Consensus native-like hepatitis C virus E1E2 engages broadly neutralizing antibody precursors
A major goal for hepatitis C virus (HCV) vaccine development is to elicit broadly neutralizing antibodies (bNAbs) against the E1E2 glycoprotein complex located on the viral surface. Inducing HCV bNAbs requires engagement of their germline B cell precursors. HCV glycoproteins usually do not bind and activate inferred germline precursors of bNAbs (igl-bNAbs), possibly because most circulating…
The development of a hepatitis C virus (HCV) vaccine aims to generate broadly neutralizing antibodies (bNAbs) against the E1E2 glycoprotein complex on the virus's surface. To achieve this, researchers engineered stabilized native-like soluble E1E2 (sE1E2) antigens using a consensus sequence of HCV called HepCon. This modification minimizes exposure to antigenically rare residues, which are often present in most circulating strains.
The sE1E2 antigen displayed antigenicity and glycosylation profiles similar to a native-like E1E2 heterodimer. When administered to animals as a soluble protein or membrane-anchored mRNA, it triggered cross-reactive neutralizing antibody responses. Crucially, sE1E2 interacted with multiple inferred germline bNAbs (igl-bNAbs) targeting two key epitopes: antigenic region 3 (AR3) and antigenic region 4 (AR4).
AR3 is recognized by igl-bNAbs from the widely expressed human VH1-69 B cell gene, while AR4 is exclusive to native-like E1E2.
In vitro experiments showed that nanoparticles containing sE1E2 could activate B cell lines expressing AR3 and AR4 igl-bNAb B cell receptors. Furthermore, using sE1E2, researchers determined the atomic contacts of an AR3 igl-bNAb via cryo-electron microscopy. Overall, the HepCon sE1E2 antigen represents a promising candidate for germline-targeting vaccination strategies against HCV.
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