SARS-CoV-2 and Influenza A virus Co-infections in Ferrets

2021 ◽  
Author(s):  
Ying Huang ◽  
Amanda L. Skarlupka ◽  
Hyesun Jang ◽  
Uriel Blas-Machado ◽  
Nathan Holladay ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Direct Contact ◽  
Human Population ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Severe Disease ◽  
Influenza Viruses ◽  
Single Infection ◽  
Influenza A Viruses ◽  
Severe Morbidity

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seasonal influenza viruses are co-circulating in the human population. However, only a few cases of viral co-infection with these two viruses have been documented in humans with some people having severe disease and others mild disease. In order to examine this phenomenon, ferrets were co-infected with SARS-CoV-2 and human seasonal influenza A viruses (IAVs) (H1N1 or H3N2) and were compared to animals that received each virus alone. Ferrets were either immunologically naïve to both viruses or vaccinated with the 2019-2020 split-inactivated influenza virus vaccine. Co-infected naive ferrets lost significantly more body weight than ferrets infected with each virus alone and induced more severe inflammation in both the nose and lungs than ferrets single-infected with each virus. Co-infected naïve animals had predominantly higher IAV titers than SARS-CoV-2 titers, and IAVs efficiently transmitted to the co-housed ferrets by direct contact. Comparatively, SARS-CoV-2 failed to transmit to the ferrets that co-housed with co-infected ferrets by direct contact. Moreover, vaccination significantly reduced IAVs virus titers and shortened the viral shedding, but did not completely block influenza virus direct contact transmission. Notably, vaccination significantly ameliorated the influenza associated disease by protecting vaccinated animals from severe morbidity after IAV single infection or IAV and SARS-CoV-2 co-infection, suggesting that seasonal influenza virus vaccination is pivotal to prevent severe disease induced by IAVs and SARS-CoV-2 co-infection during the COVID-19 pandemic. Importance Influenza A viruses cause severe morbidity and mortality during each influenza virus season. The emergence of SARS-CoV-2 infection in the human population offers the opportunity to potential co-infections of both viruses. The development of useful animal models to asses pathogenesis, transmission, and viral evolution of these viruses as the co-infect a host is of critical importance for the development of vaccines and therapeutics. The ability to prevent the most severe effects of viral co-infections can be studied using effect co-infection ferret models described in this report.

scholarly journals Broadly Reactive H2 Hemagglutinin Vaccines Elicit Cross-Reactive Antibodies in Ferrets Preimmune to Seasonal Influenza A Viruses

mSphere ◽  
2021 ◽  
Vol 6 (2) ◽  
Author(s):  
Z. Beau Reneer ◽  
Amanda L. Skarlupka ◽  
Parker J. Jamieson ◽  
Ted M. Ross
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Recombinant Proteins ◽  
Human Population ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Wild Type ◽  
Influenza A Viruses ◽  
Global Pandemic

ABSTRACT Influenza vaccines have traditionally been tested in naive mice and ferrets. However, humans are first exposed to influenza viruses within the first few years of their lives. Therefore, there is a pressing need to test influenza virus vaccines in animal models that have been previously exposed to influenza viruses before being vaccinated. In this study, previously described H2 computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) vaccines (Z1 and Z5) were tested in influenza virus “preimmune” ferret models. Ferrets were infected with historical, seasonal influenza viruses to establish preimmunity. These preimmune ferrets were then vaccinated with either COBRA H2 HA recombinant proteins or wild-type H2 HA recombinant proteins in a prime-boost regimen. A set of naive preimmune or nonpreimmune ferrets were also vaccinated to control for the effects of the multiple different preimmunities. All of the ferrets were then challenged with a swine H2N3 influenza virus. Ferrets with preexisting immune responses influenced recombinant H2 HA-elicited antibodies following vaccination, as measured by hemagglutination inhibition (HAI) and classical neutralization assays. Having both H3N2 and H1N1 immunological memory regardless of the order of exposure significantly decreased viral nasal wash titers and completely protected all ferrets from both morbidity and mortality, including the mock-vaccinated ferrets in the group. While the vast majority of the preimmune ferrets were protected from both morbidity and mortality across all of the different preimmunities, the Z1 COBRA HA-vaccinated ferrets had significantly higher antibody titers and recognized the highest number of H2 influenza viruses in a classical neutralization assay compared to the other H2 HA vaccines. IMPORTANCE H1N1 and H3N2 influenza viruses have cocirculated in the human population since 1977. Nearly every human alive today has antibodies and memory B and T cells against these two subtypes of influenza viruses. H2N2 influenza viruses caused the 1957 global pandemic and people born after 1968 have never been exposed to H2 influenza viruses. It is quite likely that a future H2 influenza virus could transmit within the human population and start a new global pandemic, since the majority of people alive today are immunologically naive to viruses of this subtype. Therefore, an effective vaccine for H2 influenza viruses should be tested in an animal model with previous exposure to influenza viruses that have circulated in humans. Ferrets were infected with historical influenza A viruses to more accurately mimic the immune responses in people who have preexisting immune responses to seasonal influenza viruses. In this study, preimmune ferrets were vaccinated with wild-type (WT) and COBRA H2 recombinant HA proteins in order to examine the effects that preexisting immunity to seasonal human influenza viruses have on the elicitation of broadly cross-reactive antibodies from heterologous vaccination.

