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  • Review Article
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Co-evolution of immunity and seasonal influenza viruses

Nature Reviews Microbiology volume 21, pages 805–817 (2023)Cite this article

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Abstract

Seasonal influenza viruses cause recurring global epidemics by continually evolving to escape host immunity. The viral constraints and host immune responses that limit and drive the evolution of these viruses are increasingly well understood. However, it remains unclear how most of these advances improve the capacity to reduce the impact of seasonal influenza viruses on human health. In this Review, we synthesize recent progress made in understanding the interplay between the evolution of immunity induced by previous infections or vaccination and the evolution of seasonal influenza viruses driven by the heterogeneous accumulation of antibody-mediated immunity in humans. We discuss the functional constraints that limit the evolution of the viruses, the within-host evolutionary processes that drive the emergence of new virus variants, as well as current and prospective options for influenza virus control, including the viral and immunological barriers that must be overcome to improve the effectiveness of vaccines and antiviral drugs.

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Fig. 1: The evolution of seasonal influenza viruses.
Fig. 2: Factors affecting seasonal influenza virus antibody dynamics and their effects on viral evolution.
Fig. 3: Within-host evolution of seasonal influenza viruses.

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References

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

    Article  PubMed  Google Scholar 

  2. Chambers, B. S., Parkhouse, K., Ross, T. M., Alby, K. & Hensley, S. E. Identification of hemagglutinin residues responsible for H3N2 antigenic drift during the 2014–2015 influenza season. Cell Rep. 12, 1–6 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tenforde, M. W. et al. Effect of antigenic drift on influenza vaccine effectiveness in the United States—2019–2020. Clin. Infect. Dis. 73, e4244–e4250 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Petrova, V. N. & Russell, C. A. The evolution of seasonal influenza viruses. Nat. Rev. Microbiol. 16, 47–60 (2017).

    Article  PubMed  Google Scholar 

  5. Neumann, G. & Kawaoka, Y. Transmission of influenza A viruses. Virology 479–480, 234–246 (2015).

    Article  PubMed  Google Scholar 

  6. Koutsakos, M., Nguyen, T. H., Barclay, W. S. & Kedzierska, K. Knowns and unknowns of influenza B viruses. Future Microbiol. 11, 119–135 (2015).

    Article  PubMed  Google Scholar 

  7. van de Sandt, C. E., Bodewes, R., Rimmelzwaan, G. F. & de Vries, R. D. Influenza B viruses: not to be discounted. Future Microbiol. 10, 1447–1465 (2015).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  9. Rota, P. A. et al. Cocirculation of two distinct evolutionary lineages of influenza type B virus since 1983. Virology 175, 59–68 (1990).

    Article  CAS  PubMed  Google Scholar 

  10. Zamarin, D., García-Sastre, A., Xiao, X., Wang, R. & Palese, P. Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog. 1, e4 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  11. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fernandez-Sesma, A. et al. Influenza virus evades innate and adaptive immunity via the NS1 protein. J. Virol. 80, 6295–6304 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Krammer, F. The human antibody response to influenza A virus infection and vaccination. Nat. Rev. Immunol. 19, 383–397 (2019).

    Article  CAS  PubMed  Google Scholar 

  14. Nelson, M. I. & Holmes, E. C. The evolution of epidemic influenza. Nat. Rev. Genet. 8, 196–205 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Garten, R. J. et al. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 325, 197–201 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  18. Smith, D. J. et al. Mapping the antigenic and genetic evolution of influenza virus. Science 305, 371–376 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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. Epidemiol. Infect. 70, 767–777 (1972).

    Article  CAS  Google Scholar 

  21. Bedford, T. et al. Global circulation patterns of seasonal influenza viruses vary with antigenic drift. Nature 523, 217–220 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  23. Virk, R. K. et al. Divergent evolutionary trajectories of influenza B viruses underlie their contemporaneous epidemic activity. Proc. Natl Acad. Sci. USA 117, 619–628 (2020).

    Article  CAS  PubMed  Google Scholar 

  24. Langat, P. et al. Genome-wide evolutionary dynamics of influenza B viruses on a global scale. PLoS Pathog. 13, e1006749 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Minter, A. et al. Estimation of seasonal influenza attack rates and antibody dynamics in children using cross-sectional serological data. J. Infect. Dis. 225, 1750–1754 (2022).

