Publications

the repeated introduction of the h3n2 virus from human to swine during 1979-1993 in china.	limited data are available regarding the swine influenza viruses (sivs) that circulated in mainland china prior to the 1990s. eleven h3n2 virus strains were isolated from swine populations from 1979 to 1992. to determine the origin and tendency of these sivs, the phylogenetic and antigenic properties of these viruses were analyzed based on the whole genome sequenced and the hi titrations with post-infection ferret antisera against influenza a (h3n2) virus isolates of swine and human origin. the ...	2015	25858119
replication of live attenuated cold-adapted h2n2 influenza virus vaccine candidates in non human primates.	the development of an h2n2 vaccine is a priority in pandemic preparedness planning. we previously showed that a single dose of a cold-adapted (ca) h2n2 live attenuated influenza vaccine (laiv) based on the influenza a/ann arbor/6/60 (aa ca) virus was immunogenic and efficacious in mice and ferrets. however, in a phase i clinical trial, viral replication was restricted and immunogenicity was poor. in this study, we compared the replication of four h2n2 laiv candidate viruses, aa ca, a/tecumseh/3/ ...	2015	25444799
environmental conditions affect exhalation of h3n2 seasonal and variant influenza viruses and respiratory droplet transmission in ferrets.	the seasonality of influenza virus infections in temperate climates and the role of environmental conditions like temperature and humidity in the transmission of influenza virus through the air are not well understood. using ferrets housed at four different environmental conditions, we evaluated the respiratory droplet transmission of two influenza viruses (a seasonal h3n2 virus and an h3n2 variant virus, the etiologic virus of a swine to human summertime infection) and concurrently characterize ...	2015	25969995
optimization of an enzyme-linked lectin assay suitable for rapid antigenic characterization of the neuraminidase of human influenza a(h3n2) viruses.	antibodies to neuraminidase (na), the second most abundant surface protein of the influenza virus, contribute to protection against influenza virus infection. although traditional and miniaturized thiobarbituric acid (tba) neuraminidase inhibition (ni) assays have been successfully used to characterize the antigenic properties of na, these methods are cumbersome and not easily amendable to rapid screening. an additional difficulty of the ni assay is the interference by hemagglutinin (ha)-specifi ...	2015	25712563
comparative analysis of virulence of a novel, avian-origin h3n2 canine influenza virus in various host species.	a novel avian-origin h3n2 canine influenza a virus (civ) that showed high sequence similarities in hemagglutinin and neuraminidase genes with those of non-pathogenic avian influenza viruses was isolated in our routine surveillance program in south korea. we previously reported that the pathogenicity of this strain could be reproduced in dogs and cats. in the present study, the host tropism of h3n2 civ was examined by experimental inoculation into several host species, including chickens, pigs, m ...	2015	25218482
new reassortant and enzootic european swine influenza viruses transmit efficiently through direct contact in the ferret model.	the reverse zoonotic events that introduced the 2009 pandemic influenza virus into pigs have drastically increased the diversity of swine influenza viruses in europe. the pandemic potential of these novel reassortments is still unclear, necessitating enhanced surveillance of european pigs with additional focus on risk assessment of these new viruses. in this study, four european swine influenza viruses were assessed for their zoonotic potential. two of the four viruses were enzootic viruses of s ...	2015	25701826
generation and characterization of live attenuated influenza a(h7n9) candidate vaccine virus based on russian donor of attenuation.	avian influenza a (h7n9) virus has emerged recently and continues to cause severe disease with a high mortality rate in humans prompting the development of candidate vaccine viruses. live attenuated influenza vaccines (laiv) are 6:2 reassortant viruses containing the ha and na gene segments from wild type influenza viruses to induce protective immune responses and the six internal genes from master donor viruses (mdv) to provide temperature sensitive, cold-adapted and attenuated phenotypes.	2015	26405798
a single dose of an avian h3n8 influenza virus vaccine is highly immunogenic and efficacious against a recently emerged seal influenza virus in mice and ferrets.	h3n8 influenza viruses are a commonly found subtype in wild birds, usually causing mild or no disease in infected birds. however, they have crossed the species barrier and have been associated with outbreaks in dogs, pigs, donkeys, and seals and therefore pose a threat to humans. a live attenuated, cold-adapted (ca) h3n8 vaccine virus was generated by reverse genetics using the wild-type (wt) hemagglutinin (ha) and neuraminidase (na) genes from the a/blue-winged teal/texas/sg-00079/2007 (h3n8) ( ...	2015	25903333
nonreplicating influenza a virus vaccines confer broad protection against lethal challenge.	new vaccine technologies are being investigated for their ability to elicit broadly cross-protective immunity against a range of influenza viruses. we compared the efficacies of two intranasally delivered nonreplicating influenza virus vaccines (h1 and h5 s-flu) that are based on the suppression of the hemagglutinin signal sequence, with the corresponding h1n1 and h5n1 cold-adapted (ca) live attenuated influenza virus vaccines in mice and ferrets. administration of two doses of h1 or h5 s-flu va ...	2015	26489862
induction of broad-based immunity and protective efficacy by self-amplifying mrna vaccines encoding influenza virus hemagglutinin.	seasonal influenza is a vaccine-preventable disease that remains a major health problem worldwide, especially in immunocompromised populations. the impact of influenza disease is even greater when strains drift, and influenza pandemics can result when animal-derived influenza virus strains combine with seasonal strains. in this study, we used the sam technology and characterized the immunogenicity and efficacy of a self-amplifying mrna expressing influenza virus hemagglutinin (ha) antigen [sam(h ...	2015	26468547
the soft palate is an important site of adaptation for transmissible influenza viruses.	influenza a viruses pose a major public health threat by causing seasonal epidemics and sporadic pandemics. their epidemiological success relies on airborne transmission from person to person; however, the viral properties governing airborne transmission of influenza a viruses are complex. influenza a virus infection is mediated via binding of the viral haemagglutinin (ha) to terminally attached α2,3 or α2,6 sialic acids on cell surface glycoproteins. human influenza a viruses preferentially bin ...	2015	26416728
