Development of a structural epitope mimic: an idiotypic approach to HCV vaccine design

Vanessa M. Cowton; Ania M. Owsianka; Valeria Fadda; Ana Maria Ortega-Prieto; Sarah J. Cole; Jane A. Potter; Jessica K. Skelton; Nathan Jeffrey; Caterina Di Lorenzo; Marcus Dorner; Garry L. Taylor; Arvind H. Patel

doi:10.1038/s41541-020-00269-1

Development of a structural epitope mimic: an idiotypic approach to HCV vaccine design

Vanessa M. Cowton, Ania M. Owsianka, Valeria Fadda, Ana Maria Ortega-Prieto, Sarah J. Cole, Jane A. Potter, Jessica K. Skelton, Nathan Jeffrey, Caterina Di Lorenzo, Marcus Dorner, Garry L. Taylor, Arvind H. Patel^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

HCV vaccine development is stymied by the high genetic diversity of the virus and the variability of the envelope glycoproteins. One strategy to overcome this is to identify conserved, functionally important regions—such as the epitopes of broadly neutralizing antibodies (bNAbs)—and use these as a basis for structure-based vaccine design. Here, we report an anti-idiotype approach that has generated an antibody that mimics a highly conserved neutralizing epitope on HCV E2. Crucially, a mutagenesis screen was used to identify the antibody, designated B2.1 A, whose binding characteristics to the bNAb AP33 closely resemble those of the original antigen. Protein crystallography confirmed that B2.1 A is a structural mimic of the AP33 epitope. When used as an immunogen B2.1 A induced antibodies that recognized the same epitope and E2 residues as AP33 and most importantly protected against HCV challenge in a mouse model.

Original language	English
Article number	7
Number of pages	10
Journal	npj Vaccines
Volume	6
DOIs	https://doi.org/10.1038/s41541-020-00269-1
Publication status	Published - 8 Jan 2021

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title = "Development of a structural epitope mimic: an idiotypic approach to HCV vaccine design",

abstract = "HCV vaccine development is stymied by the high genetic diversity of the virus and the variability of the envelope glycoproteins. One strategy to overcome this is to identify conserved, functionally important regions—such as the epitopes of broadly neutralizing antibodies (bNAbs)—and use these as a basis for structure-based vaccine design. Here, we report an anti-idiotype approach that has generated an antibody that mimics a highly conserved neutralizing epitope on HCV E2. Crucially, a mutagenesis screen was used to identify the antibody, designated B2.1 A, whose binding characteristics to the bNAb AP33 closely resemble those of the original antigen. Protein crystallography confirmed that B2.1 A is a structural mimic of the AP33 epitope. When used as an immunogen B2.1 A induced antibodies that recognized the same epitope and E2 residues as AP33 and most importantly protected against HCV challenge in a mouse model.",

author = "Cowton, {Vanessa M.} and Owsianka, {Ania M.} and Valeria Fadda and Ortega-Prieto, {Ana Maria} and Cole, {Sarah J.} and Potter, {Jane A.} and Skelton, {Jessica K.} and Nathan Jeffrey and {Di Lorenzo}, Caterina and Marcus Dorner and Taylor, {Garry L.} and Patel, {Arvind H.}",

note = "Funding: This work was supported by Medical Research Council grant MC_UU12014/2 and DPFS Grant MC_EX_G0801770 awarded to AHP, and by a studentship to VF from the Programma Master and Back, Regione Autonoma della Sardegna. This study was supported by funding from a Wellcome Trust New Investigator award to MD (104771/Z/14/Z) and a starting grant from the European Research Council to MD (ERC-StG-2015-637304).",

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doi = "10.1038/s41541-020-00269-1",

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T2 - an idiotypic approach to HCV vaccine design

AU - Cowton, Vanessa M.

AU - Owsianka, Ania M.

AU - Fadda, Valeria

AU - Ortega-Prieto, Ana Maria

AU - Cole, Sarah J.

AU - Potter, Jane A.

AU - Skelton, Jessica K.

AU - Jeffrey, Nathan

AU - Di Lorenzo, Caterina

AU - Dorner, Marcus

AU - Taylor, Garry L.

AU - Patel, Arvind H.

N1 - Funding: This work was supported by Medical Research Council grant MC_UU12014/2 and DPFS Grant MC_EX_G0801770 awarded to AHP, and by a studentship to VF from the Programma Master and Back, Regione Autonoma della Sardegna. This study was supported by funding from a Wellcome Trust New Investigator award to MD (104771/Z/14/Z) and a starting grant from the European Research Council to MD (ERC-StG-2015-637304).

PY - 2021/1/8

Y1 - 2021/1/8

N2 - HCV vaccine development is stymied by the high genetic diversity of the virus and the variability of the envelope glycoproteins. One strategy to overcome this is to identify conserved, functionally important regions—such as the epitopes of broadly neutralizing antibodies (bNAbs)—and use these as a basis for structure-based vaccine design. Here, we report an anti-idiotype approach that has generated an antibody that mimics a highly conserved neutralizing epitope on HCV E2. Crucially, a mutagenesis screen was used to identify the antibody, designated B2.1 A, whose binding characteristics to the bNAb AP33 closely resemble those of the original antigen. Protein crystallography confirmed that B2.1 A is a structural mimic of the AP33 epitope. When used as an immunogen B2.1 A induced antibodies that recognized the same epitope and E2 residues as AP33 and most importantly protected against HCV challenge in a mouse model.

AB - HCV vaccine development is stymied by the high genetic diversity of the virus and the variability of the envelope glycoproteins. One strategy to overcome this is to identify conserved, functionally important regions—such as the epitopes of broadly neutralizing antibodies (bNAbs)—and use these as a basis for structure-based vaccine design. Here, we report an anti-idiotype approach that has generated an antibody that mimics a highly conserved neutralizing epitope on HCV E2. Crucially, a mutagenesis screen was used to identify the antibody, designated B2.1 A, whose binding characteristics to the bNAb AP33 closely resemble those of the original antigen. Protein crystallography confirmed that B2.1 A is a structural mimic of the AP33 epitope. When used as an immunogen B2.1 A induced antibodies that recognized the same epitope and E2 residues as AP33 and most importantly protected against HCV challenge in a mouse model.

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DO - 10.1038/s41541-020-00269-1

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JO - npj Vaccines

JF - npj Vaccines

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Development of a structural epitope mimic: an idiotypic approach to HCV vaccine design

Abstract

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