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Selection of a novel anti-nicotine vaccine: influence of antigen design on antibody function in mice

Pryde, David C.; Jones, Lyn H.; Gervais, David P.; Stead, David R.; Blakemore, David C.; Selby, Matthew D.; Brown, Alan D.; Coe, Jotham W.; Badland, Matthew; Beal, David M.; Glen, Rebecca; Wharton, Yvonne; Miller, Gavin J.; White, Phil; Zhang, Ningli; Benoit, Michelle; Robertson, Karen; Merson, James R.; Davis, Heather L.; McCluskie, Michael J.

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Authors

David C. Pryde

Lyn H. Jones

David P. Gervais

David R. Stead

David C. Blakemore

Matthew D. Selby

Alan D. Brown

Jotham W. Coe

Matthew Badland

David M. Beal

Rebecca Glen

Yvonne Wharton

Phil White

Ningli Zhang

Michelle Benoit

Karen Robertson

James R. Merson

Heather L. Davis

Michael J. McCluskie



Abstract

Anti-nicotine vaccines may aid smoking cessation via the induction of anti-nicotine antibodies (Ab) which reduce nicotine entering the brain, and hence the associated reward. Ab function depends on both the quantity (titer) and the quality (affinity) of the Ab. Anti-nicotine vaccines tested previously in clinical studies had poor efficacy despite high Ab titer, and this may be due to inadequate function if Ab of low affinity were induced. In this study, we designed and synthesized a series of novel nicotine-like haptens which were all linked to diphtheria toxoid (DT) as carrier, but which differed in the site of attachment of linker to nicotine, the nature of linker used, and the handle used to attach the hapten to DT. The resulting hapten conjugates were evaluated in a mouse model, using CpG (a TLR9 agonist) and aluminum hydroxide (Al(OH)3) as adjuvants, whereby Ab titers, affinity and function were evaluated using a radiolabeled nicotine challenge model. A series of additional linkers varying in length, rigidity and polarity were used with a single hapten to generate additional DT-conjugates, which were also tested in mice. Conjugates made with different haptens resulted in various titers of anti-nicotine Ab. Several haptens gave similarly high Ab titers, but among these, Ab affinity and hence function varied considerably. Linker also influenced Ab titer, affinity and function. These results demonstrate that immune responses induced in mice by nicotine-conjugate antigens are greatly influenced by hapten design including site of attachment of linker to nicotine, the nature of linker used, and the handle used to attach the hapten to DT. While both Ab titer and affinity contributed to function, affinity was more sensitive to antigen differences.

Journal Article Type Article
Acceptance Date Aug 23, 2013
Publication Date Oct 1, 2013
Journal PLoS One
Print ISSN 1932-6203
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 8
Issue 10
Article Number e76557
DOI https://doi.org/10.1371/journal.pone.0076557
Keywords Haptens, Antibodies, Enzyme-linked immunoassays, Immunologic adjuvants, Vaccines, Antigens, Nicotine, Blood plasma
Publisher URL http://dx.doi.org/10.1371/journal.pone.0076557

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