The evolution of seasonal influenza viruses | Nature Reviews Microbiology
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The evolution of seasonal influenza viruses

Nature Reviews Microbiology volume 16, pages 47–60 (2018)Cite this article

Subjects

An Erratum to this article was published on 07 November 2017

This article has been updated

Key Points

  • The evolution of seasonal influenza viruses is an important source of disease burden, as it allows for the reinfection of previously infected or vaccinated individuals

  • Given that 5–15% of the global human population is infected with seasonal influenza viruses each year, it is surprising that new antigenic variants arise only every 3–5 years for A/H3N2 viruses and less frequently for A/H1N1 and B viruses

  • The virus surface glycoprotein haemagglutinin is the primary target of the host immune response, and evolutionary selection pressure drives it to acquire mutations to escape immune recognition without eliminating its receptor binding function

  • Host immunity has a dual role in governing the pace of virus evolution: innate immunity acts as a constraint on the generation of new virus variants, whereas adaptive immunity selects for immune escape mutants

  • The acute nature of influenza virus infections and population-level epidemics provides limited opportunities for evolutionary selection, with most virus diversity being lost before selection can operate

  • Influenza virus vaccines can provide effective protection against infection when they are well matched to circulating viruses, but there remains scope for improving vaccine production and delivery to achieve better effectiveness

Abstract

Despite decades of surveillance and pharmaceutical and non-pharmaceutical interventions, seasonal influenza viruses continue to cause epidemics around the world each year. The key process underlying these recurrent epidemics is the evolution of the viruses to escape the immunity that is induced by prior infection or vaccination. Although we are beginning to understand the processes that underlie the evolutionary dynamics of seasonal influenza viruses, the timing and nature of emergence of new virus strains remain mostly unpredictable. In this Review, we discuss recent advances in understanding the molecular determinants of influenza virus immune escape, sources of evolutionary selection pressure, population dynamics of influenza viruses and prospects for better influenza virus control.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The influenza A and B virion.
Figure 2: Bottlenecks in influenza virus diversity.
Figure 3: Models of host immune selection during primary and secondary infections with influenza virus.
Figure 4: Global dynamics of seasonal influenza viruses.

Similar content being viewed by others

Change history

  • 07 November 2017

    In Figure 4 of the original online version of the article, the influenza virus epidemic activity by month was incorrectly labelled. This has now been corrected in the online and print versions. We apologize to the authors and to readers for any confusion caused.

References

  1. Stöhr, K. Influenza—WHO cares. Lancet Infect. Dis. 2, 517 (2002).

    PubMed  Google Scholar 

  2. Zambon, M. C. Epidemiology and pathogenesis of influenza. J. Antimicrob. Chemother. 44, 3–9 (1999).

    CAS  PubMed  Google Scholar 

  3. Russell, C. A. et al. Improving pandemic influenza risk assessment. eLife 3, e03883 (2014).

    PubMed  PubMed Central  Google Scholar 

  4. Tong, S. et al. New World bats harbor diverse influenza A viruses. PLoS Pathog. 9, e1003657 (2013).

    PubMed  PubMed Central  Google Scholar 

  5. Francis, T. A. New type of virus from epidemic influenza. Science 92, 405–408 (1940).

    PubMed  Google Scholar 

  6. Biere, B., Bauer, B. & Schweiger, B. Differentiation of influenza B virus lineages Yamagata & Victoria by real-time PCR. J. Clin. Microbiol. 48, 1425–1427 (2010).

    PubMed  PubMed Central  Google Scholar 

  7. Kanegae, Y. et al. Evolutionary pattern of the hemagglutinin gene of influenza B viruses isolated in Japan: cocirculating lineages in the same epidemic season. J. Virol. 64, 2860–2865 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  9. 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 

  10. Cohen, M. et al. Influenza A penetrates host mucus by cleaving sialic acids with neuraminidase. Virol. J. 10, 321 (2013).

    PubMed  PubMed Central  Google Scholar 

  11. Westgeest, K. B. et al. Genomewide analysis of reassortment and evolution of human influenza A(H3N2) viruses circulating between 1968 and 2011. J. Virol. 88, 2844–2857 (2014).

    PubMed  PubMed Central  Google Scholar 

  12. Smith, D. J. et al. Mapping the antigenic and genetic evolution of influenza virus. Science 305, 371–376 (2004). This is a seminal study that documented the continuous genetic but punctuated antigenic evolution of A/H3N2 viruses and introduced antigenic cartography — a computational tool for quantifying differences in virus antigenic phenotype.

    CAS  PubMed  Google Scholar 

  13. Westgeest, K. B. et al. Genetic evolution of the neuraminidase of influenza A (H3N2) viruses from 1968 to 2009 and its correspondence to haemagglutinin evolution. J. Gen. Virol. 93, 1996–2007 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 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  Google Scholar 

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

    CAS  Google Scholar 

  16. Kilbourne, E. D. et al. The total influenza vaccine failure of 1947 revisited: major intrasubtypic antigenic change can explain failure of vaccine in a post-World War II epidemic. Proc. Natl Acad. Sci. USA 99, 10748–10752 (2002).

    CAS  PubMed  Google Scholar 

  17. Tricco, A. C. et al. Comparing influenza vaccine efficacy against mismatched and matched strains: a systematic review and meta-analysis. BMC Med. 11, 153 (2013).

