Cargando…

A Hepatitis C Virus DNA Vaccine Encoding a Secreted, Oligomerized Form of Envelope Proteins Is Highly Immunogenic and Elicits Neutralizing Antibodies in Vaccinated Mice

Hepatitis C virus (HCV) persistently infects approximately 71 million people globally. To prevent infection a vaccine which elicits neutralizing antibodies against the virus envelope proteins (E1/E2) which are required for entry into host cells is desirable. DNA vaccines are cost-effective to manufa...

Descripción completa

Detalles Bibliográficos
Autores principales: Masavuli, Makutiro Ghislain, Wijesundara, Danushka K., Underwood, Alexander, Christiansen, Dale, Earnest-Silveira, Linda, Bull, Rowena, Torresi, Joseph, Gowans, Eric J., Grubor-Bauk, Branka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543710/
https://www.ncbi.nlm.nih.gov/pubmed/31178869
http://dx.doi.org/10.3389/fimmu.2019.01145
_version_ 1783423133447880704
author Masavuli, Makutiro Ghislain
Wijesundara, Danushka K.
Underwood, Alexander
Christiansen, Dale
Earnest-Silveira, Linda
Bull, Rowena
Torresi, Joseph
Gowans, Eric J.
Grubor-Bauk, Branka
author_facet Masavuli, Makutiro Ghislain
Wijesundara, Danushka K.
Underwood, Alexander
Christiansen, Dale
Earnest-Silveira, Linda
Bull, Rowena
Torresi, Joseph
Gowans, Eric J.
Grubor-Bauk, Branka
author_sort Masavuli, Makutiro Ghislain
collection PubMed
description Hepatitis C virus (HCV) persistently infects approximately 71 million people globally. To prevent infection a vaccine which elicits neutralizing antibodies against the virus envelope proteins (E1/E2) which are required for entry into host cells is desirable. DNA vaccines are cost-effective to manufacture globally and despite recent landmark studies highlighting the therapeutic efficacy of DNA vaccines in humans against cervical cancer, DNA vaccines encoding E1/E2 developed thus far are poorly immunogenic. We now report a novel and highly immunogenic DNA vaccination strategy that incorporates secreted E1 and E2 (sE1 and sE2) into oligomers by fusion with the oligomerization domain of the C4b-binding protein, IMX313P. The FDA approved plasmid, pVax, was used to encode sE1, sE2, or sE1E2 with or without IMX313P, and intradermal prime-boost vaccination studies in BALB/c mice showed that vaccines encoding IMX313P were the most effective in eliciting humoral and cell-mediated immunity against the envelope proteins. Further boosting with recombinant E1E2 proteins but not DNA nor virus-like particles (VLPs) expressing E1E2 increased the immunogenicity of the DNA prime-boost regimen. Nevertheless, the antibodies generated by the homologous DNA prime-boost vaccinations more effectively inhibited the binding of VLPs to target cells and neutralized transduction with HCV pseudoparticles (HCVpp) derived from different genotypes including genotypes 1, 2, 3, 4, 5, and 6. This report provides the first evidence that IMX313P can be used as an adjuvant for E1/E2-based DNA vaccines and represents a translatable approach for the development of a HCV DNA vaccine.
format Online
Article
Text
id pubmed-6543710
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-65437102019-06-07 A Hepatitis C Virus DNA Vaccine Encoding a Secreted, Oligomerized Form of Envelope Proteins Is Highly Immunogenic and Elicits Neutralizing Antibodies in Vaccinated Mice Masavuli, Makutiro Ghislain Wijesundara, Danushka K. Underwood, Alexander Christiansen, Dale Earnest-Silveira, Linda Bull, Rowena Torresi, Joseph Gowans, Eric J. Grubor-Bauk, Branka Front Immunol Immunology Hepatitis C virus (HCV) persistently infects approximately 71 million people globally. To prevent infection a vaccine which elicits neutralizing antibodies against the virus envelope proteins (E1/E2) which are required for entry into host cells is desirable. DNA vaccines are cost-effective to manufacture globally and despite recent landmark studies highlighting the therapeutic efficacy of DNA vaccines in humans against cervical cancer, DNA vaccines encoding E1/E2 developed thus far are poorly immunogenic. We now report a novel and highly immunogenic DNA vaccination strategy that incorporates secreted E1 and E2 (sE1 and sE2) into oligomers by fusion with the oligomerization domain of the C4b-binding protein, IMX313P. The FDA approved