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:

Opportunities and challenges for T cell-based influenza vaccines

Nature Reviews Immunology (2024)Cite this article

Subjects

Abstract

Vaccination remains our main defence against influenza, which causes substantial annual mortality and poses a serious pandemic threat. Influenza virus evades immunity by rapidly changing its surface antigens but, even when the vaccine is well matched to the current circulating virus strains, influenza vaccines are not as effective as many other vaccines. Influenza vaccine development has traditionally focused on the induction of protective antibodies, but there is mounting evidence that T cell responses are also protective against influenza. Thus, future vaccines designed to promote both broad T cell effector functions and antibodies may provide enhanced protection. As we discuss, such vaccines present several challenges that require new strategic and economic considerations. Vaccine-induced T cells relevant to protection may reside in the lungs or lymphoid tissues, requiring more invasive assays to assess the immunogenicity of vaccine candidates. T cell functions may contain and resolve infection rather than completely prevent infection and early illness, requiring vaccine effectiveness to be assessed based on the prevention of severe disease and death rather than symptomatic infection. It can be complex and costly to measure T cell responses and infrequent clinical outcomes, and thus innovations in clinical trial design are needed for economic reasons. Nevertheless, the goal of more effective influenza vaccines justifies renewed and intensive efforts.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Burden of influenza in the USA.
Fig. 2: When and where do antibodies and T cells intercept the early stages of influenza virus infection?
Fig. 3: Relocation and expansion of T cell subpopulations during and between influenza virus infections or vaccinations.

Similar content being viewed by others

References

  1. Potter, C. W. A history of influenza. J. Appl. Microbiol. 91, 572–579 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Creighton, C. A History of Epidemics in Britain from A.D. 664 to the Extinction of Plague (Cambridge Univ. Press, 1891).

  3. Dowdle, W. R. Influenza A virus recycling revisited. Bull. World Health Organ. 77, 820–828 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Taubenberger, J. K., Reid, A. H., Krafft, A. E., Bijwaard, K. E. & Fanning, T. G. Initial genetic characterization of the 1918 “Spanish” influenza virus. Science 275, 1793–1796 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. World Health Organization. Recommended composition of influenza virus vaccines for use in the 2021–2022 northern hemisphere influenza season. Wkly. Epidemiological Rec. 96, 77–88 (2021).

    Google Scholar 

  7. World Health Organization. Recommended composition of influenza virus vaccines for use in the 2022–2023 northern hemisphere influenza season. Wkly Epidemiological Rec. 97, 109–132 (2022).

    Google Scholar 

  8. Jackson, L. A. Using surveillance to evaluate influenza vaccine effectiveness. J. Infect. Dis. 199, 155–158 (2009).

    Article  PubMed  Google Scholar 

  9. Jackson, M. L. & Nelson, J. C. The test-negative design for estimating influenza vaccine effectiveness. Vaccine 31, 2165–2168 (2013).

    Article  PubMed  Google Scholar 

  10. Sullivan, S. G., Tchetgen Tchetgen, E. J. & Cowling, B. J. Theoretical basis of the test-negative study design for assessment of influenza vaccine effectiveness. Am. J. Epidemiol. 184, 345–353 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Feng, S., Cowling, B. J., Kelly, H. & Sullivan, S. G. Estimating influenza vaccine effectiveness with the test-negative design using alternative control groups: a systematic review and meta-analysis. Am. J. Epidemiol. 187, 389–397 (2018).

    Article  PubMed  Google Scholar 

  12. Li, L. et al. Heterogeneity in estimates of the impact of influenza on population mortality: a systematic review. Am. J. Epidemiol. 187, 378–388 (2018).

    Article  PubMed  Google Scholar 

  13. Kissling, E. et al. Influenza vaccine effectiveness against influenza A subtypes in Europe: results from the 2021-2022 I-MOVE primary care multicentre study. Influenza Other Respir. Viruses 17, e13069 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  14. McLean, H. Q. et al. Interim estimates of 2022-23 seasonal influenza vaccine effectiveness - Wisconsin, October 2022-February 2023. MMWR Morb. Mortal. Wkly Rep. 72, 201–205 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Skowronski, D. M. et al. Vaccine effectiveness estimates from an early-season influenza A(H3N2) epidemic, including unique genetic diversity with reassortment, Canada, 2022/23. Eur. Surveill. 28, 2300043 (2023).

    Article  CAS  Google Scholar 

  16. CDC. Manual for the Surveillance of Vaccine-preventable Disease. Chapter 6, Influenza. https://www.cdc.gov/vaccines/pubs/surv-manual/chpt06-influenza.html (2023).