    PubMed  PubMed Central  Google Scholar 

  18. 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  Google Scholar 

  19. Cobey, S. & Hensley, S. E. Immune history and influenza virus susceptibility. Curr. Opin. Virol. 22, 105–111 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 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).

    PubMed  PubMed Central  Google Scholar 

  21. Terajima, M. et al. Complement-dependent lysis of influenza A virus-infected cells by broadly cross-reactive human monoclonal antibodies. J. Virol. 85, 13463–13467 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 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 

  23. Chen, R. & Holmes, E. C. The evolutionary dynamics of human influenza B virus. J. Mol. Evol. 66, 655–663 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Bedford, T. et al. Global circulation patterns of seasonal influenza viruses vary with antigenic drift. Nature 523, 217–220 (2015). This is the first detailed comparison of the global circulation dynamics of all four seasonal influenza viruses and is the most complete characterization of the global dynamics of seasonal influenza viruses to date.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Vijaykrishna, D. et al. The contrasting phylodynamics of human influenza B viruses. eLife 4, e05055 (2015).

    PubMed  PubMed Central  Google Scholar 

  26. Kucharski, A. J. et al. Estimating the life course of influenza A(H3N2) antibody responses from cross-sectional data. PLoS Biol. 13, e1002082 (2015).

    PubMed  PubMed Central  Google Scholar 

  27. Fonville, J. M. et al. Antibody landscapes after influenza virus infection or vaccination. Science 346, 996–1000 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Cheung, P. P. H. et al. Generation and characterization of influenza A viruses with altered polymerase fidelity. Nat. Commun. 5, 4794 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Virelizier, J.-L. Host defenses against influenza virus: the role of anti-hemagglutinin antibody. J. Immunol. 115, 434–439 (1975).

    CAS  PubMed  Google Scholar 

  30. Bizebard, T. et al. Structure of influenza virus haemagglutinin complexed with a neutralizing antibody. Nature 376, 92–94 (1995).

    CAS  PubMed  Google Scholar 

  31. Margine, I. et al. H3N2 influenza virus infection induces broadly reactive hemagglutinin stalk antibodies in humans and mice. J. Virol. 87, 4728–4737 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Moody, M. A. et al. H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination. PLoS ONE 6, e25797 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Nachbagauer, R. et al. Age dependence and isotype specificity of influenza virus hemagglutinin stalk-reactive antibodies in humans. mBio 7, e01996-15 (2016). This is a detailed analysis of how broadly influenza neutralizing antibodies accumulate with age and of their possible role in the decreased rate of influenza infection among elderly individuals.

    PubMed  PubMed Central  Google Scholar 

  34. Wiley, D. C., Wilson, I. A. & Skehel, J. J. Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation. Nature 289, 373–378 (1981).

    CAS  PubMed  Google Scholar 

  35. Skehel, J. J. et al. A carbohydrate side chain on hemagglutinins of Hong Kong influenza viruses inhibits recognition by a monoclonal antibody. Proc. Natl Acad. Sci. USA 81, 1779–1783 (1984).

    CAS  PubMed  Google Scholar 

  36. 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 

  37. Koel, B. F. et al. Substitutions near the receptor binding site determine major antigenic change during influenza virus evolution. Science 342, 976–979 (2013). This is a key paper showing that the majority of substantial antigenic changes as determined by experimental assays from 1968 to – have been associated with amino acid substitutions in just seven positions in the HA protein.

    CAS  PubMed  Google Scholar 

  38. 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 

  39. Klimov, A. I. et al. WHO recommendations for the viruses to be used in the 2012 Southern Hemisphere influenza vaccine: epidemiology, antigenic and genetic characteristics of influenza A(H1N1)pdm09, A(H3N2) and B influenza viruses collected from February to September 2011. Vaccine 30, 6461–6471 (2012).

    PubMed  Google Scholar 

  40. 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, e01070-14 (2014).

    PubMed  PubMed Central  Google Scholar 

  41. Abente, E. J. et al. The molecular determinants of antibody recognition and antigenic drift in the H3 hemagglutinin of swine influenza A virus. J. Virol. 90, 8266–8280 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lewis, N. S. et al. The global antigenic diversity of swine influenza A viruses. eLife 5, e12217 (2016).

    PubMed  PubMed Central  Google Scholar 

  43. 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 

  44. Doud, M. B., Hensley, S. E. & Bloom, J. D. Complete mapping of viral escape from neutralizing antibodies. PLoS Pathog. 13, e1006271 (2017). This study demonstrates the excellent use of tools for deep mutational scanning to investigate the virus genetic consequences of antibody selection.

    PubMed  PubMed Central  Google Scholar 

  45. Kirchenbaum, G. A., Carter, D. M. & Ross, T. M. Sequential infection in ferrets with antigenically distinct seasonal H1N1 influenza viruses boosts hemagglutinin stalk-specific antibodies. J. Virol. 90, 1116–1128 (2016).

    CAS  PubMed  Google Scholar 

  46. Nachbagauer, R. et al. Induction of broadly reactive anti-hemagglutinin stalk antibodies by an H5N1 vaccine in humans. J. Virol. 88, 13260–13268 (2014).

    PubMed  PubMed Central  Google Scholar 

  47. Okuno, Y., Isegawa, Y., Sasao, F. & Ueda, S. A common neutralizing epitope conserved between the hemagglutinins of influenza A virus H1 and H2 strains. J. Virol. 67, 2552–2558 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Chai, N. et al. Two escape mechanisms of influenza A Virus to a broadly neutralizing stalk-binding antibody. PLoS Pathog. 12, e1005702 (2016). This study provides an important functional demonstration of the ability of influenza viruses to escape broadly neutralizing antibodies through a small number of amino acid substitutions.

