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Influenza

Nature Reviews Disease Primers volume 4, Article number: 3 (2018) Cite this article

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Abstract

Influenza is an infectious respiratory disease that, in humans, is caused by influenza A and influenza B viruses. Typically characterized by annual seasonal epidemics, sporadic pandemic outbreaks involve influenza A virus strains of zoonotic origin. The WHO estimates that annual epidemics of influenza result in ~1 billion infections, 3–5 million cases of severe illness and 300,000–500,000 deaths. The severity of pandemic influenza depends on multiple factors, including the virulence of the pandemic virus strain and the level of pre-existing immunity. The most severe influenza pandemic, in 1918, resulted in >40 million deaths worldwide. Influenza vaccines are formulated every year to match the circulating strains, as they evolve antigenically owing to antigenic drift. Nevertheless, vaccine efficacy is not optimal and is dramatically low in the case of an antigenic mismatch between the vaccine and the circulating virus strain. Antiviral agents that target the influenza virus enzyme neuraminidase have been developed for prophylaxis and therapy. However, the use of these antivirals is still limited. Emerging approaches to combat influenza include the development of universal influenza virus vaccines that provide protection against antigenically distant influenza viruses, but these vaccines need to be tested in clinical trials to ascertain their effectiveness.

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Fig. 1: Influenza A and influenza B.
Fig. 2: Influenza pandemics.
Fig. 3: Emergence of influenza A virus from aquatic wild bird reservoirs.
Fig. 4: Influenza virus life cycle.
Fig. 5: Influenza antigenic shift and antigenic drift.
Fig. 6: Rapid recovery from avian influenza A H7N9 virus infection is associated with early CD8+ T cell responses.
Fig. 7: Inactivated influenza A virus vaccine manufacture.

References

  1. Sellers, S. A., Hagan, R. S., Hayden, F. G. & Fischer, W. A. 2nd. The hidden burden of influenza: A review of the extra-pulmonary complications of influenza infection. Influenza Other Respir. Viruses 11, 372–393 (2017).

    PubMed  PubMed Central  Google Scholar 

  2. Kwong, J. C. et al. Acute myocardial infarction after laboratory-confirmed influenza infection. N. Engl. J. Med. 378, 345–353 (2018).

    PubMed  Google Scholar 

  3. Matsuzaki, Y. et al. Clinical features of influenza C virus infection in children. J. Infect. Dis. 193, 1229–1235 (2006).

    PubMed  Google Scholar 

  4. Olsen, B. et al. Global patterns of influenza a virus in wild birds. Science 312, 384–388 (2006).

    CAS  PubMed  Google Scholar 

  5. Webster, R. G., Bean, W. J., Gorman, O. T., Chambers, T. M. & Kawaoka, Y. Evolution and ecology of influenza A viruses. Microbiol. Rev. 56, 152–179 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Tong, S. et al. A distinct lineage of influenza A virus from bats. Proc. Natl Acad. Sci. USA 109, 4269–4274 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Ma, W., García-Sastre, A. & Schwemmle, M. Expected and unexpected features of the newly discovered bat influenza A-like viruses. PLOS Pathog. 11, e1004819 (2015).

    Google Scholar 

  8. Fouchier, R. A. et al. Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls. J. Virol. 79, 2814–2822 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Osterhaus, A. D., Rimmelzwaan, G. F., Martina, B. E., Bestebroer, T. M. & Fouchier, R. A. Influenza B virus in seals. Science 288, 1051–1053 (2000).

    CAS  PubMed  Google Scholar 

  10. Guo, Y. J., Jin, F. G., Wang, P., Wang, M. & Zhu, J. M. Isolation of influenza C virus from pigs and experimental infection of pigs with influenza C virus. J. Gen. Virol. 64, 177–182 (1983).

    PubMed  Google Scholar 

  11. Hause, B. M. et al. Isolation of a novel swine influenza virus from Oklahoma in 2011 which is distantly related to human influenza C viruses. PLOS Pathog. 9, e1003176 (2013).

    Google Scholar 

  12. Hause, B. M. et al. Characterization of a novel influenza virus in cattle and Swine: proposal for a new genus in the Orthomyxoviridae family. MBio 5, e00031–00014 (2014).

    PubMed  PubMed Central  Google Scholar 

  13. Smith, G. J. et al. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature 459, 1122–1125 (2009).

    CAS  PubMed  Google Scholar 

  14. Mena, I. et al. Origins of the 2009 H1N1 influenza pandemic in swine in Mexico. elife 5, e.16777 (2016). This reference tracks the origins of a human pandemic influenza A virus for the first time.

    Google Scholar 

  15. Hayden, F. Developing new antiviral agents for influenza treatment: what does the future hold? Clin. Infect. Dis. 48 (Suppl. 1), S3–S13 (2009).

    CAS  PubMed  Google Scholar 

  16. Hurt, A. C. et al. Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspectives. Lancet Infect. Dis. 12, 240–248 (2012).

    PubMed  Google Scholar 

  17. Rambaut, A. et al. The genomic and epidemiological dynamics of human influenza A virus. Nature 453, 615–619 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Russell, C. A. et al. The global circulation of seasonal influenza A (H3N2) viruses. Science 320, 340–346 (2008). Together with reference 17, this seminal study proposes intriguing models of how influenza viruses are maintained in the human population and transmitted globally during seasonal epidemics.

    CAS  PubMed  Google Scholar 

  19. Bahl, J. et al. Temporally structured metapopulation dynamics and persistence of influenza A H3N2 virus in humans. Proc. Natl Acad. Sci. USA 108, 19359–19364 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Yu, H. et al. Characterization of regional influenza seasonality patterns in China and implications for vaccination strategies: spatio-temporal modeling of surveillance data. PLOS Med. 10, e1001552 (2013).

    Google Scholar 

  21. Centers for Disease Control and Prevention. Estimated influenza illnesses and hospitalizations averted by vaccination — United States, 2014–15 influenza season. CDC https://www.cdc.gov/flu/about/disease/2014-15.htm (2015).

  22. Cohen, S. A., Chui, K. K. & Naumova, E. N. Influenza vaccination in young children reduces influenza-associated hospitalizations in older adults, 2002–2006. J. Am. Geriatr. Soc. 59, 327–332 (2011).

    PubMed  PubMed Central  Google Scholar 

  23. Gostic, K. M., Ambrose, M., Worobey, M. & Lloyd-Smith, J. O. Potent protection against H5N1 and H7N9 influenza via childhood hemagglutinin imprinting. Science 354, 722–726 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Lozano, R. et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2095–2128 (2012).

    PubMed  Google Scholar 

  25. Iuliano, A. D. et al. Estimates of global seasonal influenza-associated respiratory mortality: a modelling study. Lancet 391, 1285–1300 (2018).

