Review Article | Published:

Emergence and pandemic potential of swine-origin H1N1 influenza virus

Nature volume 459, pages 931939 (18 June 2009) | Download Citation


Influenza viruses cause annual epidemics and occasional pandemics that have claimed the lives of millions. The emergence of new strains will continue to pose challenges to public health and the scientific communities. A prime example is the recent emergence of swine-origin H1N1 viruses that have transmitted to and spread among humans, resulting in outbreaks internationally. Efforts to control these outbreaks and real-time monitoring of the evolution of this virus should provide us with invaluable information to direct infectious disease control programmes and to improve understanding of the factors that determine viral pathogenicity and/or transmissibility.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445, 319–323 (2007)

  2. 2.

    , & 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)

  3. 3.

    , , , & Initial genetic characterization of the 1918 “Spanish” influenza virus. Science 275, 1793–1796 (1997)This is an important paper that describes the deciphering of the genomic sequence of the 1918 pandemic influenza virus.

  4. 4.

    , , & Origin and evolution of the 1918 “Spanish” influenza virus hemagglutinin gene. Proc. Natl Acad. Sci. USA 96, 1651–1656 (1999)

  5. 5.

    et al. Generation of influenza A viruses entirely from cloned cDNA. Proc. Natl Acad. Sci. USA 96, 9345–9350 (1999)This paper describes the artificial generation of influenza viruses, a breakthrough technology that allows the molecular characterization of influenza viruses and the generation of influenza virus vaccines.

  6. 6.

    et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 310, 77–80 (2005)This is a pivotal paper that describes the re-creation of the 1918 pandemic influenza virus.

  7. 7.

    et al. Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature 443, 578–581 (2006)

  8. 8.

    et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nature Med. 12, 1203–1207 (2006)This important paper describes high levels of cytokines in humans infected with highly pathogenic avian H5N1 viruses.

  9. 9.

    et al. Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus. Nature 431, 703–707 (2004)

  10. 10.

    et al. Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus. Proc. Natl Acad. Sci. USA 99, 13849–13854 (2002)

  11. 11.

    et al. Pathogenicity and immunogenicity of influenza viruses with genes from the 1918 pandemic virus. Proc. Natl Acad. Sci. USA 101, 3166–3171 (2004)

  12. 12.

    et al. Viral RNA polymerase complex promotes optimal growth of 1918 virus in the lower respiratory tract of ferrets. Proc. Natl Acad. Sci. USA 106, 588–592 (2009)

  13. 13.

    et al. Human HA and polymerase subunit PB2 proteins confer transmission of an avian influenza virus through the air. Proc. Natl Acad. Sci. USA 106, 3366–3371 (2009)

  14. 14.

    et al. Cellular transcriptional profiling in influenza A virus-infected lung epithelial cells: the role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza. Proc. Natl Acad. Sci. USA 99, 10736–10741 (2002)

  15. 15.

    et al. Expression of the 1918 influenza A virus PB1–F2 enhances the pathogenesis of viral and secondary bacterial pneumonia. Cell Host Microbe 2, 240–249 (2007)

  16. 16.

    , & Recent human influenza A (H1N1) viruses are closely related genetically to strains isolated in 1950. Nature 274, 334–339 (1978).This paper established that the Russian influenza in 1977 was genetically closely related to viruses circulating in humans in the 1950s.

  17. 17.

    et al. Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 279, 393–396 (1998)

  18. 18.

    et al. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet 351, 472–477 (1998)

  19. 19.

    et al. Emergence and predominance of an H5N1 influenza variant in China. Proc. Natl Acad. Sci. USA 103, 16936–16941 (2006)

  20. 20.

    et al. Establishment of multiple sublineages of H5N1 influenza virus in Asia: Implications for pandemic control. Proc. Natl. Acad. Sci. USA 103, 2845–2850 (2006)

  21. 21.

    et al. Emergence of multiple genotypes of H5N1 avian influenza viruses in Hong Kong SAR. Proc. Natl Acad. Sci. USA 99, 8950–8955 (2002)

  22. 22.

    et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature 430, 209–213 (2004)This paper describes the frequent reassortment events of highly pathogenic avian H5N1 viruses that led to the emergence of the dominant ‘genotype Z’.

  23. 23.

    et al. Avian flu: multiple introductions of H5N1 in Nigeria. Nature 442, 37 (2006)

  24. 24.

    et al. Avian influenza A (H5N1) in 10 patients in Vietnam. N. Engl. J. Med. 350, 1179–1188 (2004)

  25. 25.

