Mutation L319Q in the PB1 Polymerase Subunit Improves Attenuation of a Candidate Live-Attenuated Influenza A Virus Vaccine

15 Pág. Centro de Investigación en Sanidad Animal (CISA)

Detalles Bibliográficos
Autores: Nogales, Aitor, Steel, John, Liu, Wen-Chun, Lowen, Anice C., Rodriguez, Laura, Chiem, Kevin, Cox, Andrew, García-Sastre, Adolfo, Albrecht, Randy A., Dewhurst, Stephen, Martínez-Sobrido, Luis
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/279181
Acceso en línea:http://hdl.handle.net/10261/279181
https://api.elsevier.com/content/abstract/scopus_id/85133214171
Access Level:acceso abierto
Palabra clave:Attenuated
Cold-adapted
Ferrets
Guinea pigs
Influenza A virus
Live-attenuated influenza vaccines
Master donor virus
Protection efficacy
Temperature sensitive
Transmission
Vaccines
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oai_identifier_str oai:digital.csic.es:10261/279181
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Mutation L319Q in the PB1 Polymerase Subunit Improves Attenuation of a Candidate Live-Attenuated Influenza A Virus Vaccine
title Mutation L319Q in the PB1 Polymerase Subunit Improves Attenuation of a Candidate Live-Attenuated Influenza A Virus Vaccine
spellingShingle Mutation L319Q in the PB1 Polymerase Subunit Improves Attenuation of a Candidate Live-Attenuated Influenza A Virus Vaccine
Nogales, Aitor
Attenuated
Cold-adapted
Ferrets
Guinea pigs
Influenza A virus
Live-attenuated influenza vaccines
Master donor virus
Protection efficacy
Temperature sensitive
Transmission
Vaccines
title_short Mutation L319Q in the PB1 Polymerase Subunit Improves Attenuation of a Candidate Live-Attenuated Influenza A Virus Vaccine
title_full Mutation L319Q in the PB1 Polymerase Subunit Improves Attenuation of a Candidate Live-Attenuated Influenza A Virus Vaccine
title_fullStr Mutation L319Q in the PB1 Polymerase Subunit Improves Attenuation of a Candidate Live-Attenuated Influenza A Virus Vaccine
title_full_unstemmed Mutation L319Q in the PB1 Polymerase Subunit Improves Attenuation of a Candidate Live-Attenuated Influenza A Virus Vaccine
title_sort Mutation L319Q in the PB1 Polymerase Subunit Improves Attenuation of a Candidate Live-Attenuated Influenza A Virus Vaccine
dc.creator.none.fl_str_mv Nogales, Aitor
Steel, John
Liu, Wen-Chun
Lowen, Anice C.
Rodriguez, Laura
Chiem, Kevin
Cox, Andrew
García-Sastre, Adolfo
Albrecht, Randy A.
Dewhurst, Stephen
Martínez-Sobrido, Luis
author Nogales, Aitor
author_facet Nogales, Aitor
Steel, John
Liu, Wen-Chun
Lowen, Anice C.
Rodriguez, Laura
Chiem, Kevin
Cox, Andrew
García-Sastre, Adolfo
Albrecht, Randy A.
Dewhurst, Stephen
Martínez-Sobrido, Luis
author_role author
author2 Steel, John
Liu, Wen-Chun
Lowen, Anice C.
Rodriguez, Laura
Chiem, Kevin
Cox, Andrew
García-Sastre, Adolfo
Albrecht, Randy A.
Dewhurst, Stephen
Martínez-Sobrido, Luis
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv New York Influenza Center of Excellence
National Institute of Allergy and Infectious Diseases (US)
Department of Health and Human Services (US)
Centers of Excellence for Influenza Research and Surveillance (US)
Department of Defense (US)
Center for Research for Influenza Pathogenesis (US)
Ministerio de Ciencia e Innovación (España)
Icahn School of Medicine at Mount Sinai
Nogales, Aitor [0000-0002-2424-7900]
Lowen, Anice C. [0000-0002-9829-112X]
Chiem, Kevin [0000-0002-3892-5944]
García-Sastre, Adolfo [0000-0002-6551-1827]
Albrecht, Randy A. [0000-0003-4008-503X]
Dewhurst, Stephen [0000-0001-7729-7920]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Attenuated
Cold-adapted
Ferrets
Guinea pigs
Influenza A virus
Live-attenuated influenza vaccines
Master donor virus
Protection efficacy
Temperature sensitive
Transmission
Vaccines
topic Attenuated
Cold-adapted
Ferrets
Guinea pigs
Influenza A virus
Live-attenuated influenza vaccines
Master donor virus
Protection efficacy
Temperature sensitive
Transmission
Vaccines
description 15 Pág. Centro de Investigación en Sanidad Animal (CISA)
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
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/10261/279181
https://api.elsevier.com/content/abstract/scopus_id/85133214171
url http://hdl.handle.net/10261/279181
https://api.elsevier.com/content/abstract/scopus_id/85133214171
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Microbiology spectrum
https://doi.org/10.1128/spectrum.00078-22
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv ASM International
publisher.none.fl_str_mv ASM International
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
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869404969343385600