changes to the dynamic nature of hemagglutinin and the emergence of the 2009 pandemic h1n1 influenza virus.	the virologic factors that limit the transmission of swine influenza viruses between humans are unresolved. while it has been shown that acquisition of the neuraminidase (na) and matrix (m) gene segments from a eurasian-lineage swine virus was required for airborne transmission of the 2009 pandemic h1n1 virus (h1n1pdm09), we show here that an arginine to lysine change in the hemagglutinin (ha) was also necessary. this change at position 149 was distal to the receptor binding site but affected vi ...	2015	26269288
possible basis for the emergence of h1n1 viruses with pandemic potential from avian hosts.	influenza a viruses of the h1n1 subtype have emerged from the avian influenza gene pool in aquatic birds and caused human pandemics at least twice during the past century. despite this fact, surprisingly little is known about the h1n1 gene pool in the aquatic bird reservoir. a preliminary study showed that an h1n1 virus from a shorebird of the charadriiformes order was transmitted between animals through the airborne route of infection, whereas an h1n1 virus from a bird of the anseriformes order ...	2015	26251829
evaluation of a dry powder delivery system for laninamivir in a ferret model of influenza infection.	laninamivir is a long-acting antiviral requiring only a single dose for the treatment of influenza infection, making it an attractive alternative to existing neuraminidase inhibitors that require multiple doses over many days. like zanamivir, laninamivir is administered to patients by inhalation of dry powder. to date, studies investigating the effectiveness of laninamivir or zanamivir in a ferret model of influenza infection have administered the drug in a solubilised form. to better mimic the ...	2015	26022199
replication and transmission of mammalian-adapted h9 subtype influenza virus in pigs and quail.	influenza a virus is a major pathogen of birds, swine and humans. strains can jump between species in a process often requiring mutations and reassortment, resulting in outbreaks and, potentially, pandemics. h9n2 avian influenza is predominant in poultry across asia and occasionally infects humans and swine. pandemic h1n1 (h1n1pdm) is endemic in humans and swine and has a history of reassortment in pigs. previous studies have shown the compatibility of h9n2 and h1n1pdm for reassortment in ferret ...	2015	25986634
interval between infections and viral hierarchy are determinants of viral interference following influenza virus infection in a ferret model.	epidemiological studies suggest that, following infection with influenza virus, there is a short period during which a host experiences a lower susceptibility to infection with other influenza viruses. this viral interference appears to be independent of any antigenic similarities between the viruses. we used the ferret model of human influenza to systematically investigate viral interference.	2015	25943206
vector optimization and needle-free intradermal application of a broadly protective polyvalent influenza a dna vaccine for pigs and humans.	the threat posed by the 2009 pandemic h1n1 virus emphasized the need for new influenza a virus vaccines inducing a broad cross-protective immune response for use in both humans and pigs. an effective and broad influenza vaccine for pigs would greatly benefit the pork industry and contribute to public health by diminishing the risk of emerging highly pathogenic reassortants. current inactivated protein vaccines against swine influenza produce only short-lived immunity and have no efficacy against ...	2015	25746201
the use of nonhuman primates in research on seasonal, pandemic and avian influenza, 1893-2014.	attempts to reproduce the features of human influenza in laboratory animals date from the early 1890s, when richard pfeiffer inoculated apes with bacteria recovered from influenza patients and produced a mild respiratory illness. numerous studies employing nonhuman primates (nhps) were performed during the 1918 pandemic and the following decade. most used bacterial preparations to infect animals, but some sought a filterable agent for the disease. since the viral etiology of influenza was establ ...	2015	25746173
characterization of a large cluster of influenza a(h1n1)pdm09 viruses cross-resistant to oseltamivir and peramivir during the 2013-2014 influenza season in japan.	between september 2013 and july 2014, 2,482 influenza 2009 pandemic a(h1n1) [a(h1n1)pdm09] viruses were screened in japan for the h275y substitution in their neuraminidase (na) protein, which confers cross-resistance to oseltamivir and peramivir. we found that a large cluster of the h275y mutant virus was present prior to the main influenza season in sapporo /: hokkaido, with the detection rate for this mutant virus reaching 29% in this area. phylogenetic analysis suggested the clonal expansion ...	2015	25691635
identification of amino acid substitutions supporting antigenic change of influenza a(h1n1)pdm09 viruses.	the majority of currently circulating influenza a(h1n1) viruses are antigenically similar to the virus that caused the 2009 influenza pandemic. however, antigenic variants are expected to emerge as population immunity increases. amino acid substitutions in the hemagglutinin protein can result in escape from neutralizing antibodies, affect viral fitness, and change receptor preference. in this study, we constructed mutants with substitutions in the hemagglutinin of a/netherlands/602/09 in an atte ...	2015	25609810
host adaptation and the alteration of viral properties of the first influenza a/h1n1pdm09 virus isolated in japan.	a/narita/1/2009 (a/n) was the first h1n1 virus from the 2009 pandemic (h1pdm) to be isolated in japan. to better understand and predict the possible development of this virus strain, the effect of passaging a/n was investigated in madin-darby canine kidney cells, chicken eggs and mice. a/n that had been continuously passaged in cells, eggs, or mice obtained the ability to grow efficiently in each host. moreover, a/n grown in mice had both a high level of pathogenicity in mice and an increased gr ...	2015	26079133
pathogenesis of infection with 2009 pandemic h1n1 influenza virus in isogenic guinea pigs after intranasal or intratracheal inoculation.	to elucidate the pathogenesis and transmission of influenza virus, the ferret model is typically used. to investigate protective immune responses, the use of inbred mouse strains has proven invaluable. here, we describe a study with isogenic guinea pigs, which would uniquely combine the advantages of the mouse and ferret models for influenza virus infection. strain 2 isogenic guinea pigs were inoculated with h1n1pdm09 influenza virus a/netherlands/602/09 by the intranasal or intratracheal route. ...	2015	25555619
sequential infection in ferrets with antigenically distinct seasonal h1n1 influenza viruses boosts hemagglutinin stalk-specific antibodies.	broadly reactive antibodies targeting the conserved hemagglutinin (ha) stalk region are elicited following sequential infection or vaccination with influenza viruses belonging to divergent subtypes and/or expressing antigenically distinct ha globular head domains. here, we demonstrate, through the use of novel chimeric ha proteins and competitive binding assays, that sequential infection of ferrets with antigenically distinct seasonal h1n1 (sh1n1) influenza virus isolates induced an ha stalk-spe ...	2015	26559834
