Generation of DelNS1 Influenza Viruses: a Strategy for Optimizing Live Attenuated Influenza Vaccines

ABSTRACT Nonstructural protein 1 (NS1) of influenza virus is a key virulence element with multifunctional roles in virus replication and a potent antagonist of host immune response. Deletion of NS1 (DelNS1) would create a safer and more extensively immunogenic live attenuated influenza virus (LAIV)...

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Autores principales:	Pui Wang, Min Zheng, Siu-Ying Lau, Pin Chen, Bobo Wing-Yee Mok, Siwen Liu, Honglian Liu, Xiaofeng Huang, Conor J. Cremin, Wenjun Song, Yixin Chen, Yik-Chun Wong, Haode Huang, Kelvin Kai-Wong To, Zhiwei Chen, Ningshao Xia, Kwok-Yung Yuen, Honglin Chen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	live attenuated vaccine NS1 influenza vaccines Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8881e0d1dc374c51a365ffa1af2aebdd
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spelling	oai:doaj.org-article:8881e0d1dc374c51a365ffa1af2aebdd2021-11-15T15:59:42ZGeneration of DelNS1 Influenza Viruses: a Strategy for Optimizing Live Attenuated Influenza Vaccines10.1128/mBio.02180-192150-7511https://doaj.org/article/8881e0d1dc374c51a365ffa1af2aebdd2019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02180-19https://doaj.org/toc/2150-7511ABSTRACT Nonstructural protein 1 (NS1) of influenza virus is a key virulence element with multifunctional roles in virus replication and a potent antagonist of host immune response. Deletion of NS1 (DelNS1) would create a safer and more extensively immunogenic live attenuated influenza virus (LAIV) vaccine. However, DelNS1 viruses are very difficult to grow in regular vaccine-producing systems, which has hampered the application of DelNS1 LAIV vaccines in humans. We have developed two master backbones of deleted-NS1 (DelNS1) viral genomes from influenza A or B viruses which contain novel adaptive mutations to support DelNS1-LAIV replication. These DelNS1-LAIVs are highly attenuated in human cells in vitro and nonpathogenic in mice but replicate well in vaccine-producing cells. Both influenza A and influenza B DelNS1 LAIVs grow better at 33°C than at 37 to 39°C. Vaccination with DelNS1 LAIV performed once is enough to provide potent protection against lethal challenge with homologous virus and strong long-lasting cross protection against heterosubtypic or antigenically distantly related influenza viruses in mice. Mechanistic investigations revealed that DelNS1-LAIVs induce cross protective neutralizing antibody and CD8+ and CD4+ T cell immunities. Importantly, it has been shown that DelNS1-LAIV can be used to enhance specific anti-influenza immunity through expression of additional antigens from the deleted-NS1 site. Generation of DelNS1 viruses which are nonpathogenic and able to grow in vaccine-producing systems is an important strategy for making highly immunogenic LAIV vaccines that induce broad cross protective immunity against seasonal and emerging influenza. IMPORTANCE Current seasonal influenza vaccines are suboptimal and low in immunogenicity and do not provide long-lasting immunity and cross protection against influenza virus strains that have antigenically drifted. More-effective influenza vaccines which can induce both humoral immunity and T cell immunity are needed. The NS1 protein of influenza virus is a virulence element and the critical factor for regulation of the host immune response during virus infection. Deletion of the NS1 protein is a strategy to make an optimal LAIV vaccine. However, DelNS1 viruses are very difficult to grow in regular vaccine-producing systems, hampering the application of DelNS1 LAIV vaccines in humans. We have generated a panel of both influenza A and influenza B DelNS1 LAIVs which are able to grow in regular vaccine-producing cells. These DelNS1 LAIV vaccines are completely nonpathogenic, exhibit potent and long-lasting immunity, and can be used to express extra viral antigen to induce cross protective immunity against seasonal and emerging influenza.Pui WangMin ZhengSiu-Ying LauPin ChenBobo Wing-Yee MokSiwen LiuHonglian LiuXiaofeng HuangConor J. CreminWenjun SongYixin ChenYik-Chun WongHaode HuangKelvin Kai-Wong ToZhiwei ChenNingshao XiaKwok-Yung YuenHonglin ChenAmerican Society for Microbiologyarticlelive attenuated vaccineNS1influenza vaccinesMicrobiologyQR1-502ENmBio, Vol 10, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	live attenuated vaccine NS1 influenza vaccines Microbiology QR1-502
