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

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

doi:10.1038/s41541-020-00269-1

Vanessa M Cowton, Sarah J Cole + Show 10 more

Open Access

https://doi.org/10.1038/s41541-020-00269-1

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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.

Highlights

There is an urgent need for a vaccine to prevent infection with hepatitis C virus (HCV)
The broadly neutralizing antibody AP33 was selected as an Ab1 as it has proven to be a potent neutralizing antibody that can protect against HCV infection
Mouse monoclonal antibodies to AP33 were produced and screened by ELISA to identify those that could (i) bind to biotinylated AP33 and (ii) block binding of AP33 to HCV E2 glycoprotein

Summary

Introduction

There is an urgent need for a vaccine to prevent infection with hepatitis C virus (HCV). Over 70 million people are chronically infected with the virus[1]. Effective drugs are available to treat chronic infections[2,3,4] but we still lack a prophylactic vaccine to prevent primary infection. A minority of newly-infected individuals (10–40%), clear HCV infection, but the majority develop a chronic infection[5,6]. Successful clearance of virus correlates with a broad, strong. The rate of spontaneous clearance in individuals who have previously cleared the virus increases to about 80% upon reinfection, showing that a protective immune response has been induced, indicating that vaccination is a realistic strategy[9,10]

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