  17. Pulendran, B., Arunachalam, P. S. & O’Hagan, D. T. Emerging concepts in the science of vaccine adjuvants. Nat. Rev. Drug Discov. 20, 454–475 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Coffman, R. L., Sher, A. & Seder, R. A. Vaccine adjuvants: putting innate immunity to work. Immunity 33, 492–503 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Geckin, B., Fohse, F. K., Dominguez-Andres, J. & Netea, M. G. Trained immunity: implications for vaccination. Curr. Opin. Immunol. 77, 102190 (2022).

    Article  CAS  PubMed  Google Scholar 

  20. Parker, L. et al. Effects of egg-adaptation on receptor-binding and antigenic properties of recent influenza A (H3N2) vaccine viruses. J. Gen. Virol. 97, 1333–1344 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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). Description of an antibody that bound to a conserved epitope in the fusion subdomain of haemagglutinin and offered protection in mice against influenza A (H1N1) and influenza A (H3N2) viruses and in ferrets against influenza A (H5N1) virus.

    Article  CAS  PubMed  Google Scholar 

  22. Ekiert, D. C. et al. Antibody recognition of a highly conserved influenza virus epitope. Science 324, 246–251 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ekiert, D. C. et al. A highly conserved neutralizing epitope on group 2 influenza A viruses. Science 333, 843–850 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kallewaard, N. L. et al. Structure and function analysis of an antibody recognizing all influenza A subtypes. Cell 166, 596–608 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Xiao, H. et al. Light chain modulates heavy chain conformation to change protection profile of monoclonal antibodies against influenza A viruses. Cell Discov. 5, 21 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Krammer, F., Li, L. & Wilson, P. C. Emerging from the shadow of hemagglutinin: neuraminidase is an important target for influenza vaccination. Cell Host Microbe 26, 712–713 (2019).

    Article  CAS  PubMed  Google Scholar 

  27. Doyle, T. M. et al. Universal anti-neuraminidase antibody inhibiting all influenza A subtypes. Antivir. Res. 100, 567–574 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Rijal, P. et al. Broadly inhibiting antineuraminidase monoclonal antibodies induced by trivalent influenza vaccine and H7N9 infection in humans. J. Virol. 94, e01182-19 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Moore, K. A. et al. A research and development (R&D) roadmap for influenza vaccines: looking toward the future. Vaccine 39, 6573–6584 (2021). This describes a pathway to improved and universal influenza vaccines with links to an up-to-date tracking of their research and development.

    Article  PubMed  Google Scholar 

  30. Nachbagauer, R. et al. A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial. Nat. Med. 27, 106–114 (2021).

    Article  CAS  PubMed  Google Scholar 

  31. Folschweiller, N. et al. Reactogenicity, safety, and immunogenicity of chimeric haemagglutinin influenza split-virion vaccines, adjuvanted with AS01 or AS03 or non-adjuvanted: a phase 1-2 randomised controlled trial. Lancet Infect. Dis. 22, 1062–1075 (2022).

    Article  CAS  PubMed  Google Scholar 

  32. Lewis, N. M. et al. Interpretation of relative efficacy and effectiveness for influenza vaccines. Clin. Infect. Dis. 75, 170–175 (2022).

    Article  PubMed  Google Scholar 

  33. Izurieta, H. S. et al. Relative effectiveness of cell-cultured and egg-based influenza vaccines among elderly persons in the United States, 2017-2018. J. Infect. Dis. 220, 1255–1264 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Izurieta, H. S. et al. Relative effectiveness of influenza vaccines among the United States elderly, 2018-2019. J. Infect. Dis. 222, 278–287 (2020).

    Article  CAS  PubMed  Google Scholar 

  35. Izurieta, H. S. et al. Comparative effectiveness of influenza vaccines among US medicare beneficiaries ages 65 years and older during the 2019-2020 season. Clin. Infect. Dis. 73, e4251–e4259 (2021). The third of a series of reports on the relative vaccine effectiveness of enhanced seasonal influenza vaccines compared with standard egg-based vaccines in preventing hospital encounters among people aged >65 during the last influenza season prior to the emergence of COVID-19.

    Article  CAS  PubMed  Google Scholar 

  36. Boikos, C. et al. Relative effectiveness of adjuvanted trivalent inactivated influenza vaccine versus egg-derived quadrivalent inactivated influenza vaccines and high-dose trivalent influenza vaccine in preventing influenza-related medical encounters in US adults ≥65 years during the 2017-2018 and 2018-2019 influenza seasons. Clin. Infect. Dis. 73, 816–823 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Boikos, C. et al. Relative effectiveness of the cell-derived inactivated quadrivalent influenza vaccine versus egg-derived inactivated quadrivalent influenza vaccines in preventing influenza-related medical encounters during the 2018-2019 influenza season in the United States. Clin. Infect. Dis. 73, e692–e698 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Whitney, C. G. et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N. Engl. J. Med. 348, 1737–1746 (2003).