spellingShingle	live attenuated vaccine NS1 influenza vaccines Microbiology QR1-502 Pui Wang Min Zheng Siu-Ying Lau Pin Chen Bobo Wing-Yee Mok Siwen Liu Honglian Liu Xiaofeng Huang Conor J. Cremin Wenjun Song Yixin Chen Yik-Chun Wong Haode Huang Kelvin Kai-Wong To Zhiwei Chen Ningshao Xia Kwok-Yung Yuen Honglin Chen Generation of DelNS1 Influenza Viruses: a Strategy for Optimizing Live Attenuated Influenza Vaccines
description	ABSTRACT Nonstructural protein 1 (NS1) of influenza virus is a key virulence element with multifunctional roles in virus replication and a potent antagonist of host immune response. Deletion of NS1 (DelNS1) would create a safer and more extensively immunogenic live attenuated influenza virus (LAIV) vaccine. However, DelNS1 viruses are very difficult to grow in regular vaccine-producing systems, which has hampered the application of DelNS1 LAIV vaccines in humans. We have developed two master backbones of deleted-NS1 (DelNS1) viral genomes from influenza A or B viruses which contain novel adaptive mutations to support DelNS1-LAIV replication. These DelNS1-LAIVs are highly attenuated in human cells in vitro and nonpathogenic in mice but replicate well in vaccine-producing cells. Both influenza A and influenza B DelNS1 LAIVs grow better at 33°C than at 37 to 39°C. Vaccination with DelNS1 LAIV performed once is enough to provide potent protection against lethal challenge with homologous virus and strong long-lasting cross protection against heterosubtypic or antigenically distantly related influenza viruses in mice. Mechanistic investigations revealed that DelNS1-LAIVs induce cross protective neutralizing antibody and CD8+ and CD4+ T cell immunities. Importantly, it has been shown that DelNS1-LAIV can be used to enhance specific anti-influenza immunity through expression of additional antigens from the deleted-NS1 site. Generation of DelNS1 viruses which are nonpathogenic and able to grow in vaccine-producing systems is an important strategy for making highly immunogenic LAIV vaccines that induce broad cross protective immunity against seasonal and emerging influenza. IMPORTANCE Current seasonal influenza vaccines are suboptimal and low in immunogenicity and do not provide long-lasting immunity and cross protection against influenza virus strains that have antigenically drifted. More-effective influenza vaccines which can induce both humoral immunity and T cell immunity are needed. The NS1 protein of influenza virus is a virulence element and the critical factor for regulation of the host immune response during virus infection. Deletion of the NS1 protein is a strategy to make an optimal LAIV vaccine. However, DelNS1 viruses are very difficult to grow in regular vaccine-producing systems, hampering the application of DelNS1 LAIV vaccines in humans. We have generated a panel of both influenza A and influenza B DelNS1 LAIVs which are able to grow in regular vaccine-producing cells. These DelNS1 LAIV vaccines are completely nonpathogenic, exhibit potent and long-lasting immunity, and can be used to express extra viral antigen to induce cross protective immunity against seasonal and emerging influenza.
format	article
author	Pui Wang Min Zheng Siu-Ying Lau Pin Chen Bobo Wing-Yee Mok Siwen Liu Honglian Liu Xiaofeng Huang Conor J. Cremin Wenjun Song Yixin Chen Yik-Chun Wong Haode Huang Kelvin Kai-Wong To Zhiwei Chen Ningshao Xia Kwok-Yung Yuen Honglin Chen
author_facet	Pui Wang Min Zheng Siu-Ying Lau Pin Chen Bobo Wing-Yee Mok Siwen Liu Honglian Liu Xiaofeng Huang Conor J. Cremin Wenjun Song Yixin Chen Yik-Chun Wong Haode Huang Kelvin Kai-Wong To Zhiwei Chen Ningshao Xia Kwok-Yung Yuen Honglin Chen
author_sort	Pui Wang
title	Generation of DelNS1 Influenza Viruses: a Strategy for Optimizing Live Attenuated Influenza Vaccines
title_short	Generation of DelNS1 Influenza Viruses: a Strategy for Optimizing Live Attenuated Influenza Vaccines
title_full	Generation of DelNS1 Influenza Viruses: a Strategy for Optimizing Live Attenuated Influenza Vaccines
title_fullStr	Generation of DelNS1 Influenza Viruses: a Strategy for Optimizing Live Attenuated Influenza Vaccines
title_full_unstemmed	Generation of DelNS1 Influenza Viruses: a Strategy for Optimizing Live Attenuated Influenza Vaccines
title_sort	generation of delns1 influenza viruses: a strategy for optimizing live attenuated influenza vaccines
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/8881e0d1dc374c51a365ffa1af2aebdd
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Generation of DelNS1 Influenza Viruses: a Strategy for Optimizing Live Attenuated Influenza Vaccines

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