Generation of a Live Attenuated Influenza Vaccine that Elicits Broad Protection in Mice and Ferrets

Lulan Wang; Su Yang Liu; Hsiang Wen Chen; Juan Xu; Maxime Chapon; Tao Zhang; Fan Zhou; Yao E. Wang; Natalie Quanquin; Guiqin Wang; Xiaoli Tian; Zhanlong He; Longding Liu; Wenhai Yu; David Jesse Sanchez; Yuying Liang; Taijiao Jiang; Robert Modlin; Barry R. Bloom; Qihan Li; Jane C. Deng; Paul Zhou; F. Xiao Feng Qin; Genhong Cheng

doi:10.1016/j.chom.2017.02.007

Generation of a Live Attenuated Influenza Vaccine that Elicits Broad Protection in Mice and Ferrets

Lulan Wang, Su Yang Liu, Hsiang Wen Chen, Juan Xu, Maxime Chapon, Tao Zhang, Fan Zhou, Yao E. Wang, Natalie Quanquin, Guiqin Wang, Xiaoli Tian, Zhanlong He, Longding Liu, Wenhai Yu, David Jesse Sanchez, Yuying Liang, Taijiao Jiang, Robert Modlin, Barry R. Bloom, Qihan LiJane C. Deng, Paul Zhou, F. Xiao Feng Qin, Genhong Cheng

Veterinary and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

New influenza vaccines that provide effective and broad protection are desperately needed. Live attenuated viruses are attractive vaccine candidates because they can elicit both humoral and cellular immune responses. However, recent formulations of live attenuated influenza vaccines (LAIVs) have not been protective. We combined high-coverage transposon mutagenesis of influenza virus with a rapid high-throughput screening for attenuation to generate W7-791, a live attenuated mutant virus strain. W7-791 produced only a transient asymptomatic infection in adult and neonatal mice even at doses 100-fold higher than the LD₅₀ of the parent strain. A single administration of W7-791 conferred full protection to mice against lethal challenge with H1N1, H3N2, and H5N1 strains, and improved viral clearance in ferrets. Adoptive transfer of T cells from W7-791-immunized mice conferred heterologous protection, indicating a role for T cell-mediated immunity. These studies present an LAIV development strategy to rapidly generate and screen entire libraries of viral clones.

Original language	English (US)
Pages (from-to)	334-343
Number of pages	10
Journal	Cell Host and Microbe
Volume	21
Issue number	3
DOIs	https://doi.org/10.1016/j.chom.2017.02.007
State	Published - Mar 8 2017

Bibliographical note

Funding Information:
We would like to thank Drs. Yuying Liang and David Sanchez for providing the influenza 8-plasmid reverse genetics system. We would like to thank Dr. Ren Sun for his help in the mutagenesis assay. This work was supported by grants from the Chinese Academy of Medical Sciences, including CAMS Initiative for Innovative Medicine (2016-I2M-1-005), the institutional research fund for Thousand Talents Program at the CAMS, the national special research fund for public welfare industry at the CAMS, and PUMC Youth Fund (3332015124); grants from the National Natural Science Foundation of China (91542201, 81590765, and 81501351); the Ministry of Health of China grant (201302018); Ministry of Science and Technology of China grant (2013CB911103); the national key scientific and technological special project of China for the development of major innovative drug (2015ZX09102023); the national special research fund for public welfare industry from the Ministry of Health and Family Planning of China (201302018); and NIH grants AI069120, AI056154, AI078389, and T32 AI089398.

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

flu vaccine
genome-wide mutagenesis
influenza vaccine
matrix protein

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Wang, L., Liu, S. Y., Chen, H. W., Xu, J., Chapon, M., Zhang, T., Zhou, F., Wang, Y. E., Quanquin, N., Wang, G., Tian, X., He, Z., Liu, L., Yu, W., Sanchez, D. J., Liang, Y., Jiang, T., Modlin, R., Bloom, B. R., ... Cheng, G. (2017). Generation of a Live Attenuated Influenza Vaccine that Elicits Broad Protection in Mice and Ferrets. Cell Host and Microbe, 21(3), 334-343. https://doi.org/10.1016/j.chom.2017.02.007

Wang, L, Liu, SY, Chen, HW, Xu, J, Chapon, M, Zhang, T, Zhou, F, Wang, YE, Quanquin, N, Wang, G, Tian, X, He, Z, Liu, L, Yu, W, Sanchez, DJ, Liang, Y, Jiang, T, Modlin, R, Bloom, BR, Li, Q, Deng, JC, Zhou, P, Qin, FXF & Cheng, G 2017, 'Generation of a Live Attenuated Influenza Vaccine that Elicits Broad Protection in Mice and Ferrets', Cell Host and Microbe, vol. 21, no. 3, pp. 334-343. https://doi.org/10.1016/j.chom.2017.02.007

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abstract = "New influenza vaccines that provide effective and broad protection are desperately needed. Live attenuated viruses are attractive vaccine candidates because they can elicit both humoral and cellular immune responses. However, recent formulations of live attenuated influenza vaccines (LAIVs) have not been protective. We combined high-coverage transposon mutagenesis of influenza virus with a rapid high-throughput screening for attenuation to generate W7-791, a live attenuated mutant virus strain. W7-791 produced only a transient asymptomatic infection in adult and neonatal mice even at doses 100-fold higher than the LD50 of the parent strain. A single administration of W7-791 conferred full protection to mice against lethal challenge with H1N1, H3N2, and H5N1 strains, and improved viral clearance in ferrets. Adoptive transfer of T cells from W7-791-immunized mice conferred heterologous protection, indicating a role for T cell-mediated immunity. These studies present an LAIV development strategy to rapidly generate and screen entire libraries of viral clones.",

