Construction and Immunogenicity Evaluation of Recombinant Influenza A Viruses Containing Chimeric Hemagglutinin Genes Derived from Genetically Divergent Influenza A H1N1 Subtype Viruses.

Kara Mccormick,Longchao Zhu,Robert Langenhorst,Steven R Lawson,Ying Fang,Richard J Webby,Russell Ransburgh,Colin Brunick,Victor C Huber,Leah M Mabee,Yanhua Li,Zhiyong Jiang,Heather R Hurtig,Mark Mingo,Miranda C Tracy

doi:10.1371/journal.pone.0127649

Kara Mccormick, Longchao Zhu + Show 13 more

Open Access

https://doi.org/10.1371/journal.pone.0127649

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Abstract

Background and ObjectivesInfluenza A viruses cause highly contagious diseases in a variety of hosts, including humans and pigs. To develop a vaccine that can be broadly effective against genetically divergent strains of the virus, in this study we employed molecular breeding (DNA shuffling) technology to create a panel of chimeric HA genes.Methods and ResultsEach chimeric HA gene contained genetic elements from parental swine influenza A viruses that had a history of zoonotic transmission, and also from a 2009 pandemic virus. Each parental virus represents a major phylogenetic clade of influenza A H1N1 viruses. Nine shuffled HA constructs were initially screened for immunogenicity in mice by DNA immunization, and one chimeric HA (HA-129) was expressed on both a A/Puerto Rico/8/34 backbone with mutations associated with a live, attenuated phenotype (PR8LAIV-129) and a A/swine/Texas/4199-2/98 backbone (TX98-129). When delivered to mice, the PR8LAIV-129 induced antibodies against all four parental viruses, which was similar to the breadth of immunity observed when HA-129 was delivered as a DNA vaccine. This chimeric HA was then tested as a candidate vaccine in a nursery pig model, using inactivated TX98-129 virus as the backbone. The results demonstrate that pigs immunized with HA-129 developed antibodies against all four parental viruses, as well as additional primary swine H1N1 influenza virus field isolates.ConclusionThis study established a platform for creating novel genes of influenza viruses using a molecular breeding approach, which will have important applications toward future development of broadly protective influenza virus vaccines.

Highlights

Influenza A viruses infect a variety of avian and mammalian hosts, including humans and pigs, and pose a significant pandemic threat [1]
Nine shuffled HA constructs were initially screened for immunogenicity in mice by DNA immunization, and one chimeric HA (HA-129) was expressed on both a A/Puerto Rico/8/34 backbone with mutations associated with a live, attenuated phenotype (PR8LAIV-129) and a A/swine/ Texas/4199-2/98 backbone (TX98-129)
This study established a platform for creating novel genes of influenza viruses using a molecular breeding approach, which will have important applications toward future development of broadly protective influenza virus vaccines

Summary

Introduction

Influenza A viruses infect a variety of avian and mammalian hosts, including humans and pigs, and pose a significant pandemic threat [1]. Vaccines against influenza viruses are available for both pigs and humans, with human vaccines receiving annual updates based on surveillance [2]. These vaccines are designed to limit transmission and infection with host species-restricted variants within a single influenza A virus subtype [3,4], and they demonstrate efficacy within their respective populations [5,6]. A vaccine that could limit the circulation of influenza viruses among pigs, as well as prevent interspecies transmission events from pigs to humans, would strengthen these efforts. To develop a vaccine that can be broadly effective against genetically divergent strains of the virus, in this study we employed molecular breeding (DNA shuffling) technology to create a panel of chimeric HA genes

Methods

Results

Conclusion