    Article  CAS  PubMed  Google Scholar 

  26. Victora, G. D. & Wilson, P. C. Germinal center selection and the antibody response to influenza. Cell 163, 545–548 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Guthmiller, J. J. et al. Broadly neutralizing antibodies target a haemagglutinin anchor epitope. Nature 602, 314–320 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Tsang, T. K. et al. Reconstructing antibody dynamics to estimate the risk of influenza virus infection. Nat. Commun. 13, 1557 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yang, B. et al. Life course exposures continually shape antibody profiles and risk of seroconversion to influenza. PLoS Pathog. 16, e1008635 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ranjeva, S. et al. Age-specific differences in the dynamics of protective immunity to influenza. Nat. Commun. 10, 1660 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ng, S. et al. Novel correlates of protection against pandemic H1N1 influenza A virus infection. Nat. Med. 25, 962–967 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hoa, L. N. M. et al. Influenza A(H1N1)pdm09 but not A(H3N2) virus infection induces durable seroprotection: results from the Ha Nam cohort. J. Infect. Dis. 226, 59–69 (2022).

    Article  CAS  PubMed  Google Scholar 

  33. Wraith, S. et al. Homotypic protection against influenza in a pediatric cohort in Managua, Nicaragua. Nat. Commun. 13, 1190 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  35. Amitai, A. et al. Defining and manipulating B cell immunodominance hierarchies to elicit broadly neutralizing antibody responses against influenza virus. Cell Syst. 11, 573–588.e9 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Labombarde, J. G. et al. Induction of broadly reactive influenza antibodies increases susceptibility to autoimmunity. Cell Rep. 38, 110482 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  39. Nachbagauer, R. et al. Age dependence and isotype specificity of influenza virus hemagglutinin stalk-reactive antibodies in humans. mBio 7, e01996-15 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  40. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tan, G. S. et al. A pan-H1 anti-hemagglutinin monoclonal antibody with potent broad-spectrum efficacy in vivo. J. Virol. 86, 6179–6188 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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).

    Article  CAS  PubMed  Google Scholar 

  43. Meade, P. et al. Influenza virus infection induces a narrow antibody response in children but a broad recall response in adults. mBio 11, e03243-19 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chen, Y.-Q. et al. Influenza infection in humans induces broadly cross-reactive and protective neuraminidase-reactive antibodies. Cell 173, 417–429.e10 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Monto, A. S. et al. Antibody to influenza virus neuraminidase: an independent correlate of protection. J. Infect. Dis. 212, 1191–1199 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. Weiss, C. D. et al. Neutralizing and neuraminidase antibodies correlate with protection against influenza during a late season A/H3N2 outbreak among unvaccinated military recruits. Clin. Infect. Dis. 71, 3096–3102 (2020).

    Article  CAS  PubMed  Google Scholar 

  49. Maier, H. E. et al. Pre-existing antineuraminidase antibodies are associated with shortened duration of influenza A(H1N1)pdm virus shedding and illness in naturally infected adults. Clin. Infect. Dis. 70, 2290–2297 (2020).

    Article  CAS  PubMed  Google Scholar 

  50. Dugan, H. L. et al. Preexisting immunity shapes distinct antibody landscapes after influenza virus infection and vaccination in humans. Sci. Transl Med. 12, eabd3601 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Auladell, M. et al. Influenza virus infection history shapes antibody responses to influenza vaccination. Nat. Med. 28, 363–372 (2022).

    Article  CAS  PubMed  Google Scholar 

  52. Lee, J. M. et al. Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin. eLife 8, e49324 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Doud, M. B., Lee, J. M. & Bloom, J. D. How single mutations affect viral escape from broad and narrow antibodies to H1 influenza hemagglutinin. Nat. Commun. 9, 1386 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Medina, R. A. et al. Glycosylations in the globular head of the hemagglutinin protein modulate the virulence and antigenic properties of the H1N1 influenza viruses. Sci. Transl Med. 5, 187ra70 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Altman, M. O. et al. Human influenza a virus hemagglutinin glycan evolution follows a temporal pattern to a glycan limit. mBio 10, e00204-19 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. Webster, R. G. & Laver, W. G. Determination of the number of nonoverlapping antigenic areas on Hong Kong (H3N2) influenza virus hemagglutinin with monoclonal antibodies and the selection of variants with potential epidemiological significance. Virology 104, 139–148 (1980).

    Article  CAS  PubMed  Google Scholar 

  58. 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).