h3n2 canine influenza virus with the matrix gene from the pandemic a/h1n1 virus: infection dynamics in dogs and ferrets.	after an outbreak of pandemic influenza a/h1n1 (ph1n1) virus, we had previously reported the emergence of a recombinant canine influenza virus (civ) between the ph1n1 virus and the classic h3n2 civ. our ongoing routine surveillance isolated another reassortant h3n2 civ carrying the matrix gene of the ph1n1 virus from 2012. the infection dynamics of this h3n2 civ variant (civ/h3n2mv) were investigated in dogs and ferrets via experimental infection and transmission. the civ/h3n2mv-infected dogs an ...	2015	24977303
lower respiratory tract infection of the ferret by 2009 h1n1 pandemic influenza a virus triggers biphasic, systemic, and local recruitment of neutrophils.	infection of the lower respiratory tract by influenza a viruses results in increases in inflammation and immune cell infiltration in the lung. the dynamic relationships among the lung microenvironments, the lung, and systemic host responses during infection remain poorly understood. here we used extensive systematic histological analysis coupled with live imaging to gain access to these relationships in ferrets infected with the 2009 h1n1 pandemic influenza a virus (h1n1pdm virus). neutrophil le ...	2015	26063430
evaluation of the zoonotic potential of a novel reassortant h1n2 swine influenza virus with gene constellation derived from multiple viral sources.	in 2011-2012, contemporary north american-like h3n2 swine influenza viruses (sivs) possessing the 2009 pandemic h1n1 matrix gene (h3n2pm-like virus) were detected in domestic pigs of south korea where h1n2 siv strains are endemic. more recently, we isolated novel reassortant h1n2 sivs bearing the eurasian avian-like swine h1-like hemagglutinin and korean swine h1n2-like neuraminidase in the internal gene backbone of the h3n2pm-like virus. in the present study, we clearly provide evidence on the ...	2015	26051886
characterization of the localized immune response in the respiratory tract of ferrets following infection with influenza a and b viruses.	the burden of infection with seasonal influenza viruses is significant. each year is typically characterized by the dominance of one (sub)type or lineage of influenza a or b virus, respectively. the incidence of disease varies annually, and while this may be attributed to a particular virus strain or subtype, the impacts of prior immunity, population differences, and variations in clinical assessment are also important. to improve our understanding of the impacts of seasonal influenza viruses, w ...	2015	26719259
prevalence, genetics, and transmissibility in ferrets of eurasian avian-like h1n1 swine influenza viruses.	pigs are important intermediate hosts for generating novel influenza viruses. the eurasian avian-like h1n1 (eah1n1) swine influenza viruses (sivs) have circulated in pigs since 1979, and human cases associated with eah1n1 sivs have been reported in several countries. however, the biologic properties of eah1n1 sivs are largely unknown. here, we performed extensive influenza surveillance in pigs in china and isolated 228 influenza viruses from 36,417 pigs. we found that 139 of the 228 strains from ...	2016	26711995
molecular requirements for a pandemic influenza virus: an acid-stable hemagglutinin protein.	influenza pandemics require that a virus containing a hemagglutinin (ha) surface antigen previously unseen by a majority of the population becomes airborne-transmissible between humans. although the ha protein is central to the emergence of a pandemic influenza virus, its required molecular properties for sustained transmission between humans are poorly defined. during virus entry, the ha protein binds receptors and is triggered by low ph in the endosome to cause membrane fusion; during egress, ...	2016	26811446
influenza virus vaccine for neglected hosts: horses and dogs.	this study provides information regarding vaccine research and the epidemiology of influenza virus in neglected hosts (horses and dogs). equine influenza virus (eiv) causes a highly contagious disease in horses and other equids, and outbreaks have occurred worldwide. eiv has resulted in costly damage to the horse industry and has the ability of cross the host species barrier from horses to dogs. canine influenza is a virus of equine or avian origin and infects companion animals that live in clos ...	2016	27489801
pandemic seasonal h1n1 reassortants recovered from patient material display a phenotype similar to that of the seasonal parent.	we have previously shown that 11 patients became naturally coinfected with seasonal h1n1 (a/h1n1) and pandemic h1n1 (pdm/h1n1) during the southern hemisphere winter of 2009 in new zealand. reassortment of influenza a viruses is readily observed during coinfection of host animals and in vitro; however, reports of reassortment occurring naturally in humans are rare. using clinical specimen material, we show reassortment between the two coinfecting viruses occurred with high likelihood directly in ...	2016	27279619
influenza a (h10n7) virus causes respiratory tract disease in harbor seals and ferrets.	avian influenza viruses sporadically cross the species barrier to mammals, including humans, in which they may cause epidemic disease. recently such an epidemic occurred due to the emergence of avian influenza virus of the subtype h10n7 (seal/h10n7) in harbor seals (phoca vitulina). this epidemic caused high mortality in seals along the north-west coast of europe and represented a potential risk for human health. to characterize the spectrum of lesions and to identify the target cells and viral ...	2016	27448168
human monoclonal antibody 81.39a effectively neutralizes emerging influenza a viruses of group 1 and 2 hemagglutinins.	the pandemic threat posed by emerging zoonotic influenza a viruses necessitates development of antiviral agents effective against various antigenic subtypes. human monoclonal antibody (hmab) targeting the hemagglutinin (ha) stalk offers a promising approach to control influenza virus infections. here, we investigated the ability of the hmab 81.39a to inhibit in vitro replication of human and zoonotic viruses, representing 16 ha subtypes. the majority of viruses were effectively neutralized by 81 ...	2016	27630240
a defective interfering influenza rna inhibits infectious influenza virus replication in human respiratory tract cells: a potential new human antiviral.	defective interfering (di) viruses arise during the replication of influenza a virus and contain a non-infective version of the genome that is able to interfere with the production of infectious virus. in this study we hypothesise that a cloned di influenza a virus rna may prevent infection of human respiratory epithelial cells with infection by influenza a. the di rna (244/pr8) was derived by a natural deletion process from segment 1 of influenza a/pr/8/34 (h1n1); it comprises 395 nucleotides a ...	2016	27556481
