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.
| Language | English |
|---|---|
| Pages | 1569-1580 |
| Number of pages | 12 |
| Journal | Journal of Clinical Investigation |
| Volume | 128 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2 Apr 2018 |
Cite this
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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 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.
In: Journal of Clinical Investigation, Vol. 128, No. 4, 02.04.2018, p. 1569-1580.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry
AU - Miles, John J.
AU - Tan, Mai Ping
AU - Dolton, Garry
AU - Edwards, Emily S.J.
AU - Galloway, Sarah A.E.
AU - Laugel, Bruno
AU - Clement, Mathew
AU - Makinde, Julia
AU - Ladell, Kristin
AU - Matthews, Katherine K.
AU - Watkins, Thomas S.
AU - Tungatt, Katie
AU - Wong, Yide
AU - Lee, Han Siean
AU - Clark, Richard J.
AU - Pentier, Johanne M.
AU - Attaf, Meriem
AU - Lissina, Anya
AU - Ager, Ann
AU - Gallimore, Awen
AU - Rizkallah, Pierre J.
AU - Gras, Stephanie
AU - Rossjohn, Jamie
AU - Burrows, Scott R.
AU - Cole, David K.
AU - Price, David A.
AU - Sewell, Andrew K.
PY - 2018/4/2
Y1 - 2018/4/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85045052493&partnerID=8YFLogxK
U2 - 10.1172/JCI91512
DO - 10.1172/JCI91512
M3 - Article
VL - 128
SP - 1569
EP - 1580
JO - Journal of Clinical Investigation
T2 - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 4
ER -