title: Alternative live-attenuated influenza vaccines based on modifications in the polymerase genes protect against epidemic and pandemic flu.
abstract: Human influenza is a seasonal disease associated with significant morbidity and mortality. Influenza vaccination is the most effective means for disease prevention. We have previously shown that mutations in the PB1 and PB2 genes of the live-attenuated influenza vaccine (LAIV) from the cold-adapted (ca) influenza virus A/Ann Arbor/6/60 (H2N2) could be transferred to avian influenza viruses and produce partially attenuated viruses. We also demonstrated that avian influenza viruses carrying the PB1 and PB2 mutations could be further attenuated by stably introducing a hemagglutinin (HA) epitope tag in the PB1 gene. In this work, we wanted to determine whether these modifications would also result in attenuation of a so-called triple reassortant (TR) swine influenza virus (SIV). Thus, the TR influenza A/swine/Wisconsin/14094/99 (H3N2) virus was generated by reverse genetics and subsequently mutated in the PB1 and PB2 genes. Here we show that a combination of mutations in this TR backbone results in an attenuated virus in vitro and in vivo. Furthermore, we show the potential of our TR backbone as a vaccine that provides protection against the 2009 swine-origin pandemic influenza H1N1 virus (S-OIV) when carrying the surface of a classical swine strain. We propose that the availability of alternative backbones to the conventional ca A/Ann Arbor/6/60 LAIV strain could also be useful in epidemic and pandemic influenza and should be considered for influenza vaccine development. In addition, our data provide evidence that the use of these alternative backbones could potentially circumvent the effects of original antigenic sin (OAS) in certain circumstances.
authors.affiliation: Virginia-Maryland Regional College of Veterinary Medicine and Department of Veterinary Medicine, University of Maryland, 8075 Greenmead Drive, College Park, MD 20742, USA. asolor@umd.edu
authors.forename: Alicia
authors.initials: A
authors.lastname: Solórzano
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Ye
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Pérez
mesh_terms: D000818:Animals; D001835:Body Weight; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics* / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D007928:Lethal Dose 50; D008168:Lung / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics*; D014613:Vaccines, Attenuated / Q000276:immunology; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; C057027:PB2 protein, Influenzavirus A; D014613:Vaccines, Attenuated; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; D012324:RNA-Dependent RNA Polymerase