    Article  CAS  PubMed  Google Scholar 

  59. Wang, Q., Cheng, F., Lu, M., Tian, X. & Ma, J. Crystal structure of unliganded influenza B virus hemagglutinin. J. Virol. 82, 3011–3020 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rosu, M. E. et al. Substitutions near the HA receptor binding site explain the origin and major antigenic change of the B/Victoria and B/Yamagata lineages. Proc. Natl Acad. Sci. USA 119, e2211616119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 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).

    Article  PubMed  Google Scholar 

  62. Chai, N. et al. Two escape mechanisms of influenza A virus to a broadly neutralizing stalk-binding antibody. PLoS Pathog. 12, e1005702 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Anderson, C. S. et al. Natural and directed antigenic drift of the H1 influenza virus hemagglutinin stalk domain. Sci. Rep. 7, 4265 (2017).

    Article  Google Scholar 

  64. Wang, W. et al. Generation of a protective murine monoclonal antibody against the stem of influenza hemagglutinins from group 1 viruses and identification of resistance mutations against it. PLoS ONE 14, e0222436 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Park, J. K. et al. Pre-existing immunity to influenza virus hemagglutinin stalk might drive selection for antibody-escape mutant viruses in a human challenge model. Nat. Med. 26, 1240–1246 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lee, C.-Y. et al. Epistasis reduces fitness costs of influenza A virus escape from stem-binding antibodies. Proc. Natl Acad. Sci. USA 120, e2208718120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wu, N. C. et al. Different genetic barriers for resistance to HA stem antibodies in influenza H3 and H1 viruses. Science 368, 1335–1340 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Colman, P. M., Varghese, J. N. & Laver, W. G. Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature 303, 41–44 (1983).

    Article  CAS  PubMed  Google Scholar 

  69. Colman, P. M. et al. Three-dimensional structure of a complex of antibody with influenza virus neuraminidase. Nature 326, 358–363 (1987).

    Article  CAS  PubMed  Google Scholar 

  70. Webster, R. G., Brown, L. E. & Laver, W. G. Antigenic and biological characterization of influenza virus neuraminidase (N2) with monoclonal antibodies. Virology 135, 30–42 (1984).

    Article  CAS  PubMed  Google Scholar 

  71. Krammer, F. et al. NAction! how can neuraminidase-based immunity contribute to better influenza virus vaccines? mBio 9, e02332-17 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Air, G. M., Els, M. C., Brown, L. E., Laver, W. G. & Webster, R. G. Location of antigenic sites on the three-dimensional structure of the influenza N2 virus neuraminidase. Virology 145, 237–248 (1985).

    Article  CAS  PubMed  Google Scholar 

  73. Varghese, J. N., Webster, R. G., Laver, W. G. & Colman, P. M. Structure of an escape mutant of glycoprotein N2 neuraminidase of influenza virus A/Tokyo/3/67 at 3 Å. J. Mol. Biol. 200, 201–203 (1988).

    Article  CAS  PubMed  Google Scholar 

  74. Gulati, U. et al. Antibody epitopes on the neuraminidase of a recent H3N2 influenza virus (A/Memphis/31/98). J. Virol. 76, 12274–12280 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wan, H. et al. The neuraminidase of A(H3N2) influenza viruses circulating since 2016 is antigenically distinct from the A/Hong Kong/4801/2014 vaccine strain. Nat. Microbiol. 4, 2216–2225 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Powell, H. & Pekosz, A. Neuraminidase antigenic drift of H3N2 clade 3c.2a viruses alters virus replication, enzymatic activity and inhibitory antibody binding. PLoS Pathog. 16, e1008411 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Li, Z.-N. et al. Antibody landscape analysis following influenza vaccination and natural infection in humans with a high-throughput multiplex influenza antibody detection assay. mBio 12, e02808–e02820 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kucharski, A. J., Lessler, J., Cummings, D. A. T. & Riley, S. Timescales of influenza A/H3N2 antibody dynamics. PLoS Biol. 16, e2004974 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Linderman, S. L. & Hensley, S. E. Antibodies with ‘original antigenic sin’ properties are valuable components of secondary immune responses to influenza viruses. PLoS Pathog. 12, e1005806 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Arevalo, C. P. et al. Original antigenic sin priming of influenza virus hemagglutinin stalk antibodies. Proc. Natl Acad. Sci. USA 117, 17221–17227 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Dugan, H. L. & Wilson, P. C. Teach ’em young: influenza vaccines induce broadly neutralizing antibodies in children. Cell Rep. Med. 3, 100531 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Gostic, K. M. et al. Childhood immune imprinting to influenza A shapes birth year-specific risk during seasonal H1N1 and H3N2 epidemics. PLoS Pathog. 15, e1008109 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Brouwer, A. F. et al. Birth cohort relative to an influenza A virus’s antigenic cluster introduction drives patterns of children’s antibody titers. PLoS Pathog. 18, e1010317 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Arevalo, P., McLean, H. Q., Belongia, E. A. & Cobey, S. Earliest infections predict the age distribution of seasonal influenza A cases. eLife 9, e50060 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Vieira, M. C. et al. Lineage-specific protection and immune imprinting shape the age distributions of influenza B cases. Nat. Commun. 12, 4313 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Gagnon, A., Acosta, E. & Miller, M. S. Age-specific incidence of influenza A responds to change in virus subtype dominance. Clin. Infect. Dis. 71, e195–e198 (2020).