    Article  PubMed  Google Scholar 

  39. Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).

    Article  CAS  PubMed  Google Scholar 

  40. Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021).

    Article  CAS  PubMed  Google Scholar 

  41. Rachlin, A. et al. Progress toward polio eradication — worldwide, January 2020-April 2022. MMWR Morb. Mortal. Wkly Rep. 71, 650–655 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  42. de Quadros, C. A., Andrus, J. K., Danovaro-Holliday, M. C. & Castillo-Solorzano, C. Feasibility of global measles eradication after interruption of transmission in the Americas. Expert Rev. Vaccines 7, 355–362 (2008).

    Article  PubMed  Google Scholar 

  43. Minta, A. A. et al. Progress toward regional measles elimination — worldwide, 2000-2021. MMWR Morb. Mortal. Wkly Rep. 71, 1489–1495 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  44. 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 

  45. Francis, T. On the doctrine of original antigenic sin. Proc. Am. Philos. Soc. 104, 572–578 (1960). A perspective of the early work done by Francis, Davenport and Hennessey on how the recognition of influenza viruses is affected by an imprint established by the original virus infection governing later antibody responses.

    Google Scholar 

  46. Shanks, G. D., Hussell, T. & Brundage, J. F. Epidemiological isolation causing variable mortality in Island populations during the 1918-1920 influenza pandemic. Influenza Other Respir. Viruses 6, 417–423 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Mantle, J. & Tyrrell, D. A. An epidemic of influenza on Tristan da Cunha. J. Hyg. 71, 89–95 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nogales, A., Martinez-Sobrido, L., Topham, D. J. & DeDiego, M. L. Modulation of innate immune responses by the influenza A NS1 and PA-X proteins. Viruses 10, 708 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Harper, D. M. et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 364, 1757–1765 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Villa, L. L. et al. Immunologic responses following administration of a vaccine targeting human papillomavirus types 6, 11, 16, and 18. Vaccine 24, 5571–5583 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Falsey, A. R. et al. Efficacy and safety of an Ad26.RSV.preF-RSV preF protein vaccine in older adults. N. Engl. J. Med. 388, 609–620 (2023).

    Article  CAS  PubMed  Google Scholar 

  52. Leroux-Roels, I. et al. Safety and immunogenicity of a respiratory syncytial virus prefusion F (RSVPreF3) candidate vaccine in older adults: phase I/II randomized clinical trial. J. Infect. Dis. 227, 761–772 (2023).

    Article  CAS  PubMed  Google Scholar 

  53. Tsang, T. K. et al. Investigation of CD4 and CD8 T cell-mediated protection against influenza A virus in a cohort study. BMC Med. 20, 230 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Phillips, R. E. et al. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature 354, 453–459 (1991).

    Article  CAS  PubMed  Google Scholar 

  55. GeurtsvanKessel, C. H. et al. Divergent SARS-CoV-2 Omicron-reactive T and B cell responses in COVID-19 vaccine recipients. Sci. Immunol. 7, eabo2202 (2022).

    Article  CAS  PubMed  Google Scholar 

  56. Deng, N., Weaver, J. M. & Mosmann, T. R. Cytokine diversity in the Th1-dominated human anti-influenza response caused by variable cytokine expression by Th1 cells, and a minor population of uncommitted IL-2+IFNγ– Thpp cells. PLoS One 9, e95986 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  57. de Jong, M. D. et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat. Med. 12, 1203–1207 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Crotty, S. T follicular helper cell biology: a decade of discovery and diseases. Immunity 50, 1132–1148 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Nguyen, T. H. O. et al. Immune cellular networks underlying recovery from influenza virus infection in acute hospitalized patients. Nat. Commun. 12, 2691 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Herati, R. S. et al. Vaccine-induced ICOS+CD38+ circulating Tfh are sensitive biosensors of age-related changes in inflammatory pathways. Cell Rep. Med. 2, 100262 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Koutsakos, M. et al. Circulating TFH cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity. Sci. Transl. Med. 10, eaan8405 (2018).