    PubMed  Google Scholar 

  26. Thompson, W. W. et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289, 179–186 (2003).This study represents a classic analysis of hospital-acquired pneumonia and influenza deaths that establishes the impact of seasonal influenza in the United States.

    PubMed  Google Scholar 

  27. Flannery, B. et al. Influenza vaccine effectiveness against pediatric deaths: 2010–2014. Pediatrics 139, https://doi.org/10.1542/peds.2016-4244 (2017).

  28. Thompson, W. W. et al. Influenza-associated hospitalizations in the United States. JAMA 292, 1333–1340 (2004).

    CAS  PubMed  Google Scholar 

  29. Walsh, E. E., Cox, C. & Falsey, A. R. Clinical features of influenza A virus infection in older hospitalized persons. J. Am. Geriatr. Soc. 50, 1498–1503 (2002).

    PubMed  Google Scholar 

  30. Jain, S. et al. Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. N. Engl. J. Med. 361, 1935–1944 (2009).

    CAS  PubMed  Google Scholar 

  31. Keren, R. et al. Neurological and neuromuscular disease as a risk factor for respiratory failure in children hospitalized with influenza infection. JAMA 294, 2188–2194 (2005).

    CAS  PubMed  Google Scholar 

  32. Neuzil, K. M., Reed, G. W., Mitchel, E. F., Simonsen, L. & Griffin, M. R. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am. J. Epidemiol. 148, 1094–1102 (1998).

    CAS  PubMed  Google Scholar 

  33. Van Kerkhove, M. D. et al. Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: a global pooled analysis. PLOS Med. 8, e1001053 (2011).

    Google Scholar 

  34. Karlsson, E. A. et al. A perfect storm: Increased colonization and failure of vaccination leads to severe secondary bacterial infection in influenza virus-infected obese mice. MBio 8, e00889-17 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ciancanelli, M. J. et al. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science 348, 448–453 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Everitt, A. R. et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484, 519–523 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Allen, E. K. et al. SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans. Nat. Med. 23, 975–983 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. van Gils, J. A. et al. Hampered foraging and migratory performance in swans infected with low-pathogenic avian influenza A virus. PLOS ONE 2, e184 (2007).

    Google Scholar 

  39. Guan, Y. & Smith, G. J. The emergence and diversification of panzootic H5N1 influenza viruses. Virus Res. 178, 35–43 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Ip, H. S. et al. Novel Eurasian highly pathogenic avian influenza A H5 viruses in wild birds, WA, USA, 2014. Emerg. Infect. Dis. 21, 886–890 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Ke, C. et al. Human infection with highly pathogenic avian influenza A(H7N9) virus. China. Emerg. Infect. Dis. 23, 1332–1340 (2017).

    CAS  PubMed  Google Scholar 

  42. Lee, C. T. et al. Outbreak of influenza A(H7N2) among cats in an animal shelter with cat-to-human transmission-New York City, 2016. Clin. Infect. Dis. 65, 1927–1929 (2017).

    PubMed  Google Scholar 

  43. Fouchier, R. A. et al. Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc. Natl Acad. Sci. USA 101, 1356–1361 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Perkins, L. E. & Swayne, D. E. Pathogenicity of a Hong Kong-origin H5N1 highly pathogenic avian influenza virus for emus, geese, ducks, and pigeons. Avian Dis. 46, 53–63 (2002).

    PubMed  Google Scholar 

  45. Hulse-Post, D. J. et al. Role of domestic ducks in the propagation and biological evolution of highly pathogenic H5N1 influenza viruses in Asia. Proc. Natl Acad. Sci. USA 102, 10682–10687 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Fournie, G. et al. Interventions for avian influenza A (H5N1) risk management in live bird market networks. Proc. Natl Acad. Sci. USA 110, 9177–9182 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Vincent, A. et al. Review of influenza A virus in swine worldwide: a call for increased surveillance and research. Zoonoses Publ. Health 61, 4–17 (2014).

    CAS  Google Scholar 

  48. Neumann, G. & Kawaoka, Y. The first influenza pandemic of the new millennium. Influenza Other Respir. Viruses 5, 157–166 (2011).

    PubMed  PubMed Central  Google Scholar 

  49. Jhung, M. A. et al. Outbreak of variant influenza A(H3N2) virus in the United States. Clin. Infect. Dis. 57, 1703–1712 (2013).

    CAS  PubMed  Google Scholar 

  50. Crawford, P. C. et al. Transmission of equine influenza virus to dogs. Science 310, 482–485 (2005).

    CAS  PubMed  Google Scholar 

  51. Li, S. et al. Avian-origin H3N2 canine influenza A viruses in Southern China. Infect. Genet. Evol. 10, 1286–1288 (2010).

    PubMed  PubMed Central  Google Scholar 

  52. Yamada, S. et al. Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature 444, 378–382 (2006).

    CAS  PubMed  Google Scholar 

  53. van Riel, D. et al. H5N1 virus attachment to lower respiratory tract. Science 312, 399 (2006).

    PubMed  Google Scholar 

  54. Hirst, G. K. Studies of antigenic differences among strains of influenza A by means of red cell agglutination. J. Exp. Med. 78, 407–423 (1943).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Barr, I. G. et al. WHO recommendations for the viruses used in the 2013–2014 Northern Hemisphere influenza vaccine: epidemiology, antigenic and genetic characteristics of influenza A(H1N1)pdm09, A(H3N2) and B influenza viruses collected from October 2012 to January 2013. Vaccine 32, 4713–4725 (2014).

    PubMed  Google Scholar 

  56. Sandbulte, M. R. et al. Discordant antigenic drift of neuraminidase and hemagglutinin in H1N1 and H3N2 influenza viruses. Proc. Natl Acad. Sci. USA 108, 20748–20753 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Kilbourne, E. D., Laver, W. G., Schulman, J. L. & Webster, R. G. Antiviral activity of antiserum specific for an influenza virus neuraminidase. J. Virol. 2, 281–288 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Couzens, L. et al. An optimized enzyme-linked lectin assay to measure influenza A virus neuraminidase inhibition antibody titers in human sera. J. Virol. Methods 210, 7–14 (2014).

    CAS  PubMed  Google Scholar 

  59. Voeten, J. T. et al. Antigenic drift in the influenza A virus (H3N2) nucleoprotein and escape from recognition by cytotoxic T lymphocytes. J. Virol. 74, 6800–6807 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Smith, D. J. et al. Mapping the antigenic and genetic evolution of influenza virus. Science 305, 371–376 (2004).This study describes the concept of antigenic cartography and uses antigenic cartography for the visualization and quantification of antigenic drift of human H3N2 influenza A viruses over 35 years.