scholarly journals Broadly Reactive H2 Hemagglutinin Vaccines Elicit Cross-Reactive Antibodies in Ferrets Pre-Immune to Seasonal Influenza A Viruses

2021 ◽  
Author(s):  
Z. Beau Reneer ◽  
Amanda S. Skarlupka ◽  
Parker J. Jamieson ◽  
Ted M. Ross
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Recombinant Proteins ◽  
Human Population ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Morbidity And Mortality ◽  
Influenza A Viruses ◽  
Global Pandemic

AbstractInfluenza vaccines have traditionally been tested in naïve mice and ferrets. However, humans are first exposed to influenza viruses within the first few years of their lives. Therefore, there is a pressing need to test influenza virus vaccines in animal models that have been previously exposed to influenza viruses before being vaccinated. In this manuscript, previously described H2 computationally optimized broadly reactive antigen (COBRA) HA vaccines (Z1, Z5) were tested in influenza virus ‘pre-immune’ ferret models. Ferrets were infected with historical, seasonal influenza viruses to establish pre-immunity. These pre-immune ferrets were then vaccinated with either COBRA H2 HA recombinant proteins or WT H2 HA recombinant proteins in a prime-boost regimen. A set of naïve pre-immune or non pre-immune ferrets were also vaccinated to control of the effects of the multiple different pre-immunities. All of the ferrets were then challenged with a swine H2N3 influenza virus. Ferrets with pre-existing immune responses influenced recombinant H2 HA elicited antibodies following vaccination as measured by HAI and classical neutralization assays. Having both H3N2 and H1N1 immunological memory regardless of the order of exposure significantly decreased viral nasal wash titers and completely protected all ferrets from both morbidity and mortality, including the mock vaccinated ferrets in the group. While the vast majority of the pre-immune ferrets were protected from both morbidity and mortality across all of the different pre-immunities, the Z1 COBRA HA vaccinated ferrets had significantly higher antibody titers and recognized the highest number H2 influenza viruses in a classical neutralization assay compared to the other H2 HA vaccines.ImportanceH1N1 and H3N2 influenza viruses have co-circulated in the human population since 1977. Nearly every human alive today has antibodies and memory B and T cells against these two subtypes of influenza viruses. H2N2 influenza viruses caused the 1957 global pandemic and people born after 1968 have never been exposed to H2 influenza viruses. It is quite likely that a future H2 influenza virus could transmit within the human population and start a new global pandemic, since the majority of people alive today are immunologically naïve to viruses of this subtype. Therefore, an effective vaccine for H2 influenza viruses should be tested in an animal model with previous exposure to influenza viruses that have circulated in humans. Ferrets were infected with historical influenza A viruses to more accurately mimic the immune responses in people who have pre-existing immune responses to seasonal influenza viruses. In this study, pre-immune ferrets were vaccinated with WT and COBRA H2 recombinant HA proteins in order to examine the effects of pre-existing immunity to seasonal human influenza viruses have on the elicitation of broadly cross-reactive antibodies from heterologous vaccination.