    Article  CAS  PubMed  Google Scholar 

  89. Gouma, S. et al. Middle-aged individuals may be in a perpetual state of H3N2 influenza virus susceptibility. Nat. Commun. 11, 4566 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Xu, R. et al. Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus. Science 328, 357–360 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Horns, F., Vollmers, C., Dekker, C. L. & Quake, S. R. Signatures of selection in the human antibody repertoire: selective sweeps, competing subclones, and neutral drift. Proc. Natl Acad. Sci. USA 116, 1261–1266 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Vollmers, C., Sit, R. V., Weinstein, J. A., Dekker, C. L. & Quake, S. R. Genetic measurement of memory B-cell recall using antibody repertoire sequencing. Proc. Natl Acad. Sci. USA 110, 13463–13468 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  97. Horns, F., Dekker, C. L. & Quake, S. R. Memory B cell activation, broad anti-influenza antibodies, and bystander activation revealed by single-cell transcriptomics. Cell Rep. 30, 905–913.e6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lee, J. et al. Persistent antibody clonotypes dominate the serum response to influenza over multiple years and repeated vaccinations. Cell Host Microbe 25, 367–376.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hoehn, K. B. et al. Human B cell lineages associated with germinal centers following influenza vaccination are measurably evolving. eLife 10, e70873 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Hoehn, K. B. et al. Repertoire-wide phylogenetic models of B cell molecular evolution reveal evolutionary signatures of aging and vaccination. Proc. Natl Acad. Sci. USA 116, 22664–22672 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Schmidt, A. G. et al. Immunogenic stimulus for germline precursors of antibodies that engage the influenza hemagglutinin receptor-binding site. Cell Rep. 13, 2842–2850 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Tesini, B. L. et al. Broad hemagglutinin-specific memory B cell expansion by seasonal influenza virus infection reflects early-life imprinting and adaptation to the infecting virus. J. Virol. 93, e00169-19 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  104. de Bourcy, C. F. A. et al. Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging. Proc. Natl Acad. Sci. USA 114, 1105–1110 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Ju, C.-H. et al. Plasmablast antibody repertoires in elderly influenza vaccine responders exhibit restricted diversity but increased breadth of binding across influenza strains. Clin. Immunol. 193, 70–79 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Henry, C. et al. Influenza virus vaccination elicits poorly adapted B cell responses in elderly individuals. Cell Host Microbe 25, 357–366.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lee, J. M. et al. Deep mutational scanning of hemagglutinin helps predict evolutionary fates of human H3N2 influenza variants. Proc. Natl Acad. Sci. USA 115, E8276–E8285 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Das, S. R. et al. Fitness costs limit influenza A virus hemagglutinin glycosylation as an immune evasion strategy. Proc. Natl Acad. Sci. USA 108, E1417-22 (2011).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Broecker, F. et al. Immunodominance of antigenic site B in the hemagglutinin of the current H3N2 influenza virus in humans and mice. J. Virol. 92, e01100-18 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Wu, N. C. & Wilson, I. A. A perspective on the structural and functional constraints for immune evasion: insights from influenza virus. J. Mol. Biol. 429, 2694–2709 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Wu, N. C. et al. Major antigenic site B of human influenza H3N2 viruses has an evolving local fitness landscape. Nat. Commun. 11, 1233 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wu, N. C. et al. A complex epistatic network limits the mutational reversibility in the influenza hemagglutinin receptor-binding site. Nat. Commun. 9, 1264 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Wu, N. C. et al. Diversity of functionally permissive sequences in the receptor-binding site of influenza hemagglutinin. Cell Host Microbe 21, 742–753.e8 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Duan, S. et al. Epistatic interactions between neuraminidase mutations facilitated the emergence of the oseltamivir-resistant H1N1 influenza viruses. Nat. Commun. 5, 5029 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. Wang, Y., Lei, R., Nourmohammad, A. & Wu, N. C. Antigenic evolution of human influenza H3N2 neuraminidase is constrained by charge balancing. eLife 10, e72516 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lei, R. et al. Prevalence and mechanisms of evolutionary contingency in human influenza H3N2 neuraminidase. Nat. Commun. 13, 6443 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kosik, I. & Yewdell, J. W. Influenza hemagglutinin and neuraminidase: Yin–Yang proteins coevolving to thwart immunity. Viruses 11, 346 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lakdawala, S. S. et al. Eurasian-origin gene segments contribute to the transmissibility, aerosol release, and morphology of the 2009 pandemic H1N1 influenza virus. PLoS Pathog. 7, e1002443 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Xu, R. et al. Functional balance of the hemagglutinin and neuraminidase activities accompanies the emergence of the 2009 H1N1 influenza pandemic. J. Virol. 86, 9221–9232 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. de Vries, E., Du, W., Guo, H. & de Haan, C. A. M. Influenza A virus hemagglutinin–neuraminidase–receptor balance: preserving virus motility. Trends Microbiol. 28, 57–67 (2020).

