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Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry

Miles, John J., Tan, Mai Ping, Dolton, Garry, Edwards, Emily S. J., Galloway, Sarah A. E., Laugel, Bruno, Clement, Mathew, Makinde, Julia, Ladell, Kristin, Matthews, Katherine K., Watkins, Thomas S., Tungatt, Katie, Wong, Yide, Lee, Han Siean, Clark, Richard J., Pentier, Johanne, Attaf, Meriem, Lissina, Anya, Ager, Ann, Gallimore, Awen, Rizkallah, Pierre J., Gras, Stephanie, Rossjohn, Jamie, Burrows, Scott R., Cole, David K., Price, David A. and Sewell, Andrew K. 2018. Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry. The Journal of Clinical Investigation 128 (4) , pp. 1569-1580. 10.1172/JCI91512

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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 Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Publisher: American Society for Clinical Investigation
ISSN: 0021-9738
Funders: BBSRC & Wellcome Trust
Date of First Compliant Deposit: 22 March 2018
Date of Acceptance: 18 January 2018
Last Modified: 28 Jun 2019 19:42
URI: http://orca.cf.ac.uk/id/eprint/110090

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