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Vaccine Adjuvants pp 107–125Cite as

In Silico Adjuvant Design and Validation

Part of the Methods in Molecular Biology book series (MIMB,volume 1494)

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.

Key words

  • CCR4
  • Regulatory T cell
  • Adjuvant
  • Small molecule
  • Vaccine in silico
  • Dendritic cells

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Acknowledgements

M.N.D., D.R.F., D.F.T., and J.B. were affiliated to Edward Jenner Institute for Vaccine Research, University of Oxford, UK, when the work was initiated. Supported by the Institut National de la Santé et de la Recherche Médicale, Université Pierre et Marie Curie and Université Paris Descartes, Canceropole Ile de France, Agence Nationale de la Recherche, Ligue contre le Cancer, Association pour la Recherche sur le Cancer, Pole de compétitivité Medicen (Immucan) Centre d’investigation Clinique en Biothérapie (CIC-BT505), SIRIC-CARPEM and Labex Immuno-Oncology, France; European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement HEALTH-2010.2.4.5-2 ALLFUN; and the Indo-French Center for Promotion of Advanced Research (CEFIPRA, Reference No: 4803-1).

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Authors and Affiliations

  1. Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, Division of Molecular Pathology, The Institute of Cancer Research, London, SM2 5NG, UK

    Matthew N. Davies

  2. INSERM U970 PARCC (Paris Cardiovascular Research Center), Université Paris Descartes, Sorbonne Paris Cité, Paris, 75015, France

    Helene Pere & Eric Tartour

  3. Hôpital Européen Georges-Pompidou, Service d’Immunologie Biologique, AP-HP, Paris, 75015, France

    Helene Pere & Eric Tartour

  4. Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium

    Iris Bosschem, Freddy Haesebrouck & Bram Flahou

  5. School of Life and Health Sciences, University of Aston, Aston Triangle, Birmingham, B4 7ET, UK

    Darren R. Flower

  6. Epinova Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Medicines Discovery Centre, SG1 2NY, Stevenage, UK

    David F. Tough

  7. Institut National de la Santé et de la Recherche Médicale, Unité 1138, Paris, 75006, France

    Jagadeesh Bayry

  8. Equipe-Immunopathology and Therapeutic Immunointervention, Centre de Recherche des Cordeliers, 15 rue de l’Ecole de Médicine, Paris, 75006, France

    Jagadeesh Bayry

  9. Sorbonne Universités, UPMC Universités Paris 06, UMR S 1138, Paris, 75006, France

    Jagadeesh Bayry

  10. Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, 75006, France

    Jagadeesh Bayry

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  1. Matthew N. Davies
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  2. Helene Pere
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  3. Iris Bosschem
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  8. David F. Tough
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  9. Jagadeesh Bayry
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Correspondence to Jagadeesh Bayry .

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Editors and Affiliations

  1. Infectious Disease Research Institute, Seattle, Washington, USA

    Christopher B. Fox

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Davies, M.N. et al. (2017). In Silico Adjuvant Design and Validation. In: Fox, C. (eds) Vaccine Adjuvants. Methods in Molecular Biology, vol 1494. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6445-1_8

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  • DOI: https://doi.org/10.1007/978-1-4939-6445-1_8

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  • Publisher Name: Humana Press, New York, NY

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