Rationally Designed Influenza Virus Vaccines That Are Antigenically Stable during Growth in Eggs

ABSTRACT Influenza virus vaccine production is currently limited by the ability to grow circulating human strains in chicken eggs or in cell culture. To facilitate cost-effective growth, vaccine strains are serially passaged under production conditions, which frequently results in mutations of the m...

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Autores principales:	Alfred T. Harding, Brook E. Heaton, Rebekah E. Dumm, Nicholas S. Heaton
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	antigenic instability genetic engineering influenza A virus influenza B virus vaccines Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/903553c0d64a420585785726adc1a281
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spelling	oai:doaj.org-article:903553c0d64a420585785726adc1a2812021-11-15T15:51:29ZRationally Designed Influenza Virus Vaccines That Are Antigenically Stable during Growth in Eggs10.1128/mBio.00669-172150-7511https://doaj.org/article/903553c0d64a420585785726adc1a2812017-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00669-17https://doaj.org/toc/2150-7511ABSTRACT Influenza virus vaccine production is currently limited by the ability to grow circulating human strains in chicken eggs or in cell culture. To facilitate cost-effective growth, vaccine strains are serially passaged under production conditions, which frequently results in mutations of the major antigenic protein, the viral hemagglutinin (HA). Human vaccination with an antigenically drifted strain is known to contribute to poor vaccine efficacy. To address this problem, we developed a replication-competent influenza A virus (IAV) with an artificial genomic organization that allowed the incorporation of two independent and functional HA proteins with different growth requirements onto the same virion. Vaccination with these viruses induced protective immunity against both strains from which the HA proteins were derived, and the magnitude of the response was as high as or higher than vaccination with either of the monovalent parental strains alone. Dual-HA viruses also displayed remarkable antigenic stability; even when using an HA protein known to be highly unstable during growth in eggs, we observed high-titer virus amplification without a single adaptive mutation. Thus, the viral genomic design described in this work can be used to grow influenza virus vaccines to high titers without introducing antigenic mutations. IMPORTANCE Influenza A virus (IAV) is a major public health threat, and vaccination is currently the best available strategy to prevent infection. While there have been many advances in influenza vaccine production, the fact that we cannot predict the growth characteristics of a given strain under vaccine production conditions a priori introduces fundamental uncertainty into the process. Clinically relevant IAV strains frequently grow poorly under vaccine conditions, and this poor growth can result in the delay of vaccine production or the exchange of the recommended strain for one with favorable growth properties. Even in strains that grow to high titers, adaptive mutations in the antigenic protein hemagglutinin (HA) that make it antigenically dissimilar to the circulating strain are common. The genomic restructuring of the influenza virus described in this work offers a solution to the problem of uncertain or unstable growth of IAV during vaccine production.Alfred T. HardingBrook E. HeatonRebekah E. DummNicholas S. HeatonAmerican Society for Microbiologyarticleantigenic instabilitygenetic engineeringinfluenza A virusinfluenza B virusvaccinesMicrobiologyQR1-502ENmBio, Vol 8, Iss 3 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	antigenic instability genetic engineering influenza A virus influenza B virus vaccines Microbiology QR1-502
spellingShingle	antigenic instability genetic engineering influenza A virus influenza B virus vaccines Microbiology QR1-502 Alfred T. Harding Brook E. Heaton Rebekah E. Dumm Nicholas S. Heaton Rationally Designed Influenza Virus Vaccines That Are Antigenically Stable during Growth in Eggs
description	ABSTRACT Influenza virus vaccine production is currently limited by the ability to grow circulating human strains in chicken eggs or in cell culture. To facilitate cost-effective growth, vaccine strains are serially passaged under production conditions, which frequently results in mutations of the major antigenic protein, the viral hemagglutinin (HA). Human vaccination with an antigenically drifted strain is known to contribute to poor vaccine efficacy. To address this problem, we developed a replication-competent influenza A virus (IAV) with an artificial genomic organization that allowed the incorporation of two independent and functional HA proteins with different growth requirements onto the same virion. Vaccination with these viruses induced protective immunity against both strains from which the HA proteins were derived, and the magnitude of the response was as high as or higher than vaccination with either of the monovalent parental strains alone. Dual-HA viruses also displayed remarkable antigenic stability; even when using an HA protein known to be highly unstable during growth in eggs, we observed high-titer virus amplification without a single adaptive mutation. Thus, the viral genomic design described in this work can be used to grow influenza virus vaccines to high titers without introducing antigenic mutations. IMPORTANCE Influenza A virus (IAV) is a major public health threat, and vaccination is currently the best available strategy to prevent infection. While there have been many advances in influenza vaccine production, the fact that we cannot predict the growth characteristics of a given strain under vaccine production conditions a priori introduces fundamental uncertainty into the process. Clinically relevant IAV strains frequently grow poorly under vaccine conditions, and this poor growth can result in the delay of vaccine production or the exchange of the recommended strain for one with favorable growth properties. Even in strains that grow to high titers, adaptive mutations in the antigenic protein hemagglutinin (HA) that make it antigenically dissimilar to the circulating strain are common. The genomic restructuring of the influenza virus described in this work offers a solution to the problem of uncertain or unstable growth of IAV during vaccine production.
format	article
author	Alfred T. Harding Brook E. Heaton Rebekah E. Dumm Nicholas S. Heaton
author_facet	Alfred T. Harding Brook E. Heaton Rebekah E. Dumm Nicholas S. Heaton
author_sort	Alfred T. Harding
title	Rationally Designed Influenza Virus Vaccines That Are Antigenically Stable during Growth in Eggs
title_short	Rationally Designed Influenza Virus Vaccines That Are Antigenically Stable during Growth in Eggs
title_full	Rationally Designed Influenza Virus Vaccines That Are Antigenically Stable during Growth in Eggs
title_fullStr	Rationally Designed Influenza Virus Vaccines That Are Antigenically Stable during Growth in Eggs
title_full_unstemmed	Rationally Designed Influenza Virus Vaccines That Are Antigenically Stable during Growth in Eggs
title_sort	rationally designed influenza virus vaccines that are antigenically stable during growth in eggs
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/903553c0d64a420585785726adc1a281
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Rationally Designed Influenza Virus Vaccines That Are Antigenically Stable during Growth in Eggs

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