{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:59:02Z","timestamp":1782280742492,"version":"3.54.5"},"posted":{"date-parts":[[2025,5,16]]},"group-title":"Microbiology","reference-count":132,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T00:00:00Z","timestamp":1747353600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,16]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Hepatitis C virus (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. E1E2-based HCV vaccine development has been hindered by the challenge of producing a soluble E1E2 (sE1E2) antigen that faithfully recapitulates the native glycoprotein heterodimer found on virions. Based on available cryo-electron microscopy (cryo-EM) structures, we rationally engineered sE1E2 for genotype 1a H77 by truncating the E1 and E2 stems (Cut\n                  <jats:sub>1<\/jats:sub>\n                  ), removing a putative fusion peptide (pFP)-containing region in E1 (Cut\n                  <jats:sub>2<\/jats:sub>\n                  ), and stabilizing the E1-E2 interface with diverse heterodimeric scaffolds. All H77 sE1E2.Cut\n                  <jats:sub>1+2<\/jats:sub>\n                  scaffolds showed native-like E1-E2 association and robust binding to the broadly neutralizing antibody (bNAb) AR4A. A genotype 1a HCV-1 sE1E2.Cut\n                  <jats:sub>1+2<\/jats:sub>\n                  variant scaffolded by a modified SpyTag\/SpyCatcher (SPY\u0394N) was selected for in vitro, structural, and immunogenic characterization. The structure of this sE1E2 scaffold in complex with bNAbs was analyzed by cryo-EM and negative-stain EM (nsEM), with an nsEM-based approach developed for antibody epitope mapping. HCV-1 sE1E2.Cut\n                  <jats:sub>1+2<\/jats:sub>\n                  .SPY\u0394N was displayed on self-assembling protein nanoparticles (SApNPs) to enhance immunogenicity. HCV-1 sE1E2.Cut\n                  <jats:sub>1+2<\/jats:sub>\n                  .SPY\u0394N heterodimer and SApNPs with wildtype and modified glycans were tested in mice, revealing the beneficial effects of multivalent display and oligomannose enrichment. Our study provides a rigorous foundation for next-generation HCV vaccine development.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>ONE-SENTENCE SUMMARY<\/jats:title>\n                  <jats:p>Rational design, characterization, and in vivo assessment of HCV soluble E1E2 heterodimer and nanoparticles will inform vaccine development.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.16.654559","type":"posted-content","created":{"date-parts":[[2025,5,17]],"date-time":"2025-05-17T00:30:13Z","timestamp":1747441813000},"source":"Crossref","is-referenced-by-count":2,"title":["Native-like soluble E1E2 glycoprotein heterodimers on self-assembling protein nanoparticles for hepatitis C virus vaccine design"],"prefix":"10.64898","author":[{"given":"Linling","family":"He","sequence":"first","affiliation":[{"name":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, 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