Structure-Based Design of Hepatitis C Virus Vaccines That Elicit Neutralizing Antibody Responses to a Conserved Epitope.

نویسندگان

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

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.IMPORTANCE Hepatitis C virus is a leading cause of liver disease and liver cancer, with approximately 3% of the world's population infected. To combat this virus, an effective vaccine would have distinct advantages over current therapeutic options, yet experimental vaccines have not been successful to date, due in part to the virus's high sequence variability leading to immune escape. In this study, we rationally designed several vaccine immunogens based on the structure of a conserved epitope that is the target of broadly neutralizing antibodies. In vivo results in mice indicated that these antigens elicited epitope-specific neutralizing antibodies, with various degrees of potency and breadth. These promising results suggest that a rational design approach can be used to generate an effective vaccine for this virus.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Structure-Based Design of Hepatitis C Virus Vaccines that Elicit Neutralizing Antibody Responses to a Conserved Epitope

Structure-Based Design of Hepatitis C Virus Vaccines that Elicit Neutralizing Antibody Responses to a Conserved Epitope. Title Structure-Based Design of Hepatitis C Virus Vaccines that Elicit Neutralizing Antibody Responses to a Conserved Epitope. Publication Type Journal Article Year of Publication 2017 Authors Pierce, BG, Boucher, EN, Piepenbrink, KH, Ejemel, M, Rapp, CA, Thomas, WD, Sundberg...

متن کامل

Development of Preventive Vaccines for Hepatitis C Virus E1/E2 Protein

Hepatitis C virus (HCV) is responsible for a vast majority of liver failure cases. HCV is a kind of blood disease appraised to chronically infect 3% of the worlds’ population causing significant morbidity and mortality. Therefore, a complete knowledge of humoral responses against HCV, resulting antibodies, and virus-receptor and virus-antibody interactions, are essential to design a vaccine. HC...

متن کامل

Structural Basis for Broad Neutralization of Hepatitis C Virus Quasispecies

Monoclonal antibodies directed against hepatitis C virus (HCV) E2 protein can neutralize cell-cultured HCV and pseudoparticles expressing envelopes derived from multiple HCV subtypes. For example, based on antibody blocking experiments and alanine scanning mutagenesis, it was proposed that the AR3B monoclonal antibody recognized a discontinuous conformational epitope comprised of amino acid res...

متن کامل

A Novel Multi-Epitope Vaccine For Cross Protection Against Hepatitis C Virus (HCV): An Immunoinformatics Approach

Background: Hepatitis C virus (HCV) causes acute and chronic human hepatitis infections. Due to the high genetic diversity and high rates of mutations in the genetic material so far there is no approved vaccine against HCV. Materials and Methods: The aim of this study was to determination B and T cell conserved epitopes of E1 and E2 proteins from HCV and construction of a chimeric pepti...

متن کامل

Strong Immune Responses Induced by a DNA Vaccine Containing HPV16 Truncated E7 C-terminal Linked to HSP70 Gene

Background: Vaccines capable of controlling tumor virus based infections are found difficult to develop due to the consistence latent infection in the host. DNA vaccines are attractive tools for the development of HPV vaccines and inducing antigen-specific immunity owing to the stability, simplicity of delivery, safety and cost effectiveness. However, there is a need to increase their potency b...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Journal of virology

دوره 91 20  شماره 

صفحات  -

تاریخ انتشار 2017