    PubMed  PubMed Central  Google Scholar 

  49. Schulman, J. L., Khakpour, M. & Kilbourne, E. D. Protective effects of specific immunity to viral neuraminidase on influenza virus infection of mice. J. Virol. 2, 778–786 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Murphy, B. R., Kasel, J. A. & Chanock, R. M. Association of serum anti-neuraminidase antibody with resistance to influenza in man. N. Engl. J. Med. 286, 1329–1332 (1972).

    CAS  PubMed  Google Scholar 

  51. Eichelberger, M. C. & Wan, H. Influenza neuraminidase as a vaccine antigen. Curr. Top. Microbiol. Immunol. 386, 275–299 (2015).

    CAS  PubMed  Google Scholar 

  52. Sultana, I. et al. Stability of neuraminidase in inactivated influenza vaccines. Vaccine 32, 2225–2230 (2014).

    CAS  PubMed  Google Scholar 

  53. Koelle, K., Cobey, S., Grenfell, B. & Pascual, M. Epochal evolution shapes the phylodynamics of interpandemic influenza A (H3N2) in humans. Science 314, 1898–1903 (2006).

    CAS  PubMed  Google Scholar 

  54. Koelle, K. & Rasmussen, D. A. The effects of a deleterious mutation load on patterns of influenza A/H3N2's antigenic evolution in humans. eLife 4, e07361 (2015).

    PubMed  PubMed Central  Google Scholar 

  55. Zinder, D., Bedford, T., Gupta, S. & Pascual, M. The roles of competition and mutation in shaping antigenic and genetic diversity in influenza. PLoS Pathog. 9, e1003104 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Recker, M., Pybus, O. G., Nee, S. & Gupta, S. The generation of influenza outbreaks by a network of host immune responses against a limited set of antigenic types. Proc. Natl Acad. Sci. USA 104, 7711–7716 (2007).

    CAS  PubMed  Google Scholar 

  57. Meyer, A. G. & Wilke, C. O. Geometric constraints dominate the antigenic evolution of influenza H3N2 hemagglutinin. PLoS Pathog. 11, e1004940 (2015).

    PubMed  PubMed Central  Google Scholar 

  58. Bedford, T., Rambaut, A. & Pascual, M. Canalization of the evolutionary trajectory of the human influenza virus. BMC Biol. 10, 38 (2012).

    PubMed  PubMed Central  Google Scholar 

  59. Gog, J. R. The impact of evolutionary constraints on influenza dynamics. Vaccine 26, C15–C24 (2008).

    PubMed  Google Scholar 

  60. Andreasen, V. & Sasaki, A. Shaping the phylogenetic tree of influenza by cross-immunity. Theor. Popul. Biol. 70, 164–173 (2006).

    PubMed  Google Scholar 

  61. Hensley, S. E. et al. Hemagglutinin receptor binding avidity drives influenza A virus antigenic drift. Science 326, 734–736 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Gong, L. I. & Bloom, J. D. Epistatically interacting substitutions are enriched during adaptive protein evolution. PLoS Genet. 10, e1004328 (2014). The study is a key example of how the specific genetic context in which mutations occur can have substantial effect on the resulting fitness of viruses.

    PubMed  PubMed Central  Google Scholar 

  63. Bloom, J. D., Gong, L. I. & Baltimore, D. Permissive secondary mutations enable the evolution of influenza oseltamivir resistance. Science 328, 1272–1275 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Leonard, A. S. et al. Deep sequencing of influenza A virus from a human challenge study reveals a selective bottleneck and only limited intrahost genetic diversification. J. Virol. 90, 11247–11258 (2016).

    CAS  Google Scholar 

  65. Debbink, K. et al. Vaccination has minimal impact on the intrahost diversity of H3N2 influenza viruses. PLoS Pathog. 13, e1006194 (2017). This study provides an interesting analysis of human virus samples relating within-host virus data to vaccination status and finds a minimal role for vaccine-induced immunity as a source of evolutionary selection pressure.

    PubMed  PubMed Central  Google Scholar 

  66. McCrone, J. T. et al. The evolutionary dynamics of influenza A virus within and between human hosts. bioRxiv http://dx.doi.org/10.1101/176362 (2017).

  67. Xue, K. S. et al. Parallel evolution of influenza across multiple spatiotemporal scales. eLife 6, e26875 (2017).

    PubMed  PubMed Central  Google Scholar 

  68. Parvin, J. D., Moscona, A., Pan, W. T., Leider, J. M. & Palese, P. Measurement of the mutation rates of animal viruses: influenza A virus and poliovirus type 1. J. Virol. 59, 377–383 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Nobusawa, E. & Sato, K. Comparison of the mutation rates of human influenza A and B viruses. J. Virol. 80, 3675–3678 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Bloom, J. D. An experimentally determined evolutionary model dramatically improves phylogenetic fit. Mol. Biol. Evol. 31, 1956–1978 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Pauly, M. D., Procario, M. C. & Lauring, A. S. A novel twelve class fluctuation test reveals higher than expected mutation rates for influenza A viruses. eLife 6, e26437 (2017).

    PubMed  PubMed Central  Google Scholar 

  72. Sidorenko, Y. & Reichl, U. Structured model of influenza virus replication in MDCK cells. Biotechnol. Bioeng. 88, 1–14 (2004).