    Article  PubMed  Google Scholar 

  62. Laidlaw, B. J., Craft, J. E. & Kaech, S. M. The multifaceted role of CD4+ T cells in CD8+ T cell memory. Nat. Rev. Immunol. 16, 102–111 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Cullen, J. G. et al. CD4+ T help promotes influenza virus-specific CD8+ T cell memory by limiting metabolic dysfunction. Proc. Natl Acad. Sci. USA 116, 4481–4488 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lu, Y. J. et al. CD4 T cell help prevents CD8 T cell exhaustion and promotes control of Mycobacterium tuberculosis infection. Cell Rep. 36, 109696 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Son, Y. M. et al. Tissue-resident CD4+ T helper cells assist the development of protective respiratory B and CD8+ T cell memory responses. Sci. Immunol. 6, eabb6852 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Busselaar, J., Tian, S., van Eenennaam, H. & Borst, J. Helpless priming sends CD8+ T cells on the road to exhaustion. Front. Immunol. 11, 592569 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sant, A. J. & McMichael, A. Revealing the role of CD4+ T cells in viral immunity. J. Exp. Med. 209, 1391–1395 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cenerenti, M., Saillard, M., Romero, P. & Jandus, C. The era of cytotoxic CD4 T cells. Front. Immunol. 13, 867189 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  70. Brown, D. M., Lampe, A. T. & Workman, A. M. The differentiation and protective function of cytolytic CD4 T cells in influenza infection. Front. Immunol. 7, 93 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Hua, L. et al. Cytokine-dependent induction of CD4+ T cells with cytotoxic potential during influenza virus infection. J. Virol. 87, 11884–11893 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. van Leeuwen, E. M., Remmerswaal, E. B., Heemskerk, M. H., ten Berge, I. J. & van Lier, R. A. Strong selection of virus-specific cytotoxic CD4+ T-cell clones during primary human cytomegalovirus infection. Blood 108, 3121–3127 (2006).

    Article  PubMed  Google Scholar 

  73. Chen, M. & Wang, J. Programmed cell death of dendritic cells in immune regulation. Immunol. Rev. 236, 11–27 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Zweerink, H. J., Courtneidge, S. A., Skehel, J. J., Crumpton, M. J. & Askonas, B. A. Cytotoxic T cells kill influenza virus infected cells but do not distinguish between serologically distinct type A viruses. Nature 267, 354–356 (1977).

    Article  CAS  PubMed  Google Scholar 

  75. Doherty, P. C., Biddison, W. E., Bennink, J. R. & Knowles, B. B. Cytotoxic T-cell responses in mice infected with influenza and vaccinia viruses vary in magnitude with H-2 genotype. J. Exp. Med. 148, 534–543 (1978).

    Article  CAS  PubMed  Google Scholar 

  76. Effros, R. B., Doherty, P. C., Gerhard, W. & Bennink, J. Generation of both cross-reactive and virus-specific T-cell populations after immunization with serologically distinct influenza A viruses. J. Exp. Med. 145, 557–568 (1977).

    Article  CAS  PubMed  Google Scholar 

  77. McMichael, A. J., Ting, A., Zweerink, H. J. & Askonas, B. A. HLA restriction of cell-mediated lysis of influenza virus-infected human cells. Nature 270, 524–526 (1977).

    Article  CAS  PubMed  Google Scholar 

  78. Bennink, J. R., Yewdell, J. W. & Gerhard, W. A viral polymerase involved in recognition of influenza virus-infected cells by a cytotoxic T-cell clone. Nature 296, 75–76 (1982).

    Article  CAS  PubMed  Google Scholar 

  79. Gotch, F., McMichael, A., Smith, G. & Moss, B. Identification of viral molecules recognized by influenza-specific human cytotoxic T lymphocytes. J. Exp. Med. 165, 408–416 (1987).

    Article  CAS  PubMed  Google Scholar 

  80. Townsend, A. R., Skehel, J. J., Taylor, P. M. & Palese, P. Recognition of influenza A virus nucleoprotein by an H-2-restricted cytotoxic T-cell clone. Virology 133, 456–459 (1984).

    Article  CAS  PubMed  Google Scholar 

  81. Topham, D. J. & Reilly, E. C. Tissue-resident memory CD8+ T cells: from phenotype to function. Front. Immunol. 9, 515 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Farber, D. L. Tissues, not blood, are where immune cells function. Nature 593, 506–509 (2021).

    Article  CAS  PubMed  Google Scholar 

  83. Zheng, M. Z. M. & Wakim, L. M. Tissue resident memory T cells in the respiratory tract. Mucosal Immunol. 15, 379–388 (2022).

    Article  CAS  PubMed  Google Scholar 

  84. Rotrosen, E. & Kupper, T. S. Assessing the generation of tissue resident memory T cells by vaccines. Nat. Rev. Immunol. 23, 655–665 (2023).