association between hemagglutinin stem-reactive antibodies and influenza a/h1n1 virus infection during the 2009 pandemic.	the discovery of influenza virus broadly neutralizing (brn) antibodies prompted efforts to develop universal vaccines. influenza virus stem-reactive (sr) broadly neutralizing antibodies have been detected by screening antibody phage display libraries. however, studies of sr brn antibodies in human serum, and their association with natural infection, are limited. to address this, pre- and postpandemic sera from a prospective community cohort study in vietnam were assessed for antibodies that inhi ...	2016	27170747
particle and subunit-based hemagglutinin vaccines provide protective efficacy against h1n1 influenza in pigs.	the increasing diversity of influenza strains circulating in swine herds escalates the potential for the emergence of novel pandemic viruses and highlights the need for swift development of new vaccines. baculovirus has proven to be a flexible platform for the generation of recombinant forms of hemagglutinin (ha) including subunit, vlp-displayed, and baculovirus-displayed antigens. these presentations have been shown to be efficacious in mouse, chicken, and ferret models but little is known abou ...	2016	27374905
flow cytometric and cytokine elispot approaches to characterize the cell-mediated immune response in ferrets following influenza virus infection.	influenza virus infections represent a significant socioeconomic and public health burden worldwide. although ferrets are considered by many to be ideal for modeling human responses to influenza infection and vaccination, efforts to understand the cellular immune response have been severely hampered by a paucity of standardized procedures and reagents. in this study, we developed flow cytometric and t cell enzyme-linked immunosorbent spot (elispot) approaches to characterize the leukocyte compos ...	2016	27356897
characterisation of the epidemic strain of h3n8 equine influenza virus responsible for outbreaks in south america in 2012.	an extensive outbreak of equine influenza occurred across multiple countries in south america during 2012. the epidemic was first reported in chile then spread to brazil, uruguay and argentina, where both vaccinated and unvaccinated animals were affected. in brazil, infections were widespread within 3months of the first reported cases. affected horses included animals vaccinated with outdated vaccine antigens, but also with the oie-recommended florida clade 1 strain south africa/4/03.	2016	26993620
correlation between the interval of influenza virus infectivity and results of diagnostic assays in a ferret model.	the relationship between influenza virus infectivity and virus shedding, based on different diagnostic methods, has not been defined.	2016	26068783
evaluation of the human adaptation of influenza a/h7n9 virus in pb2 protein using human and swine respiratory tract explant cultures.	novel avian h7n9 virus emerged in china in 2013 resulting in a case fatality rate of around 39% and continues to pose zoonotic and pandemic risk. amino acid substitutions in pb2 protein were shown to influence the pathogenicity and transmissibility of h7n9 following experimental infection of ferrets and mice. in this study, we evaluated the role of amino acid substitution pb2-627k or compensatory changes at pb2-591k and pb2-701n, on the tropism and replication competence of h7n9 viruses for huma ...	2016	27739468
supplementation of h1n1pdm09 split vaccine with heterologous tandem repeat m2e5x virus-like particles confers improved cross-protection in ferrets.	current influenza vaccines induce strain-specific immunity to the highly variable hemagglutinin (ha) protein. it is therefore a high priority to develop vaccines that induce broadly cross-protective immunity to different strains of influenza. since influenza a m2 proteins are highly conserved among different strains, five tandem repeats of the extracellular peptide of m2 in a membrane-anchored form on virus-like particles (vlps) have been suggested to be a promising candidate for universal influ ...	2016	26709639
development of a high-yield reassortant influenza vaccine virus derived from the a/anhui/1/2013 (h7n9) strain.	in april 2013, the first three fatal cases of human infection with an avian influenza a virus (h7n9) were reported in china. because of a pandemic threat by this virus, we have commenced to develop candidate vaccine viruses (cvvs). three 6:2 genetic reassortant viruses with different hemagglutinin (ha) sequences, niidrg-10, -10.1 and -10.2, were generated by a reverse genetics technique between the high egg-growth master virus, a/puerto rico/8/34 (h1n1) and a/anhui/1/2013 (h7n9), kindly provided ...	2016	26657023
evaluation of the attenuation, immunogenicity, and efficacy of a live virus vaccine generated by codon-pair bias de-optimization of the 2009 pandemic h1n1 influenza virus, in ferrets.	codon-pair bias de-optimization (cpbd) of viruses involves re-writing viral genes using statistically underrepresented codon pairs, without any changes to the amino acid sequence or codon usage. previously, this technology has been used to attenuate the influenza a/puerto rico/8/34 (h1n1) virus. the de-optimized virus was immunogenic and protected inbred mice from challenge. in order to assess whether cpbd could be used to produce a live vaccine against a clinically relevant influenza virus, we ...	2016	26655630
peripheral leukocyte migration in ferrets in response to infection with seasonal influenza virus.	in order to better understand inflammation associated with influenza virus infection, we measured cell trafficking, via flow cytometry, to various tissues in the ferret model following infection with an a(h3n2) human seasonal influenza virus (a/perth/16/2009). changes in immune cells were observed in the blood, bronchoalveolar lavage fluid, and spleen, as well as lymph nodes associated with the site of infection or distant from the respiratory system. nevertheless clinical symptoms were mild, wi ...	2016	27315117
antigenic maps of influenza a(h3n2) produced with human antisera obtained after primary infection.	antigenic characterization of influenza viruses is typically based on hemagglutination inhibition (hi) assay data for viral isolates tested against strain-specific postinfection ferret antisera. here, similar virus characterizations were performed using serological data from humans with primary influenza a(h3n2) infection.	2016	26142433
h7n9 live attenuated influenza vaccine is highly immunogenic, prevents virus replication, and protects against severe bronchopneumonia in ferrets.	avian influenza viruses continue to cross the species barrier, and if such viruses become transmissible among humans, it would pose a great threat to public health. since its emergence in china in 2013, h7n9 has caused considerable morbidity and mortality. in the absence of a universal influenza vaccine, preparedness includes development of subtype-specific vaccines. in this study, we developed and evaluated in ferrets an intranasal live attenuated influenza vaccine (laiv) against h7n9 based on ...	2016	26796670
effects of egg-adaptation on receptor-binding and antigenic properties of recent influenza a (h3n2) vaccine viruses.	influenza a virus (subtype h3n2) causes seasonal human influenza and is included as a component of influenza vaccines. the majority of vaccine viruses are isolated and propagated in eggs, which commonly results in amino acid substitutions in the haemagglutinin (ha) glycoprotein. these substitutions can affect virus receptor-binding and alter virus antigenicity, thereby, obfuscating the choice of egg-propagated viruses for development into candidate vaccine viruses. to evaluate the effects of egg ...	2016	26974849