    CAS  PubMed  Google Scholar 

  61. Koel, B. F. et al. Substitutions near the receptor binding site determine major antigenic change during influenza virus evolution. Science 342, 976–979 (2013).

    CAS  PubMed  Google Scholar 

  62. Koel, B. F. et al. Antigenic variation of clade 2.1 H5N1 virus is determined by a few amino acid substitutions immediately adjacent to the receptor binding site. MBio 5, e01070-01014 (2014).

    PubMed  PubMed Central  Google Scholar 

  63. Lewis, N. S. et al. Antigenic and genetic evolution of equine influenza A (H3N8) virus from 1968 to 2007. J. Virol. 85, 12742–12749 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. de Jong, J. C. et al. Antigenic and genetic evolution of swine influenza A (H3N2) viruses in Europe. J. Virol. 81, 4315–4322 (2007).

    PubMed  PubMed Central  Google Scholar 

  65. Kendal, A. P., Noble, G. R., Skehel, J. J. & Dowdle, W. R. Antigenic similarity of influenza A (H1N1) viruses from epidemics in 1977—1978 to “Scandinavian” strains isolated in epidemics of 1950–1951. Virology 89, 632–636 (1978).

    CAS  PubMed  Google Scholar 

  66. Herfst, S. et al. Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336, 1534–1541 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Imai, M. et al. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486, 420–428 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Russell, C. A. et al. The potential for respiratory droplet-transmissible A/H5N1 influenza virus to evolve in a mammalian host. Science 336, 1541–1547 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Yoon, S. W., Webby, R. J. & Webster, R. G. Evolution and ecology of influenza A viruses. Curr. Top. Microbiol. Immunol. 385, 359–375 (2014).

    PubMed  Google Scholar 

  70. Webster, R. G. & Hulse, D. J. Microbial adaptation and change: avian influenza. Rev. Sci. Tech. 23, 453–465 (2004).

    CAS  PubMed  Google Scholar 

  71. Andino, R. & Domingo, E. Viral quasispecies. Virology 479–480, 46–51 (2015).

    PubMed  Google Scholar 

  72. Tumpey, T. M. et al. A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science 315, 655–659 (2007). This study provides the first evidence that the receptor specificity of the HA of influenza A virus plays a major role in the respiratory transmission of these viruses.

    CAS  PubMed  Google Scholar 

  73. Mitnaul, L. J. et al. Balanced hemagglutinin and neuraminidase activities are critical for efficient replication of influenza A virus. J. Virol. 74, 6015–6020 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Reed, M. L. et al. The pH of activation of the hemagglutinin protein regulates H5N1 influenza virus pathogenicity and transmissibility in ducks. J. Virol. 84, 1527–1535 (2010).

    CAS  PubMed  Google Scholar 

  75. Hatta, M., Gao, P., Halfmann, P. & Kawaoka, Y. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293, 1840–1842 (2001).

    CAS  PubMed  Google Scholar 

  76. Mehle, A. & Doudna, J. A. Adaptive strategies of the influenza virus polymerase for replication in humans. Proc. Natl Acad. Sci. USA 106, 21312–21316 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Riegger, D. et al. The nucleoprotein of newly emerged H7N9 influenza A virus harbors a unique motif conferring resistance to antiviral human MxA. J. Virol. 89, 2241–2252 (2015).

    PubMed  Google Scholar 

  78. Campbell, P. J. et al. The M segment of the 2009 pandemic influenza virus confers increased neuraminidase activity, filamentous morphology, and efficient contact transmissibility to A/Puerto Rico/8/1934-based reassortant viruses. J. Virol. 88, 3802–3814 (2014).

    PubMed  PubMed Central  Google Scholar 

  79. Medina, R. A. & García-Sastre, A. Influenza A viruses: new research developments. Nat. Rev. Microbiol. 9, 590–603 (2011).

    CAS  PubMed  Google Scholar 

  80. Tong, S. et al. New world bats harbor diverse influenza A viruses. PLOS Pathog. 9, e1003657 (2013).

    Google Scholar 

  81. Moreira, E. A. et al. Synthetically derived bat influenza A-like viruses reveal a cell type- but not species-specific tropism. Proc. Natl Acad. Sci. USA 113, 12797–12802 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Mibayashi, M. et al. Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J. Virol. 81, 514–524 (2007).

    CAS  PubMed  Google Scholar 

  83. Pichlmair, A. et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314, 997–1001 (2006).

    CAS  PubMed  Google Scholar 

  84. Rajsbaum, R. et al. Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein. PLOS Pathog. 8, e1003059 (2012).

    Google Scholar 

  85. Nemeroff, M. E., Barabino, S. M., Li, Y., Keller, W. & Krug, R. M. Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3′end formation of cellular pre-mRNAs. Mol. Cell 1, 991–1000 (1998).

    CAS  PubMed  Google Scholar 

  86. Satterly, N. et al. Influenza virus targets the mRNA export machinery and the nuclear pore complex. Proc. Natl Acad. Sci. USA 104, 1853–1858 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Marazzi, I. et al. Suppression of the antiviral response by an influenza histone mimic. Nature 483, 428–433 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Chauche, C. et al. Mammalian adaptation of an avian influenza A virus involves stepwise changes in NS1. J. Virol. e01875-17 (2017).

  89. Li, S., Min, J. Y., Krug, R. M. & Sen, G. C. Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA. Virology 349, 13–21 (2006).

    CAS  PubMed  Google Scholar 

  90. Min, J. Y. & Krug, R. M. The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: Inhibiting the 2′-5′ oligo (A) synthetase/RNase L pathway. Proc. Natl Acad. Sci. USA 103, 7100–7105 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Conenello, G. M. & Palese, P. Influenza A virus PB1-F2: a small protein with a big punch. Cell Host Microbe 2, 207–209 (2007).

    CAS  PubMed  Google Scholar 

  92. Graef, K. M. et al. The PB2 subunit of the influenza virus RNA polymerase affects virulence by interacting with the mitochondrial antiviral signaling protein and inhibiting expression of beta interferon. J. Virol. 84, 8433–8445 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Jagger, B. W. et al. An overlapping protein-coding region in influenza A virus segment 3 modulates the host response. Science 337, 199–204 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Crotta, S. et al. Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia. PLOS Pathog. 9, e1003773 (2013).

    Google Scholar 

  95. Helft, J. et al. Cross-presenting CD103+ dendritic cells are protected from influenza virus infection. J. Clin. Invest. 122, 4037–4047 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhu, L. et al. High level of neutrophil extracellular traps correlates with poor prognosis of severe influenza A infection. J. Infect. Dis. 217, 428–437 (2018).