    Article  PubMed  Google Scholar 

  125. Liu, T., Wang, Y., Tan, T. J. C., Wu, N. C. & Brooke, C. B. The evolutionary potential of influenza A virus hemagglutinin is highly constrained by epistatic interactions with neuraminidase. Cell Host Microbe 30, 1363–1369.e4 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 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).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Müller, N. F., Stolz, U., Dudas, G., Stadler, T. & Vaughan, T. G. Bayesian inference of reassortment networks reveals fitness benefits of reassortment in human influenza viruses. Proc. Natl Acad. Sci. USA 117, 17104–17111 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Potter, B. I. et al. Evolution and rapid spread of a reassortant A(H3N2) virus that predominated the 2017–2018 influenza season. Virus Evol. 5, vez046 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Dudas, G., Bedford, T., Lycett, S. & Rambaut, A. Reassortment between influenza B lineages and the emergence of a coadapted PB1-PB2-HA gene complex. Mol. Biol. Evol. 32, 162–172 (2015).

    Article  CAS  PubMed  Google Scholar 

  132. Kim, Jil. et al. Reassortment compatibility between PB1, PB2, and HA genes of the two influenza B virus lineages in mammalian cells. Sci. Rep. 6, 27480 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Lakdawala, S. S. et al. Influenza A virus assembly intermediates fuse in the cytoplasm. PLoS Pathog. 10, e1003971 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Gog, J. R. et al. Codon conservation in the influenza A virus genome defines RNA packaging signals. Nucleic Acids Res. 35, 1897–1907 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Dadonaite, B. et al. The structure of the influenza A virus genome. Nat. Microbiol. 4, 1781–1789 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. le Sage, V. et al. Mapping of influenza virus RNA-RNA interactions reveals a flexible network. Cell Rep. 31, 107823 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Jones, J. E. et al. Parallel evolution between genomic segments of seasonal human influenza viruses reveals RNA-RNA relationships. eLife 10, e66525 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  138. McCrone, J. T. et al. Stochastic processes constrain the within and between host evolution of influenza virus. eLife 7, e35962 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Debbink, K. et al. Vaccination has minimal impact on the intrahost diversity of H3N2 influenza viruses. PLoS Pathog. 13, e1006194 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Sobel Leonard, A. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Dinis, J. M. et al. Deep sequencing reveals potential antigenic variants at low frequencies in influenza A virus-infected humans. J. Virol. 90, 3355–3365 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Valesano, A. L. et al. Influenza B viruses exhibit lower within-host diversity than influenza A viruses in human hosts. J. Virol. 94, e01710–e01719 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Han, A. X., Maurer-Stroh, S. & Russell, C. A. Individual immune selection pressure has limited impact on seasonal influenza virus evolution. Nat. Ecol. Evol. 3, 302–311 (2019).