scholarly journals Efficient Inhibition of Avian and Seasonal Influenza A Viruses by a Virus-Specific Dicer-Substrate Small Interfering RNA Swarm in Human Monocyte-Derived Macrophages and Dendritic Cells

2018 ◽  
Vol 93 (4) ◽  
Author(s):  
Miao Jiang ◽  
Pamela Österlund ◽  
Veera Westenius ◽  
Deyin Guo ◽  
Minna M. Poranen ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Influenza Virus ◽  
Small Interfering Rna ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Primary Monocyte ◽  
Prevention And Treatment ◽  
Interfering Rna

ABSTRACTInfluenza A viruses (IAVs) are viral pathogens that cause epidemics and occasional pandemics of significant mortality. The generation of efficacious vaccines and antiviral drugs remains a challenge due to the rapid appearance of new influenza virus types and antigenic variants. Consequently, novel strategies for the prevention and treatment of IAV infections are needed, given the limitations of the presently available antivirals. Here, we used enzymatically produced IAV-specific double-stranded RNA (dsRNA) molecules andGiardia intestinalisDicer for the generation of a swarm of small interfering RNA (siRNA) molecules. The siRNAs target multiple conserved genomic regions of the IAVs. In mammalian cells, the produced 25- to 27-nucleotide-long siRNA molecules are processed by endogenous Dicer into 21-nucleotide siRNAs and are thus designated Dicer-substrate siRNAs (DsiRNAs). We evaluated the efficacy of the above DsiRNA swarm at preventing IAV infections in human primary monocyte-derived macrophages and dendritic cells. The replication of different IAV strains, including avian influenza H5N1 and H7N9 viruses, was significantly inhibited by pretransfection of the cells with the IAV-specific DsiRNA swarm. Up to 7 orders of magnitude inhibition of viral RNA expression was observed, which led to a dramatic inhibition of IAV protein synthesis and virus production. The IAV-specific DsiRNA swarm inhibited virus replication directly through the RNA interference pathway although a weak induction of innate interferon responses was detected. Our results provide direct evidence for the feasibility of the siRNA strategy and the potency of DsiRNA swarms in the prevention and treatment of influenza, including the highly pathogenic avian influenza viruses.IMPORTANCEIn spite of the enormous amount of research, influenza virus is still one of the major challenges for medical virology due to its capacity to generate new variants, which potentially lead to severe epidemics and pandemics. We demonstrated here that a swarm of small interfering RNA (siRNA) molecules, including more than 100 different antiviral RNA molecules targeting the most conserved regions of the influenza A virus genome, could efficiently inhibit the replication of all tested avian and seasonal influenza A variants in human primary monocyte-derived macrophages and dendritic cells. The wide antiviral spectrum makes the virus-specific siRNA swarm a potentially efficient treatment modality against both avian and seasonal influenza viruses.

scholarly journals Kallikrein-Related Peptidase 5 Contributes to H3N2 Influenza Virus Infection in Human Lungs

2017 ◽  
Vol 91 (16) ◽  
Author(s):  
Mélia Magnen ◽  
Fabien Gueugnon ◽  
Antoine Guillon ◽  
Thomas Baranek ◽  
Virginie C. Thibault ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Respiratory Tract ◽  
Serine Proteases ◽  
Lower Respiratory Tract ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
H3n2 Virus ◽  
Influenza A Viruses