    CAS  PubMed  Google Scholar 

  97. Walsh, K. B. et al. Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus. Proc. Natl Acad. Sci. USA 108, 12018–12023 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Sridhar, S. et al. Cellular immune correlates of protection against symptomatic pandemic influenza. Nat. Med. 19, 1305–1312 (2013).

    CAS  PubMed  Google Scholar 

  99. Wilkinson, T. M. et al. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat. Med. 18, 274–280 (2012).

    CAS  PubMed  Google Scholar 

  100. Quinones-Parra, S. et al. Preexisting CD8+ T cell immunity to the H7N9 influenza A virus varies across ethnicities. Proc. Natl Acad. Sci. USA 111, 1049–1054 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Wang, Z. et al. Recovery from severe H7N9 disease is associated with diverse response mechanisms dominated by CD8+ T cells. Nat. Commun. 6, 6833 (2015).This manuscript provides evidence that early cross-reactive CD8 + T cell immunity plays an important part in recovery from severe avian influenza A H7N9 virus-induced disease.

    CAS  PubMed  Google Scholar 

  102. van de Sandt, C. E. et al. Human influenza A virus-specific CD8+ T cell response is long-lived. J. Infect. Dis. 212, 81–85 (2015).

    PubMed  PubMed Central  Google Scholar 

  103. Sun, J. C. & Bevan, M. J. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300, 339–342 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. McKinstry, K. K. et al. Memory CD4+ T cells protect against influenza through multiple synergizing mechanisms. J. Clin. Invest. 122, 2847–2856 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Deliyannis, G. et al. Intranasal lipopeptide primes lung-resident memory CD8+ T cells for long-term pulmonary protection against influenza. Eur. J. Immunol. 36, 770–778 (2006).

    CAS  PubMed  Google Scholar 

  106. Pejoski, D., Zeng, W., Rockman, S., Brown, L. E. & Jackson, D. C. A lipopeptide based on the M2 and HA proteins of influenza A viruses induces protective antibody. Immunol. Cell. Biol. 88, 605–611 (2010).

    CAS  PubMed  Google Scholar 

  107. McMichael, A. J., Gotch, F. M., Noble, G. R. & Beare, P. A. Cytotoxic T cell immunity to influenza. N. Engl. J. Med. 309, 13–17 (1983).

    CAS  PubMed  Google Scholar 

  108. Topham, D. J., Tripp, R. A. & Doherty, P. C. CD8+ T cells clear influenza virus by perforin or Fas-dependent processes. J. Immunol. 159, 5197–5200 (1997).

    CAS  PubMed  Google Scholar 

  109. Doherty, P. C., Turner, S. J., Webby, R. G. & Thomas, P. G. Influenza and the challenge for immunology. Nat. Immunol. 7, 449–455 (2006).

    CAS  PubMed  Google Scholar 

  110. Sridhar, S., Brokstad, K. A. & Cox, R. J. Influenza vaccination strategies: comparing inactivated and live attenuated influenza vaccines. Vaccines 3, 373–389 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Russ, B. E. et al. Distinct epigenetic signatures delineate transcriptional programs during virus-specific CD8+ T cell differentiation. Immunity 41, 853–865 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Valkenburg, S. A. et al. Early priming minimizes the age-related immune compromise of CD8+ T cell diversity and function. PLOS Pathog. 8, e1002544 (2012).

    Google Scholar 

  113. Smith, W., Andrewes, C. H. & Laidlaw, P. P. A virus obtained from influenza patients. Lancet 222, 66–68 (1933).This study describes the first isolation of influenza virus. Importantly, it includes proof of protection from influenza virus infection by passive transfer of antibodies in the ferret model of influenza.

    Google Scholar 

  114. Wrammert, J. et al. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature 453, 667–671 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Gerhard, W., Yewdell, J., Frankel, M. E. & Webster, R. Antigenic structure of influenza virus haemagglutinin defined by hybridoma antibodies. Nature 290, 713–717 (1981).

    CAS  PubMed  Google Scholar 

  116. Angeletti, D. et al. Defining B cell immunodominance to viruses. Nat. Immunol. 18, 456–463 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Andrews, S. F. et al. Immune history profoundly affects broadly protective B cell responses to influenza. Sci. Transl Med. 7, 316ra192 (2015).

    PubMed  PubMed Central  Google Scholar 

  118. Hobson, D., Curry, R. L., Beare, A. S. & Ward-Gardner, A. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J. Hyg. 70, 767–777 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Yu, X. et al. Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors. Nature 455, 532–536 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Novel Swine-Origin Influenza A Virus Investigation Team et al. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N. Engl. J. Med. 360, 2605–2615 (2009).

    Google Scholar 

  121. Manicassamy, B. et al. Protection of mice against lethal challenge with 2009 H1N1 influenza A virus by 1918-like and classical swine H1N1 based vaccines. PLOS Pathog. 6, e1000745 (2010).

    Google Scholar 

  122. Steens, A. et al. Age-dependent patterns of infection and severity explaining the low impact of 2009 influenza A (H1N1): evidence from serial serologic surveys in the Netherlands. Am. J. Epidemiol. 174, 1307–1315 (2011).

    PubMed  Google Scholar 

  123. Heaton, N. S., Sachs, D., Chen, C. J., Hai, R. & Palese, P. Genome-wide mutagenesis of influenza virus reveals unique plasticity of the hemagglutinin and NS1 proteins. Proc. Natl Acad. Sci. USA 110, 20248–20253 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Doud, M. B. & Bloom, J. D. Accurate measurement of the effects of all amino-acid mutations on influenza hemagglutinin. Viruses 8, 155 (2016).

    PubMed Central  Google Scholar 

  125. Monto, A. S., Malosh, R. E., Petrie, J. G. & Martin, E. T. The doctrine of original antigenic sin: separating good from evil. J. Infect. Dis. 215, 1782–1788 (2017).

    PubMed  PubMed Central  Google Scholar 

  126. Henry, C., Palm, A. E., Krammer, F. & Wilson, P. C. From original antigenic sin to the universal influenza virus vaccine. Trends Immunol. 39, 70–79 (2017).

    PubMed  PubMed Central  Google Scholar 

  127. Linderman, S. L. et al. Potential antigenic explanation for atypical H1N1 infections among middle-aged adults during the 2013–2014 influenza season. Proc. Natl Acad. Sci. USA 111, 15798–15803 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Li, Y. et al. Immune history shapes specificity of pandemic H1N1 influenza antibody responses. J. Exp. Med. 210, 1493–1500 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Krammer, F. & Palese, P. Influenza virus hemagglutinin stalk-based antibodies and vaccines. Curr. Opin. Virol. 3, 521–530 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Ekiert, D. C. & Wilson, I. A. Broadly neutralizing antibodies against influenza virus and prospects for universal therapies. Curr. Opin. Virol. 2, 134–141 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Neirynck, S. et al. A universal influenza A vaccine based on the extracellular domain of the M2 protein. Nat. Med. 5, 1157–1163 (1999).