    CAS  PubMed  Google Scholar 

  73. Wu, N.-H. et al. The differentiated airway epithelium infected by influenza viruses maintains the barrier function despite a dramatic loss of ciliated cells. Sci. Rep. 6, 39668 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Guillot, L. et al. Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus. J. Biol. Chem. 280, 5571–5580 (2005).

    CAS  PubMed  Google Scholar 

  75. Alexopoulou, L., Holt, A. C., Medzhitov, R. & Flavell, R. A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001).

    CAS  PubMed  Google Scholar 

  76. Marois, I., Cloutier, A., Garneau, E. & Richter, M. V. Initial infectious dose dictates the innate, adaptive, and memory responses to influenza in the respiratory tract. J. Leukoc. Biol. 92, 107–121 (2012).

    CAS  PubMed  Google Scholar 

  77. Le Goffic, R. et al. Influenza A virus protein PB1-F2 exacerbates IFN-β expression of human respiratory epithelial cells. J. Immunol. 185, 4812–4823 (2010).

    CAS  PubMed  Google Scholar 

  78. Le Goffic, R. et al. Transcriptomic analysis of host immune and cell death responses associated with the influenza A virus PB1-F2 protein. PLoS Pathog. 7, e1002202 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 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 

  80. Zimmermann, P., Manz, B., Haller, O., Schwemmle, M. & Kochs, G. The viral nucleoprotein determines Mx sensitivity of influenza A viruses. J. Virol. 85, 8133–8140 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Gnirss, K. et al. Tetherin sensitivity of influenza A viruses is strain specific: role of hemagglutinin and neuraminidase. J. Virol. 89, 9178–9188 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 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 

  83. Slütter, B. et al. Dynamics of influenza-induced lung-resident memory T cells underlie waning heterosubtypic immunity. Sci. Immunol. 2, eaag2031 (2017).

    PubMed  PubMed Central  Google Scholar 

  84. Baccam, P., Beauchemin, C., Macken, C. A., Hayden, F. G. & Perelson, A. S. Kinetics of influenza A virus infection in humans. J. Virol. 80, 7590–7599 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Kitphati, R. et al. Kinetics and longevity of antibody response to influenza A H5N1 virus infection in humans. Clin. Vaccine Immunol. 16, 978–981 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Ochsenbein, A. F. et al. Protective long-term antibody memory by antigen-driven and T help-dependent differentiation of long-lived memory B cells to short-lived plasma cells independent of secondary lymphoid organs. Proc. Natl Acad. Sci. USA 97, 13263–13268 (2000).

    CAS  PubMed  Google Scholar 

  87. Neuzil, K. M. et al. Immunogenicity and reactogenicity of 1 versus 2 doses of trivalent inactivated influenza vaccine in vaccine-naive 5–8-year-old children. J. Infect. Dis. 194, 1032–1039 (2006).

    CAS  PubMed  Google Scholar 

  88. Renegar, K. B., Small, P. A., Boykins, L. G. & Wright, P. F. Role of IgA versus IgG in the control of influenza viral infection in the murine respiratory tract. J. Immunol. 173, 1978–1986 (2004).

    CAS  PubMed  Google Scholar 

  89. Stokes, C. R., Soothill, J. F. & Turner, M. W. Immune exclusion is a function of IgA. Nature 255, 745–746 (1975).

    CAS  PubMed  Google Scholar 

  90. Nachbagauer, R. & Krammer, F. Universal influenza virus vaccines and therapeutic antibodies. Clin Microbiol. Infect. 23, 222–228 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Wrammert, J. et al. Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J. Exp. Med. 208, 181–193 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Davenport, F. M., Hennessy, A. V. & Francis, T. Epidemiologic and immunologic significance of age distribution of antibody to antigenic variants of influenza virus. J. Exp. Med. 98, 641–656 (1953).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Davenport, F. M., Hennessy, A. V., Stuart-Harris, C. H. & Francis, T. Epidemiology of influenza; comparative serological observations in England and the United States. Lancet 269, 469–474 (1955).

    CAS  PubMed  Google Scholar 

  94. Miller, M. S. et al. Neutralizing antibodies against previously encountered influenza virus strains increase over time: a longitudinal analysis. Sci Transl Med 5, 198ra107 (2013).

    PubMed  PubMed Central  Google Scholar 

  95. Lessler, J. et al. Evidence for antigenic seniority in influenza A (H3N2) antibody responses in southern China. PLoS Pathog. 8, e1002802 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Davenport, F. M. & Hennessy, A. V. A serologic recapitulation of past experiences with influenza A; antibody response to monovalent vaccine. J. Exp. Med. 104, 85–97 (1956).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 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  Google Scholar 

  98. Swayne, D. E. et al. Antibody titer has positive predictive value for vaccine protection against challenge with natural antigenic-drift variants of H5N1 high-pathogenicity avian influenza viruses from Indonesia. J. Virol. 89, 3746–3762 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Fox, A. et al. Hemagglutination inhibiting antibodies and protection against seasonal and pandemic influenza infection. J. Infect. 70, 187–196 (2015).

    PubMed  PubMed Central  Google Scholar 

  100. Ohmit, S. E., Petrie, J. G., Cross, R. T., Johnson, E. & Monto, A. S. Influenza hemagglutination-inhibition antibody titer as a correlate of vaccine-induced protection. J. Infect. Dis. 204, 1879–1885 (2011).

