Structural and biochemical insights into HCV envelope proteins for germline-targeting vaccines
4 affiliations
- 1Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Faculty of Mathematics & Science, The Hebrew University of Jerusalem, Jerusalem, Israel.
- 2Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
- 3Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.
- 4The Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem, Israel.
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.
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BibTeX
@article{yechezkel2026structural,
title = {{Structural and biochemical insights into HCV envelope proteins for germline-targeting vaccines}},
author = {ItaiG Yechezkel and Hila E Maimon and Ariel Tennenhouse and Fang Chen and Haneen Tarabih and Jenna Weisz and Rina Fraenkel and Sarel J Fleishman and Mansun Law and Netanel Tzarum},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014651},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014651},
note = {CC BY},
}
RIS
TY - JOUR
TI - Structural and biochemical insights into HCV envelope proteins for germline-targeting vaccines
AU - ItaiG Yechezkel
AU - Hila E Maimon
AU - Ariel Tennenhouse
AU - Fang Chen
AU - Haneen Tarabih
AU - Jenna Weisz
AU - Rina Fraenkel
AU - Sarel J Fleishman
AU - Mansun Law
AU - Netanel Tzarum
PY - 2026
DA - 2026/10/12
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014651
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014651
AB - 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.
SN - 1553-7374
SN - 1553-7366
ER -