Optimized hepatitis C virus (HCV) E2 glycoproteins and their immunogenicity in combination with MVA-HCV

Hepatitis C virus (HCV) represents a major global health challenge and an efficient vaccine is urgently needed. Many HCV vaccination strategies employ recombinant versions of the viral E2 glycoprotein. However, recombinant E2 readily forms disulfide-bonded aggregates that might not be optimally suit...

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Autores: Marín, María Q., Sliepen, Kwinten, García-Arriaza, Juan, Koekkoek, Sylvie M., Pérez Ramírez, Patricia, Sorzano, Carlos Óscar S., Gómez, Carmen E., Sanders, Rogier W., Esteban, Mariano
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/220269
Acceso en línea:http://hdl.handle.net/10261/220269
Access Level:acceso abierto
Palabra clave:HCV
E2 protein
Cysteines
Disulfide bonds
MVA
vaccine
Mice
Immune responses
CD4 and CD8 T cells
Antibodies
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spelling Optimized hepatitis C virus (HCV) E2 glycoproteins and their immunogenicity in combination with MVA-HCVMarín, María Q.Sliepen, KwintenGarcía-Arriaza, JuanKoekkoek, Sylvie M.Pérez Ramírez, PatriciaSorzano, Carlos Óscar S.Gómez, Carmen E.Sanders, Rogier W.Esteban, MarianoHCVE2 proteinCysteinesDisulfide bondsMVAvaccineMiceImmune responsesCD4 and CD8 T cellsAntibodiesHepatitis C virus (HCV) represents a major global health challenge and an efficient vaccine is urgently needed. Many HCV vaccination strategies employ recombinant versions of the viral E2 glycoprotein. However, recombinant E2 readily forms disulfide-bonded aggregates that might not be optimally suited for vaccines. Therefore, we have designed an E2 protein in which we strategically changed eight cysteines to alanines (E2.C8A). E2.C8A formed predominantly monomers and virtually no aggregates. Furthermore, E2.C8A also interacted more efficiently with broadly neutralizing antibodies than conventional E2. We used mice to evaluate different prime/boost immunization strategies involving a modified vaccinia virus Ankara (MVA) expressing the nearly full-length genome of HCV (MVA-HCV) in combination with either the E2 aggregates or the E2.C8A monomers. The combined MVA-HCV/E2 aggregates prime/boost strategy markedly enhanced HCV-specific effector memory CD4<sup>+</sup> T cell responses and antibody levels compared to MVA-HCV/MVA-HCV. Moreover, the aggregated form of E2 induced higher levels of anti-E2 antibodies in vaccinated mice than E2.C8A monomers. These antibodies were cross-reactive and mainly of the IgG1 isotype. Our findings revealed how two E2 viral proteins that differ in their capacity to form aggregates are able to enhance to different extent the HCV-specific cellular and humoral immune responses, either alone or in combination with MVA-HCV. These combined protocols of MVA-HCV/E2 could serve as a basis for the development of a more effective HCV vaccine.This research was supported by MINECO Spanish grants SAF-2013-45232-R and SAF-2017-88089-R (to M.E.) and the Fondation Dormeur, Vaduz (to R.W.S.). R.W.S. is a recipient of a Vici grant from The Netherlands Organization for Scientific Research (NWO).Peer reviewedMultidisciplinary Digital Publishing InstituteMinisterio de Economía y Competitividad (España)Ministerio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Fondation Dormeur, VaduzNetherlands Organization for Scientific ResearchConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020202020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/220269reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF-2013-45232-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF-2017-88089-RSAF-2017-88089-R/AEI/10.13039/501100011033https://doi.org/10.3390/vaccines8030440Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2202692026-05-22T06:33:51Z
dc.title.none.fl_str_mv Optimized hepatitis C virus (HCV) E2 glycoproteins and their immunogenicity in combination with MVA-HCV
title Optimized hepatitis C virus (HCV) E2 glycoproteins and their immunogenicity in combination with MVA-HCV
spellingShingle Optimized hepatitis C virus (HCV) E2 glycoproteins and their immunogenicity in combination with MVA-HCV
Marín, María Q.
