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ACS Chem Biol. 2017 Nov 17;12(11):2898-2905. doi: 10.1021/acschembio.7b00845. Epub 2017 Oct 27.

Augmenting Influenza-Specific T Cell Memory Generation with a Natural Killer T Cell-Dependent Glycolipid-Peptide Vaccine.

Author information

1
The Ferrier Research Institute, Victoria University of Wellington , PO Box 33436, Lower Hutt 5046, New Zealand.
2
Department of Microbiology, Biomedical Discovery Institute, Monash University , Clayton, Victoria 3800, Australia.
3
Malaghan Institute of Medical Research , PO Box 7060, Wellington 6242, New Zealand.
4
Department of Microbiology and Immunology, at the Doherty Institute for Infection and Immunity, The University of Melbourne , 792 Elizabeth St, Melbourne, Victoria 3010, Australia.
5
Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne , Parkville, Victoria 3010, Australia.
6
School of Biological Sciences, The University of Auckland , 3 Symonds St, Auckland Central 1142, New Zealand.
7
Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland , 3 Symonds St, Auckland Central 1142, New Zealand.
8
Avalia Immunotherapies Limited , Gracefield Innovation Quarter, 69 Gracefield Rd, Lower Hutt 5010, New Zealand.

Abstract

The development of a universal vaccine for influenza A virus (IAV) that does not require seasonal modification is a long-standing health goal, particularly in the context of the increasing threat of new global pandemics. Vaccines that specifically induce T cell responses are of considerable interest because they can target viral proteins that are more likely to be shared between different virus strains and subtypes and hence provide effective cross-reactive IAV immunity. From a practical perspective, such vaccines should induce T cell responses with long-lasting memory, while also being simple to manufacture and cost-effective. Here we describe the synthesis and evaluation of a vaccine platform based on solid phase peptide synthesis and bio-orthogonal conjugation methodologies. The chemical approach involves covalently attaching synthetic long peptides from a virus-associated protein to a powerful adjuvant molecule, α-galactosylceramide (α-GalCer). Strain-promoted azide-alkyne cycloaddition is used as a simple and efficient method for conjugation, and pseudoproline methodology is used to increase the efficiency of the peptide synthesis. α-GalCer is a glycolipid that stimulates NKT cells, a population of lymphoid-resident immune cells that can provide potent stimulatory signals to antigen-presenting cells engaged in driving proliferation and differentiation of peptide-specific T cells. When used in mice, the vaccine induced T cell responses that provided effective prophylactic protection against IAV infection, with the speed of viral clearance greater than that seen from previous viral exposure. These findings are significant because the vaccines are highly defined, quick to synthesize, and easily characterized and are therefore appropriate for large scale affordable manufacture.

PMID:
29043774
DOI:
10.1021/acschembio.7b00845
[Indexed for MEDLINE]

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