ABSTRACT Hemagglutinin (HA) of influenza virus must be activated by proteolysis before the virus can become infectious. Previous studies indicated that HA cleavage is driven by membrane-bound or extracellular serine proteases in the respiratory tract. However, there is still uncertainty as to which proteases are critical for activating HAs of seasonal influenza A viruses (IAVs) in humans. This study focuses on human KLK1 and KLK5, 2 of the 15 serine proteases known as the kallikrein-related peptidases (KLKs). We find that their mRNA expression in primary human bronchial cells is stimulated by IAV infection. Both enzymes cleaved recombinant HA from several strains of the H1 and/or H3 virus subtype in vitro, but only KLK5 promoted the infectivity of A/Puerto Rico/8/34 (H1N1) and A/Scotland/20/74 (H3N2) virions in MDCK cells. We assessed the ability of treated viruses to initiate influenza in mice. The nasal instillation of only the KLK5-treated virus resulted in weight loss and lethal outcomes. The secretion of this protease in the human lower respiratory tract is enhanced during influenza. Moreover, we show that pretreatment of airway secretions with a KLK5-selective inhibitor significantly reduced the activation of influenza A/Scotland/20/74 virions, providing further evidence of its importance. Differently, increased KLK1 secretion appeared to be associated with the recruitment of inflammatory cells in human airways regardless of the origin of inflammation. Thus, our findings point to the involvement of KLK5 in the proteolytic activation and spread of seasonal influenza viruses in humans. IMPORTANCE Influenza A viruses (IAVs) cause acute infection of the respiratory tract that affects millions of people during seasonal outbreaks every year. Cleavage of the hemagglutinin precursor by host proteases is a critical step in the life cycle of these viruses. Consequently, host proteases that activate HA can be considered promising targets for the development of new antivirals. However, the specific proteases that activate seasonal influenza viruses, especially H3N2 viruses, in the human respiratory tract have remain undefined despite many years of work. Here we demonstrate that the secreted, extracellular protease KLK5 (kallikrein-related peptidase 5) is efficient in promoting the infectivity of H3N2 IAV in vitro and in vivo. Furthermore, we found that its secretion was selectively enhanced in the human lower respiratory tract during a seasonal outbreak dominated by an H3N2 virus. Collectively, our data support the clinical relevance of this protease in human influenza pathogenesis.

Influenza A virus transmission: contributing factors and clinical implications

2010 ◽  
Vol 12 ◽  
Author(s):  
Jessica A. Belser ◽  
Taronna R. Maines ◽  
Terrence M. Tumpey ◽  
Jacqueline M. Katz
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
Influenza A ◽  
Severe Disease ◽  
Virus Transmission ◽  
Influenza Viruses ◽  
Clinical Implications ◽  
Influenza A Viruses ◽  
Molecular Features ◽  
Efficient Transmission

Efficient human-to-human transmission is a necessary property for the generation of a pandemic influenza virus. To date, only influenza A viruses within the H1–H3 subtypes have achieved this capacity. However, sporadic cases of severe disease in individuals following infection with avian influenza A viruses over the past decade, and the emergence of a pandemic H1N1 swine-origin virus in 2009, underscore the need to better understand how influenza viruses acquire the ability to transmit efficiently. In this review, we discuss the biological constraints and molecular features known to affect virus transmissibility to and among humans. Factors influencing the behaviour of aerosols in the environment are described, and the mammalian models used to study virus transmission are presented. Recent progress in understanding the molecular determinants that confer efficient transmission has identified crucial roles for the haemagglutinin and polymerase proteins; nevertheless, influenza virus transmission remains a polygenic trait that is not completely understood. The clinical implications of this research, including methods currently under investigation to mitigate influenza virus human-to-human transmission, are discussed. A better understanding of the viral determinants necessary for efficient transmission will allow us to identify avian influenza viruses with pandemic potential.

scholarly journals Next generation methodology for updating HA vaccines against emerging human seasonal influenza A(H3N2) viruses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
James D. Allen ◽  
Ted M. Ross
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Next Generation ◽  
Virus Infections ◽  
Wild Type ◽  
Influenza Hemagglutinin ◽  
H3n2 Influenza

AbstractWhile vaccines remain the best tool for preventing influenza virus infections, they have demonstrated low to moderate effectiveness in recent years. Seasonal influenza vaccines typically consist of wild-type influenza A and B viruses that are limited in their ability to elicit protective immune responses against co-circulating influenza virus variant strains. Improved influenza virus vaccines need to elicit protective immune responses against multiple influenza virus drift variants within each season. Broadly reactive vaccine candidates potentially provide a solution to this problem, but their efficacy may begin to wane as influenza viruses naturally mutate through processes that mediates drift. Thus, it is necessary to develop a method that commercial vaccine manufacturers can use to update broadly reactive vaccine antigens to better protect against future and currently circulating viral variants. Building upon the COBRA technology, nine next-generation H3N2 influenza hemagglutinin (HA) vaccines were designed using a next generation algorithm and design methodology. These next-generation broadly reactive COBRA H3 HA vaccines were superior to wild-type HA vaccines at eliciting antibodies with high HAI activity against a panel of historical and co-circulating H3N2 influenza viruses isolated over the last 15 years, as well as the ability to neutralize future emerging H3N2 isolates.