    Avian influenza A (H5N1) infection in humans. N. Engl. J. Med. 353, 1374–1385 (2005)

  26. 26.

    et al. Human disease from influenza A (H5N1), Thailand, 2004. Emerg. Infect. Dis. 11, 201–209 (2005)

  27. 27.

    et al. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet 363, 617–619 (2004).This paper describes the re-emergence of human infections with highly pathogenic avian H5N1 viruses in 2003, and also emphasises the high concentrations of cytokines found in infected individuals.

  28. 28.

    et al. Pathology of fatal human infection associated with avian influenza A H5N1 virus. J. Med. Virol. 63, 242–246 (2001)

  29. 29.

    et al. Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir. Res. 6, 135 (2005)

  30. 30.

    et al. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 360, 1831–1837 (2002)

  31. 31.

    et al. Pandemic potential of a strain of influenza A (H1N1): early findings. Science 10.1126/science.1176062 (in the press)

  32. 32.

    Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N. Engl. J Med. 10.1056/NEJMoa0903810 (in the press)This highly important paper presents the first summary of epidemiological and virological data on the new swine-origin H1N1 viruses.

  33. 33.

    & Receptor determinants of human and animal influenza virus isolates: differences in receptor specificity of the H3 hemagglutinin based on species of origin. Virology 127, 361–373 (1983)This paper establishes differences between human and avian influenza viruses in receptor-binding specificity.

  34. 34.

    et al. Molecular basis for the generation in pigs of influenza A viruses with pandemic potential. J. Virol. 72, 7367–7373 (1998)

  35. 35.

    , , & The surface glycoproteins of H5 influenza viruses isolated from humans, chickens, and wild aquatic birds have distinguishable properties. J. Virol. 73, 1146–1155 (1999)

  36. 36.

    et al. Avian flu: influenza virus receptors in the human airway. Nature 440, 435–436 (2006)

  37. 37.

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

  38. 38.

    et al. Tropism of avian influenza A (H5N1) in the upper and lower respiratory tract. Nature Med. 13, 147–149 (2007)

  39. 39.

    et al. Structure of the uncleaved human H1 hemagglutinin from the extinct 1918 influenza virus. Science 303, 1866–1870 (2004)

  40. 40.

    et al. A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science 315, 655–659 (2007)

  41. 41.

    et al. Evolution of the receptor binding phenotype of influenza A (H5) viruses. Virology 344, 432–438 (2006)

  42. 42.

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

  43. 43.

    et al. An avian influenza H5N1 virus that binds to a human-type receptor. J. Virol. 81, 9950–9955 (2007)

  44. 44.

    et al. Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 312, 404–410 (2006)

  45. 45.

    & Sequence requirements for cleavage activation of influenza virus hemagglutinin expressed in mammalian cells. Proc. Natl Acad. Sci. USA 85, 324–328 (1988)

  46. 46.

    , & A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J. Virol. 67, 1761–1764 (1993)

  47. 47.

    , , & Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293, 1840–1842 (2001)

  48. 48.

    & An inhibitory activity in human cells restricts the function of an avian-like influenza virus polymerase. Cell Host Microbe 4, 111–122 (2008)

  49. 49.

    , , , & Avian influenza A virus polymerase association with nucleoprotein, but not polymerase assembly, is impaired in human cells during the course of infection. J. Virol. 83, 1320–1331 (2009)

  50. 50.

    et al. Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice. PLoS Pathog. 3, e133 (2007)

  51. 51.

    , & Residue 627 of PB2 is a determinant of cold sensitivity in RNA replication of avian influenza viruses. J. Virol. 75, 5398–5404 (2001)

  52. 52.

    , , & Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E/701N. PLoS Pathog. 5, e1000252 (2009)

  53. 53.

    et al. Molecular basis of replication of duck H5N1 influenza viruses in a mammalian mouse model. J. Virol. 79, 12058–12064 (2005)

  54. 54.

    et al. Differential polymerase activity in avian and mammalian cells determines host range of influenza virus. J. Virol. 81, 9601–9604 (2007)

  55. 55.

