Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry

Miles, John J, Tan, Mai Ping, Dolton, Garry, Edwards, Emily Sj, Galloway, Sarah Ae, 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 M, 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, . doi:10.1172/JCI91512

Author Miles, John J
Tan, Mai Ping
Dolton, Garry
Edwards, Emily Sj
Galloway, Sarah Ae
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 M
Attaf, Meriem
Lissina, Anya
Ager, Ann
Gallimore, Awen
Rizkallah, Pierre J
Gras, Stephanie
Rossjohn, Jamie
Burrows, Scott R
Cole, David K
Price, David A
Sewell, Andrew K
Title Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry
Journal name The Journal of clinical investigation   Check publisher's open access policy
ISSN 1558-8238
Publication date 2018-03-12
Sub-type Article (original research)
DOI 10.1172/JCI91512
Open Access Status Not yet assessed
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.
Keyword Immunology
Infectious disease
T cells
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Pubmed Import
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Created: Wed, 14 Mar 2018, 10:00:54 EST