Estimates of the Number of Human Infections With Influenza A(H3N2) Variant Virus, United States, August 2011–April 2012

Biggerstaff, Matthew; Reed, Carrie; Epperson, Scott; Jhung, Michael A.; Gambhir, Manoj; Bresee, Joseph S.; Jernigan, Daniel B.; Swerdlow, David L.; Finelli, Lyn

doi:10.1093/cid/cit273

Cited by 33 publications

(40 citation statements)

References 9 publications

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“…Fortunately the symptoms of A(H3N2)v infection were generally mild, although some patients had to be hospitalized, and one case was fatal (9). It is estimated that only 1 out of approximately 200 A(H3N2)v human infections are laboratory confirmed; therefore, the number of actual human cases might be much greater than that of reported cases (10).…”

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confidence: 99%

Amino Acids in Hemagglutinin Antigenic Site B Determine Antigenic and Receptor Binding Differences between A(H3N2)v and Ancestral Seasonal H3N2 Influenza Viruses

Wang

Ilyushina

Lugovtsev

et al. 2017

J Virol

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Influenza A H3N2 variant [A(H3N2)v] viruses, which have caused human infections in the UnitedStates 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 difference between A(H3N2)v and the ancestral viruses. Viruses containing wild-type and mutant MN/10 or BJ/92 hemagglutinins (HAs) were constructed and probed for reactivity with ferret antisera against MN/10 and BJ/92 in hemagglutination inhibition assays. Among the amino acids that differ between the MN/10 and BJ/92 HAs, those in antigenic site A had little impact on the antigenic phenotype. Within antigenic site B, mutations at residues 156, 158, 189, and 193 of MN/10 HA to those in BJ/92 switched the MN/10 antigenic phenotype to that of BJ/ 92. Mutations at residues 156, 157, 158, 189, and 193 of BJ/92 HA to amino acids present in MN/10 were necessary for BJ/92 to become antigenically similar to MN/ 10. The HA amino acid substitutions responsible for switching the antigenic phenotype also impacted HA binding to sialyl receptors that are usually present in the human respiratory tract. Our study demonstrates that antigenic site B residues play a critical role in determining both the unique antigenic phenotype and receptor specificity of A(H3N2)v viruses, a finding that may facilitate future surveillance and risk assessment of novel influenza viruses. IMPORTANCE Influenza A H3N2 variant [A(H3N2)v] viruses have caused hundreds of human infections in multiple states in the UnitedStates since 2009. Most cases have been children who had contact with swine in agricultural fairs. These viruses originated from human seasonal H3N2 viruses that were introduced into the U.S. swine population in the mid-1990s, but they are different from both these ancestral viruses and current circulating human seasonal H3N2 strains in terms of their antigenic characteristics as measured by hemagglutination inhibition (HI) assay. In this study, we identified amino acids in antigenic site B of the surface glycoprotein hemagglutinin (HA) that explain the antigenic difference between A(H3N2)v and the ancestral H3N2 strains. These amino acid mutations also alter binding to minor human-type glycans, suggesting that host adaptation may contribute to the selection of antigenically distinct H3N2 variants which pose a threat to public health.

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confidence: 99%

Amino Acids in Hemagglutinin Antigenic Site B Determine Antigenic and Receptor Binding Differences between A(H3N2)v and Ancestral Seasonal H3N2 Influenza Viruses

Wang

Ilyushina

Lugovtsev

et al. 2017

J Virol

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“…Current endemic swine IAVs in the United States are composed of the classical swine H1N1 viruses and reassortant TRIG viruses (18). The genotypic components of the TRIG cassette exhibit high genetic stability, resulting in a backbone that can support different glycoprotein combinations, providing a potential mechanism for reassortment resulting in evasion of herd immunity (20). These findings suggest that the TRIG cassette may provide a selective advantage for influenza virus reassortment in a species-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

“…Initial findings suggested that the differential distribution of ␣2,3-and ␣2,6-sialic acids along the swine respiratory tract was key to supporting the mixing vessel hypothesis, but more recent studies examining sialic acid receptor distribution profiles in swine and humans indicate that such differences are not significant or observed (48)(49)(50). The swine influenza virus TRIG cassette has been hypothesized to have a role in supporting increased glycoprotein exchange in swine, a feature that may increase the reassortment prevalence and increase the overall fitness of influenza virus in swine, perhaps by evasion of herd immunity (20). Calu-3 and LLC-PK1 cells do not have detectable differences in the levels of ␣2,3-and ␣2,6-sialic acid expression profiles (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…The influenza virus PA gene encodes a second protein, PA-X, which is expressed, based on a ribosomal frameshift (70). PA-X has been shown to have a role in modulation of the innate immune response through upregulation of antiviral cytokine and chemokine expression through a host protein shutdown mechanism (20,70,71). Clustal W analysis of the amino acid sequences from the N-terminal and C-terminal regions of the PA from huH1N1 and swH1N2 shows extensive amino acid changes (Fig.…”

Section: Figmentioning

confidence: 99%

“…virus zoonosis involving a swine H3N2 variant (H3N2v) were observed in Iowa (19,20). H3N2v viruses resulted from reassortment of H3N2 TRIG viruses with inclusion of the pH1N1 M gene.…”

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confidence: 99%

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Swine Influenza Virus PA and Neuraminidase Gene Reassortment into Human H1N1 Influenza Virus Is Associated with an Altered Pathogenic Phenotype Linked to Increased MIP-2 Expression