spelling Mutation L319Q in the PB1 Polymerase Subunit Improves Attenuation of a Candidate Live-Attenuated Influenza A Virus VaccineNogales, AitorSteel, JohnLiu, Wen-ChunLowen, Anice C.Rodriguez, LauraChiem, KevinCox, AndrewGarcía-Sastre, AdolfoAlbrecht, Randy A.Dewhurst, StephenMartínez-Sobrido, LuisAttenuatedCold-adaptedFerretsGuinea pigsInfluenza A virusLive-attenuated influenza vaccinesMaster donor virusProtection efficacyTemperature sensitiveTransmissionVaccines15 Pág. Centro de Investigación en Sanidad Animal (CISA)Influenza A viruses (IAV) remain emerging threats to human public health. Live-attenuated influenza vaccines (LAIV) are one of the most effective prophylactic options to prevent disease caused by influenza infections. However, licensed LAIV remain restricted for use in 2- to 49-year-old healthy and nonpregnant people. Therefore, development of LAIV with increased safety, immunogenicity, and protective efficacy is highly desired. The U.S.-licensed LAIV is based on the master donor virus (MDV) A/Ann Arbor/6/60 H2N2 backbone, which was generated by adaptation of the virus to growth at low temperatures. Introducing the genetic signature of the U.S. MDV into the backbone of other IAV strains resulted in varying levels of attenuation. While the U.S. MDV mutations conferred an attenuated phenotype to other IAV strains, the same amino acid changes did not significantly attenuate the pandemic A/California/04/09 H1N1 (pH1N1) strain. To attenuate pH1N1, we replaced the conserved leucine at position 319 with glutamine (L319Q) in PB1 and analyzed the in vitro and in vivo properties of pH1N1 viruses containing either PB1 L319Q alone or in combination with the U.S. MDV mutations using two animal models of influenza infection and transmission, ferrets and guinea pigs. Our results demonstrated that L319Q substitution in the pH1N1 PB1 alone or in combination with the mutations of the U.S. MDV resulted in reduced pathogenicity (ferrets) and transmission (guinea pigs), and an enhanced temperature sensitive phenotype. These results demonstrate the feasibility of generating an attenuated MDV based on the backbone of a contemporary pH1N1 IAV strain. IMPORTANCE Vaccination represents the most effective strategy to reduce the impact of seasonal IAV infections. Although LAIV are superior in inducing protection and sterilizing immunity, they are not recommended for many individuals who are at high risk for severe disease. Thus, development of safer and more effective LAIV are needed. A concern with the current MDV used to generate the U.S.-licensed LAIV is that it is based on a virus isolated in 1960. Moreover, mutations that confer the temperature-sensitive, cold-adapted, and attenuated phenotype of the U.S. MDV resulted in low level of attenuation in the contemporary pandemic A/California/04/09 H1N1 (pH1N1). Here, we show that introduction of PB1 L319Q substitution, alone or in combination with the U.S. MDV mutations, resulted in pH1N1 attenuation. These findings support the development of a novel LAIV MDV based on a contemporary pH1N1 strain as a medical countermeasure against currently circulating H1N1 IAV.This research was partially funded by the New York Influenza Center of Excellence (NYICE) (HHSN 272201400005C), and Emory-UGA (HHSN 272201400004C), members of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Department of Health and Human Services, Centers of Excellence for Influenza Research and Surveillance (CEIRS) network. The work was also supported by grants W81XWH-18-1-0460-PRMRP-DA (to L.M.-S.) and W81XWH-17-1-0168 (to S.D.) from the Department of Defense (DoD) Peer Reviewed Medical Research Program (PRMRP), as well as NIH R01 AI145332-01 (to L.M.-S.). This research was also partly funded by NIAID grant P01AI097092, by CEIRR (Center for Research on Influenza Pathogenesis and Transmission), a NIAID funded Center of Excellence for Influenza Research and Response (CEIRR, contract # 75N93021C00014) and by the Collaborative Influenza Vaccine Innovation Centers NIAID contract 75N93019C00051 to AG-S. A.N. received a “Ramon y Cajal” Incorporation grant (RYC-2017) from the Spanish Ministry of Science, Innovation. Finally, A.C. received support from NIH grants T32GM068411 and T32GM007356. Use of the Zeiss AxioImager.Z2 microscope and image analysis was performed at the Microscopy CoRE at the Icahn School of Medicine at Mount Sinai.Peer reviewedASM InternationalNew York Influenza Center of ExcellenceNational Institute of Allergy and Infectious Diseases (US)Department of Health and Human Services (US)Centers of Excellence for Influenza Research and Surveillance (US)Department of Defense (US)Center for Research for Influenza Pathogenesis (US)Ministerio de Ciencia e Innovación (España)Icahn School of Medicine at Mount SinaiNogales, Aitor [0000-0002-2424-7900]Lowen, Anice C. [0000-0002-9829-112X]Chiem, Kevin [0000-0002-3892-5944]García-Sastre, Adolfo [0000-0002-6551-1827]Albrecht, Randy A. [0000-0003-4008-503X]Dewhurst, Stephen [0000-0001-7729-7920]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202220222022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/279181https://api.elsevier.com/content/abstract/scopus_id/85133214171reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésMicrobiology spectrumhttps://doi.org/10.1128/spectrum.00078-22Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2791812026-05-22T06:33:51Z
score 15,811543

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