impact of a large deletion in the neuraminidase protein identified in a laninamivir-selected influenza a/brisbane/10/2007 (h3n2) variant on viral fitness in vitro and in ferrets.	viral fitness of a laninamivir-selected influenza a/brisbane/10/2007-like (h3n2) isolate (lrvp9) containing a 237-amino acid neuraminidase deletion and a p194l hemagglutinin mutation was evaluated in vitro and in ferrets. lrvp9 and the wild-type (wt) virus showed comparable replication kinetics in mdck-st6gali cells. cultured virus was recovered between days 2 and 5 post-infection in nasal washes (nw) from the 4 wt-infected ferrets whereas no virus was recovered from the lrvp9-infected animals. ...	2016	26526406
vaccination is more effective than prophylactic oseltamivir in preventing cns invasion by h5n1 virus via the olfactory nerve.	influenza a viruses can replicate in the olfactory mucosa and subsequently use the olfactory nerve to enter the central nervous system (cns). it is currently unknown whether intervention strategies are able to reduce or prevent influenza virus replication within the olfactory mucosa and subsequent spread to the cns. therefore, we tested the efficacy of homologous vaccination and prophylactic oseltamivir to prevent h5n1 virus cns invasion via the olfactory nerve in our ferret model.	2016	27448390
a cationic liposome-dna complexes adjuvant (jvrs-100) enhances the immunogenicity and cross-protective efficacy of pre-pandemic influenza a (h5n1) vaccine in ferrets.	influenza a (h5n1) viruses continue to pose a public health threat. as inactivated h5n1 vaccines are poorly immunogenic, adjuvants are needed to improve the immunogenicity of h5n1 vaccine in humans. here, we investigated the immunogenicity and cross-protective efficacy in ferrets of a clade 2.2-derived vaccine with addition of jvrs-100, an adjuvant consisting of cationic liposome-dna complexes (cldc). after the first vaccination, significantly higher levels of hemagglutination-inhibition (hai) a ...	2016	26967975
the replication of bangladeshi h9n2 avian influenza viruses carrying genes from h7n3 in mammals.	h9n2 avian influenza viruses are continuously monitored by the world health organization because they are endemic; they continually reassort with h5n1, h7n9 and h10n8 viruses; and they periodically cause human infections. we characterized h9n2 influenza viruses carrying internal genes from highly pathogenic h7n3 viruses, which were isolated from chickens or quail from live-bird markets in bangladesh between 2010 and 2013. all of the h9n2 viruses used in this study carried mammalian host-specific ...	2016	27094903
selective bottlenecks shape evolutionary pathways taken during mammalian adaptation of a 1918-like avian influenza virus.	avian influenza virus reassortants resembling the 1918 human pandemic virus can become transmissible among mammals by acquiring mutations in hemagglutinin (ha) and polymerase. using the ferret model, we trace the evolutionary pathway by which an avian-like virus evolves the capacity for mammalian replication and airborne transmission. during initial infection, within-host ha diversity increased drastically. then, airborne transmission fixed two polymerase mutations that do not confer a detectabl ...	2016	26867176
structure and function analysis of an antibody recognizing all influenza a subtypes.	influenza virus remains a threat because of its ability to evade vaccine-induced immune responses due to antigenic drift. here, we describe the isolation, evolution, and structure of a broad-spectrum human monoclonal antibody (mab), medi8852, effectively reacting with all influenza a hemagglutinin (ha) subtypes. medi8852 uses the heavy-chain vh6-1 gene and has higher potency and breadth when compared to other anti-stem antibodies. medi8852 is effective in mice and ferrets with a therapeutic wind ...	2016	27453466
a polyvalent influenza dna vaccine applied by needle-free intradermal delivery induces cross-reactive humoral and cellular immune responses in pigs.	pigs are natural hosts for influenza a viruses, and the infection is widely prevalent in swine herds throughout the world. current commercial influenza vaccines for pigs induce a narrow immune response and are not very effective against antigenically diverse viruses. to control influenza in pigs, the development of more effective swine influenza vaccines inducing broader cross-protective immune responses is needed. previously, we have shown that a polyvalent influenza dna vaccine using vectors c ...	2016	27211039
highly pathogenic reassortant avian influenza a(h5n1) virus clade 2.3.2.1a in poultry, bhutan.	highly pathogenic avian influenza a(h5n1), clade 2.3.2.1a, with an h9-like polymerase basic protein 1 gene, isolated in bhutan in 2012, replicated faster in vitro than its h5n1 parental genotype and was transmitted more efficiently in a chicken model. these properties likely help limit/eradicate outbreaks, combined with strict control measures.	2016	27584733
pathogenesis and transmission assessments of two h7n8 influenza a viruses recently isolated from turkey farms in indiana using mouse and ferret models.	avian influenza a h7 viruses have caused multiple outbreaks in domestic poultry throughout north america, resulting in occasional infections of humans in close contact with affected birds. in early 2016, the presence of h7n8 highly pathogenic avian influenza (hpai) viruses and closely related h7n8 low-pathogenic avian influenza (lpai) viruses was confirmed in commercial turkey farms in indiana. these h7n8 viruses represent the first isolation of this subtype in domestic poultry in north america, ...	2016	27681133
the comparison of pathology in ferrets infected by h9n2 avian influenza viruses with different genomic features.	h9n2 avian influenza virus circulates widely in poultry and has been responsible for sporadic human infections in several regions. few studies have been conducted on the pathogenicity of h9n2 aiv isolates that have different genomic features. we compared the pathology induced by a novel reassortant h9n2 virus and two currently circulating h9n2 viruses that have different genomic features in ferrets. the results showed that the three viruses can induce infections with various amounts of viral she ...	2016	26638019
influenza a virus transmission via respiratory aerosols or droplets as it relates to pandemic potential.	many respiratory viruses of humans originate from animals. for instance, there are now eight paramyxoviruses, four coronaviruses and four orthomxoviruses that cause recurrent epidemics in humans but were once confined to other hosts. in the last decade, several members of the same virus families have jumped the species barrier from animals to humans. fortunately, these viruses have not become established in humans, because they lacked the ability of sustained transmission between humans. however ...	2016	26385895
