{
  "abstract": "Despite effective antivirals, Hepatitis C remains a global health burden, reflecting the difficulty of eliciting broadly neutralizing antibodies (bnAbs). For the Hepatitis C virus, bnAb responses are biased toward VH1-69-encoded Abs targeting a conserved epitope on the E2 glycoprotein, suggesting that effective immunogens must engage the corresponding germline (GL) B cell receptors. However, the structural basis of GL recognition remains unclear. Here, we show that GL-reverted VH1-69 bnAbs recognize the E2 core domain in a manner closely resembling mature Abs binding. High-resolution structures reveal a conserved mode of engagement, indicating that key epitope features are accessible prior to affinity maturation. Guided by these insights, we engineered E2 variants to enhance GL Ab interactions and stability. Although these designs increased affinity, they did not improve engagement of naïve B cells, highlighting a key constraint in GL-targeting strategies. Together, our findings define principles governing GL recognition and inform the rational design of an HCV vaccine. Author summary: Hepatitis C virus (HCV) infects millions of people worldwide and remains a leading cause of chronic liver disease. Although highly effective antiviral drugs can cure infection, they do not prevent new infections, making the development of a preventive vaccine a global priority. One promising strategy is to stimulate rare naïve B cells that can develop into broadly neutralizing antibody-producing cells capable of recognizing many different HCV strains. In this study, we determined how putative antibody precursors recognize a conserved region of the HCV envelope protein at atomic resolution. Using this structural information, we engineered modified viral proteins designed to improve recognition by these precursor antibodies. While the engineered proteins showed binding in biochemical assays, they did not increase recognition of naïve B cells. These findings reveal that improving antibody affinity alone is insufficient to enhance the earliest stages of the immune response. Our work provides new insights into how broadly neutralizing antibodies develop and identifies important considerations for designing next-generation vaccines against HCV and other rapidly evolving viruses.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Faculty of Mathematics & Science, The Hebrew University of Jerusalem, Jerusalem, Israel.",
    "Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.",
    "Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.",
    "The Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem, Israel."
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "ItaiG Yechezkel"
    },
    {
      "affs": [
        0
      ],
      "name": "Hila E Maimon"
    },
    {
      "affs": [
        1
      ],
      "name": "Ariel Tennenhouse"
    },
    {
      "affs": [
        2
      ],
      "name": "Fang Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Haneen Tarabih"
    },
    {
      "affs": [
        0
      ],
      "name": "Jenna Weisz"
    },
    {
      "affs": [
        0
      ],
      "name": "Rina Fraenkel"
    },
    {
      "affs": [
        1
      ],
      "name": "Sarel J Fleishman"
    },
    {
      "affs": [
        2
      ],
      "name": "Mansun Law"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Netanel Tzarum",
      "orcid": "0000-0001-6401-1356"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5jvn1b93eg2mh.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.ppat.1014651",
  "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014651",
  "id": "5jvn1b93eg2mh",
  "issns": [
    "1553-7374",
    "1553-7366"
  ],
  "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014651",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2721|Hepatitis C virus research"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Immune system proteins/Antigens"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/B cells"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/Antibody-producing cells/B cells"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/B cells"
    ],
    [
      "plos",
      "/Biology and life sciences/Immunology/Immune cells/Antibody-producing cells/B cells"
    ],
    [
      "plos",
      "/Biology and life sciences/Immunology/Immune cells/White blood cells/B cells"
    ],
    [
      "plos",
      "/Biology and life sciences/Immunology/Immune system proteins/Antigens"
    ],
    [
      "plos",
      "/Biology and life sciences/Immunology/Vaccination and immunization/Vaccine development"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Flaviviruses/Hepacivirus/Hepatitis C virus"
    ],
    [
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      "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Hepatitis viruses/Hepatitis C virus"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Virology/Viral vaccines"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Virology/Viral vaccines/HIV vaccines"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Viruses/RNA viruses/Flaviviruses/Hepacivirus/Hepatitis C virus"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Flaviviruses/Hepacivirus/Hepatitis C virus"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Hepatitis viruses/Hepatitis C virus"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Immune physiology/Antigens"
    ],
    [
      "plos",
      "/Medicine and health sciences/Immunology/Immune cells/Antibody-producing cells/B cells"
    ],
    [
      "plos",
      "/Medicine and health sciences/Immunology/Immune cells/White blood cells/B cells"
    ],
    [
      "plos",
      "/Medicine and health sciences/Immunology/Immune system proteins/Antigens"
    ],
    [
      "plos",
      "/Medicine and health sciences/Immunology/Vaccination and immunization/Vaccine development"
    ],
    [
      "plos",
      "/Medicine and health sciences/Medical conditions/Infectious diseases/Infectious disease control/Vaccines/Viral vaccines"
    ],
    [
      "plos",
      "/Medicine and health sciences/Medical conditions/Infectious diseases/Infectious disease control/Vaccines/Viral vaccines/HIV vaccines"
    ],
    [
      "plos",
      "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Flaviviruses/Hepacivirus/Hepatitis C virus"
    ],
    [
      "plos",
      "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Hepatitis viruses/Hepatitis C virus"
    ],
    [
      "plos",
      "/Medicine and health sciences/Public and occupational health/Preventive medicine/Vaccination and immunization/Vaccine development"
    ],
    [
      "plos",
      "/Physical sciences/Physics/Condensed matter physics/Solid state physics/Crystallography/Crystal structure"
    ],
    [
      "plos",
      "/Research and analysis methods/Chemical characterization/Binding analysis"
    ]
  ],
  "openalex": "W7221527456",
  "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014651&type=printable",
  "pmcid": "PMC13690239",
  "pmid": "42862868",
  "published": "2026-10-12",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/5jvn1b93eg2mh.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:30Z",
      "native_id": "10.1371/journal.ppat.1014651",
      "source": "plos",
      "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014651"
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    {
      "first_seen": "2026-10-30T12:19:00Z",
      "native_id": "MED:42862868",
      "source": "europepmc",
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  "subjects": [
    {
      "field": "biology",
      "origin": "plos:immunology",
      "subfield": "immunology"
    },
    {
      "field": "biology",
      "origin": "plos:microbiology",
      "subfield": "microbiology"
    }
  ],
  "title": "Structural and biochemical insights into HCV envelope proteins for germline-targeting vaccines",
  "title_text": "Structural and biochemical insights into HCV envelope proteins for germline-targeting vaccines",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:00Z",
  "url": "https://research.draconitic.com/paper/5jvn1b93eg2mh",
  "venue": "PLOS Pathogens",
  "versions": []
}