scholarly journals Influenza: An Emerging and Re-emerging Public Health Threat in Nepal

2018 ◽  
Vol 3 (2) ◽  
pp. 1-2
Author(s):  
Bishnu Prasad Upadhyay
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Winter Season ◽  
Emerging Infectious Diseases ◽  
Influenza Viruses ◽  
Influenza B ◽  
Influenza A Viruses ◽  
Influenza A H1n1 ◽  
New Variant ◽  
Seasonal Epidemics

Influenza virus type A and B are responsible for seasonal epidemics as well as pandemics in human. Influenza A viruses are further divided into two major groups namely, low pathogenic seasonal influenza (A/H1N1, A/H1N1 pdm09, A/H3N2) and highly pathogenic influenza virus (H5N1, H5N6, H7N9) on the basis of two surface antigens: hemagglutinin (HA) and neuraminidase (NA). Mutations, including substitutions, deletions, and insertions, are one of the most important mechanisms for producing new variant of influenza viruses. During the last 30 years; more than 50 viral threat has been evolved in South-East Asian countriesof them influenza is one of the major emerging and re-emerging infectious diseases of global concern. Similar to tropical and sub-tropical countries of Southeast Asia; circulation of A/H1N1 pdm09, A/H3N2 and influenza B has been circulating throughout the year with the peak during July-November in Nepal. However; the rate of infection transmission reach peak during the post-rain and winter season of Nepal.

scholarly journals Plasticity of the Influenza Virus H5 HA Protein

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huihui Kong ◽  
David F. Burke ◽  
Tiago Jose da Silva Lopes ◽  
Kosuke Takada ◽  
Masaki Imai ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Mammalian Cells ◽  
Influenza A ◽  
Viral Antigen ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Highly Pathogenic ◽  
Antigenic Properties ◽  
Ha Protein

ABSTRACT Since the emergence of highly pathogenic avian influenza viruses of the H5 subtype, the major viral antigen, hemagglutinin (HA), has undergone constant evolution, resulting in numerous genetic and antigenic (sub)clades. To explore the consequences of amino acid changes at sites that may affect the antigenicity of H5 viruses, we simultaneously mutated 17 amino acid positions of an H5 HA by using a synthetic gene library that, theoretically, encodes all combinations of the 20 amino acids at the 17 positions. All 251 mutant viruses sequenced possessed ≥13 amino acid substitutions in HA, demonstrating that the targeted sites can accommodate a substantial number of mutations. Selection with ferret sera raised against H5 viruses of different clades resulted in the isolation of 39 genotypes. Further analysis of seven variants demonstrated that they were antigenically different from the parental virus and replicated efficiently in mammalian cells. Our data demonstrate the substantial plasticity of the influenza virus H5 HA protein, which may lead to novel antigenic variants. IMPORTANCE The HA protein of influenza A viruses is the major viral antigen. In this study, we simultaneously introduced mutations at 17 amino acid positions of an H5 HA expected to affect antigenicity. Viruses with ≥13 amino acid changes in HA were viable, and some had altered antigenic properties. H5 HA can therefore accommodate many mutations in regions that affect antigenicity. The substantial plasticity of H5 HA may facilitate the emergence of novel antigenic variants.

scholarly journals International Laboratory Comparison of Influenza Microneutralization Assays for A(H1N1)pdm09, A(H3N2), and A(H5N1) Influenza Viruses by CONSISE

2015 ◽  
Vol 22 (8) ◽  
pp. 957-964 ◽  
Author(s):  
Karen L. Laurie ◽  
Othmar G. Engelhardt ◽  
John Wood ◽  
Alan Heath ◽  
Jacqueline M. Katz ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Incubation Time ◽  
Influenza A ◽  
Influenza Viruses ◽  
Enzyme Linked Immunosorbent Assay ◽  
Influenza A Viruses ◽  
H5n1 Influenza ◽  
The World ◽  
International Laboratory ◽  
The Impact