generation of influenza a viruses as live but replication-incompetent virus vaccines.	the conversion of life-threatening viruses into live but avirulent vaccines represents a revolution in vaccinology. in a proof-of-principle study, we expanded the genetic code of the genome of influenza a virus via a transgenic cell line containing orthogonal translation machinery. this generated premature termination codon (ptc)-harboring viruses that exerted full infectivity but were replication-incompetent in conventional cells. genome-wide optimization of the sites for incorporation of multi ...	2016	27934767
antiviral efficacy of verdinexor in vivo in two animal models of influenza a virus infection.	influenza a virus (iav) causes seasonal epidemics of respiratory illness that can cause mild to severe illness and potentially death. antiviral drugs are an important countermeasure against iav; however, drug resistance has developed, thus new therapeutic approaches are being sought. previously, we demonstrated the antiviral activity of a novel nuclear export inhibitor drug, verdinexor, to reduce influenza replication in vitro and pulmonary virus burden in mice. in this study, in vivo efficacy o ...	2016	27893810
antigenic characterization of h3 subtypes of avian influenza a viruses from north america.	besides humans, h3 subtypes of influenza a viruses (iavs) can infect various animal hosts, including avian, swine, equine, canine, and sea mammal species. these h3 viruses are both antigenically and genetically diverse. here, we characterized the antigenic diversity of contemporary h3 avian iavs recovered from migratory birds in north america. hemagglutination inhibition (hi) assays were performed on 37 h3 isolates of avian iavs recovered from 2007 to 2011 using generated reference chicken sera. ...	2016	27309078
neutralizing inhibitors in the airways of naïve ferrets do not play a major role in modulating the virulence of h3 subtype influenza a viruses.	many insights regarding the pathogenesis of human influenza a virus (iav) infections have come from studies in mice and ferrets. surfactant protein (sp)-d is the major neutralizing inhibitor of iav in mouse airway fluids and sp-d-resistant iav mutants show enhanced virus replication and virulence in mice. herein, we demonstrate that sialylated glycoproteins, rather than sp-d, represent the major neutralizing inhibitors against h3 subtype viruses in airway fluids from naïve ferrets. moreover, whi ...	2016	27110707
detection of influenza c virus but not influenza d virus in scottish respiratory samples.	a newly proposed genus of influenza virus (influenza d) is associated with respiratory disease in pigs and cattle. the novel virus is most closely related to human influenza c virus and can infect ferrets but infection has not been reported in humans.	2016	26655269
companion animals as a source of viruses for human beings and food production animals.	companion animals comprise a wide variety of species, including dogs, cats, horses, ferrets, guinea pigs, reptiles, birds and ornamental fish, as well as food production animal species, such as domestic pigs, kept as companion animals. despite their prominent place in human society, little is known about the role of companion animals as sources of viruses for people and food production animals. therefore, we reviewed the literature for accounts of infections of companion animals by zoonotic viru ...	2016	27522300
neuraminidase-based recombinant virus-like particles protect against lethal avian influenza a(h5n1) virus infection in ferrets.	avian influenza a (h5n1) viruses represent a growing threat for an influenza pandemic. the presence of widespread avian influenza virus infections further emphasizes the need for vaccine strategies for control of pre-pandemic h5n1 and other avian influenza subtypes. influenza neuraminidase (na) vaccines represent a potential strategy for improving vaccines against avian influenza h5n1 viruses. to evaluate a strategy for na vaccination, we generated a recombinant influenza virus-like particle (vl ...	2017	28624679
pathogenic analysis of the pandemic 2009 h1n1 influenza a viruses in ferrets.	the pandemic 2009 h1n1 influenza a virus emerged in humans and caused the first influenza pandemic of the 21st century. mexican isolates, a/mexico/4108/2009 (h1n1) (mex4108) and a/mexico/indre4478/2009 (h1n1) (mex4487) derived from a mild case and from a cluster of severe cases, showed heterogeneity in virulence in a cynomolgus macaque model. to compare the more pathogenic differences, we generated recombinant viruses and compared their virulence in ferrets. ferrets infected with recombinant mex ...	2017	28674309
stockpiled pre-pandemic h5n1 influenza virus vaccines with as03 adjuvant provide cross-protection from h5n2 clade 2.3.4.4 virus challenge in ferrets.	avian influenza viruses, notably h5 subtype viruses, pose a continuous threat to public health due to their pandemic potential. in recent years, influenza virus h5 subtype split vaccines with novel oil-in-water emulsion based adjuvants (e.g. as03, mf59) have been shown to be safe, immunogenic, and able to induce broad immune responses in clinical trials, providing strong scientific support for vaccine stockpiling. however, whether such vaccines can provide protection from infection with emerging ...	2017	28554058
novel hemagglutinin nanoparticle influenza vaccine with matrix-m™ adjuvant induces hemagglutination inhibition, neutralizing, and protective responses in ferrets against homologous and drifted a(h3n2) subtypes.	influenza viruses frequently acquire mutations undergoing antigenic drift necessitating annual evaluation of vaccine strains. highly conserved epitopes have been identified in the hemagglutinin (ha) head and stem regions, however, current influenza vaccines induce only limited responses to these conserved sites. here, we describe a novel seasonal recombinant ha nanoparticle influenza vaccine (niv) formulated with a saponin-based adjuvant, matrix-m™. niv induced hemagglutination inhibition (hai) ...	2017	28844407
zoonotic risk, pathogenesis, and transmission of avian-origin h3n2 canine influenza virus.	two subtypes of influenza a virus (iav), avian-origin canine influenza virus h3n2 (civ-h3n2) and equine-origin civ-h3n8, are enzootic in the canine population. dogs have demonstrated seroconversion to diverse iavs and naturally occurring reassortants of civ-h3n2 and the 2009 h1n1 pandemic virus (pdmh1n1) have been isolated. we conducted a thorough phenotypic evaluation of civ-h3n2 in order to assess its threat to human health. using ferret-generated antisera we determined that civ-h3n2 is antige ...	2017	28814512
m2sr, a novel live influenza vaccine, protects mice and ferrets against highly pathogenic avian influenza.	the emergence of highly pathogenic avian influenza h5n1 viruses has heightened global concern about the threat posed by pandemic influenza. to address the need for a highly effective universal influenza vaccine, we developed a novel m2-deficient single replication (m2sr) influenza vaccine virus and previously reported that it provided strong heterosubtypic protection against seasonal influenza viruses in mice. in the current study, we assessed m2sr induced protection against h5n1 influenza in mi ...	2017	28668565