HCV
E2 protein
Cysteines
Disulfide bonds
MVA
vaccine
Mice
Immune responses
CD4 and CD8 T cells
Antibodies
title_short Optimized hepatitis C virus (HCV) E2 glycoproteins and their immunogenicity in combination with MVA-HCV
title_full Optimized hepatitis C virus (HCV) E2 glycoproteins and their immunogenicity in combination with MVA-HCV
title_fullStr Optimized hepatitis C virus (HCV) E2 glycoproteins and their immunogenicity in combination with MVA-HCV
title_full_unstemmed Optimized hepatitis C virus (HCV) E2 glycoproteins and their immunogenicity in combination with MVA-HCV
title_sort Optimized hepatitis C virus (HCV) E2 glycoproteins and their immunogenicity in combination with MVA-HCV
dc.creator.none.fl_str_mv Marín, María Q.
Sliepen, Kwinten
García-Arriaza, Juan
Koekkoek, Sylvie M.
Pérez Ramírez, Patricia
Sorzano, Carlos Óscar S.
Gómez, Carmen E.
Sanders, Rogier W.
Esteban, Mariano
author Marín, María Q.
author_facet Marín, María Q.
Sliepen, Kwinten
García-Arriaza, Juan
Koekkoek, Sylvie M.
Pérez Ramírez, Patricia
Sorzano, Carlos Óscar S.
Gómez, Carmen E.
Sanders, Rogier W.
Esteban, Mariano
author_role author
author2 Sliepen, Kwinten
García-Arriaza, Juan
Koekkoek, Sylvie M.
Pérez Ramírez, Patricia
Sorzano, Carlos Óscar S.
Gómez, Carmen E.
Sanders, Rogier W.
Esteban, Mariano
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Fondation Dormeur, Vaduz
Netherlands Organization for Scientific Research
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv HCV
E2 protein
Cysteines
Disulfide bonds
MVA
vaccine
Mice
Immune responses
CD4 and CD8 T cells
Antibodies
topic HCV
E2 protein
Cysteines
Disulfide bonds
MVA
vaccine
Mice
Immune responses
CD4 and CD8 T cells
Antibodies
description Hepatitis C virus (HCV) represents a major global health challenge and an efficient vaccine is urgently needed. Many HCV vaccination strategies employ recombinant versions of the viral E2 glycoprotein. However, recombinant E2 readily forms disulfide-bonded aggregates that might not be optimally suited for vaccines. Therefore, we have designed an E2 protein in which we strategically changed eight cysteines to alanines (E2.C8A). E2.C8A formed predominantly monomers and virtually no aggregates. Furthermore, E2.C8A also interacted more efficiently with broadly neutralizing antibodies than conventional E2. We used mice to evaluate different prime/boost immunization strategies involving a modified vaccinia virus Ankara (MVA) expressing the nearly full-length genome of HCV (MVA-HCV) in combination with either the E2 aggregates or the E2.C8A monomers. The combined MVA-HCV/E2 aggregates prime/boost strategy markedly enhanced HCV-specific effector memory CD4<sup>+</sup> T cell responses and antibody levels compared to MVA-HCV/MVA-HCV. Moreover, the aggregated form of E2 induced higher levels of anti-E2 antibodies in vaccinated mice than E2.C8A monomers. These antibodies were cross-reactive and mainly of the IgG1 isotype. Our findings revealed how two E2 viral proteins that differ in their capacity to form aggregates are able to enhance to different extent the HCV-specific cellular and humoral immune responses, either alone or in combination with MVA-HCV. These combined protocols of MVA-HCV/E2 could serve as a basis for the development of a more effective HCV vaccine.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/220269
url http://hdl.handle.net/10261/220269
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF-2013-45232-R
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF-2017-88089-R
SAF-2017-88089-R/AEI/10.13039/501100011033
https://doi.org/10.3390/vaccines8030440
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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