plasmid, pVax, was used to encode sE1, sE2, or sE1E2 with or without IMX313P, and intradermal prime-boost vaccination studies in BALB/c mice showed that vaccines encoding IMX313P were the most effective in eliciting humoral and cell-mediated immunity against the envelope proteins. Further boosting with recombinant E1E2 proteins but not DNA nor virus-like particles (VLPs) expressing E1E2 increased the immunogenicity of the DNA prime-boost regimen. Nevertheless, the antibodies generated by the homologous DNA prime-boost vaccinations more effectively inhibited the binding of VLPs to target cells and neutralized transduction with HCV pseudoparticles (HCVpp) derived from different genotypes including genotypes 1, 2, 3, 4, 5, and 6. This report provides the first evidence that IMX313P can be used as an adjuvant for E1/E2-based DNA vaccines and represents a translatable approach for the development of a HCV DNA vaccine. Frontiers Media S.A. 2019-05-24 /pmc/articles/PMC6543710/ /pubmed/31178869 http://dx.doi.org/10.3389/fimmu.2019.01145 Text en Copyright © 2019 Masavuli, Wijesundara, Underwood, Christiansen, Earnest-Silveira, Bull, Torresi, Gowans and Grubor-Bauk. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Masavuli, Makutiro Ghislain
Wijesundara, Danushka K.
Underwood, Alexander
Christiansen, Dale
Earnest-Silveira, Linda
Bull, Rowena
Torresi, Joseph
Gowans, Eric J.
Grubor-Bauk, Branka
A Hepatitis C Virus DNA Vaccine Encoding a Secreted, Oligomerized Form of Envelope Proteins Is Highly Immunogenic and Elicits Neutralizing Antibodies in Vaccinated Mice
title A Hepatitis C Virus DNA Vaccine Encoding a Secreted, Oligomerized Form of Envelope Proteins Is Highly Immunogenic and Elicits Neutralizing Antibodies in Vaccinated Mice
title_full A Hepatitis C Virus DNA Vaccine Encoding a Secreted, Oligomerized Form of Envelope Proteins Is Highly Immunogenic and Elicits Neutralizing Antibodies in Vaccinated Mice
title_fullStr A Hepatitis C Virus DNA Vaccine Encoding a Secreted, Oligomerized Form of Envelope Proteins Is Highly Immunogenic and Elicits Neutralizing Antibodies in Vaccinated Mice
title_full_unstemmed A Hepatitis C Virus DNA Vaccine Encoding a Secreted, Oligomerized Form of Envelope Proteins Is Highly Immunogenic and Elicits Neutralizing Antibodies in Vaccinated Mice
title_short A Hepatitis C Virus DNA Vaccine Encoding a Secreted, Oligomerized Form of Envelope Proteins Is Highly Immunogenic and Elicits Neutralizing Antibodies in Vaccinated Mice
title_sort hepatitis c virus dna vaccine encoding a secreted, oligomerized form of envelope proteins is highly immunogenic and elicits neutralizing antibodies in vaccinated mice
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543710/
https://www.ncbi.nlm.nih.gov/pubmed/31178869
http://dx.doi.org/10.3389/fimmu.2019.01145
work_keys_str_mv AT masavulimakutiroghislain ahepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT wijesundaradanushkak ahepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT underwoodalexander ahepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT christiansendale ahepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT earnestsilveiralinda ahepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT bullrowena ahepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT torresijoseph ahepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT gowansericj ahepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT gruborbaukbranka ahepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT masavulimakutiroghislain hepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT wijesundaradanushkak hepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT underwoodalexander hepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT christiansendale hepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT earnestsilveiralinda hepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT bullrowena hepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT torresijoseph hepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT gowansericj hepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice
AT gruborbaukbranka hepatitiscvirusdnavaccineencodingasecretedoligomerizedformofenvelopeproteinsishighlyimmunogenicandelicitsneutralizingantibodiesinvaccinatedmice