Structurebased design of hepatitis C virus vaccines that elicit neutralizing antibody responses to a conserved epitope

Brian G. Pierce, Elisabeth N. Boucher, Kurt H Piepenbrink, Monir Ejemel, Chelsea A. Rapp, William D. Thomas, Eric J. Sundberg, Zhiping Weng, Yang Wang

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Despite recent advances in therapeutic options, hepatitis C virus (HCV) remains a severe global disease burden, and a vaccine can substantially reduce its incidence. Due to its extremely high sequence variability, HCV can readily escape the immune response; thus, an effective vaccine must target conserved, functionally important epitopes. Using the structure of a broadly neutralizing antibody in complex with a conserved linear epitope from the HCV E2 envelope glycoprotein (residues 412 to 423; epitope I), we performed structure-based design of immunogens to induce antibody responses to this epitope. This resulted in epitope-based immunogens based on a cyclic defensin protein, as well as a bivalent immunogen with two copies of the epitope on the E2 surface. We solved the X-ray structure of a cyclic immunogen in complex with the HCV1 antibody and confirmed preservation of the epitope conformation and the HCV1 interface. Mice vaccinated with our designed immunogens produced robust antibody responses to epitope I, and their serum could neutralize HCV. Notably, the cyclic designs induced greater epitope-specific responses and neutralization than the native peptide epitope. Beyond successfully designing several novel HCV immunogens, this study demonstrates the principle that neutralizing anti-HCV antibodies can be induced by epitope-based, engineered vaccines and provides the basis for further efforts in structure-based design of HCV vaccines.

Original languageEnglish (US)
Article numbere01032-17
JournalJournal of virology
Volume91
Issue number20
DOIs
StatePublished - Oct 1 2017

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Hepatitis C virus
Neutralizing Antibodies
neutralizing antibodies
Hepacivirus
epitopes
Antibody Formation
Epitopes
Vaccines
vaccines
antigens
antibodies
neutralization
Defensins
burden of disease
Hepatitis C Antibodies
glycoproteins
X-radiation
X-Rays
immune response
peptides

Keywords

  • Immunogen
  • Neutralizing antibodies
  • Protein design
  • Vaccines
  • hepatitis C virus

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Structurebased design of hepatitis C virus vaccines that elicit neutralizing antibody responses to a conserved epitope. / Pierce, Brian G.; Boucher, Elisabeth N.; Piepenbrink, Kurt H; Ejemel, Monir; Rapp, Chelsea A.; Thomas, William D.; Sundberg, Eric J.; Weng, Zhiping; Wang, Yang.

In: Journal of virology, Vol. 91, No. 20, e01032-17, 01.10.2017.

Research output: Contribution to journalArticle

Pierce, BG, Boucher, EN, Piepenbrink, KH, Ejemel, M, Rapp, CA, Thomas, WD, Sundberg, EJ, Weng, Z & Wang, Y 2017, 'Structurebased design of hepatitis C virus vaccines that elicit neutralizing antibody responses to a conserved epitope', Journal of virology, vol. 91, no. 20, e01032-17. https://doi.org/10.1128/JVI.01032-17
Pierce, Brian G. ; Boucher, Elisabeth N. ; Piepenbrink, Kurt H ; Ejemel, Monir ; Rapp, Chelsea A. ; Thomas, William D. ; Sundberg, Eric J. ; Weng, Zhiping ; Wang, Yang. / Structurebased design of hepatitis C virus vaccines that elicit neutralizing antibody responses to a conserved epitope. In: Journal of virology. 2017 ; Vol. 91, No. 20.
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