Structurally distinct nicotine immunogens elicit antibodies with non-overlapping specificities

Abstract

Nicotine conjugate vaccine efficacy is limited by the concentration of nicotine-specific antibodies that can be reliably generated in serum. Previous studies suggest that the concurrent use of 2 structurally distinct nicotine immunogens in rats can generate additive antibody responses by stimulating distinct B cell populations. In the current study we investigated whether it is possible to identify a third immunologically distinct nicotine immunogen. The new 1′-SNic immunogen (2S)-N,N′-(disulfanediyldiethane-2,1-diyl)bis[4-(2-pyridin-3-ylpyrrolidin-1-yl)butanamide] conjugated to keyhole limpet hemocyanin (KLH) differed from the existing immunogens 3′-AmNic-rEPA and 6-CMUNic-BSA in linker position, linker composition, conjugation chemistry, and carrier protein. Vaccination of rats with 1′-SNic-KLH elicited high concentrations of high affinity nicotine-specific antibodies. The antibodies produced in response to 1′-SNic-KLH did not appreciably cross-react in ELISA with either 3′-AmNic-rEPA or 6-CMUNic-BSA or vice-versa, showing that the B cell populations activated by each of these nicotine immunogens were non-overlapping and distinct. Nicotine retention in serum was increased and nicotine distribution to brain substantially reduced in rats vaccinated with 1′-SNic-KLH compared to controls. Effects of 1′-SNic-KLH on nicotine distribution were comparable to those of 3′-AmNic-rEPA which has progressed to late stage clinical trials as an adjunct to smoking cessation. These data show that it is possible to design multiple immunogens from a small molecule such as nicotine which elicit independent immune responses. This approach could be applicable to other addiction vaccines or small molecule targets as well.

Opioid Dose- and Route-Dependent Efficacy of Oxycodone and Heroin Vaccines in Rats

“…These concentrations are higher than have generally been reported with nicotine or cocaine vaccines using similar linkers and carrier proteins, suggesting that opioid-based haptens are particularly immunogenic, perhaps due to their larger size (Kantak et al, 2000;Keyler et al, 2008;Roiko et al, 2008;Pravetoni et al, 2012a). In clinical trials of nicotine or cocaine vaccines, serum antibody concentrations have been considerably lower than those elicited in animals and this likely contributed to their limited efficacy in reducing smoking or cocaine use (Martell et al, 2009;Hatsukami et al, 2011;Esterlis et al, 2013).…”

A novel and efficient nicotine vaccine using nano-lipoplex as a delivery vehicle

“…Nicotine is non-immunogenic by itself; it has to be conjugated to carrier proteins in order to elicit immune response. 15 The nicotine hapten used in this study is rac-trans 3′-hydroxymethylnicotine hemisuccinate, which possesses a carboxyl sidearm functional group enabling covalent link with an amino group on carrier proteins. In previous studies, rac-trans 3′-hydroxymethylnicotine hemisuccinate coupled to human serum albumin and KLH was found to generate highly effective antibodies in rabbits.…”

Biologics to treat substance use disorders: Current status and new directions

“…75,[85][86][87] Increased efficacy of a heroin vaccine correlated with higher haptenization ratios in conjugates containing a tetanus toxoid (TT) carrier but not the diphtheria toxin crossreactive material (CRM 197 ) carrier. 88 Yet, haptenization ratio did not correlate with anti-heroin Ab titer nor affinity.…”