in vitro and in vivo evidence of a potential a(h1n1)pdm09 antigenic drift mediated by escape mutations in the haemagglutinin sa antigenic site.	influenza a(h1n1)pdm09 virus continues to circulate worldwide without evidence of significant antigenic drift between 2009 and 2016. by using escape mutants, we previously identified six haemagglutinin (ha) changes (t80r, g143e, g158e, n159d, k166e and a198e) that were located within antigenic sites. combinations of these mutations were introduced into the a(h1n1)pdm09 ha plasmid by mutagenesis. reassortant 6 : 2 viruses containing both the ha and na genes of the a(h1n1)pdm09 and the six interna ...	2017	28631598
inhibition of the infectivity and inflammatory response of influenza virus by arbidol hydrochloride in vitro and in vivo (mice and ferret).	influenza virus infections are the main contagious respiratory disease with high levels of morbidity and mortality worldwide. antiviral drugs are indispensable for the prophylaxis and treatment of influenza and other respiratory viral infections. in this study, the arbidol hydrochloride (arb), which has been licensed in russia and china, is used to investigate its anti-viral and anti-inflammatory efficacy in vitro and in vivo. the antiviral results in vitro showed that arb had a better inhibitio ...	2017	28475918
pathogenicity and transmission of a swine influenza a(h6n6) virus.	subtype h6 influenza a viruses (iavs) are commonly detected in wild birds and domestic poultry and can infect humans. in 2010, a h6n6 virus emerged in southern china, and since then, it has caused sporadic infections among swine. we show that this virus binds to α2,6-linked and α2,3-linked sialic acids. mutations at residues 222 (alanine to valine) and 228 (glycine to serine) of the virus hemagglutinin (ha) affected its receptor-binding properties. experiments showed that the virus has limited t ...	2017	28400591
an amino acid in the stalk domain of n1 neuraminidase is critical for enzymatic activity.	neuraminidase (na) is a sialidase expressed on the surface of influenza a viruses that releases progeny viruses from the surface of infected cells and prevents viruses becoming trapped in mucus. it is a homotetramer, with each monomer consisting of a transmembrane region, a stalk, and a globular head with sialidase activity. we recently characterized two swine viruses of the pandemic h1n1 lineage, a/swine/virginia/1814-1/2012 (ph1n1low-1) and a/swine/virginia/1814-2/2012 (ph1n1low-2), with almos ...	2017	27847354
enhanced virulence of clade 2.3.2.1 highly pathogenic avian influenza a h5n1 viruses in ferrets.	sporadic avian to human transmission of highly pathogenic avian influenza (hpai) a(h5n1) viruses necessitates the analysis of currently circulating and evolving clades to assess their potential risk. following the spread and sustained circulation of clade 2 viruses across multiple continents, numerous subclades and genotypes have been described. to better understand the pathogenesis associated with the continued diversification of clade 2a(h5n1) influenza viruses, we investigated the relative vi ...	2017	28038412
assessment of pathogenicity and antigenicity of american lineage influenza h5n2 viruses in taiwan.	during december 2003 and march 2004, large scale epidemics of low-pathogenic avian influenza (lpai) h5n2 occurred in poultry farms in central and southern taiwan. based on genomic analysis, these h5n2 viruses contain ha and na genes of american-lineage h5n2 viruses and six internal genes from avian influenza a/h6n1 viruses endemic in poultry in taiwan. after disappearing for several years, these novel influenza h5n2 viruses caused outbreaks in poultry farms again in 2008, 2010 and 2012, and have ...	2017	28549236
carbohydrate fatty acid monosulphate esters are safe and effective adjuvants for humoral responses.	carbohydrate fatty acid sulphate esters (cfases) formulated in a squalane-in-water emulsion are effective adjuvants for humoral responses to a wide range of antigens in various animal species but rise in body temperature and local reactions albeit mild or minimal hampers application in humans. in rabbits, body temperature increased 1°c one day after intramuscular (im) injection, which returned to normal during the next day. the effect increased with increasing dose of cfase but not with the numb ...	2017	28479181
influenza-omics and the host response: recent advances and future prospects.	influenza a viruses (iav) continually evolve and have the capacity to cause global pandemics. because iav represents an ongoing threat, identifying novel therapies and host innate immune factors that contribute to iav pathogenesis is of considerable interest. this review summarizes the relevant literature as it relates to global host responses to influenza infection at both the proteome and transcriptome level. the various-omics infection systems that include but are not limited to ferrets, mice ...	2017	28604586
pathogenicity testing of influenza candidate vaccine viruses in the ferret model.	the development of influenza candidate vaccine viruses (cvvs) for pre-pandemic vaccine production represents a critical step in pandemic preparedness. the multiple subtypes and clades of avian or swine origin influenza viruses circulating world-wide at any one time necessitates the continuous generation of cvvs to provide an advanced starting point should a novel zoonotic virus cross the species barrier and cause a pandemic. furthermore, the evolution and diversity of novel influenza viruses tha ...	2017	28846898
development of clade-specific and broadly reactive live attenuated influenza virus vaccines against rapidly evolving h5 subtype viruses.	we have developed pandemic live attenuated influenza vaccines (plaivs) against clade 1 h5n1 viruses on an ann arbor cold-adapted (ca) backbone that induced long-term immune memory. in 2015, many human infections caused by a new clade (clade 2.2.1.1) of goose/guangdong (gs/gd) lineage h5n1 viruses were reported in egypt, which prompted updating of the h5n1 plaiv. we explored two strategies to generate suitable plaivs. the first approach was to modify the hemagglutinin gene of a highly pathogenic ...	2017	28490598
a novel a(h7n2) influenza virus isolated from a veterinarian caring for cats in a new york city animal shelter causes mild disease and transmits poorly in the ferret model.	in december 2016, a low-pathogenic avian influenza (lpai) a(h7n2) virus was identified to be the causative source of an outbreak in a cat shelter in new york city, which subsequently spread to multiple shelters in the states of new york and pennsylvania. one person with occupational exposure to infected cats became infected with the virus, representing the first lpai h7n2 virus infection in a human in north america since 2003. considering the close contact that frequently occurs between companio ...	2017	28515300
a formulated tlr7/8 agonist is a flexible, highly potent and effective adjuvant for pandemic influenza vaccines.	since 1997, highly pathogenic avian influenza viruses of the h5n1 subtype have been transmitted from avian hosts to humans. the severity of h5n1 infection in humans, as well as the sporadic nature of h5n1 outbreaks, both geographically and temporally, make generation of an effective vaccine a global public health priority. an effective h5n1 vaccine must ultimately provide protection against viruses from diverse clades. toll-like receptor (tlr) agonist adjuvant formulations have a demonstrated ab ...	2017	28429728