    CAS  PubMed  Google Scholar 

  101. Hensley, S. E. Challenges of selecting seasonal influenza vaccine strains for humans with diverse pre-exposure histories. Curr. Opin. Virol. 8, 85–89 (2014).

    CAS  PubMed  Google Scholar 

  102. Frise, R. et al. Contact transmission of influenza virus between ferrets imposes a looser bottleneck than respiratory droplet transmission allowing propagation of antiviral resistance. Sci. Rep. 6, 29793 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Varble, A. et al. Influenza A virus transmission bottlenecks are defined by infection route and recipient host. Cell Host Microbe 16, 691–700 (2014). This is an elegant experimental paper showing how route of transmission is an important factor in virus population bottleneck size.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Moncla, L. H. et al. Selective bottlenecks shape evolutionary pathways taken during mammalian adaptation of a 1918-like avian influenza virus. Cell Host Microbe 19, 169–180 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Poon, L. L. M. et al. Quantifying influenza virus diversity and transmission in humans. Nat. Genet. 48, 195–200 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Tamerius, J. D. et al. Environmental predictors of seasonal influenza epidemics across temperate and tropical climates. PLoS Pathog. 9, e1003194 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Viboud, C., Alonso, W. J. & Simonsen, L. Influenza in tropical regions. PLoS Med. 3, e89 (2006).

    PubMed  PubMed Central  Google Scholar 

  108. Hirve, S. et al. Influenza seasonality in the tropics and subtropics — when to vaccinate? PLoS ONE 11, e0153003 (2016).

    PubMed  PubMed Central  Google Scholar 

  109. Lowen, A. C., Mubareka, S., Steel, J. & Palese, P. Influenza virus transmission is dependent on relative humidity and temperature. PLoS Pathog. 3, e151 (2007).

    PubMed Central  Google Scholar 

  110. Deyle, E. R., Maher, M. C., Hernandez, R. D., Basu, S. & Sugihara, G. Global environmental drivers of influenza. Proc. Natl Acad. Sci. USA 113, 13081–13086 (2016).

    CAS  PubMed  Google Scholar 

  111. Shaman, J. & Kohn, M. Absolute humidity modulates influenza survival, transmission, and seasonality. Proc. Natl Acad. Sci. USA 106, 3243–3248 (2009).

    CAS  PubMed  Google Scholar 

  112. Young, L. C. et al. Summer outbreak of respiratory disease in an Australian prison due to an influenza A/Fujian/411/2002(H3N2)-like virus. Epidemiol. Infect. 133, 107–112 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Finnie, T. J. R., Copley, V. R., Hall, I. M. & Leach, S. An analysis of influenza outbreaks in institutions and enclosed societies. Epidemiol. Infect. 142, 107–113 (2014).

    CAS  PubMed  Google Scholar 

  114. Gaillat, J., Dennetière, G., Raffin-Bru, E., Valette, M. & Blanc, M. C. Summer influenza outbreak in a home for the elderly: application of preventive measures. J. Hosp. Infect. 70, 272–277 (2008).

    CAS  PubMed  Google Scholar 

  115. Cauchemez, S., Valleron, A.-J., Boëlle, P.-Y., Flahault, A. & Ferguson, N. M. Estimating the impact of school closure on influenza transmission from Sentinel data. Nature 452, 750–754 (2008).

    CAS  PubMed  Google Scholar 

  116. Dopico, X. C. et al. Widespread seasonal gene expression reveals annual differences in human immunity and physiology. Nat. Commun. 6, 7000 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Hirsch, A. & Creighton, C. Handbook of geographical and historical pathology. (London: The New Sydenham Society, 1883).

    Google Scholar 

  118. Hope-Simpson, R. E. The role of season in the epidemiology of influenza. J. Hyg. 86, 35–47 (1981).

    CAS  PubMed  Google Scholar 

  119. Shortridge, K. F., Peiris, J. S. M. & Guan, Y. The next influenza pandemic: lessons from Hong Kong. J. Appl. Microbiol. 94 (Suppl.), 70S–79S (2003).

    PubMed  Google Scholar 

  120. Nelson, M. I., Simonsen, L., Viboud, C., Miller, M. A. & Holmes, E. C. Phylogenetic analysis reveals the global migration of seasonal influenza A viruses. PLoS Pathog. 3, e131 (2007).

    PubMed Central  Google Scholar 

  121. Russell, C. A. et al. The global circulation of seasonal influenza A (H3N2) viruses. Science 320, 340–346 (2008).

    CAS  PubMed  Google Scholar 

  122. 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 

  123. Chan, J., Holmes, A. & Rabadan, R. Network analysis of global influenza spread. PLoS Comput. Biol. 6, e1001005 (2010).

    PubMed  PubMed Central  Google Scholar 

  124. Lemey, P. et al. Unifying viral genetics and human transportation data to predict the global transmission dynamics of human influenza H3N2. PLoS Pathog. 10, e1003932 (2014).

    PubMed  PubMed Central  Google Scholar 

  125. Bielejec, F., Lemey, P., Baele, G., Rambaut, A. & Suchard, M. A. Inferring heterogeneous evolutionary processes through time: from sequence substitution to phylogeography. Syst. Biol. 63, 493–504 (2014).

    PubMed  PubMed Central  Google Scholar 

  126. Bedford, T., Cobey, S., Beerli, P. & Pascual, M. Global migration dynamics underlie evolution and persistence of human influenza A (H3N2). PLoS Pathog. 6, e1000918 (2010).

