Vaccine 24 (2006) 3399–3407 Review Co-stimulatory agonists as immunological adjuvants Tom A. Barr a , Jennifer Carlring b , Andrew W. Heath b,∗ a Institute of Cell, Animal and Population Biology (ICAPB), University of Edinburgh, Ashworth Laboratories, King’s Buildings, West Mains Road, Edinburgh EH9 3JT, United Kingdom b Division of Genomic Medicine, Academic Unit of Infection and Immunity, University of Sheffield Medical School, Beech Hill Rd., Sheffield S10 2RX, United Kingdom Received 9 January 2006; received in revised form 25 January 2006; accepted 6 February 2006 Available online 24 February 2006 Abstract The considerable advances made in the fields of molecular biology, genomics, proteomics and protein engineering have led to the identifi- cation of a vast range of potential vaccine antigens for a host of man’s most serious diseases. However, experience informs us that vaccines based on recombinant proteins and synthetic peptides lack the immunogenicity of the whole, killed pathogens used in traditional vaccines and, as such, clinical use of these immunogens remains negligible. In order to fully realize the potential benefits of recombinant antigen-based vaccines there is a pressing need to identify powerful adjuvants which can safely enhance these weak responses with a minimum of undesirable side effects. Adjuvant research represents a vibrant and fast moving field and recent developments suggest the goal of generating effective, safe and affordable ways of enhancing immune responses appears to be almost within our grasp. The purpose of this article is to review recent advances in adjuvant development using approaches that directly exploit the immune system’s own co-stimulatory pathways to exert their function; with a particular emphasis on CD40 and CD28 based therapies. © 2006 Elsevier Ltd. All rights reserved. Keywords: Adjuvant; CD40; CD28; Costimulatory Contents 1. Introduction ........................................................................................................ 3400 2. Balancing reactogenicity versus adjuvanticity—the case for co-stimulatory adjuvants ...................................... 3401 3. Mechanisms of co-stimulation ........................................................................................ 3401 4. CD40 .............................................................................................................. 3402 5. CD134 (OX40) ..................................................................................................... 3403 6. CD137 (4-1BB) ..................................................................................................... 3404 7. CD28 .............................................................................................................. 3404 8. CD70 .............................................................................................................. 3405 9. Concluding comments ............................................................................................... 3405 Acknowledgements ................................................................................................. 3405 References ......................................................................................................... 3405 ∗ Corresponding author. Tel.: +44 114 271 3516; fax: +44 114 273 9926. E-mail addresses: tom.barr@ed.ac.uk (T.A. Barr), j.u.carlring-wright@shef.ac.uk (J. Carlring), a.w.heath@sheffield.ac.uk, a.w.heath@shef.ac.uk (A.W. Heath). 0264-410X/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2006.02.022