Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry

John J. Miles, Mai Ping Tan, Garry Dolton, Emily S.J. Edwards, Sarah A.E. Galloway, Bruno Laugel, Mathew Clement, Julia Makinde, Kristin Ladell, Katherine K. Matthews, Thomas S. Watkins, Katie Tungatt, Yide Wong, Han Siean Lee, Richard J. Clark, Johanne M. Pentier, Meriem Attaf, Anya Lissina, Ann Ager, Awen GallimorePierre J. Rizkallah, Stephanie Gras, Jamie Rossjohn, Scott R. Burrows, David K. Cole, David A. Price, Andrew K. Sewell

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1569-1580
Number of pages12
JournalJournal of Clinical Investigation
Volume128
Issue number4
DOIs
Publication statusPublished - 2 Apr 2018

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