ABSTRACTThe microneutralization assay is commonly used to detect antibodies to influenza virus, and multiple protocols are used worldwide. These protocols differ in the incubation time of the assay as well as in the order of specific steps, and even within protocols there are often further adjustments in individual laboratories. The impact these protocol variations have on influenza serology data is unclear. Thus, a laboratory comparison of the 2-day enzyme-linked immunosorbent assay (ELISA) and 3-day hemagglutination (HA) microneutralization (MN) protocols, using A(H1N1)pdm09, A(H3N2), and A(H5N1) viruses, was performed by the CONSISE Laboratory Working Group. Individual laboratories performed both assay protocols, on multiple occasions, using different serum panels. Thirteen laboratories from around the world participated. Within each laboratory, serum sample titers for the different assay protocols were compared between assays to determine the sensitivity of each assay and were compared between replicates to assess the reproducibility of each protocol for each laboratory. There was good correlation of the results obtained using the two assay protocols in most laboratories, indicating that these assays may be interchangeable for detecting antibodies to the influenza A viruses included in this study. Importantly, participating laboratories have aligned their methodologies to the CONSISE consensus 2-day ELISA and 3-day HA MN assay protocols to enable better correlation of these assays in the future.

scholarly journals Divergent Human-Origin Influenza Viruses Detected in Australian Swine Populations

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Frank Y. K. Wong ◽  
Celeste Donato ◽  
Yi-Mo Deng ◽  
Don Teng ◽  
Naomi Komadina ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Swine Influenza ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Human Origin ◽  
Human Influenza ◽  
Influenza A Viruses ◽  
Data Set ◽  
Antigenic Properties

ABSTRACTGlobal swine populations infected with influenza A viruses pose a persistent pandemic risk. With the exception of a few countries, our understanding of the genetic diversity of swine influenza viruses is limited, hampering control measures and pandemic risk assessment. Here we report the genomic characteristics and evolutionary history of influenza A viruses isolated in Australia from 2012 to 2016 from two geographically isolated swine populations in the states of Queensland and Western Australia. Phylogenetic analysis with an expansive human and swine influenza virus data set comprising >40,000 sequences sampled globally revealed evidence of the pervasive introduction and long-term establishment of gene segments derived from several human influenza viruses of past seasons, including the H1N1/1977, H1N1/1995, H3N2/1968, and H3N2/2003, and the H1N1 2009 pandemic (H1N1pdm09) influenza A viruses, and a genotype that contained gene segments derived from the past three pandemics (1968, reemerged 1977, and 2009). Of the six human-derived gene lineages, only one, comprising two viruses isolated in Queensland during 2012, was closely related to swine viruses detected from other regions, indicating a previously undetected circulation of Australian swine lineages for approximately 3 to 44 years. Although the date of introduction of these lineages into Australian swine populations could not be accurately ascertained, we found evidence of sustained transmission of two lineages in swine from 2012 to 2016. The continued detection of human-origin influenza virus lineages in swine over several decades with little or unpredictable antigenic drift indicates that isolated swine populations can act as antigenic archives of human influenza viruses, raising the risk of reemergence in humans when sufficient susceptible populations arise.IMPORTANCEWe describe the evolutionary origins and antigenic properties of influenza A viruses isolated from two separate Australian swine populations from 2012 to 2016, showing that these viruses are distinct from each other and from those isolated from swine globally. Whole-genome sequencing of virus isolates revealed a high genotypic diversity that had been generated exclusively through the introduction and establishment of human influenza viruses that circulated in past seasons. We detected six reassortants with gene segments derived from human H1N1/H1N1pdm09 and various human H3N2 viruses that circulated during various periods since 1968. We also found that these swine viruses were not related to swine viruses collected elsewhere, indicating independent circulation. The detection of unique lineages and genotypes in Australia suggests that isolated swine populations that are sufficiently large can sustain influenza virus for extensive periods; we show direct evidence of a sustained transmission for at least 4 years between 2012 and 2016.

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