    Article  PubMed  Google Scholar 

  144. Xue, K. S. & Bloom, J. D. Linking influenza virus evolution within and between human hosts. Virus Evol. 6, 812016 (2020).

    Article  Google Scholar 

  145. Lumby, C. K., Zhao, L., Breuer, J. & Illingworth, C. J. R. A large effective population size for established within-host influenza virus infection. eLife 9, e56915 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  147. Xue, K. S. & Bloom, J. D. Reconciling disparate estimates of viral genetic diversity during human influenza infections. Nat. Genet. 51, 1298–1301 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Ghafari, M., Lumby, C. K., Weissman, D. B. & Illingworth, C. J. R. Inferring transmission bottleneck size from viral sequence data using a novel haplotype reconstruction method. J. Virol. 94, e00014-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Morris, D. H. et al. Asynchrony between virus diversity and antibody selection limits influenza virus evolution. eLife 9, e62105 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Amato, K. A. et al. Influenza A virus undergoes compartmentalized replication in vivo dominated by stochastic bottlenecks. Nat. Commun. 13, 3416 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. 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).

    Article  CAS  PubMed  Google Scholar 

  152. Ng, S. et al. The timeline of influenza virus shedding in children and adults in a household transmission study of influenza in Managua, Nicaragua. Pediatr. Infect. Dis. J. 35, 583–586 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Han, A. X. et al. Within-host evolutionary dynamics of seasonal and pandemic human influenza A viruses in young children. eLife 10, e68917 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Hurt, A. C. Antiviral therapy for the next influenza pandemic. Trop. Med. Infect. Dis. 4, 67 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Hayden, F. G. et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus Infections. N. Engl. J. Med. 337, 874–880 (1997).

    Article  CAS  PubMed  Google Scholar 

  156. Nicholson, K. G. et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Lancet 355, 1845–1850 (2000).

    Article  CAS  PubMed  Google Scholar 

  157. Kohno, S., Kida, H., Mizuguchi, M. & Shimada, J. Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection. Antimicrob. Agents Chemother. 54, 4568–4574 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Hayden, F. G. et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N. Engl. J. Med. 379, 913–923 (2018).

    Article  CAS  PubMed  Google Scholar 

  159. Koel, B. F. et al. Longitudinal sampling is required to maximize detection of intrahost A/H3N2 virus variants. Virus Evol. 6, veaa088 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Omoto, S. et al. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci. Rep. 8, 9633 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Holmes, E. C. et al. Understanding the impact of resistance to influenza antivirals. Clin. Microbiol. Rev. 34, e00224-20 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Du, Z., Nugent, C., Galvani, A. P., Krug, R. M. & Meyers, L. A. Modeling mitigation of influenza epidemics by baloxavir. Nat. Commun. 11, 2750 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Han, A. X. et al. Estimating the potential need and impact of SARS-CoV-2 test-and-treat programs with oral antivirals in low-and-middle-income countries. Preprint at medRxiv, https://doi.org/10.1101/2022.10.05.22280727 (2022).

  164. Clark, T. W. et al. Clinical impact of a routine, molecular, point-of-care, test-and-treat strategy for influenza in adults admitted to hospital (FluPOC): a multicentre, open-label, randomised controlled trial. Lancet Respir. Med. 9, 419–429 (2021).

    Article  CAS  PubMed  Google Scholar 

  165. Gal, M. et al. Matching diagnostics development to clinical need: target product profile development for a point of care test for community-acquired lower respiratory tract infection. PLoS ONE 13, e0200531 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Kotnik, J. H. et al. Flu@home: the comparative accuracy of an at-home influenza rapid diagnostic test using a prepositioned test kit, mobile app, mail-in reference sample, and symptom-based testing trigger. J. Clin. Microbiol. 60, e0207021 (2022).

    Article  PubMed  Google Scholar 

  167. Yamayoshi, S. & Kawaoka, Y. Current and future influenza vaccines. Nat. Med. 25, 212–220 (2019).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  169. Gouma, S., Weirick, M. & Hensley, S. E. Antigenic assessment of the H3N2 component of the 2019-2020 Northern Hemisphere influenza vaccine. Nat. Commun. 11, 2445 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Flannery, B. et al. Spread of antigenically drifted influenza A(H3N2) viruses and vaccine effectiveness in the United States during the 2018–2019 season. J. Infect. Dis. 221, 8–15 (2020).

