title: 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.
authors.affiliation: Minneapolis Medical Research Foundation, 600 Shapiro Bldg, 914 S 8th Street, Minneapolis, MN 55404, USA. prave001@umn.edu
authors.forename: M
authors.initials: M
authors.lastname: Pravetoni
authors.forename: D E
authors.initials: DE
authors.lastname: Keyler
authors.forename: R R
authors.initials: RR
authors.lastname: Pidaparthi
authors.forename: F I
authors.initials: FI
authors.lastname: Carroll
authors.forename: S P
authors.initials: SP
authors.lastname: Runyon
authors.forename: M P
authors.initials: MP
authors.lastname: Murtaugh
authors.forename: C A
authors.initials: CA
authors.lastname: Earley
authors.forename: P R
authors.initials: PR
authors.lastname: Pentel
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology* / Q000378:metabolism; D000918:Antibody Specificity / Q000276:immunology*; D006433:Hemocyanins; D015394:Molecular Structure; D009538:Nicotine / Q000737:chemistry / Q000276:immunology*; D011725:Pyridines / Q000737:chemistry / Q000276:immunology*; D011759:Pyrrolidines / Q000737:chemistry / Q000276:immunology*; D051381:Rats; D014614:Vaccines, Synthetic / Q000737:chemistry / Q000276:immunology*
chemical_list: C570480:(2S)-N,N'-(disulfanediyldiethane-2,1-diyl)bis(4-(2-pyridin-3-ylpyrrolidin-1-yl)butanamide); D000906:Antibodies; D011725:Pyridines; D011759:Pyrrolidines; D014614:Vaccines, Synthetic; D009538:Nicotine; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin
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