    PubMed  PubMed Central  Google Scholar 

  127. Bedford, T. et al. Integrating influenza antigenic dynamics with molecular evolution. eLife 3, e01914 (2014).

    PubMed  PubMed Central  Google Scholar 

  128. Ferguson, N. M., Galvani, A. P. & Bush, R. M. Ecological and immunological determinants of influenza evolution. Nature 422, 428–433 (2003).

    CAS  PubMed  Google Scholar 

  129. Partridge, J. & Kieny, M. P. Global production capacity of seasonal influenza vaccine in 2011. Vaccine 31, 728–731 (2013).

    PubMed  Google Scholar 

  130. Flannery, B. et al. Enhanced genetic characterization of influenza A(H3N2) Viruses and vaccine effectiveness by genetic group, 2014–2015. J. Infect. Dis. 214, 1010–1019 (2016).

    PubMed  PubMed Central  Google Scholar 

  131. Skowronski, D. M. et al. A perfect storm: impact of genomic variation and serial vaccination on low influenza vaccine effectiveness during the 2014–2015 season. Clin. Infect. Dis. 63, 21–32 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. WHO Writing Group et al. Improving influenza vaccine virus selection: report of a WHO informal consultation held at WHO headquarters, Geneva, Switzerland, 14–16 June 2010. Influenza Other Respir. Viruses 6, 142–152 (2012).

  133. de Jong, J. C., Beyer, W. E. P., Palache, A. M., Rimmelzwaan, G. F. & Osterhaus, A. D. M. E. Mismatch between the 1997/1998 influenza vaccine and the major epidemic A(H3N2) virus strain as the cause of an inadequate vaccine-induced antibody response to this strain in the elderly. J. Med. Virol. 61, 94–99 (2000).

    CAS  PubMed  Google Scholar 

  134. Skowronski, D. M. et al. Low 2012–2013 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses. PLoS ONE 9, e92153 (2014).

    PubMed  PubMed Central  Google Scholar 

  135. Wong, S.-S. & Webby, R. J. Traditional and new influenza vaccines. Clin. Microbiol. Rev. 26, 476–492 (2013). This is an excellent review of the processes, challenges and future directions for influenza virus vaccine production.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  137. Brand, C. & Palese, P. Sequential passage of influenza virus in embryonated eggs or tissue culture: emergence of mutants. Virology 107, 424–433 (1980).

    CAS  PubMed  Google Scholar 

  138. McWhite, C. D., Meyer, A. G. & Wilke, C. O. Sequence amplification via cell passaging creates spurious signals of positive adaptation in influenza virus H3N2 hemagglutinin. Virus Evol. 2, vew026 (2016).

    PubMed  PubMed Central  Google Scholar 

  139. Łuksza, M. & Lässig, M. A predictive fitness model for influenza. Nature 507, 57–61 (2014).

    PubMed  Google Scholar 

  140. Neher, R. A., Russell, C. A. & Shraiman, B. I. Predicting evolution from the shape of genealogical trees. eLife 3, e03568 (2014).

    PubMed Central  Google Scholar 

  141. Neher, R. A., Bedford, T., Daniels, R. S., Russell, C. A. & Shraiman, B. I. Prediction, dynamics, and visualization of antigenic phenotypes of seasonal influenza viruses. Proc. Natl Acad. Sci. USA 113, E1701–E1709 (2016).

    CAS  PubMed  Google Scholar 

  142. Neher, R. A. & Bedford, T. nextflu: real-time tracking of seasonal influenza virus evolution in humans. Bioinformatics 31, 3546–3548 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Nolan, T. et al. Safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in infants and children. Vaccine 26, 6383–6391 (2008).

    CAS  PubMed  Google Scholar 

  144. Van Damme, P. et al. Long-term persistence of humoral and cellular immune responses induced by an AS03A-adjuvanted H1N1 2009 influenza vaccine: an open-label, randomized study in adults aged 18–60 years and older. Hum. Vaccin. Immunother. 9, 1512–1522 (2013).

    CAS  PubMed  Google Scholar 

  145. Andrews, N. J. et al. Predictors of immune response and reactogenicity to AS03B-adjuvanted split virion and non-adjuvanted whole virion H1N1 pandemic influenza vaccines. Vaccine 29, 7913–7919 (2011).

    CAS  PubMed  Google Scholar 

  146. Huijskens, E. et al. Immunogenicity, boostability, and sustainability of the immune response after vaccination against Influenza A virus (H1N1) 2009 in a healthy population. Clin. Vaccine Immunol. 18, 1401–1405 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Smith, D. J., Forrest, S., Ackley, D. H. & Perelson, A. S. Variable efficacy of repeated annual influenza vaccination. Proc. Natl Acad. Sci. USA 96, 14001–14006 (1999).

    CAS  PubMed  Google Scholar 

  148. Skowronski, D. M. et al. Serial vaccination and the antigenic distance hypothesis: effects on influenza vaccine effectiveness during A(H3N2) epidemics in Canada, 2010–2011 to 2014–2015. J. Infect. Dis. 215, 1059–1099 (2017).