    Article  CAS  PubMed  Google Scholar 

  171. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Wu, N. C. et al. A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine. PLoS Pathog. 13, e1006682 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Wu, N. C. et al. Preventing an antigenically disruptive mutation in egg-based H3N2 seasonal influenza vaccines by mutational incompatibility. Cell Host Microbe 25, 836–844.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Wei, C. J. et al. Next-generation influenza vaccines: opportunities and challenges. Nat. Rev. Drug Discov. 19, 239–252 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Dunkle, L. M. et al. Efficacy of recombinant influenza vaccine in adults 50 years of age or older. N. Engl. J. Med. 376, 2427–2436 (2017).

    Article  CAS  PubMed  Google Scholar 

  176. Pardi, N., Hogan, M. J. & Weissman, D. Recent advances in mRNA vaccine technology. Curr. Opin. Immunol. 65, 14–20 (2020).

    Article  CAS  PubMed  Google Scholar 

  177. Moderna. Moderna announces positive interim phase 1 data for mRNA flu vaccine and provides program update. Moderna https://investors.modernatx.com/news/news-details/2021/Moderna-Announces-Positive-Interim-Phase-1-Data-for-mRNA-Flu-Vaccine-and-Provides-Program-Update/default.aspx (2021).

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Impagliazzo, A. et al. A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen. Science 349, 1301–1306 (2015).

    Article  CAS  PubMed  Google Scholar 

  180. Yassine, H. M. et al. Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nat. Med. 21, 1065–1070 (2015).

    Article  CAS  PubMed  Google Scholar 

  181. Bernstein, D. I. et al. Immunogenicity of chimeric haemagglutinin-based, universal influenza virus vaccine candidates: interim results of a randomised, placebo-controlled, phase 1 clinical trial. Lancet Infect. Dis. 20, 80–91 (2020).

    Article  CAS  PubMed  Google Scholar 

  182. Boyoglu-Barnum, S. et al. Quadrivalent influenza nanoparticle vaccines induce broad protection. Nature 592, 623–628 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Freyn, A. W. et al. A multi-targeting, nucleoside-modified mRNA influenza virus vaccine provides broad protection in mice. Mol. Ther. 28, 1569–1584 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. McMahon, M. et al. Assessment of a quadrivalent nucleoside-modified mRNA vaccine that protects against group 2 influenza viruses. Proc. Natl Acad. Sci. USA 119, e2206333119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Pardi, N. et al. Development of a pentavalent broadly protective nucleoside-modified mRNA vaccine against influenza B viruses. Nat. Commun. 13, 4677 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Arevalo, C. P. et al. A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes. Science 378, 899–904 (2022).

    Article  CAS  PubMed  Google Scholar 

  187. Turner, J. S. et al. Human germinal centres engage memory and naive B cells after influenza vaccination. Nature 586, 127–132 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Zarnitsyna, V. I. et al. Masking of antigenic epitopes by antibodies shapes the humoral immune response to influenza. Philos. Trans. R. Soc. B Biol. Sci. 370, 20140248 (2015).

    Article  Google Scholar 

  189. Kim, J. H., Skountzou, I., Compans, R. & Jacob, J. Original antigenic sin responses to influenza viruses. J. Immunol. 183, 3294–3301 (2009).

    Article  CAS  PubMed  Google Scholar 

  190. Mesin, L. et al. Restricted clonality and limited germinal center reentry characterize memory B cell reactivation boosting. Cell 180, 92–106.e11 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. 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).

    Article  PubMed  Google Scholar 

  192. Olson, S. M. et al. Vaccine effectiveness against life-threatening influenza illness in US children. Clin. Infect. Dis. 75, 230–238 (2022).

    Article  PubMed  Google Scholar 

  193. Tenforde, M. W. et al. Influenza vaccine effectiveness against hospitalization in the United States, 2019–2020. J. Infect. Dis. 224, 813–820 (2021).

    Article  CAS  PubMed  Google Scholar 

  194. Ortiz, J. R. & Neuzil, K. M. Influenza immunization in low- and middle-income countries: preparing for next-generation influenza vaccines. J. Infect. Dis. 219, S97–S106 (2019).

    Article  PubMed  Google Scholar 

  195. Yang, H. et al. Structure and receptor binding preferences of recombinant human A(H3N2) virus hemagglutinins. Virology 477, 18–31 (2015).

