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A self-adjuvanting vaccine induces cytotoxic T lymphocytes that suppress allergy

Nature Chemical Biology volume 10, pages 943–949 (2014)Cite this article

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Abstract

Epitope-based peptide vaccines encompass minimal immunogenic regions of protein antigens to allow stimulation of precisely targeted adaptive immune responses. However, because efficacy is largely determined by the functional status of antigen-presenting cells (APCs) that acquire and present peptides to cells of the adaptive immune system, adjuvant compounds are needed to enhance immunogenicity. We present here a vaccine consisting of an allergen-derived peptide conjugated to a prodrug of the natural killer–like T (NKT) cell agonist α-galactosylceramide, which is highly effective in reducing inflammation in a mouse model of allergic airway inflammation. Unlike other peptide-adjuvant conjugates that directly activate APCs through pattern recognition pathways, this vaccine encourages third-party interactions with NKT cells to enhance APC function. Therapeutic efficacy was correlated with marked increases in the number and functional activity of allergen-specific cytotoxic T lymphocytes (CTLs), leading to suppression of immune infiltration into the lungs after allergen challenge in sensitized hosts.

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Figure 1: Assessment of the glycolipid scaffold for vaccine design.
Figure 2: Structure and in vivo activity of a prodrug agonist of NKT cells.
Figure 3: Conjugated peptide vaccines stimulate potent CD8+ T cell–mediated immune responses.
Figure 4: Conjugated peptide vaccines stimulate NKT cells.
Figure 5: Allergen-specific conjugate vaccines reduce allergic airway inflammation in sensitized animals without affecting serum IgE levels.

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Acknowledgements

We thank the personnel of the Biomedical Research Unit of the Malaghan Institute of Medical Research for animal husbandry, K. Price for flow cytometry support, and the US National Institutes of Health Tetramer Core Facility (contract HHSN272201300006C) for provision of CD1d monomers. This research was supported by the New Zealand Ministry of Science and Innovation (C08X0808) and a research grant from the New Zealand Health Research Council to F.R. N.J.D. was supported by the Rotary Club of Wellington and the University of Otago.

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Author notes

  1. Regan J Anderson and Ching-wen Tang: These authors contributed equally to this work.

Authors and Affiliations

  1. The Ferrier Research Institute, Victoria University of Wellington, Wellington, New Zealand

    Regan J Anderson, Benjamin J Compton, Colin M Hayman, Karen A Johnston & Gavin F Painter

  2. Malaghan Institute of Medical Research, Wellington, New Zealand

    Ching-wen Tang, Naomi J Daniels, Deborah A Knight, Olivier Gasser, Hazel C Poyntz, Franca Ronchese & Ian F Hermans

  3. Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, Wellington, New Zealand

    Naomi J Daniels

  4. Capital and Coast District Health Board, Wellington, New Zealand

    Peter M Ferguson

  5. Department of Chemistry, University of Otago, Dunedin, New Zealand

    David S Larsen

  6. School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand

    Ian F Hermans

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Contributions

I.F.H. and G.F.P. led the investigation together, contributed to design of conjugates, designed in vivo experiments and interpreted data; R.J.A. was primarily responsible for design, synthesis and chemical analysis of the conjugates, with contributions from B.J.C., C.M.H., K.A.J. and D.S.L.; C.T. was primarily responsible for in vivo analysis of conjugates, with contributions from D.A.K.; O.G. conducted in vitro assessment of conjugates; N.J.D. performed allergic airway experiments with contributions from H.C.P.; K.A.J. conducted molecular modeling; F.R. led analysis of airway inflammation; P.M.F. reviewed histology; I.F.H. drafted the manuscript with editorial input from all authors.

Corresponding authors

Correspondence to Gavin F Painter or Ian F Hermans.

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Competing interests

Two PCT applications have been filed with the Intellectual Property Office of New Zealand: application no. NZ2013/000224 (with G.F.P., R.J.A., B.J.C., C.M.H, I.F.H., F.R. and D.S.L), filed 6 December 2013, and no. NZ2013/000133 (G.F.P., R.J.A., B.J.C., C.M.H, I.F.H. and D.S.L), filed 26 July 2013. These applications encompass a-GalCer peptide conjugates and prodrugs, such as compounds 4 and 5 described in this work. The intellectual property is assigned to VicLink, Victoria University of Wellington.

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Anderson, R., Tang, Cw., Daniels, N. et al. A self-adjuvanting vaccine induces cytotoxic T lymphocytes that suppress allergy. Nat Chem Biol 10, 943–949 (2014). https://doi.org/10.1038/nchembio.1640

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