Dlugolenski

Jones

Howerth

et al. 2015

J Virol

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Swine are susceptible to infection by both avian and human influenza viruses, and this feature is thought to contribute to novel reassortant influenza viruses. In this study, the influenza virus reassortment rate in swine and human cells was determined. Coinfection of swine cells with 2009 pandemic H1N1 virus (huH1N1) and an endemic swine H1N2 (A/swine/Illinois/02860/09) virus (swH1N2) resulted in a 23% reassortment rate that was independent of ␣2,3-or ␣2,6-sialic acid distribution on the cells. The reassortants had altered pathogenic phenotypes linked to introduction of the swine virus PA and neuraminidase (NA) into huH1N1. In mice, the huH1N1 PA and NA mediated increased MIP-2 expression early postinfection, resulting in substantial pulmonary neutrophilia with enhanced lung pathology and disease. The findings support the notion that swine are a mixing vessel for influenza virus reassortants independent of sialic acid distribution. These results show the potential for continued reassortment of the 2009 pandemic H1N1 virus with endemic swine viruses and for reassortants to have increased pathogenicity linked to the swine virus NA and PA genes which are associated with increased pulmonary neutrophil trafficking that is related to MIP-2 expression. IMPORTANCEInfluenza A viruses can change rapidly via reassortment to create a novel virus, and reassortment can result in possible pandemics. Reassortments among subtypes from avian and human viruses led to the 1957 (H2N2 subtype) and 1968 (H3N2 subtype) human influenza pandemics. Recent analyses of circulating isolates have shown that multiple genes can be recombined from human, avian, and swine influenza viruses, leading to triple reassortants. Understanding the factors that can affect influenza A virus reassortment is needed for the establishment of disease intervention strategies that may reduce or preclude pandemics. The findings from this study show that swine cells provide a mixing vessel for influenza virus reassortment independent of differential sialic acid distribution. The findings also establish that circulating neuraminidase (NA) and PA genes could alter the pathogenic phenotype of the pandemic H1N1 virus, resulting in enhanced disease. The identification of such factors provides a framework for pandemic modeling and surveillance. E ach year, influenza A viruses (IAVs) cause epidemics with high morbidity and some mortality in humans (1). In avian species, IAV infection generally is associated with mild disease, and it is only when the virus crosses species barriers that pathogenic traits are attributed to infection (2). IAV is frequently associated with spillover events, as numerous species are susceptible to IAV. Often, reassortment of IAV leads to a subtype or variant that has not previously infected humans, and as the virus adapts and is transmitted more easily, a pandemic event may loom. IAV is the cause of Ͼ30,000 deaths in the United States and Ͼ500,000 deaths worldwide annually (3). In the past century, four IAV pandemics have occurred, i.e....

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Likelihood of prior exposure to circulating influenza viruses resulting in cross‐protection by CD8+ T cells against emergent H3N2v swine viruses infecting humans

Komadina

Sullivan

Leder

et al. 2021

Journal of Medical Virology

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Outbreaks of influenza in swine can result in potential threats to human public health. A notable occurrence was the emergence of swine-origin H1N1 influenza viruses in 2009. Since then, there have been several documented outbreaks of swine-origin influenza infecting humans in several countries. Sustained events have occurred when H1N1v, H1N2v, and H3N2v swine-origin viruses have infected humans visiting agricultural shows in the US. The predominant H3N2v viruses gained the matrix protein from the A(H1N1)pdm09 viruses, with reported human-tohuman transmission raising fears of another pandemic. Current vaccines do not induce secondary cell-mediated immune responses, which may provide crossprotection against novel influenza A subtypes, however, population susceptibility to infection with seasonal influenza is likely to be influenced by cross-reactive CD8+ T-cells directed towards immunogenic peptides derived from viral proteins. This study involved a retrospective review of historical influenza viruses circulating in human populations from 1918 to 2020 to identify evidence of prior circulation of H3N3v immunogenic CD8+ T-cells peptides found in the NP and M1 proteins. We found evidence of prior circulation of H3N2v NP and M1 immunogenic peptides in historical influenza viruses. This provides insight into the population context in which influenza viruses emerge and may help inform immunogenic peptide selection for cytotoxic T-cell lymphocytes (CTL)-inducing influenza vaccines. Next-generation vaccines capable of eliciting CD8+ T-cell-mediated cross-protective immunity may offer a long-term alternative strategy for influenza vaccines.

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Estimates of the Number of Human Infections With Influenza A(H3N2) Variant Virus, United States, August 2011–April 2012

Cited by 33 publications

References 9 publications

Amino Acids in Hemagglutinin Antigenic Site B Determine Antigenic and Receptor Binding Differences between A(H3N2)v and Ancestral Seasonal H3N2 Influenza Viruses

Amino Acids in Hemagglutinin Antigenic Site B Determine Antigenic and Receptor Binding Differences between A(H3N2)v and Ancestral Seasonal H3N2 Influenza Viruses

Swine Influenza Virus PA and Neuraminidase Gene Reassortment into Human H1N1 Influenza Virus Is Associated with an Altered Pathogenic Phenotype Linked to Increased MIP-2 Expression

Likelihood of prior exposure to circulating influenza viruses resulting in cross‐protection by CD8+ T cells against emergent H3N2v swine viruses infecting humans

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