    Article  CAS  PubMed  Google Scholar 

  196. Feng, L. et al. Impact of COVID-19 outbreaks and interventions on influenza in China and the United States. Nat. Commun. 12, 3249 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Qi, Y., Shaman, J. & Pei, S. Quantifying the impact of COVID-19 nonpharmaceutical interventions on influenza transmission in the United States. J. Infect. Dis. 224, 1500–1508 (2021).

    Article  CAS  PubMed  Google Scholar 

  198. Huang, Q. S. et al. Impact of the COVID-19 nonpharmaceutical interventions on influenza and other respiratory viral infections in New Zealand. Nat. Commun. 12, 1001 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Dhanasekaran, V. et al. Human seasonal influenza under COVID-19 and the potential consequences of influenza lineage elimination. Nat. Commun. 13, 1721 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Koutsakos, M., Wheatley, A. K., Laurie, K., Kent, S. J. & Rockman, S. Influenza lineage extinction during the COVID-19 pandemic? Nat. Rev. Microbiol. 19, 741–742 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Baker, R. E. et al. The impact of COVID-19 nonpharmaceutical interventions on the future dynamics of endemic infections. Proc. Natl Acad. Sci. USA 117, 30547–30553 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Ali, S. T. et al. Prediction of upcoming global infection burden of influenza seasons after relaxation of public health and social measures during the COVID-19 pandemic: a modelling study. Lancet Glob. Health 10, e1612–e1622 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Nielsen, J. et al. European all-cause excess and influenza-attributable mortality in the 2017/18 season: should the burden of influenza B be reconsidered? Clin. Microbiol. Infect. 25, 1266–1276 (2019).

    Article  CAS  PubMed  Google Scholar 

  204. Borchering, R. K. et al. Anomalous influenza seasonality in the United States and the emergence of novel influenza B viruses. Proc. Natl Acad. Sci. USA 118, e2012327118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Tan, J., Asthagiri Arunkumar, G. & Krammer, F. Universal influenza virus vaccines and therapeutics: where do we stand with influenza B virus? Curr. Opin. Immunol. 53, 45–50 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the European Research Council for financial support under grant no. 818353 and the Dutch Research Council (NWO) for financial support under VICI grant number 09150182010027.

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  1. These authors contributed equally: Alvin X. Han, Simon P.J. de Jong.

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  1. Department of Medical Microbiology & Infection Prevention, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Alvin X. Han, Simon P. J. de Jong & Colin A. Russell

  2. Department of Global Health, School of Public Health, Boston University, Boston, MA, USA

    Colin A. Russell

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Glossary

Antigenic drift

Gradual accumulation of genetic mutations in the surface glycoproteins of seasonal influenza viruses that periodically result in the emergence of a novel antigenic variant.

Antigenic seniority

A concept in immunology in which immune responses of individuals to pathogens experienced earlier in life tend to be stronger and more long lasting than those to pathogens experienced later in life.

Backboosting antibody response

Antibody response to infection or vaccination based on the recall of previously acquired immune memory response to a partially cross-reactive antigen or epitope.

Bottleneck

Reduction in population size that results in a contraction in genetic diversity.

Deep mutational scanning

An experimental method that uses high-throughput sequencing technology to measure the functional capacity of amino acid substitutions across a set of, or all, positions of a protein.

Genome reassortment

Genomic rearrangement of two or more influenza viruses that infect the same cell by mixing their genetic segments to result in a genetically novel virus.

Haemagglutination inhibition (HAI) assays

Experimental assays that characterize the antigenicity of viruses by measuring the ability of host serum to inhibit agglutination of red blood cells by the virus.

Immunodominant

Describes an antigen or epitope as the preferential target of the immune system.

Neuraminidase inhibition (NAI) assays

Experimental assays that measure the ability of host serum to block the sialidase activity of neuraminidase.

Original antigenic sin

(OAS). Refers to the immunological imprinting of the first exposure to influenza viruses during childhood. Subsequent infections by antigenically distinct influenza viruses boost the response to epitopes shared between these viruses.

Within-host evolution

Evolution of viruses that occurs at the level of an individual infected host.

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Han, A.X., de Jong, S.P.J. & Russell, C.A. Co-evolution of immunity and seasonal influenza viruses. Nat Rev Microbiol 21, 805–817 (2023). https://doi.org/10.1038/s41579-023-00945-8

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