    , & Interaction of polymerase subunit PB2 and NP with importin α1 is a determinant of host range of influenza A virus. PLoS Pathog. 4, e11 (2008)

  56. 56.

    et al. The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04. J. Exp. Med. 203, 689–697 (2006)

  57. 57.

    et al. Host determinant residue lysine 627 lies on the surface of a discrete, folded domain of influenza virus polymerase PB2 subunit. PLoS Pathog. 4, e1000136 (2008)

  58. 58.

    et al. Structural basis of the influenza A virus RNA polymerase PB2 RNA-binding domain containing the pathogenicity-determinant lysine 627 residue. J. Biol. Chem. 284, 6855–6860 (2009)

  59. 59.

    Inhibition of interferon-mediated antiviral responses by influenza A viruses and other negative-strand RNA viruses. Virology 279, 375–384 (2001)

  60. 60.

    et al. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 252, 324–330 (1998)This paper establishes the NS1 protein as an interferon antagonist.

  61. 61.

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

  62. 62.

    , , , & Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004)

  63. 63.

    et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl Acad. Sci. USA 101, 5598–5603 (2004)

  64. 64.

    et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 133, 235–249 (2008)

  65. 65.

    , & Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nature Med. 8, 950–954 (2002)

  66. 66.

    et al. H5N1 influenza: a protean pandemic threat. Proc. Natl Acad. Sci. USA 101, 8156–8161 (2004)

  67. 67.

    et al. A single-amino-acid substitution in the NS1 protein changes the pathogenicity of H5N1 avian influenza viruses in mice. J. Virol. 82, 1146–1154 (2008)

  68. 68.

    et al. The NS1 gene contributes to the virulence of H5N1 avian influenza viruses. J. Virol. 80, 11115–11123 (2006)

  69. 69.

    et al. Large-scale sequence analysis of avian influenza isolates. Science 311, 1576–1580 (2006)

  70. 70.

    , , , & A new influenza virus virulence determinant: the NS1 protein four C-terminal residues modulate pathogenicity. Proc. Natl Acad. Sci. USA 105, 4381–4386 (2008)

  71. 71.

    et al. A novel influenza A virus mitochondrial protein that induces cell death. Nature Med. 7, 1306–1312 (2001)

  72. 72.

    , , , & Influenza virus PB1–F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog. 1, e4 (2005)

  73. 73.

    et al. The proapoptotic influenza A virus protein PB1–F2 regulates viral polymerase activity by interaction with the PB1 protein. Cell. Microbiol. 10, 1140–1152 (2008)

  74. 74.

    , , , & A single mutation in the PB1–F2 of H5N1 (HK/97) and 1918 influenza A viruses contributes to increased virulence. PLoS Pathog. 3, e141 (2007)

  75. 75.

    et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 364, 759–765 (2004)

  76. 76.

    , & Influenza virus resistance to antiviral agents: a plea for rational use. Clin. Infect. Dis. 48, 1254–1256 (2009)

  77. 77.

    et al. Avian flu: isolation of drug-resistant H5N1 virus. Nature 437, 1108 (2005)

  78. 78.

    et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N. Engl. J. Med. 353, 2667–2672 (2005)

  79. 79.

    , & Prolonged shedding of multidrug-resistant influenza A virus in an immunocompromised patient. N. Engl. J. Med. 348, 867–868 (2003)

  80. 80.

    , , & Characterization of multidrug-resistant influenza A/H3N2 viruses shed during 1 year by an immunocompromised child. Clin. Infect. Dis. 43, 1555–1561 (2006)

  81. 81.

    , , , & Recovery of drug-resistant influenza virus from immunocompromised patients: a case series. J. Infect. Dis. 193, 760–764 (2006)

  82. 82.

    et al. Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants. Nature 453, 1258–1261 (2008)

  83. 83.

    , , , & Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J. Infect. Dis. 178, 1257–1262 (1998)

  84. 84.

    et al. BCX-1812 (RWJ-270201): discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. J. Med. Chem. 43, 3482–3486 (2000)

  85. 85.

    et al. CS-8958, a prodrug of the new neuraminidase inhibitor R-125489, shows long-acting anti-influenza virus activity. Antimicrob. Agents Chemother. 53, 186–192 (2009)

  86. 86.

    et al. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob. Agents Chemother. 46, 977–981 (2002)

  87. 87.

    et al. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nature Struct. Mol. Biol. 16, 265–273 (2009)

  88. 88.

    et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N. Engl. J. Med. 356, 685–696 (2007)

  89. 89.

    , , , & Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N. Engl. J. Med. 354, 1343–1351 (2006)

  90. 90.

    et al. Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial. Lancet 367, 1657–1664 (2006)

  91. 91.

    et al. Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase I randomised controlled trial. Lancet 368, 991–997 (2006)

  92. 92.

    et al. Effects of adjuvants on the safety and immunogenicity of an avian influenza H5N1 vaccine in adults. J. Infect. Dis. 197, 667–675 (2008)

  93. 93.

    et al. Antigenically distinct MF59-adjuvanted vaccine to boost immunity to H5N1. N. Engl. J. Med. 359, 1631–1633 (2008)

  94. 94.

    et al. An adjuvanted, low-dose, pandemic influenza A (H5N1) vaccine candidate is safe, immunogenic, and induces cross-reactive immune responses in healthy adults. J. Infect. Dis. 198, 642–649 (2008)

  95. 95.

    et al. Live, attenuated influenza A H5N1 candidate vaccines provide broad cross-protection in mice and ferrets. PLoS Med. 3, e360 (2006)

  96. 96.

    et al. Immunogenicity and protective efficacy of a live attenuated H5N1 vaccine in nonhuman primates. PLoS Pathog. 5, e1000409 (2009)

  97. 97.

    , , & Universal M2 ectodomain-based influenza A vaccines: preclinical and clinical developments. Expert Rev. Vaccines 8, 499–508 (2009)

  98. 98.

    et al. H5N1 VLP vaccine induced protection in ferrets against lethal challenge with highly pathogenic H5N1 influenza viruses. Vaccine 26, 5393–5399 (2008)

  99. 99.

    et al. Protection of mice and poultry from lethal H5N1 avian influenza virus through adenovirus-based immunization. J. Virol. 80, 1959–1964 (2006)

  100. 100.

    et al. Development of adenoviral-vector-based pandemic influenza vaccine against antigenically distinct human H5N1 strains in mice. Lancet 367, 475–481 (2006)

Download references


We apologize to our colleagues whose critical contributions to influenza virus research could not be cited owing to the number of references permitted. We thank K. Wells for editing the manuscript. We also thank M. Ozawa and others in our laboratories who contributed to the data cited in this review. Our original research was supported by National Institute of Allergy and Infectious Diseases Public Health Service research grants; by the Center for Research on Influenza Pathogenesis (CRIP) funded by the National Institute of Allergy and Infectious Diseases (Contract HHSN266200700010C), Grant-in-Aid for Specially Promoted Research, by a contract research fund for the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases from the Ministry of Education, Culture, Sports, Science, and Technology, by grants-in-aid from the Ministry of Health and by ERATO (Japan Science and Technology Agency). G.N. is named as co-inventor on several patents about influenza virus reverse genetics and/or the development of influenza virus vaccines or antivirals. Y.K. is named as inventor/co-inventor on several patents about influenza virus reverse genetics and/or the development of influenza virus vaccines or antivirals. Figures 1 and 2 were modified from Orthomyxoviruses: influenza, in Topley and Wilson's Microbiology and Microbial Infections: Virology (Hodder Arnold, 2005); Fig. 3 was modified from Orthomyxoviruses, in Fields Virology (Lippincott Williams & Wilkins, 2007).

Author Contributions G.N. wrote the manuscript. T.N. provided the electron microscopic picture. Y.K. also wrote the manuscript.

Author information


  1. Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA

    • Gabriele Neumann
    •  & Yoshihiro Kawaoka
  2. International Research Center for Infectious Diseases,

    • Takeshi Noda
    •  & Yoshihiro Kawaoka
  3. Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

    • Yoshihiro Kawaoka
  4. ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan

    • Yoshihiro Kawaoka


  1. Search for Gabriele Neumann in:

  2. Search for Takeshi Noda in:

  3. Search for Yoshihiro Kawaoka in:

Competing interests

[Competing Interests: Y.K. has received speaker’s honoraria from Chugai Pharmaceuticals, Novartis, Sankyo, Toyama Chemical, Wyeth and GlaxoSmithKline; grant support from Chugai Pharmaceuticals, Daiichi Sankyo Pharmaceutical and Toyama Chemical; consulting fee from Theraclone Sciences and Fort Dodge Animal Health; and is a founder of FluGen. G.N. has received consulting fee from Theraclone Sciences and is a founder of FluGen.]

Corresponding author

Correspondence to Yoshihiro Kawaoka.

The authors declare competing financial interests: details accompany the full-text HTML version of the paper at

About this article

Publication history





Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.