Display options
Cite
Carter D, Fox CB, Day TA, et al. A structure-function approach to optimizing TLR4 ligands for human vaccines. Clin Transl Immunology. 2016;5(11):e108doi: 10.1038/cti.2016.63.
Carter, D., Fox, C. B., Day, T. A., Guderian, J. A., Liang, H., Rolf, T., Vergara, J., Sagawa, Z. K., Ireton, G., Orr, M. T., Desbien, A., Duthie, M. S., Coler, R. N., & Reed, S. G. (2016). A structure-function approach to optimizing TLR4 ligands for human vaccines. Clinical & translational immunology, 5(11), e108. https://doi.org/10.1038/cti.2016.63
Carter, Darrick, et al. "A structure-function approach to optimizing TLR4 ligands for human vaccines." Clinical & translational immunology vol. 5,11 (2016): e108. doi: https://doi.org/10.1038/cti.2016.63
Carter D, Fox CB, Day TA, Guderian JA, Liang H, Rolf T, Vergara J, Sagawa ZK, Ireton G, Orr MT, Desbien A, Duthie MS, Coler RN, Reed SG. A structure-function approach to optimizing TLR4 ligands for human vaccines. Clin Transl Immunology. 2016 Nov 02;5(11):e108. doi: 10.1038/cti.2016.63. eCollection 2016 Nov. PMID: 27990284; PMCID: PMC5133366.
Copy Download .nbib Format: NLM
Share it on

Clin Transl Immunology. 2016 Nov 02;5(11):e108. doi: 10.1038/cti.2016.63. eCollection 2016 Nov.

A structure-function approach to optimizing TLR4 ligands for human vaccines.

Clinical & translational immunology

Darrick Carter, Christopher B Fox, Tracey A Day, Jeffrey A Guderian, Hong Liang, Tom Rolf, Julie Vergara, Zachary K Sagawa, Greg Ireton, Mark T Orr, Anthony Desbien, Malcolm S Duthie, Rhea N Coler, Steven G Reed

Affiliations

  1. Infectious Disease Research Institute (IDRI), Seattle, WA, USA; PAI Life Sciences, Seattle, WA, USA; Department of Medicine and Global Health, University of Washington, Seattle, WA, USA.
  2. Infectious Disease Research Institute (IDRI), Seattle, WA, USA; Department of Medicine and Global Health, University of Washington, Seattle, WA, USA.
  3. Infectious Disease Research Institute (IDRI) , Seattle, WA, USA.

PMID: 27990284 PMCID: PMC5133366 DOI: 10.1038/cti.2016.63

Abstract

Adjuvants are combined with vaccine antigens to enhance and modify immune responses, and have historically been primarily crude, undefined entities. Introducing toll-like receptor (TLR) ligands has led to a new generation of adjuvants, with TLR4 ligands being the most extensively used in human vaccines. The TLR4 crystal structures demonstrate extensive contact with their ligands and provide clues as to how they discriminate a broad array of molecules and activate or attenuate innate, as well as adaptive, responses resulting from these interactions. Leveraging this discerning ability, we made subtle chemical alterations to the structure of a synthetic monophosphoryl lipid-A molecule to produce SLA, a designer TLR4 ligand that had a number of desirable adjuvant effects. The SLA molecule stimulated human TLR4 and induced Th1 biasing cytokines and chemokines. On human cells, the activity of SLA plateaued at lower concentrations than the lipid A comparator, and induced cytokine profiles distinct from other known TLR4 agonists, indicating the potential for superior adjuvant performance. SLA was formulated in an oil-in-water emulsion, producing an adjuvant that elicited potent Th1-biased adaptive responses. This was verified using a recombinant

Conflict of interest statement

SGR is a founder of, and holds an equity interest in, Immune Design, a licensee of certain rights associated with GLA and SLA. SGR and DC are inventors on issued patents for GLA-based formulations and

References

  1. Adv Exp Med Biol. 2005;560:11-8 - PubMed
  2. PLoS One. 2011 Jan 26;6(1):e16333 - PubMed
  3. Colloids Surf B Biointerfaces. 2010 Jan 1;75(1):123-32 - PubMed
  4. J Virol. 2011 Jul;85(13):6390-402 - PubMed
  5. Eur J Immunol. 2013 Sep;43(9):2398-408 - PubMed
  6. Sci Signal. 2012 Feb 14;5(211):ra13 - PubMed
  7. Vaccine. 2006 Aug 14;24(33-34):5937-49 - PubMed
  8. Clin Transl Immunology. 2015 Apr 10;4(4):e35 - PubMed
  9. J Cheminform. 2012 Aug 13;4(1):17 - PubMed
  10. Eur J Immunol. 2015 Feb;45(2):407-17 - PubMed
  11. J Immunol. 2009 Nov 15;183(10):6186-97 - PubMed
  12. Cytokine. 2008 May;42(2):145-51 - PubMed
  13. Semin Immunol. 2004 Feb;16(1):23-6 - PubMed
  14. Expert Rev Vaccines. 2015 Jun;14(6):861-76 - PubMed
  15. Sci Transl Med. 2011 Jul 27;3(93):93ra69 - PubMed
  16. Expert Opin Biol Ther. 2004 Jul;4(7):1129-38 - PubMed
  17. Pharm Biotechnol. 1995;6:495-524 - PubMed
  18. Hum Vaccin. 2008 Sep-Oct;4(5):347-9 - PubMed
  19. Nature. 2009 Apr 30;458(7242):1191-5 - PubMed
  20. J Mol Graph. 1996 Feb;14(1):33-8, 27-8 - PubMed
  21. Nature. 2011 Feb 24;470(7335):543-7 - PubMed
  22. J Virol. 2015 Nov;89(21):10841-59 - PubMed
  23. Science. 2007 Jun 15;316(5831):1628-32 - PubMed
  24. Bioorg Med Chem Lett. 2008 Oct 15;18(20):5350-4 - PubMed
  25. Biogerontology. 2016 Feb;17 (1):177-87 - PubMed

Publication Types

Grant support