    PubMed  PubMed Central  Google Scholar 

  149. Corti, D. et al. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science 333, 850–856 (2011).

    CAS  PubMed  Google Scholar 

  150. Tumpey, T. M., Renshaw, M., Clements, J. D. & Katz, J. M. Mucosal delivery of inactivated influenza vaccine induces B-cell-dependent heterosubtypic cross-protection against lethal influenza A H5N1 virus infection. J. Virol. 75, 5141–5150 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Hoft, D. F. et al. Comparisons of the humoral and cellular immune responses induced by live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) in adults. Clin. Vaccine Immunol. 24, e00414-16 (2016).

    Google Scholar 

  152. Li, C. et al. Selection of antigenically advanced variants of seasonal influenza viruses. Nat. Microbiol. 1, 16058 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Leroux-Roels, I. et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet Lond. Engl. 370, 580–589 (2007).

    CAS  Google Scholar 

  154. Khurana, S. et al. Vaccines with MF59 adjuvant expand the antibody repertoire to target protective sites of pandemic avian H5N1 influenza virus. Sci. Transl. Med. 2, 15ra5 (2010).

    PubMed  Google Scholar 

  155. Lee, J. et al. Molecular-level analysis of the serum antibody repertoire in young adults before and after seasonal influenza vaccination. Nat. Med. 22, 1456–1464 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Jiang, N. et al. Lineage structure of the human antibody repertoire in response to influenza vaccination. Sci. Transl. Med. 5, 171ra19 (2013).

    PubMed  PubMed Central  Google Scholar 

  157. Nakaya, H. I. et al. Systems biology of immunity to MF59-adjuvanted versus nonadjuvanted trivalent seasonal influenza vaccines in early childhood. Proc. Natl Acad. Sci. USA 113, 1853–1858 (2016).

    CAS  PubMed  Google Scholar 

  158. Wang, C. et al. B-Cell repertoire responses to varicella-zoster vaccination in human identical twins. Proc. Natl Acad. Sci. USA 112, 500–505 (2015).

    CAS  PubMed  Google Scholar 

  159. Boyd, S. D. & Jackson, K. J. L. Predicting vaccine responsiveness. Cell Host Microbe 17, 301–307 (2015).

    CAS  PubMed  Google Scholar 

  160. Monto, A. S. & Maassab, H. F. Ether treatment of type B influenza virus antigen for the hemagglutination inhibition test. J. Clin. Microbiol. 13, 54–57 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Mosterín Höpping, A., Fonville, J. M., Russell, C. A., James, S. & Smith, D. J. Influenza B vaccine lineage selection — an optimized trivalent vaccine. Vaccine 34, 1617–1622 (2016).

    PubMed  PubMed Central  Google Scholar 

  162. Heikkinen, T., Ikonen, N. & Ziegler, T. Impact of influenza B lineage-level mismatch between trivalent seasonal influenza vaccines and circulating viruses, 1999–2012. Clin. Infect. Dis. 59, 1519–1524 (2014).

    CAS  PubMed  Google Scholar 

  163. Saito, T. et al. Antigenic alteration of influenza B virus associated with loss of a glycosylation site due to host-cell adaptation. J. Med. Virol. 74, 336–343 (2004).

    CAS  PubMed  Google Scholar 

  164. WHO. FluNet. WHO http://www.who.int/influenza/gisrs_laboratory/flunet/en/ (2017).

  165. Rogers, M. B. et al. Intrahost dynamics of antiviral resistance in influenza A virus reflect complex patterns of segment linkage, reassortment, and natural selection. mBio 6, e02464-14 (2015).

    PubMed  PubMed Central  Google Scholar 

  166. 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 

  167. Österlund, P. et al. Incoming influenza A virus evades early host recognition, while influenza B virus induces interferon expression directly upon entry. J. Virol. 86, 11183–11193 (2012).

    PubMed  PubMed Central  Google Scholar 

  168. 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).

    PubMed  PubMed Central  Google Scholar 

  169. Miao, H. et al. Quantifying the early immune response and adaptive immune response kinetics in mice infected with influenza A virus. J. Virol. 84, 6687–6698 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Tas, J. M. J. et al. Visualizing antibody affinity maturation in germinal centers. Science 351, 1048–1054 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Choi, Y. S. & Baumgarth, N. Dual role for B-1a cells in immunity to influenza virus infection. J. Exp. Med. 205, 3053–3064 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Deenick, E. K. et al. Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells. J. Exp. Med. 210, 2739–2753 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Tinoco, J. C. et al. Immunogenicity, reactogenicity, and safety of inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine in healthy adults aged ≥18 years: a phase III, randomized trial. Vaccine 32, 1480–1487 (2014).

    CAS  PubMed  Google Scholar 

  174. Gerdil, C. The annual production cycle for influenza vaccine. Vaccine 21, 1776–1779 (2003).

    PubMed  Google Scholar 

  175. Cox, R. J. et al. A phase I clinical trial of a PER. C6® cell grown influenza H7 virus vaccine. Vaccine 27, 1889–1897 (2009).

    CAS  PubMed  Google Scholar 

  176. Kistner, O. et al. Development of a mammalian cell (Vero) derived candidate influenza virus vaccine. Vaccine 16, 960–968 (1998).

    CAS  PubMed  Google Scholar 

  177. Dormitzer, P. R. Rapid production of synthetic influenza vaccines. Curr. Top. Microbiol. Immunol. 386, 237–273 (2015).

    CAS  PubMed  Google Scholar 

  178. Cox, M. M. J. Recombinant protein vaccines produced in insect cells. Vaccine 30, 1759–1766 (2012).

    CAS  PubMed  Google Scholar 

  179. Cox, M. M. J., Patriarca, P. A. & Treanor, J. FluBlok, a recombinant hemagglutinin influenza vaccine. Influenza Other Respir. Viruses 2, 211–219 (2008).