the hemagglutinin a stem antibody medi8852 prevents and controls disease and limits transmission of pandemic influenza viruses.	medi8852 is a novel monoclonal antibody (mab) that neutralizes both group i and group ii influenza a viruses (iavs) in vitro. we evaluated whether medi8852 was effective for prophylaxis and therapy against representative group i (h5n1) and group ii (h7n9) pandemic iavs in mice and ferrets and could be used to block transmission of influenza h1n1pdm09 in ferrets, compared to an irrelevant control mab r347 and oseltamivir.	2017	28633457
shifting clade distribution, reassortment, and emergence of new subtypes of highly pathogenic avian influenza a(h5) viruses collected from vietnamese poultry from 2012 to 2015.	whole-genome sequences of representative highly pathogenic avian influenza a(h5) viruses from vietnam were generated, comprising samples from poultry outbreaks and active market surveillance collected from january 2012 to august 2015. six hemagglutinin gene clades were characterized. clade 1.1.2 was predominant in southern mekong provinces throughout 2012 and 2013 but gradually disappeared and was not detected after april 2014. clade 2.3.2.1c viruses spread rapidly during 2012 and were detected ...	2017	28003481
the immune correlates of protection for an avian influenza h5n1 vaccine in the ferret model using oil-in-water adjuvants.	because of the pathogenicity and low incidence of avian influenza virus infections in humans, the immune correlates of protection for avian influenza vaccines cannot be determined from clinical studies. here, we used the ferret model to address this for an avian influenza h5n1 vaccine. using oil-in-water adjuvants, we generated groups of ferrets with undetectable (geometric mean titer [gmt] < 10), low (gmt = 28.3), or high (gmt > 761.1) hemagglutination-inhibition (hai) titers to the a/viet nam/ ...	2017	28303960
evolution and divergence of h3n8 equine influenza viruses circulating in the united kingdom from 2013 to 2015.	equine influenza viruses (eiv) are a major cause of acute respiratory disease in horses worldwide and occasionally also affect vaccinated animals. like other influenza a viruses, they undergo antigenic drift, highlighting the importance of both surveillance and virus characterisation in order for vaccine strains to be kept up to date. the aim of the work reported here was to monitor the genetic and antigenic changes occurring in eiv circulating in the uk from 2013 to 2015 and to identify any evi ...	2017	28208721
amino acids in hemagglutinin antigenic site b determine antigenic and receptor binding differences between a(h3n2)v and ancestral seasonal h3n2 influenza viruses.	influenza a h3n2 variant [a(h3n2)v] viruses, which have caused human infections in the united states in recent years, originated from human seasonal h3n2 viruses that were introduced into north american swine in the mid-1990s, but they are antigenically distinct from both the ancestral and current circulating h3n2 strains. a reference a(h3n2)v virus, a/minnesota/11/2010 (mn/10), and a seasonal h3n2 strain, a/beijing/32/1992 (bj/92), were chosen to determine the molecular basis for the antigenic ...	2017	27807224
safe recombinant outer membrane vesicles that display m2e elicit heterologous influenza protection.	recombinant, escherichia coli-derived outer membrane vesicles (romvs), which display heterologous protein subunits, have potential as a vaccine adjuvant platform. one drawback to romvs is their lipopolysaccharide (lps) content, limiting their translatability to the clinic due to potential adverse effects. here, we explore a unique romv construct with structurally remodeled lipids containing only the lipid iva portion of lps, which does not stimulate human tlr4. the romvs are derived from a genet ...	2017	28215994
novel highly pathogenic avian a(h5n2) and a(h5n8) influenza viruses of clade 2.3.4.4 from north america have limited capacity for replication and transmission in mammals.	highly pathogenic influenza a(h5n8) viruses from clade 2.3.4.4 were introduced to north america by migratory birds in the fall of 2014. reassortment of a(h5n8) viruses with avian viruses of north american lineage resulted in the generation of novel a(h5n2) viruses with novel genotypes. through sequencing of recent avian influenza viruses, we identified pb1 and np gene segments very similar to those in the viruses isolated from north american waterfowl prior to the introduction of a(h5n8) to nort ...	2017	27303732
molecular epidemiology of influenza a(h1n1)pdm09 hemagglutinin gene circulating in são paulo state , brazil: 2016 anticipated influenza season.	compared to previous years, seasonal influenza activity commenced early in são paulo state, brazil, southern hemisphere during the 2016 year. in order to investigate the genetic pattern of influenza a(h1n1)pdm09 in the state of sao paulo a total of 479 respiratory samples, collected in january by sentinel surveillance units, were screened by real-time rt-pcr. a total of 6 influenza viruses a(h1n1)pdm09 presenting ct values ≤ 30 were sequenced following phylogenetic analysis. the present study id ...	2017	28380120
selection of multi-drug resistant influenza a and b viruses under zanamivir pressure and their replication fitness in ferrets.	intravenous zanamivir has been used to treat patients with severe influenza. because the majority of cases (including immunocompromised patients) require the drug for an extended period of treatment, there is a higher risk that the virus will develop resistance. therefore, knowing the possible amino acid substitutions that may arise in recently circulating influenza strains under prolonged zanamivir exposure and their impact on antiviral susceptibility is important.	2017	28195559
swine influenza virus (h1n2) characterization and transmission in ferrets, chile.	phylogenetic analysis of the influenza hemagglutinin gene (ha) has suggested that commercial pigs in chile harbor unique human seasonal h1-like influenza viruses, but further information, including characterization of these viruses, was unavailable. we isolated influenza virus (h1n2) from a swine in a backyard production farm in central chile and demonstrated that the ha gene was identical to that in a previous report. its ha and neuraminidase genes were most similar to human h1 and n2 viruses f ...	2017	28098524
recent h3n2 viruses have evolved specificity for extended, branched human-type receptors, conferring potential for increased avidity.	human and avian influenza viruses recognize different sialic acid-containing receptors, referred to as human-type (neuacα2-6gal) and avian-type (neuacα2-3gal), respectively. this presents a species barrier for aerosol droplet transmission of avian viruses in humans and ferrets. recent reports have suggested that current human h3n2 viruses no longer have strict specificity toward human-type receptors. using an influenza receptor glycan microarray with extended airway glycans, we find that h3n2 vi ...	2017	28017661