Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization

Immunity. 2022 Feb 8;55(2):341-354.e7. doi: 10.1016/j.immuni.2021.12.003. Epub 2022 Jan 5.


The high genetic diversity of hepatitis C virus (HCV) complicates effective vaccine development. We screened a cohort of 435 HCV-infected individuals and found that 2%-5% demonstrated outstanding HCV-neutralizing activity. From four of these patients, we isolated 310 HCV antibodies, including neutralizing antibodies with exceptional breadth and potency. High neutralizing activity was enabled by the use of the VH1-69 heavy-chain gene segment, somatic mutations within CDRH1, and CDRH2 hydrophobicity. Structural and mutational analyses revealed an important role for mutations replacing the serines at positions 30 and 31, as well as the presence of neutral and hydrophobic residues at the tip of the CDRH3. Based on these characteristics, we computationally created a de novo antibody with a fully synthetic VH1-69 heavy chain that efficiently neutralized multiple HCV genotypes. Our findings provide a deep understanding of the generation of broadly HCV-neutralizing antibodies that can guide the design of effective vaccine candidates.

Keywords: HCV; V(H)1-69; elite neutralizer; hepatitis C virus; machine learning; monoclonal antibody; neutralizing antibody; single B cell analysis; somatic mutation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / immunology
  • Broadly Neutralizing Antibodies / chemistry
  • Broadly Neutralizing Antibodies / genetics*
  • Broadly Neutralizing Antibodies / immunology
  • Complementarity Determining Regions / chemistry
  • Complementarity Determining Regions / genetics
  • Complementarity Determining Regions / immunology
  • Epitopes
  • Female
  • Genotype
  • Hepacivirus / genetics
  • Hepacivirus / immunology*
  • Hepatitis C / immunology
  • Hepatitis C Antibodies / chemistry
  • Hepatitis C Antibodies / genetics*
  • Hepatitis C Antibodies / immunology
  • Humans
  • Immunoglobulin Heavy Chains / chemistry
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Heavy Chains / immunology
  • Male
  • Middle Aged
  • Mutation
  • Viral Envelope Proteins / chemistry
  • Viral Envelope Proteins / immunology


  • Broadly Neutralizing Antibodies
  • Complementarity Determining Regions
  • Epitopes
  • Hepatitis C Antibodies
  • Immunoglobulin Heavy Chains
  • Viral Envelope Proteins
  • glycoprotein E2, Hepatitis C virus