    CAS  PubMed  Google Scholar 

  132. Wohlbold, T. J. et al. Broadly protective murine monoclonal antibodies against influenza B virus target highly conserved neuraminidase epitopes. Nat. Microbiol. 2, 1415–1424 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Wan, H. et al. Molecular basis for broad neuraminidase immunity: conserved epitopes in seasonal and pandemic H1N1 as well as H5N1 influenza viruses. J. Virol. 87, 9290–9300 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Rajendran, M. et al. Analysis of anti-influenza virus neuraminidase antibodies in children, adults, and the elderly by ELISA and enzyme inhibition: evidence for original antigenic sin. MBio 8, https://doi.org/10.1128/mBio.02281-16 (2017).

  135. Wohlbold, T. J. & Krammer, F. In the shadow of hemagglutinin: a growing interest in influenza viral neuraminidase and its role as a vaccine antigen. Viruses 6, 2465–2494 (2014).

    PubMed  PubMed Central  Google Scholar 

  136. DiLillo, D. J., Palese, P., Wilson, P. C. & Ravetch, J. V. Broadly neutralizing anti-influenza antibodies require Fc receptor engagement for in vivo protection. J. Clin. Invest. 126, 605–610 (2016). This study demonstrates that immune responses induced against the conserved influenza virus HA stalk domain include broadly protective antibodies that activate effector cells via Fc–FcR interactions.

    PubMed  PubMed Central  Google Scholar 

  137. Jegaskanda, S. et al. Cross-reactive influenza-specific antibody-dependent cellular cytotoxicity antibodies in the absence of neutralizing antibodies. J. Immunol. 190, 1837–1848 (2013).

    CAS  PubMed  Google Scholar 

  138. Jegaskanda, S., Weinfurter, J. T., Friedrich, T. C. & Kent, S. J. Antibody-dependent cellular cytotoxicity is associated with control of pandemic H1N1 influenza virus infection of macaques. J. Virol. 87, 5512–5522 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Seibert, C. W. et al. Recombinant IgA is sufficient to prevent influenza virus transmission in guinea pigs. J. Virol. 87, 7793–7804 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Lowen, A. C. et al. Blocking interhost transmission of influenza virus by vaccination in the guinea pig model. J. Virol. 83, 2803–2818 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Ohmit, S. E. & Monto, A. S. Symptomatic predictors of influenza virus positivity in children during the influenza season. Clin. Infect. Dis. 43, 564–568 (2006).

    PubMed  Google Scholar 

  142. Kumar, S. & Henrickson, K. J. Update on influenza diagnostics: lessons from the novel H1N1 influenza A pandemic. Clin. Microbiol. Rev. 25, 344–361 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Petric, M., Comanor, L. & Petti, C. A. Role of the laboratory in diagnosis of influenza during seasonal epidemics and potential pandemics. J. Infect. Dis. 194 (Suppl. 2), S98–S110, https://doi.org/10.1086/507554 (2006).

    PubMed  Google Scholar 

  144. Newton, D. W., Treanor, J. J. & Menegus, M. A. Clinical and laboratory diagnosis of influenza virus infections. Am. J. Manag. Care 6, S265–S275 (2000).

    CAS  PubMed  Google Scholar 

  145. Dunn, J. J., Woolstenhulme, R. D., Langer, J. & Carroll, K. C. Sensitivity of respiratory virus culture when screening with R-mix fresh cells. J. Clin. Microbiol. 42, 79–82 (2004).

    PubMed  PubMed Central  Google Scholar 

  146. Nie, S. et al. Evaluation of Alere i Influenza A&B for rapid detection of influenza viruses A and B. J. Clin. Microbiol. 52, 3339–3344 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Merckx, J. et al. Diagnostic accuracy of novel and traditional rapid tests for influenza infection compared with reverse transcriptase polymerase chain reaction: A systematic review and meta-analysis. Ann. Intern. Med. 167, 394–409 (2017).

    PubMed  Google Scholar 

  148. Bhattacharya, S. et al. Transcriptomic biomarkers to discriminate bacterial from nonbacterial infection in adults hospitalized with respiratory illness. Sci. Rep. 7, 6548 (2017).

    PubMed  PubMed Central  Google Scholar 

  149. Salk, J. E. & Suriano, P. C. Importance of antigenic composition of influenza virus vaccine in protecting against the natural disease; observations during the winter of 1947–1948. Am. J. Publ. Health Nat. Health 39, 345–355 (1949).

    CAS  Google Scholar 

  150. Plotkin, S. A., Orenstein, W. & Offit, P. (eds), Vaccines 6th edn (Saunders, 2012)

  151. Rudenko, L., Yeolekar, L., Kiseleva, I. & Isakova-Sivak, I. Development and approval of live attenuated influenza vaccines based on Russian master donor viruses: Process challenges and success stories. Vaccine 34, 5436–5441 (2016).

    PubMed  PubMed Central  Google Scholar 

  152. Caspard, H., Mallory, R. M., Yu, J. & Ambrose, C. S. Live-attenuated influenza vaccine effectiveness in children from 2009 to 2015-2016: A systematic review and meta-analysis. Open Forum Infect. Dis. 4, ofx111 (2017).

    PubMed  PubMed Central  Google Scholar 

  153. Manini, I. et al. Egg-independent influenza vaccines and vaccine candidates. Vaccines 5, 18 (2017).

    PubMed Central  Google Scholar 

  154. Centers for Disease Control and Prevention. Flublok seasonal influenza (flu) vaccine. CDC https://www.cdc.gov/flu/protect/vaccine/qa_flublok-vaccine.htm (2017).

  155. Clark, T. W. et al. Trial of 2009 influenza A (H1N1) monovalent MF59-adjuvanted vaccine. N. Engl. J. Med. 361, 2424–2435 (2009).

    CAS  PubMed  Google Scholar 

  156. Nohynek, H. et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLOS ONE 7, e33536 (2012).

    Google Scholar 

  157. DiazGranados, C. A. et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N. Engl. J. Med. 371, 635–645 (2014).

    PubMed  Google Scholar 

  158. Enami, M., Luytjes, W., Krystal, M. & Palese, P. Introduction of site-specific mutations into the genome of influenza virus. Proc. Natl Acad. Sci. USA 87, 3802–3805 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Krammer, F. & Palese, P. Advances in the development of influenza virus vaccines. Nat. Rev. Drug Discov. 14, 167–182 (2015).

    CAS  PubMed  Google Scholar 

  160. Paules, C. I., Marston, H. D., Eisinger, R. W., Baltimore, D. & Fauci, A. S. The pathway to a universal influenza vaccine. Immunity 47, 599–603 (2017).