    Article  CAS  PubMed  Google Scholar 

  85. Ray, S. J. et al. The collagen binding α1β1 integrin VLA-1 regulates CD8 T cell-mediated immune protection against heterologous influenza infection. Immunity 20, 167–179 (2004). This study of lung-resident T cells showed that CD49A was required for maintenance in the lungs but not lymphoid tissues, and loss of the lung-resident population after CD49A blockade was associated with reduced resistance to subsequent influenza virus re-infection.

    Article  CAS  PubMed  Google Scholar 

  86. Wu, T. et al. Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection. J. Leukoc. Biol. 95, 215–224 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Ariotti, S. et al. Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen. Proc. Natl Acad. Sci. USA 109, 19739–19744 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Pizzolla, A. et al. Influenza-specific lung-resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles. J. Clin. Invest. 128, 721–733 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Gaide, O. et al. Common clonal origin of central and resident memory T cells following skin immunization. Nat. Med. 21, 647–653 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Park, S. L. et al. Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses. Nat. Immunol. 19, 183–191 (2018).

    Article  CAS  PubMed  Google Scholar 

  91. Ely, K. H., Cookenham, T., Roberts, A. D. & Woodland, D. L. Memory T cell populations in the lung airways are maintained by continual recruitment. J. Immunol. 176, 537–543 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  93. Snyder, M. E. et al. Generation and persistence of human tissue-resident memory T cells in lung transplantation. Sci. Immunol. 4, eaav5581 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Moyron-Quiroz, J. E. et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat. Med. 10, 927–934 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Takamura, S. Niches for the long-term maintenance of tissue-resident memory T cells. Front. Immunol. 9, 1214 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Yap, K. L., Ada, G. L. & McKenzie, I. F. Transfer of specific cytotoxic T lymphocytes protects mice inoculated with influenza virus. Nature 273, 238–239 (1978).

    Article  CAS  PubMed  Google Scholar 

  97. Taylor, P. M. & Askonas, B. A. Influenza nucleoprotein-specific cytotoxic T-cell clones are protective in vivo. Immunology 58, 417–420 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Graham, M. B., Braciale, V. L. & Braciale, T. J. Influenza virus-specific CD4+ T helper type 2T lymphocytes do not promote recovery from experimental virus infection. J. Exp. Med. 180, 1273–1282 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Scherle, P. A., Palladino, G. & Gerhard, W. Mice can recover from pulmonary influenza virus infection in the absence of class I-restricted cytotoxic T cells. J. Immunol. 148, 212–217 (1992).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  102. Paterson, S. et al. Innate-like gene expression of lung-resident memory CD8+ T cells during experimental human influenza: a clinical study. Am. J. Respir. Crit. Care Med. 204, 826–841 (2021). This human influenza virus challenge study also incorporated local sampling by bronchoalveolar lavage, providing valuable information on T cell responses in the lung.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Omokanye, A. et al. Clonotypic analysis of protective influenza M2e-specific lung resident Th17 memory cells reveals extensive functional diversity. Mucosal Immunol. 15, 717–729 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  105. Hayward, A. C. et al. Natural T cell-mediated protection against seasonal and pandemic influenza. Results of the flu watch cohort study. Am. J. Respir. Crit. Care Med. 191, 1422–1431 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhao, M. et al. Prolonged evolution of virus-specific memory T cell immunity after severe avian influenza A (H7N9) virus infection. J. Virol. 92, e01024–18 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Von Holle, T. A. & Moody, M. A. Influenza and antibody-dependent cellular cytotoxicity. Front. Immunol. 10, 1457 (2019).

    Article  Google Scholar 

  108. Jegaskanda, S. et al. Generation and protective ability of influenza virus-specific antibody-dependent cellular cytotoxicity in humans elicited by vaccination, natural infection, and experimental challenge. J. Infect. Dis. 214, 945–952 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Edgar, J. E. et al. Antibodies elicited in humans upon chimeric hemagglutinin-based influenza virus vaccination confer FcγR-dependent protection in vivo. Proc. Natl Acad. Sci. USA 120, e2314905120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Laidlaw, B. J. et al. Cooperativity between CD8+ T cells, non-neutralizing antibodies, and alveolar macrophages is important for heterosubtypic influenza virus immunity. PLoS Pathog. 9, e1003207 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Paluch, C., Santos, A. M., Anzilotti, C., Cornall, R. J. & Davis, S. J. Immune checkpoints as therapeutic targets in autoimmunity. Front. Immunol. 9, 2306 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Rerks-Ngarm, S. et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N. Engl. J. Med. 361, 2209–2220 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Gray, G. E. et al. Vaccine efficacy of ALVAC-HIV and bivalent subtype C gp120-MF59 in adults. N. Engl. J. Med. 384, 1089–1100 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Allan, W. H., Madeley, C. R. & Kendal, A. P. Studies with avian influenza A viruses: cross protection experiments in chickens. J. Gen. Virol. 12, 79–84 (1971).

