Cargando…

Truncation of NS1 Protein Enhances T Cell-Mediated Cross-Protection of a Live Attenuated Influenza Vaccine Virus Expressing Wild-Type Nucleoprotein

Current seasonal influenza vaccines have suboptimal effectiveness, especially in seasons dominated by viruses that do not match the vaccine. Therefore, finding new approaches to improve the immunogenicity and efficacy of traditional influenza vaccines is of high priority for public health. Licensed...

Descripción completa

Detalles Bibliográficos
Autores principales: Prokopenko, Polina, Matyushenko, Victoria, Rak, Alexandra, Stepanova, Ekaterina, Chistyakova, Anna, Goshina, Arina, Kudryavtsev, Igor, Rudenko, Larisa, Isakova-Sivak, Irina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10056296/
https://www.ncbi.nlm.nih.gov/pubmed/36992084
http://dx.doi.org/10.3390/vaccines11030501
_version_ 1785016087185719296
author Prokopenko, Polina
Matyushenko, Victoria
Rak, Alexandra
Stepanova, Ekaterina
Chistyakova, Anna
Goshina, Arina
Kudryavtsev, Igor
Rudenko, Larisa
Isakova-Sivak, Irina
author_facet Prokopenko, Polina
Matyushenko, Victoria
Rak, Alexandra
Stepanova, Ekaterina
Chistyakova, Anna
Goshina, Arina
Kudryavtsev, Igor
Rudenko, Larisa
Isakova-Sivak, Irina
author_sort Prokopenko, Polina
collection PubMed
description Current seasonal influenza vaccines have suboptimal effectiveness, especially in seasons dominated by viruses that do not match the vaccine. Therefore, finding new approaches to improve the immunogenicity and efficacy of traditional influenza vaccines is of high priority for public health. Licensed live attenuated influenza vaccine (LAIV) is a promising platform for designing broadly protective vaccines due to its ability to induce cross-reactive T-cell immunity. In this study, we tested the hypothesis that truncation of the nonstructural protein 1 (NS1) and the replacement of the nucleoprotein (NP) of the A/Leningrad/17 master donor virus with a recent NP, i.e., switching to 5:3 genome composition, could improve the cross-protective potential of the LAIV virus. We generated a panel of LAIV candidates differing from the classical vaccine by the source of NP gene and/or by the length of NS1 protein. We showed that NS1-modified LAIV viruses had reduced viral replication in the respiratory tract of mice, indicating a more attenuated phenotype compared to the LAIVs with full-length NS1. Most importantly, the LAIV candidate with both NP and NS genes modified induced a robust systemic and lung-localized memory CD8 T-cell response targeting more recent viruses, and better protected immunized mice against lethal challenge with a heterosubtypic influenza virus than the control LAIV variant. Overall, these data indicate that the 5:3 LAIVs with truncated NS1 may be beneficial for protection against heterologous influenza viruses and warrant further preclinical and clinical development.
format Online
Article
Text
id pubmed-10056296
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-100562962023-03-30 Truncation of NS1 Protein Enhances T Cell-Mediated Cross-Protection of a Live Attenuated Influenza Vaccine Virus Expressing Wild-Type Nucleoprotein Prokopenko, Polina Matyushenko, Victoria Rak, Alexandra Stepanova, Ekaterina Chistyakova, Anna Goshina, Arina Kudryavtsev, Igor Rudenko, Larisa Isakova-Sivak, Irina Vaccines (Basel) Article Current seasonal influenza vaccines have suboptimal effectiveness, especially in seasons dominated by viruses that do not match the vaccine. Therefore, finding new approaches to improve the immunogenicity and efficacy of traditional influenza vaccines is of high priority for public health. Licensed live attenuated influenza vaccine (LAIV) is a promising platform for designing broadly protective vaccines due to its ability to induce cross-reactive T-cell immunity. In this study, we tested the hypothesis that truncation of the nonstructural protein 1 (NS1) and the replacement of