    CAS  PubMed  Google Scholar 

  161. Committee On Infectious Diseases. Recommendations for prevention and control of influenza in children, 2017–2018. Pediatrics 140, e20172550 (2017).

    Google Scholar 

  162. Palese, P. & Wang, T. T. H5N1 influenza viruses: facts, not fear. Proc. Natl Acad. Sci. USA 109, 2211–2213 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Gomaa, M. R. et al. Avian influenza A(H5N1) and A(H9N2) seroprevalence and risk factors for infection among Egyptians: a prospective, controlled seroepidemiological study. J. Infect. Dis. 211, 1399–1407 (2015).

    PubMed  Google Scholar 

  164. Wang, T. T., Parides, M. K. & Palese, P. Seroevidence for H5N1 influenza infections in humans: meta-analysis. Science 335, 1463 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Varble, A. et al. Influenza A virus transmission bottlenecks are defined by infection route and recipient host. Cell Host Microbe 16, 691–700 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Sobel Leonard, A., Weissman, D. B., Greenbaum, B., Ghedin, E. & Koelle, K. Transmission bottleneck size estimation from pathogen deep-sequencing data, with an application to human influenza A virus. J. Virol. 91, e00171-17 (2017).

    PubMed  PubMed Central  Google Scholar 

  167. Osterholm, M. T., Kelley, N. S., Sommer, A. & Belongia, E. A. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect. Dis. 12, 36–44 (2012).

    PubMed  Google Scholar 

  168. DiazGranados, C. A., Denis, M. & Plotkin, S. Seasonal influenza vaccine efficacy and its determinants in children and non-elderly adults: a systematic review with meta-analyses of controlled trials. Vaccine 31, 49–57 (2012).

    PubMed  Google Scholar 

  169. Beyer, W. E. et al. Reply: Letter to the editor, Cochrane rearranged. Vaccine 33, 13–14 (2015).

    CAS  PubMed  Google Scholar 

  170. Centers for Disease Control and Prevention. ACIP votes down use of LAIV for 2016–2017 flu season. CDC https://www.cdc.gov/media/releases/2016/s0622-laiv-flu.html (2016).

  171. Saito, N. et al. Negative impact of prior influenza vaccination on current influenza vaccination among people infected and not infected in prior season: a test-negative case-control study in Japan. Vaccine 35, 687–693 (2017).

    PubMed  Google Scholar 

  172. Paules, C. I., Sullivan, S. G., Subbarao, K. & Fauci, A. S. Chasing seasonal influenza - the need for a universal influenza vaccine. N. Engl. J. Med. 378, 7–9 (2018).

    PubMed  Google Scholar 

  173. Hata, A., Akashi-Ueda, R., Takamatsu, K. & Matsumura, T. Safety and efficacy of peramivir for influenza treatment. Drug. Des. Dev. Ther. 8, 2017–2038 (2014).

    Google Scholar 

  174. McKimm-Breschkin, J. L. Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance. Influenza Other Respir. Viruses 7 (Suppl. 1), 25–36 (2013).

    CAS  PubMed  Google Scholar 

  175. Okoli, G. N., Otete, H. E., Beck, C. R. & Nguyen-Van-Tam, J. S. Use of neuraminidase inhibitors for rapid containment of influenza: a systematic review and meta-analysis of individual and household transmission studies. PLOS ONE 9, e113633 (2014).

    Google Scholar 

  176. Muthuri, S. G. et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir. Med. 2, 395–404 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Dobson, J., Whitley, R. J., Pocock, S. & Monto, A. S. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Lancet 385, 1729–1737 (2015).

    CAS  PubMed  Google Scholar 

  178. Venkatesan, S. et al. Impact of outpatient neuraminidase inhibitor treatment in patients infected with influenza A(H1N1)pdm09 at high risk of hospitalization: an individual participant data metaanalysis. Clin. Infect. Dis. 64, 1328–1334 (2017).

    CAS  PubMed  Google Scholar 

  179. Deyde, V. M. et al. Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J. Infect. Dis. 196, 249–257 (2007).

    CAS  PubMed  Google Scholar 

  180. Gubareva, L. V. et al. Comprehensive assessment of 2009 pandemic influenza A (H1N1) virus drug susceptibility in vitro. Antivir. Ther 15, 1151–1159 (2010).

    CAS  PubMed  Google Scholar 

  181. Meijer, A. et al. Oseltamivir-resistant influenza virus A (H1N1), Europe, 2007–2008 season. Emerg. Infect. Dis. 15, 552–560 (2009).

    PubMed  PubMed Central  Google Scholar 

  182. Bloom, J. D., Gong, L. I. & Baltimore, D. Permissive secondary mutations enable the evolution of influenza oseltamivir resistance. Science 328, 1272–1275.

  183. Abed, Y., Pizzorno, A., Bouhy, X. & Boivin, G. Role of permissive neuraminidase mutations in influenza A/Brisbane/59/2007-like (H1N1) viruses. PLOS Pathog. 7, e1002431 (2011).

    Google Scholar 

  184. Okomo-Adhiambo, M. et al. Oseltamivir-resistant influenza A(H1N1)pdm09 viruses, United States, 2013–2014. Emerg. Infect. Dis. 21, 136–141 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Operario, D. J., Moser, M. J. & St George, K. Highly sensitive and quantitative detection of the H274Y oseltamivir resistance mutation in seasonal A/H1N1 influenza virus. J. Clin. Microbiol. 48, 3517–3524 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Memoli, M. J., Hrabal, R. J., Hassantoufighi, A., Eichelberger, M. C. & Taubenberger, J. K. Rapid selection of oseltamivir- and peramivir-resistant pandemic H1N1 virus during therapy in 2 immunocompromised hosts. Clin. Infect. Dis. 50, 1252–1255 (2010).

    CAS  PubMed  Google Scholar 

  187. Whitley, R. J. et al. Global assessment of resistance to neuraminidase inhibitors, 2008-2011: the Influenza Resistance Information Study (IRIS). Clin. Infect. Dis. 56, 1197–1205 (2013).

    CAS  PubMed  Google Scholar 

  188. Butler, J. et al. Estimating the fitness advantage conferred by permissive neuraminidase mutations in recent oseltamivir-resistant A(H1N1)pdm09 influenza viruses. PLOS Pathog. 10, e1004065 (2014).

    Google Scholar 

  189. Meijer, A. et al. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2012–2013. Antiviral Res. 110, 31–41 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Yamashita, M. Laninamivir and its prodrug, CS-8958: long-acting neuraminidase inhibitors for the treatment of influenza. Antivir. Chem. Chemother. 21, 71–84 (2010).

