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Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry
John J. Miles, … , David A. Price, Andrew K. Sewell
John J. Miles, … , David A. Price, Andrew K. Sewell
Published April 2, 2018; First published March 12, 2018
Citation Information: J Clin Invest. 2018;128(4):1569-1580. https://doi.org/10.1172/JCI91512.
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Categories: Research Article Immunology Infectious disease

Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry

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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.

Authors

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 Gallimore, Pierre J. Rizkallah, Stephanie Gras, Jamie Rossjohn, Scott R. Burrows, David K. Cole, David A. Price, Andrew K. Sewell

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Figure 1

An archetypal human CD8+ T cell clone exhibits broad but differing L– and D–amino acid recognition profiles.

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An archetypal human CD8+ T cell clone exhibits broad but differing L– an...
Clonal ALF3 CD8+ T cells were incubated with C1R-A2 target cells pulsed with CPL mixtures (100 μM) comprising nonamer L– or D–amino acids. MIP-1β release in the supernatants was quantified by ELISA. The amino acid residue in each position corresponding to the index GILGFVFTL peptide is depicted in green for the L-CPL screen and red for the D-CPL screen. Fixed amino acid positions (single letter code) along the peptide backbone are indicated. Error bars from 2 replicates depict SEM.
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