    Article  CAS  PubMed  Google Scholar 

  115. Beutner, K. R. et al. Evaluation of a neuraminidase-specific influenza A virus vaccine in children: antibody responses and effects on two successive outbreaks of natural infection. J. Infect. Dis. 140, 844–850 (1979).

    Article  CAS  PubMed  Google Scholar 

  116. Couch, R. B., Kasel, J. A., Gerin, J. L., Schulman, J. L. & Kilbourne, E. D. Induction of partial immunity to influenza by a neuraminidase-specific vaccine. J. Infect. Dis. 129, 411–420 (1974).

    Article  CAS  PubMed  Google Scholar 

  117. Skehel, J. J. Polypeptide synthesis in influenza virus-infected cells. Virology 49, 23–36 (1972).

    Article  CAS  PubMed  Google Scholar 

  118. Shapiro, G. I., Gurney, T. Jr & Krug, R. M. Influenza virus gene expression: control mechanisms at early and late times of infection and nuclear-cytoplasmic transport of virus-specific RNAs. J. Virol. 61, 764–773 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Hu, Y., Sneyd, H., Dekant, R. & Wang, J. Influenza A virus nucleoprotein: a highly conserved multi-functional viral protein as a hot antiviral drug target. Curr. Top. Med. Chem. 17, 2271–2285 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Babar, M. M. & Zaidi, N. U. Protein sequence conservation and stable molecular evolution reveals influenza virus nucleoprotein as a universal druggable target. Infect. Genet. Evol. 34, 200–210 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Wraith, D. C., Vessey, A. E. & Askonas, B. A. Purified influenza virus nucleoprotein protects mice from lethal infection. J. Gen. Virol. 68, 433–440 (1987).

    Article  CAS  PubMed  Google Scholar 

  122. Andrew, M. E., Coupar, B. E., Boyle, D. B. & Ada, G. L. The roles of influenza virus haemagglutinin and nucleoprotein in protection: analysis using vaccinia virus recombinants. Scand. J. Immunol. 25, 21–28 (1987).

    Article  CAS  PubMed  Google Scholar 

  123. Christensen, J. P., Doherty, P. C., Branum, K. C. & Riberdy, J. M. Profound protection against respiratory challenge with a lethal H7N7 influenza A virus by increasing the magnitude of CD8+ T-cell memory. J. Virol. 74, 11690–11696 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Tite, J. P. et al. Anti-viral immunity induced by recombinant nucleoprotein of influenza A virus. II. Protection from influenza infection and mechanism of protection. Immunology 71, 202–207 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Ulmer, J. B. et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 259, 1745–1749 (1993).

    Article  CAS  PubMed  Google Scholar 

  126. Ulmer, J. B. et al. Protective CD4+ and CD8+ T cells against influenza virus induced by vaccination with nucleoprotein DNA. J. Virol. 72, 5648–5653 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Xie, C., Yao, R. & Xia, X. The advances of adjuvants in mRNA vaccines. NPJ Vaccines 8, 162 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Hochheiser, K. et al. Cutting edge: the RIG-I ligand 3pRNA potently improves CTL cross-priming and facilitates antiviral vaccination. J. Immunol. 196, 2439–2443 (2016).

    Article  CAS  PubMed  Google Scholar 

  129. Valencia-Hernandez, A. M. et al. Complexing CpG adjuvants with cationic liposomes enhances vaccine-induced formation of liver TRM cells. Vaccine 41, 1094–1107 (2023).

    Article  CAS  PubMed  Google Scholar 

  130. Bonifaz, L. et al. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J. Exp. Med. 196, 1627–1638 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Iborra, S. et al. Optimal generation of tissue-resident but not circulating memory T cells during viral infection requires crosspriming by DNGR-1+ dendritic cells. Immunity 45, 847–860 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wakim, L. M., Smith, J., Caminschi, I., Lahoud, M. H. & Villadangos, J. A. Antibody-targeted vaccination to lung dendritic cells generates tissue-resident memory CD8 T cells that are highly protective against influenza virus infection. Mucosal Immunol. 8, 1060–1071 (2015).