the nucleoprotein (NP) of the A/Leningrad/17 master donor virus with a recent NP, i.e., switching to 5:3 genome composition, could improve the cross-protective potential of the LAIV virus. We generated a panel of LAIV candidates differing from the classical vaccine by the source of NP gene and/or by the length of NS1 protein. We showed that NS1-modified LAIV viruses had reduced viral replication in the respiratory tract of mice, indicating a more attenuated phenotype compared to the LAIVs with full-length NS1. Most importantly, the LAIV candidate with both NP and NS genes modified induced a robust systemic and lung-localized memory CD8 T-cell response targeting more recent viruses, and better protected immunized mice against lethal challenge with a heterosubtypic influenza virus than the control LAIV variant. Overall, these data indicate that the 5:3 LAIVs with truncated NS1 may be beneficial for protection against heterologous influenza viruses and warrant further preclinical and clinical development. MDPI 2023-02-21 /pmc/articles/PMC10056296/ /pubmed/36992084 http://dx.doi.org/10.3390/vaccines11030501 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Prokopenko, Polina
Matyushenko, Victoria
Rak, Alexandra
Stepanova, Ekaterina
Chistyakova, Anna
Goshina, Arina
Kudryavtsev, Igor
Rudenko, Larisa
Isakova-Sivak, Irina
Truncation of NS1 Protein Enhances T Cell-Mediated Cross-Protection of a Live Attenuated Influenza Vaccine Virus Expressing Wild-Type Nucleoprotein
title Truncation of NS1 Protein Enhances T Cell-Mediated Cross-Protection of a Live Attenuated Influenza Vaccine Virus Expressing Wild-Type Nucleoprotein
title_full Truncation of NS1 Protein Enhances T Cell-Mediated Cross-Protection of a Live Attenuated Influenza Vaccine Virus Expressing Wild-Type Nucleoprotein
title_fullStr Truncation of NS1 Protein Enhances T Cell-Mediated Cross-Protection of a Live Attenuated Influenza Vaccine Virus Expressing Wild-Type Nucleoprotein
title_full_unstemmed Truncation of NS1 Protein Enhances T Cell-Mediated Cross-Protection of a Live Attenuated Influenza Vaccine Virus Expressing Wild-Type Nucleoprotein
title_short Truncation of NS1 Protein Enhances T Cell-Mediated Cross-Protection of a Live Attenuated Influenza Vaccine Virus Expressing Wild-Type Nucleoprotein
title_sort truncation of ns1 protein enhances t cell-mediated cross-protection of a live attenuated influenza vaccine virus expressing wild-type nucleoprotein
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10056296/
https://www.ncbi.nlm.nih.gov/pubmed/36992084
http://dx.doi.org/10.3390/vaccines11030501
work_keys_str_mv AT prokopenkopolina truncationofns1proteinenhancestcellmediatedcrossprotectionofaliveattenuatedinfluenzavaccinevirusexpressingwildtypenucleoprotein
AT matyushenkovictoria truncationofns1proteinenhancestcellmediatedcrossprotectionofaliveattenuatedinfluenzavaccinevirusexpressingwildtypenucleoprotein
AT rakalexandra truncationofns1proteinenhancestcellmediatedcrossprotectionofaliveattenuatedinfluenzavaccinevirusexpressingwildtypenucleoprotein
AT stepanovaekaterina truncationofns1proteinenhancestcellmediatedcrossprotectionofaliveattenuatedinfluenzavaccinevirusexpressingwildtypenucleoprotein
AT chistyakovaanna truncationofns1proteinenhancestcellmediatedcrossprotectionofaliveattenuatedinfluenzavaccinevirusexpressingwildtypenucleoprotein
AT goshinaarina truncationofns1proteinenhancestcellmediatedcrossprotectionofaliveattenuatedinfluenzavaccinevirusexpressingwildtypenucleoprotein
AT kudryavtsevigor truncationofns1proteinenhancestcellmediatedcrossprotectionofaliveattenuatedinfluenzavaccinevirusexpressingwildtypenucleoprotein
AT rudenkolarisa truncationofns1proteinenhancestcellmediatedcrossprotectionofaliveattenuatedinfluenzavaccinevirusexpressingwildtypenucleoprotein
AT isakovasivakirina truncationofns1proteinenhancestcellmediatedcrossprotectionofaliveattenuatedinfluenzavaccinevirusexpressingwildtypenucleoprotein