In silico adjuvant design and validation

Matthew N. Davies, Helene Pere, Iris Bosschem, Freddy Haesebrouck, Bram Flahou, Eric Tartour, Darren R. Flower, David F. Tough, Jagadeesh Bayry*

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Adjuvants are substances that boost the protective immune response to vaccine antigens. The majority of known adjuvants have been identified through the use of empirical approaches. Our aim was to identify novel adjuvants with well-defined cellular and molecular mechanisms by combining a knowledge of immunoregulatory mechanisms with an in silico approach. CD4 + CD25 + FoxP3 + regulatory T cells (Tregs) inhibit the protective immune responses to vaccines by suppressing the activation of antigen presenting cells such as dendritic cells (DCs). In this chapter, we describe the identification and functional validation of small molecule antagonists to CCR4, a chemokine receptor expressed on Tregs. The CCR4 binds the chemokines CCL22 and CCL17 that are produced in large amounts by activated innate cells including DCs. In silico identified small molecule CCR4 antagonists inhibited the migration of Tregs both in vitro and in vivo and when combined with vaccine antigens, significantly enhanced protective immune responses in experimental models.

Original languageEnglish
Title of host publicationVaccine adjuvants
Subtitle of host publicationmethods and protocols
EditorsChristopher B. Fox
Place of PublicationNew York (US)
PublisherSpringer
Pages107-125
Number of pages19
ISBN (Electronic)978-1-4939-6445-1
ISBN (Print)978-1-4939-6443-7
DOIs
Publication statusPublished - 8 Oct 2016

Publication series

NameMethods in Molecular Biology
PublisherSpringer
Volume1494
ISSN (Print)1064-3745

Keywords

  • adjuvant
  • CCR4
  • dendritic cells
  • regulatory T cell
  • small molecule
  • vaccine in silico

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  • Manufacturing methods for liposome adjuvants

    Perrie, Y., Kastner, E., Khadke, S., Roces, C. B. & Stone, P., 8 Oct 2016, Vaccine adjuvants: methods and protocols. Fox, C. B. (ed.). New York (US): Springer, p. 127-144 18 p. (Methods in Molecular Biology; vol. 1494).

    Research output: Chapter in Book/Report/Conference proceedingChapter

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