    PubMed  PubMed Central  Google Scholar 

  180. Alexandrova, G. I. et al. Study of live recombinant cold-adapted influenza bivalent vaccine of type A for use in children: an epidemiological control trial. Vaccine 4, 114–118 (1986).

    CAS  PubMed  Google Scholar 

  181. Rudenko, L., Isakova-Sivak, I. & Donina, S. H7N3 live attenuated influenza vaccine has a potential to protect against new H7N9 avian influenza virus. Vaccine 31, 4702–4705 (2013).

    CAS  PubMed  Google Scholar 

  182. Ramezanpour, B., Pronker, E. S., Kreijtz, J. H. C. M., Osterhaus, A. D. M. E. & Claassen, E. Market implementation of the MVA platform for pre-pandemic and pandemic influenza vaccines: a quantitative key opinion leader analysis. Vaccine 33, 4349–4358 (2015).

    PubMed  PubMed Central  Google Scholar 

  183. Altenburg, A. F. et al. Modified vaccinia virus ankara (MVA) as production platform for vaccines against influenza and other viral respiratory diseases. Viruses 6, 2735–2761 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Fries, L. F., Smith, G. E. & Glenn, G. M. A. Recombinant viruslike particle influenza A (H7N9) vaccine. N. Engl. J. Med. 369, 2564–2566 (2013).

    CAS  PubMed  Google Scholar 

  185. Fiers, W. et al. M2e-based universal influenza A vaccine. Vaccine 27, 6280–6283 (2009).

    CAS  PubMed  Google Scholar 

  186. Mallajosyula, V. V. A. et al. Influenza hemagglutinin stem-fragment immunogen elicits broadly neutralizing antibodies and confers heterologous protection. Proc. Natl Acad. Sci. USA 111, E2514–E2523 (2014).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank A. Han for his help with Fig. 1b–e. This work was supported by a Wellcome Trust Ph.D. Studentship to V.N.P. and by a Royal Society University Research Fellowship and a Wellcome Trust Collaborative Award to C.A.R.

Author information

Author notes

  1. Colin A. Russell

    Present address: Present address: Laboratory of Applied Evolutionary Biology, Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands,

Authors and Affiliations

  1. Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SA, Hinxton, UK

    Velislava N. Petrova

  2. Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 0ES, UK

    Colin A. Russell

Authors
  1. Velislava N. Petrova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Colin A. Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

V.N.P. and C.A.R. contributed to researching data for article. V.N.P. and C.A.R. substantially contributed to the discussion of content. V.N.P. and C.A.R. wrote the article. V.N.P. and C.A.R. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Colin A. Russell.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Epidemics

Infectious disease outbreaks involving a large number of people in a defined geographic location over a defined period of time.

Fomites

Surfaces or objects that can be contaminated by pathogens.

Pandemics

Global infectious disease epidemics.

Genome reassortment

A form of genomic rearrangement where two or more influenza viruses infect the same cell and exchange genomic segments, resulting in a genetically novel virus.

Antigenic clusters

A set of influenza virus variants with similar antigenic profiles.

Haemagglutination inhibition (HAI) assays

Experimental assays used to antigenically characterize viruses based on the ability of host serum to inhibit the virus-induced agglutination of red blood cells.

Within-host selection

Evolutionary selection that occurs at the level of an individual host, generally pertaining to virus fitness or virus interaction with the host immune response.

Immunodominant

A property of an antigen, causing it to be the primary focus of the immune response.

Plaque assays

Experimental assays that measure virus growth rates.

Microneutralization assays

Experimental assays that measure the ability of host serum to neutralize specific antigenic strains.

Deep mutational scanning

An experimental protocol for assessing the mutability and effect of amino acid substitutions at specific positions or across entire proteins.

Epitopes

The parts of an antigen that are recognized by the host adaptive immune response.

Antigenicity

The quality determining the appearance of an antigen to the immune system.

Avidity

The strength of binding between an antigen and a receptor based on multiple chemical bonds.

Dynamical models

A mathematical abstraction of the time-dependent behaviour of an object or system.

Mucociliary clearance

The removal of pathogens by the movement of mucus in the upper respiratory tract by ciliated cells.

Infectious dose

The number of pathogen particles that initiate an infection.

Antigenic distance

A measure of antigenic similarity derived from quantitative representations of haemagglutination inhibition assay data.

Immune waning

The process by which antibody titres or general immune reactivity declines with time in the absence of stimulation.

Immunological backboosting

The recall of previously acquired immune memory upon infection or vaccination with a partially cross-reactive antigen.

Antigenic seniority

The phenomenon of having higher antibody titres to influenza virus variants encountered earlier in life than to more recent viruses.

Bottlenecks

Contractions in population diversity associated with reductions in population size.

Adjuvant

A pharmacological agent that affects the breadth and/or strength of the immune response.

Antisera

The antibody-containing portions of the blood, which are specific for a given pathogen.

Immune repertoire sequencing

Targeted genetic sequencing of the B cell or T cell receptor genes.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Petrova, V., Russell, C. The evolution of seasonal influenza viruses. Nat Rev Microbiol 16, 47–60 (2018). https://doi.org/10.1038/nrmicro.2017.118

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro.2017.118

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: Microbiology