    CAS  PubMed  Google Scholar 

  191. Furuta, Y. et al. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 100, 446–454 (2013).

    CAS  PubMed  Google Scholar 

  192. Clark, M. P. et al. Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2. J. Med. Chem. 57, 6668–6678 (2014).

    CAS  PubMed  Google Scholar 

  193. Portsmouth, S., Kawaguchi, K., Arai, M., Tsuchiya, K. & Uehara, T. Cap-dependent endonuclease inhibitor S-033188 for the treatment of influenza: results from a phase 3, randomized, double-blind, placebo- and active-controlled study in otherwise healthy adolescents and adults with seasonal influenza. Open Forum Infect. Dis. 4, S744 (2017). This paper reports clinical trial results of baloxavir marboxil, a new influenza drug approved in Japan in 2018.

    Google Scholar 

  194. Haffizulla, J. et al. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect. Dis. 14, 609–618 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Beigel, J. H. et al. Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study. Lancet Respir. Med. 5, 500–511 (2017).

    PubMed  PubMed Central  Google Scholar 

  196. Hung, I. F. N. et al. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest 144, 464–473 (2013).

    PubMed  Google Scholar 

  197. Koszalka, P., Tilmanis, D. & Hurt, A. C. Influenza antivirals currently in late-phase clinical trial. Influenza Other Respir. Viruses 11, 240–246 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Torner, N. et al. Effectiveness of non-pharmaceutical measures in preventing pediatric influenza: a case-control study. BMC Publ. Health 15, 543 (2015).

    Google Scholar 

  199. Halloran, M. E. et al. Modeling targeted layered containment of an influenza pandemic in the United States. Proc. Natl Acad. Sci. USA 105, 4639–4644 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Fiore, A. E. et al. Antiviral agents for the treatment and chemoprophylaxis of influenza — recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm. Rep. 60, 1–24 (2011).

    PubMed  Google Scholar 

  201. Uyeki, T. Antiviral treatment for patients hospitalized with 2009 pandemic influenza A (H1N1). N. Engl. J. Med. 361, e110 (2009).

    Google Scholar 

  202. Stewart, R. J. et al. Influenza antiviral prescribing for outpatients with an acute respiratory illness and at high risk for influenza-associated complications during 5 influenza seasons-United States, 2011–2016. Clin. Infect. Dis. 66, 1035–1041 (2018).

    PubMed  Google Scholar 

  203. Oboho, I. K. et al. Oseltamivir use among children and adults hospitalized with community-acquired pneumonia. Open Forum Infect. Dis. 4, ofw254 (2017).

    PubMed  Google Scholar 

  204. Coleman, B. L. et al. Pre-and post-pandemic trends in antiviral use in hospitalized patients with laboratory-confirmed influenza: 2004/05-2013/14, Toronto, Canada. Antiviral Res. 140, 158–163 (2017).

    CAS  PubMed  Google Scholar 

  205. Hung, I. F. N. et al. Efficacy of clarithromycin-naproxen-oseltamivir combination in the treatment of patients hospitalized for influenza A(H3N2) infection: an open-label randomized, controlled, phase IIb/III trial. Chest 151, 1069–1080 (2017).

    PubMed  Google Scholar 

  206. Sims, L. D. Intervention strategies to reduce the risk of zoonotic infection with avian influenza viruses: scientific basis, challenges and knowledge gaps. Influenza Other Respir. Viruses 7 (Suppl. 2), 15–25 (2013).

    PubMed  PubMed Central  Google Scholar 

  207. Domenech, J. et al. Experiences with vaccination in countries endemically infected with highly pathogenic avian influenza: the Food and Agriculture Organization perspective. Rev. Sci. Tech. 28, 293–305 (2009).

    CAS  PubMed  Google Scholar 

  208. Ellis, T. M. et al. Use of avian influenza vaccination in Hong Kong. Dev. Biol. 124, 133–143 (2006).

    CAS  Google Scholar 

  209. Leung, Y. H. et al. Avian influenza and ban on overnight poultry storage in live poultry markets, Hong Kong. Emerg. Infect. Dis. 18, 1339–1341 (2012).

    PubMed  PubMed Central  Google Scholar 

  210. Lau, E. H. et al. Effect of interventions on influenza A (H9N2) isolation in Hong Kong’s live poultry markets, 1999–2005. Emerg. Infect. Dis. 13, 1340–1347 (2007).

    PubMed  Google Scholar 

  211. Bao, C. J. et al. Live-animal markets and influenza A (H7N9) virus infection. N. Engl. J. Med. 368, 2337–2339 (2013).

    CAS  PubMed  Google Scholar 

  212. Chambers, T. M., Dubovi, E. J. & Donis, R. O. in Textbook of Influenza 2nd edn (eds Webster, R. G., Monto, A. S., Braciale, T. J. & Lamb, R. A.) (Blackwell Science, Oxford, 2013).

  213. Nichol, K. L., D’Heilly, S. J., Greenberg, M. E. & Ehlinger, E. Burden of influenza-like illness and effectiveness of influenza vaccination among working adults aged 50–64 years. Clin. Infect. Dis. 48, 292–298 (2009).

    PubMed  Google Scholar 

  214. Gozalo, P. L., Pop-Vicas, A., Feng, Z., Gravenstein, S. & Mor, V. Effect of influenza on functional decline. J. Am. Geriatr. Soc. 60, 1260–1267 (2012).

    PubMed  PubMed Central  Google Scholar 

  215. Molinari, N. A. et al. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine 25, 5086–5096 (2007).

    PubMed  Google Scholar 

  216. Rello, J. & Pop-Vicas, A. Clinical review: primary influenza viral pneumonia. Crit. Care 13, 235 (2009).

    PubMed  PubMed Central  Google Scholar 

  217. Morens, D. M., Taubenberger, J. K. & Fauci, A. S. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J. Infect. Dis. 198, 962–970 (2008).

    PubMed  Google Scholar 

  218. Chien, Y. W., Klugman, K. P. & Morens, D. M. Bacterial pathogens and death during the 1918 influenza pandemic. N. Engl. J. Med. 361, 2582–2583 (2009).

    PubMed  Google Scholar 

  219. Morris, D. E., Cleary, D. W. & Clarke, S. C. Secondary bacterial infections associated with influenza pandemics. Front. Microbiol. 8, 1041 (2017).

    PubMed  PubMed Central  Google Scholar 

  220. Taubenberger, J. K. & Morens, D. M. The pathology of influenza virus infections. Annu. Rev. Pathol. 3, 499–522 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Agyeman, P., Duppenthaler, A., Heininger, U. & Aebi, C. Influenza-associated myositis in children. Infection 32, 199–203 (2004).

