick, Future Med Chem 4(2):227–243, 2012). Extensive preclinical and clinical research has been conducted on nicotine conjugate vaccines with mixed results (Hartmann-Boyce et al. Cochrane Database Syst Rev 8:CD007072, 2012). In phase II studies of two first-generation nicotine vaccines, NicQβ and NicVAX, high-antibody levels were elicited in approximately a third of the smokers vaccinated. These high-antibody levels were significantly associated with long-term abstinence (Cornuz et al. PLoS One 3(6):2547, 2008; Hatsukami et al. Clin Pharmacol Ther 89(3):392–399, 2011). Inconsistent with these findings, a pair of large phase III studies of NicVAX (each n = ~1000) showed no statistically significant difference from placebo as an aid to smoking cessation treatment in the intent-to-treat population (Fahim et al. CNS Neurol Disord Drug Targets Review 8:905–915, 2011; Fahim et al. Expert Rev Vaccines 12(3):333–342, 2013). Notwithstanding these negative results, a correlation between high-antibody response and long-term abstinence was identified in post hoc analyses of the phase III studies of NicVAX (Fahim and Kalnik Personalized drug treatment methods. PCT/US, Patent No. PCT/US2011/061229 US20110182918, 2012). Furthermore, in vivo studies of nicotine monoclonal antibodies isolated from vaccinated mice (Keyler et al. Drug Metab Dispos 33(7):1056–1061, 2005) and humans (Beerli et al. PNAS 105(38):14336–14341, 2008) illuminate the importance of optimizing affinity and avidity (avidity is often referred to as “functional affinity”; thus “affinity” will be used as shorthand throughout this chapter to encompass affinity and avidity) of next-generation vaccines. A consensus has emerged that high levels of high-affinity nicotine-specific antibodies elicited by vaccination across all individuals are a prerequisite for success (Fahim et al. CNS Neurol Disord Drug Targets Review 8:905–915, 2011; Pravetoni et al. Biochem Pharmacol. 83(4):543–550, 2012; McCluskie et al. Int Immunopharmacol 16(1):50–56, 2013a; Pryde et al. PLoS One 8(10), e76557, 2013). Second-generation nicotine vaccines with optimized haptens (Moreno et al. Mol Pharm 7(2):431–441, 2010; Lockner et al. J Med Chem, 58(2):1005–1011, 2015), linkers, conjugation (Pryde et al. PLoS One 8(10), e76557, 2013; McCluskie et al. Int Immunopharmacol 16(1):50–6, 2015), and novel potent adjuvants (Davis et al. NIC7-DT, A novel anti-nicotine vaccine, induces better functional antibody responses in mice compares to a Nic-QBeta Mimetic, Abstract O10, 2012; Pittet et al. J Immunol 188, 2012; McCluskie et al. Int Immunopharmacol 16(1):50–56, 2013a; McCluskie et al. A novel anti-nicotine vaccine, shows significantly superior function in non-human primates (NHP) compared to a CYT002-NICQB mimetic, Abstract PA13-4, 2013b) are being actively developed. Based on extensive preclinical optimization of the vaccine design, the addition of a potent proprietary adjuvant and compelling results in both rodent and non-human primate animal models, NIC7 has entered clinical testing (Pfizer, phase I: NCT01672645) with results anticipated in 2016.