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author = "Lulan Wang and Liu, {Su Yang} and Chen, {Hsiang Wen} and Juan Xu and Maxime Chapon and Tao Zhang and Fan Zhou and Wang, {Yao E.} and Natalie Quanquin and Guiqin Wang and Xiaoli Tian and Zhanlong He and Longding Liu and Wenhai Yu and Sanchez, {David Jesse} and Yuying Liang and Taijiao Jiang and Robert Modlin and Bloom, {Barry R.} and Qihan Li and Deng, {Jane C.} and Paul Zhou and Qin, {F. Xiao Feng} and Genhong Cheng",

note = "Funding Information: We would like to thank Drs. Yuying Liang and David Sanchez for providing the influenza 8-plasmid reverse genetics system. We would like to thank Dr. Ren Sun for his help in the mutagenesis assay. This work was supported by grants from the Chinese Academy of Medical Sciences, including CAMS Initiative for Innovative Medicine (2016-I2M-1-005), the institutional research fund for Thousand Talents Program at the CAMS, the national special research fund for public welfare industry at the CAMS, and PUMC Youth Fund (3332015124); grants from the National Natural Science Foundation of China (91542201, 81590765, and 81501351); the Ministry of Health of China grant (201302018); Ministry of Science and Technology of China grant (2013CB911103); the national key scientific and technological special project of China for the development of major innovative drug (2015ZX09102023); the national special research fund for public welfare industry from the Ministry of Health and Family Planning of China (201302018); and NIH grants AI069120, AI056154, AI078389, and T32 AI089398. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

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AU - Chapon, Maxime

AU - Zhang, Tao

AU - Zhou, Fan

AU - Wang, Yao E.

AU - Quanquin, Natalie

AU - Wang, Guiqin

AU - Tian, Xiaoli

AU - He, Zhanlong

AU - Liu, Longding

AU - Yu, Wenhai

AU - Sanchez, David Jesse

AU - Liang, Yuying

AU - Jiang, Taijiao

AU - Modlin, Robert

AU - Bloom, Barry R.

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AU - Deng, Jane C.

AU - Zhou, Paul

AU - Qin, F. Xiao Feng

AU - Cheng, Genhong

N1 - Funding Information: We would like to thank Drs. Yuying Liang and David Sanchez for providing the influenza 8-plasmid reverse genetics system. We would like to thank Dr. Ren Sun for his help in the mutagenesis assay. This work was supported by grants from the Chinese Academy of Medical Sciences, including CAMS Initiative for Innovative Medicine (2016-I2M-1-005), the institutional research fund for Thousand Talents Program at the CAMS, the national special research fund for public welfare industry at the CAMS, and PUMC Youth Fund (3332015124); grants from the National Natural Science Foundation of China (91542201, 81590765, and 81501351); the Ministry of Health of China grant (201302018); Ministry of Science and Technology of China grant (2013CB911103); the national key scientific and technological special project of China for the development of major innovative drug (2015ZX09102023); the national special research fund for public welfare industry from the Ministry of Health and Family Planning of China (201302018); and NIH grants AI069120, AI056154, AI078389, and T32 AI089398. Publisher Copyright: © 2017 Elsevier Inc.

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N2 - New influenza vaccines that provide effective and broad protection are desperately needed. Live attenuated viruses are attractive vaccine candidates because they can elicit both humoral and cellular immune responses. However, recent formulations of live attenuated influenza vaccines (LAIVs) have not been protective. We combined high-coverage transposon mutagenesis of influenza virus with a rapid high-throughput screening for attenuation to generate W7-791, a live attenuated mutant virus strain. W7-791 produced only a transient asymptomatic infection in adult and neonatal mice even at doses 100-fold higher than the LD50 of the parent strain. A single administration of W7-791 conferred full protection to mice against lethal challenge with H1N1, H3N2, and H5N1 strains, and improved viral clearance in ferrets. Adoptive transfer of T cells from W7-791-immunized mice conferred heterologous protection, indicating a role for T cell-mediated immunity. These studies present an LAIV development strategy to rapidly generate and screen entire libraries of viral clones.

AB - New influenza vaccines that provide effective and broad protection are desperately needed. Live attenuated viruses are attractive vaccine candidates because they can elicit both humoral and cellular immune responses. However, recent formulations of live attenuated influenza vaccines (LAIVs) have not been protective. We combined high-coverage transposon mutagenesis of influenza virus with a rapid high-throughput screening for attenuation to generate W7-791, a live attenuated mutant virus strain. W7-791 produced only a transient asymptomatic infection in adult and neonatal mice even at doses 100-fold higher than the LD50 of the parent strain. A single administration of W7-791 conferred full protection to mice against lethal challenge with H1N1, H3N2, and H5N1 strains, and improved viral clearance in ferrets. Adoptive transfer of T cells from W7-791-immunized mice conferred heterologous protection, indicating a role for T cell-mediated immunity. These studies present an LAIV development strategy to rapidly generate and screen entire libraries of viral clones.

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Generation of a Live Attenuated Influenza Vaccine that Elicits Broad Protection in Mice and Ferrets

Abstract

Bibliographical note

Keywords

UN SDGs

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