    CAS  PubMed  Google Scholar 

  222. MacDonald, K. L. et al. Toxic shock syndrome. A newly recognized complication of influenza and influenzalike illness. JAMA 257, 1053–1058 (1987).

    CAS  PubMed  Google Scholar 

  223. Steininger, C. et al. Acute encephalopathy associated with influenza A virus infection. Clin. Infect. Dis. 36, 567–574 (2003).

    PubMed  Google Scholar 

  224. Dourmashkin, R. R. What caused the 1918–1930 epidemic of encephalitis lethargica? J. R. Soc. Med. 90, 515–520 (1997).

    CAS  Google Scholar 

  225. Zost, S. J. et al. Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains. Proc. Natl Acad. Sci. USA 114, 12578–12583 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Hayden, F. G. Experimental human influenza: observations from studies of influenza antivirals. Antivir. Ther. 17, 133–141 (2012).

    CAS  PubMed  Google Scholar 

  227. Erbelding, E. J. et al. A universal influenza vaccine: the strategic plan for the National Institute of Allergy and Infectious Diseases. J. Infect. Dis. https://doi.org/10.1093/infdis/jiy103 (2018).

  228. Freidl, G. S. et al. Influenza at the animal-human interface: a review of the literature for virological evidence of human infection with swine or avian influenza viruses other than A(H5N1). Euro Surveill. 19 https://www.eurosurveillance.org/images/dynamic/EE/V19N18/art20793.pdf (2014).

  229. Abdelwhab el, S. M., Veits, J. & Mettenleiter, T. C. Genetic changes that accompanied shifts of low pathogenic avian influenza viruses toward higher pathogenicity in poultry. Virulence 4, 441–452 (2013).

    Google Scholar 

  230. World Health Organization. Cumulative number of confirmed human cases for avian influenza A(H5N1) reported to WHO, 2003–2017. WHO http://www.who.int/influenza/human_animal_interface/2017_12_07_tableH5N1.pdf (2017).

  231. Pantin-Jackwood, M. J. et al. Role of poultry in the spread of novel H7N9 influenza virus in China. J. Virol. 88, 5381–5390 (2014).

    PubMed  PubMed Central  Google Scholar 

  232. World Health Organization. Human infection with avian influenza A(H7N9) virus – China. WHO http://www.who.int/csr/don/26-october-2017-ah7n9-china/en/ (2017).

  233. Imai, M. et al. A highly pathogenic avian H7N9 influenza virus isolated from A human is lethal in some ferrets infected via respiratory droplets. Cell Host Microbe 22, 615–626 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Li, C. et al. Evolution of H9N2 influenza viruses from domestic poultry in Mainland China. Virology 340, 70–83 (2005).

    CAS  PubMed  Google Scholar 

  235. Lam, T. T. et al. The genesis and source of the H7N9 influenza viruses causing human infections in China. Nature 502, 241–244 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Palese, P., Tumpey, T. M. & García-Sastre, A. What can we learn from reconstructing the extinct 1918 pandemic influenza virus? Immunity 24, 121–124 (2006).

    CAS  PubMed  Google Scholar 

  237. Matthey, S. et al. Rapid detection of respiratory viruses by shell vial culture and direct staining by using pooled and individual monoclonal antibodies. J. Clin. Microbiol. 30, 540–544 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Loeffelholz, M. J. et al. Comparison of the FilmArray Respiratory Panel and Prodesse real-time PCR assays for detection of respiratory pathogens. J. Clin. Microbiol. 49, 4083–4088 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Teo, J. et al. VereFlu: an integrated multiplex RT-PCR and microarray assay for rapid detection and identification of human influenza A and B viruses using lab-on-chip technology. Arch. Virol. 156, 1371–1378 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. Kim, D. K. & Poudel, B. Tools to detect influenza virus. Yonsei Med. J. 54, 560–566 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Hurt, A. C., Alexander, R., Hibbert, J., Deed, N. & Barr, I. G. Performance of six influenza rapid tests in detecting human influenza in clinical specimens. J. Clin. Virol. 39, 132–135 (2007).

    CAS  PubMed  Google Scholar 

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Acknowledgements

All authors are part of the NIAID-funded Centers of Excellence for Influenza Research and Surveillance (CEIRS) network.

Reviewer information

Nature Reviews Disease Primers thanks R.W. Compans, F. Hayden, H. Kida, H.-D. Klenk, A. Osterhaus and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Authors and Affiliations

  1. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Florian Krammer, Peter Palese, Megan L. Shaw & Adolfo García-Sastre

  2. Duke–NUS Medical School, Singapore, Singapore

    Gavin J. D. Smith

  3. Duke Global Health Institute, Duke University, Durham, NC, USA

    Gavin J. D. Smith

  4. Department of Viroscience, Erasmus MC, Rotterdam, Netherlands

    Ron A. M. Fouchier

  5. WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China

    Malik Peiris

  6. Center of Influenza Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China

    Malik Peiris

  7. Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia

    Katherine Kedzierska & Peter C. Doherty

  8. Department of Immunology, St Jude Children’s Research Hospital, Memphis, TN, USA

    Peter C. Doherty

  9. Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Peter Palese & Adolfo García-Sastre

  10. Division of Infectious Diseases, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    John Treanor

  11. Department of Infectious Diseases, St Jude Children’s Research Hospital, Memphis, TN, USA

    Robert G. Webster

  12. Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Adolfo García-Sastre

Authors
  1. Florian Krammer
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  2. Gavin J. D. Smith
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  3. Ron A. M. Fouchier
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  4. Malik Peiris
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  5. Katherine Kedzierska
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  6. Peter C. Doherty
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  7. Peter Palese
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  8. Megan L. Shaw
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  9. John Treanor
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  10. Robert G. Webster
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  11. Adolfo García-Sastre
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Contributions

Introduction (A.G.-S.); Epidemiology (G.J.D.S.); Mechanisms/pathophysiology (A.G.-S., R.A.M.F., M.P., F.K., K.K. and P.C.D.); Diagnosis, screening and prevention (P.P. and M.L.S.); Management (J.T. and R.G.W.); Quality of life (J.T.); Outlook (A.G.-S.); Overview of the Primer (A.G.-S.).

Corresponding author

Correspondence to Adolfo García-Sastre.

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Competing interests

F.K., P.P., A.G.-S. and R.G.W. are inventors of influenza vaccine technologies owned by the Icahn School of Medicine at Mount Sinai, New York, USA. All other authors declare no competing interests.

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Krammer, F., Smith, G.J.D., Fouchier, R.A.M. et al. Influenza. Nat Rev Dis Primers 4, 3 (2018). https://doi.org/10.1038/s41572-018-0002-y

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  • DOI: https://doi.org/10.1038/s41572-018-0002-y

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