    Article  CAS  PubMed  Google Scholar 

  133. Vatzia, E. et al. Immunization with matrix-, nucleoprotein and neuraminidase protects against H3N2 influenza challenge in pH1N1 pre-exposed pigs. NPJ Vaccines 8, 19 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Shin, H. & Iwasaki, A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature 491, 463–467 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Pan, Y. et al. Epicutaneous immunization with modified vaccinia Ankara viral vectors generates superior T cell immunity against a respiratory viral challenge. Vaccines 6, 1 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Oberhardt, V. et al. Rapid and stable mobilization of CD8+ T cells by SARS-CoV-2 mRNA vaccine. Nature 597, 268–273 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Gao, F. et al. Spheromers reveal robust T cell responses to the Pfizer/BioNTech vaccine and attenuated peripheral CD8+ T cell responses post SARS-CoV-2 infection. Immunity 56, 864–878.e4 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Mateus, J. et al. Low-dose mRNA-1273 COVID-19 vaccine generates durable memory enhanced by cross-reactive T cells. Science 374, eabj9853 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ssemaganda, A. et al. Expansion of cytotoxic tissue-resident CD8+ T cells and CCR6+CD161+CD4+ T cells in the nasal mucosa following mRNA COVID-19 vaccination. Nat. Commun. 13, 3357 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Mitsi, E. et al. Respiratory mucosal immune memory to SARS-CoV-2 after infection and vaccination. Nat. Commun. 14, 6815 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Xiong, F. et al. An mRNA-based broad-spectrum vaccine candidate confers cross-protection against heterosubtypic influenza A viruses. Emerg. Microbes Infect. 12, 2256422 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Lee, I. T. et al. Safety and immunogenicity of a phase 1/2 randomized clinical trial of a quadrivalent, mRNA-based seasonal influenza vaccine (mRNA-1010) in healthy adults: interim analysis. Nat. Commun. 14, 3631 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Bahl, K. et al. Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol. Ther. 25, 1316–1327 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Feldman, R. A. et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 37, 3326–3334 (2019).

    Article  CAS  PubMed  Google Scholar 

  145. Ewer, K. J. et al. T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial. Nat. Med. 27, 270–278 (2021).

    Article  CAS  PubMed  Google Scholar 

  146. Stephenson, K. E. et al. Immunogenicity of the Ad26.COV2.S vaccine for COVID-19. JAMA 325, 1535–1544 (2021).

    Article  CAS  PubMed  Google Scholar 

  147. Knight, F. C. & Wilson, J. T. Engineering vaccines for tissue-resident memory T cells. Adv. Ther. 4, 2000230 (2021).

    Article  CAS  Google Scholar 

  148. Lillie, P. J. et al. Preliminary assessment of the efficacy of a T-cell-based influenza vaccine, MVA-NP+M1, in humans. Clin. Infect. Dis. 55, 19–25 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Evans, T. G. et al. Efficacy and safety of a universal influenza A vaccine (MVA-NP+M1) in adults when given after seasonal quadrivalent influenza vaccine immunisation (FLU009): a phase 2b, randomised, double-blind trial. Lancet Infect. Dis. 22, 857–866 (2022).

    Article  CAS  PubMed  Google Scholar 

  150. Del Campo, J. et al. OVX836 heptameric nucleoprotein vaccine generates lung tissue-resident memory CD8+ T-cells for cross-protection against influenza. Front. Immunol. 12, 678483 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Leroux-Roels, I. et al. Immunogenicity, safety, and preliminary efficacy evaluation of OVX836, a nucleoprotein-based universal influenza A vaccine candidate: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet Infect. Dis. 22, 857–866 (2023).

    Google Scholar 

  152. Leroux-Roels, I. et al. Randomized, double-blind, reference-controlled, phase 2a study evaluating the immunogenicity and safety of OVX836, a nucleoprotein-based influenza vaccine. Front. Immunol. 13, 852904 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Pleguezuelos, O. et al. Efficacy of FLU-v, a broad-spectrum influenza vaccine, in a randomized phase IIb human influenza challenge study. Vaccines 5, 22 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Taylor, P. M., Esquivel, F. & Askonas, B. A. Murine CD4+ T cell clones vary in function in vitro and in influenza infection in vivo. Int. Immunol. 2, 323–328 (1990).

    Article  CAS  PubMed  Google Scholar 

  155. Enelow, R. I. et al. Structural and functional consequences of alveolar cell recognition by CD8+ T lymphocytes in experimental lung disease. J. Clin. Invest. 102, 1653–1661 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Small, B. A. et al. CD8+ T cell-mediated injury in vivo progresses in the absence of effector T cells. J. Exp. Med. 194, 1835–1846 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Hoskins, T. W., Davies, J. R., Smith, A. J., Miller, C. L. & Allchin, A. Assessment of inactivated influenza-A vaccine after three outbreaks of influenza A at Christ’s Hospital. Lancet 1, 33–35 (1979).

