National Academy of Sciences, Proceedings of the National Academy of Sciences, 3(118), 2021
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Significance Hepatitis C virus infects 1% of the world’s population, with no vaccine currently available. One vaccine candidate is the membrane-associated E1E2 envelope glycoprotein which has been used in clinical studies. However, a major challenge to both structural studies and rational vaccine design is high-yield production of homogenous E1E2. Production of E1E2 liberated from the membrane with native structure and antigenicity would thus represent a major advance. We describe the design and validation of a soluble, secreted E1E2 (sE1E2) antigen in which a scaffold replaces its transmembrane domains and enforces assembly. High-affinity sE1E2 binding to broadly neutralizing antibodies and to its receptor CD81, along with robust immunogenicity, makes this a promising platform for high-resolution structural characterization and vaccine development.