Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry

Miles, John, Tan, Mai Ping, Dolton, Garry, Edwards, Emily S.J., Galloway, Sarah A.E., Laugel, Bruno, Clement, Mathew, Makinde, Julia, Ladell, Kristin, Matthews, Katherine, Watkins, Thomas S., Tungatt, Katie, Wong, Yide, Lee, Han Siean, Clark, Richard J., Pentier, Johanne M., Attaf, Meriem, Lissina, Anya, Ager, Ann, Gallimore, Awen, Rizkallah, Pierre J., Grass, Stephanie, Rossjohn, Jamie, Burrows, Scott, Cole, David K., Price, David A., and Sewell, Andrew K. (2018) Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry. Journal of Clinical Investigation, 128 (4). pp. 1569-1580.

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Abstract

Polypeptide vaccines effectively activate human T cells but suffer from poor biological stability, which confines both transport logistics and in vivo therapeutic activity. Synthetic biology has the potential to address these limitations through the generation of highly stable antigenic "mimics" using subunits that do not exist in the natural world. We developed a platform based on D-amino acid combinatorial chemistry and used this platform to reverse engineer a fully artificial CD8+ T cell agonist that mirrored the immunogenicity profile of a native epitope blueprint from influenza virus. This nonnatural peptide was highly stable in human serum and gastric acid, reflecting an intrinsic resistance to physical and enzymatic degradation. In vitro, the synthetic agonist stimulated and expanded an archetypal repertoire of polyfunctional human influenza virus-specific CD8+ T cells. In vivo, specific responses were elicited in naive humanized mice by subcutaneous vaccination, conferring protection from subsequent lethal influenza challenge. Moreover, the synthetic agonist was immunogenic after oral administration. This proof-of-concept study highlights the power of synthetic biology to expand the horizons of vaccine design and therapeutic delivery.

Item ID: 55332
Item Type: Article (Refereed Research - C1)
Copyright Information: This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
ISSN: 1558-8238
Funders: Biotechnology and Biological Sciences Research Council (BBSRC), Cardiff Synthetic Biology Initiative, Medical Research Council, UK, National Institute of Social Care and Health Research, Australian Research Council (ARC), Wellcome Trust, Australian National Health and Medical Research Council (NHMRC)
Projects and Grants: BBSRC BB/H001085/1, Perpetual FR2013/0946, ARC FT100100476, ARC FF120100416
Date Deposited: 10 Sep 2018 23:24
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110704 Cellular Immunology @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 100%
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