    Article  CAS  PubMed  Google Scholar 

  158. Moss, P. The T cell immune response against SARS-CoV-2. Nat. Immunol. 23, 186–193 (2022).

    Article  CAS  PubMed  Google Scholar 

  159. Nishimura, Y. et al. Early antibody therapy can induce long-lasting immunity to SHIV. Nature 543, 559–563 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Zens, K. D., Chen, J. K. & Farber, D. L. Vaccine-generated lung tissue-resident memory T cells provide heterosubtypic protection to influenza infection. JCI Insight 1, e85832 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Tang, J. et al. Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination. Sci. Immunol. 7, eadd4853 (2022).

    Article  CAS  PubMed  Google Scholar 

  162. Brenna, E. et al. CD4+ T follicular helper cells in human tonsils and blood are clonally convergent but divergent from non-Tfh CD4+ cells. Cell Rep. 30, 137–152.e5 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Wagar, L. E. et al. Modeling human adaptive immune responses with tonsil organoids. Nat. Med. 27, 125–135 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Valkenburg, S. A. & Poon, L. L. M. Universal influenza vaccines are futile when benchmarked against seasonal influenza vaccines. Lancet Infect. Dis. 22, 750–751 (2022).

    Article  CAS  PubMed  Google Scholar 

  165. Wu, N. et al. Long-term effectiveness of COVID-19 vaccines against infections, hospitalisations, and mortality in adults: findings from a rapid living systematic evidence synthesis and meta-analysis up to December, 2022. Lancet Respir. Med. 11, 439–452 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Zheng, X. et al. Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge. PLoS Pathog. 15, e1008036 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Gouglas, D. et al. Estimating the cost of vaccine development against epidemic infectious diseases: a cost minimisation study. Lancet Glob. Health 6, e1386–e1396 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Bloom, D. E., Cadarette, D. & Tortorice, D. L. An ounce of prevention: our approach to vaccine finance is ill-suited to addressing epidemic risk. Finance Dev. 57, 54–57 (2020).

    Google Scholar 

  169. Plotkin, S., Robinson, J. M., Cunningham, G., Iqbal, R. & Larsen, S. The complexity and cost of vaccine manufacturing — an overview. Vaccine 35, 4064–4071 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

J.W.McC. is supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001030), the Medical Research Council (FC001030) and the Wellcome Trust (FC001030). A.J.McM. is supported by the CAMS-Oxford Institute.

Author information

Authors and Affiliations

  1. David H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, Rochester, NY, USA

    Tim R. Mosmann

  2. Centre for Immuno-Oncology, Old Road Campus Research Building, University of Oxford, Oxford, UK

    Andrew J. McMichael

  3. Osivax, Lyon, France

    Alexandre LeVert

  4. The Francis Crick Institute, London, UK

    John W. McCauley

  5. The Sir William Dunn School of Pathology, South Parks Road, University of Oxford, Oxford, UK

    Jeffrey W. Almond

Authors
  1. Tim R. Mosmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew J. McMichael
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexandre LeVert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John W. McCauley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey W. Almond
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Tim R. Mosmann.

Ethics declarations

Competing interests

T.R.M. is a member of the Osivax scientific advisory board. A.J.McM. is a member of the scientific advisory boards of Osivax, Oxford Vacmedix and T-Cypher Bio. A.L.V. is an employee and shareholder of Osivax. J.W.McC. has provided advice to CSL Seqirus, Sanofi Pasteur, Pfizer and Iceni Diagnostics. J.W.A. has provided scientific advice to Osivax, IosBios Ltd., Mynvax and Blue Lake Biotechnology. He is also a shareholder of Sanofi, Vaxcyte, Moderna and OVO Biomanufacturing Ltd.

Peer review

Peer review information

Nature Reviews Immunology thanks Katherine Kedzierska and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

CDC. About Diphtheria, Tetanus, and Pertussis Vaccines: https://www.cdc.gov/vaccines/vpd/dtap-tdap-td/hcp/about-vaccine.html

CDC. About HPV Vaccines: https://www.cdc.gov/vaccines/vpd/hpv/hcp/vaccines.html

CDC. Past Seasons Estimated Influenza Disease Burden: https://www.cdc.gov/flu/about/burden/past-seasons.html

Influenza Vaccines Roadmap: https://ivr.cidrap.umn.edu/universal-influenza-vaccine-technology-landscape

Measles & Rubella Partnership: https://measlesrubellainitiative.org/measles-rubella-strategic-framework-2021-2030/

Polio Global Eradication Initiative: https://polioeradication.org/

WHO. FluNet Summary: https://www.who.int/tools/flunet/flunet-summary

WHO. Measles: https://www.who.int/news-room/fact-sheets/detail/measles

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mosmann, T.R., McMichael, A.J., LeVert, A. et al. Opportunities and challenges for T cell-based influenza vaccines. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-024-01030-8

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41577-024-01030-8

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