Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans
Abstract
Protective immunity against influenza virus infection is mediated by neutralizing antibodies, but the precise role of T cells in human influenza immunity is uncertain. We conducted influenza infection studies in healthy volunteers with no detectable antibodies to the challenge viruses H3N2 or H1N1. We mapped T cell responses to influenza before and during infection. We found a large increase in influenza-specific T cell responses by day 7, when virus was completely cleared from nasal samples and serum antibodies were still undetectable. Preexisting CD4+, but not CD8+, T cells responding to influenza internal proteins were associated with lower virus shedding and less severe illness. These CD4+ cells also responded to pandemic H1N1 (A/CA/07/2009) peptides and showed evidence of cytotoxic activity. These cells are an important statistical correlate of homotypic and heterotypic response and may limit severity of influenza infection by new strains in the absence of specific antibody responses. Our results provide information that may aid the design of future vaccines against emerging influenza strains.
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Cross-reactive T cells can provide some degree of protective immunity against respiratory viral infections, as seen in the 2009 influenza H1N1 pandemic.
“Cross-reactive T cells can provide some degree of protective immunity against respiratory viral infections, as seen in the influenza H1N1 2009 pandemic (Sridhar et al., 2013; Wilkinson et al., 2012).”
From Adaptive immunity to SARS-CoV-2 and COVID-19 (2021) · cites this paper as Wilkinson et al., 2012
Cites
Cytotoxic T-Cell Immunity to Influenza
McMichael, A. J., Gotch, F. M., Noble, G. R., & Beare, P. A. (1983) · New England Journal of Medicine · doi:10.1056/nejm198307073090103 · Cited by 931 · see citing works
Self-citationHelping the CD8+ T-cell response
Bevan, M. J. (2004) · Nature reviews. Immunology · doi:10.1038/nri1413 · Cited by 790 · see citing works
The Critical Need for CD4 Help in Maintaining Effective Cytotoxic T Lymphocyte Responses
Kalams, S. A., & Walker, B. D. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.12.2199 · Cited by 660 · see citing works
Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10
Sun, J., Madan, R., Karp, C. L., & Braciale, T. J. (2009) · Nature Medicine · doi:10.1038/nm.1929 · Cited by 616 · see citing works
Triple-Reassortant Swine Influenza A (H1) in Humans in the United States, 2005–2009
Shinde, V., Bridges, C. B., Uyeki, T. M., Shu, B., Balish, A. L., Xu, X., Lindstrom, S., Gubareva, L. V., Deyde, V., Garten, R. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0903812 · Cited by 606 · see citing works
Self-citationGenomic analysis of increased host immune and cell death responses induced by 1918 influenza virus
Kash, J. C., Tumpey, T. M., Proll, S. C., Carter, V., Perwitasari, O., Thomas, M. J., Basler, C. F., Palese, P., Taubenberger, J. K., García-Sastre, A., et al. (2006) · Nature · doi:10.1038/nature05181 · Cited by 551 · see citing works
CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help
Nakanishi, Y., Lu, B., Gerard, C. J., & Iwasaki, A. (2009) · Nature · doi:10.1038/nature08511 · Cited by 545 · see citing works
Characterization of CD4+ CTLs Ex Vivo
Appay, V., Zaunders, J. J., Papagno, L., Sutton, J., Jaramillo, A., Waters, A., Easterbrook, P., Grey, P., Smith, D. E., McMichael, A. J., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.11.5954 · Cited by 545 · see citing works
Self-citationT Cell Responses to Whole SARS Coronavirus in Humans
Li, C. K., Wu, H., Yan, H., Ma, S., Wang, L., Zhang, M., Tang, X., Temperton, N. J., Weiss, R. A., Brenchley, J. M., et al. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.8.5490 · Cited by 499 · see citing works
Self-citationCD8+ T cells clear influenza virus by perforin or Fas-dependent processes
Topham, D. J., Tripp, R. A., & Doherty, P. C. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.159.11.5197 · Cited by 486 · see citing works
Emerging Infections: Pandemic Influenza
Glezen, W. P. (1996) · Epidemiologic Reviews · doi:10.1093/oxfordjournals.epirev.a017917 · Cited by 462 · see citing works
A question of self‐preservation: immunopathology in influenza virus infection
Gruta, N. L. L., Kedzierska, K., Stambas, J., & Doherty, P. C. (2007) · Immunology and Cell Biology · doi:10.1038/sj.icb.7100026 · Cited by 454 · see citing works
Lee, L. Y.-H., Do, L. A. H., Simmons, C. P., de Jong, M. D., Châu, N. V. V., Schumacher, R., Peng, Y. C., McMichael, A. J., Farrar, J., Smith, G. L., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci32460 · Cited by 423 · see citing works
Self-citationCasazza, J. P., Betts, M. R., Price, D. A., Precopio, M., Ruff, L. E., Brenchley, J. M., Hill, B. J., Roederer, M., Douek, D. C., & Koup, R. A. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20052246 · Cited by 338 · see citing works
Self-citationBoth, G. W., Sleigh, M. J., Cox, N. J., & Kendal, A. P. (1983) · Journal of Virology · doi:10.1128/jvi.48.1.52-60.1983 · Cited by 327 · see citing works
Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection
Shin, H., Blackburn, S. D., Blattman, J. N., & Wherry, E. J. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20061937 · Cited by 273 · see citing works
Influenza Vaccine — Outmaneuvering Antigenic Shift and Drift
Treanor, J. J. (2004) · New England Journal of Medicine · doi:10.1056/nejmp038238 · Cited by 261 · see citing works
Error thresholds and the constraints to RNA virus evolution
Holmes, E. C. (2003) · Trends in Microbiology · doi:10.1016/j.tim.2003.10.006 · Cited by 254 · see citing works
The Origins of Pandemic Influenza — Lessons from the 1918 Virus
Belshe, R. B. (2005) · New England Journal of Medicine · doi:10.1056/nejmp058281 · Cited by 235 · see citing works
Kreijtz, J. H. C. M., Bodewes, R., van Amerongen, G., Kuiken, T., Fouchier, R. A. M., Osterhaus, A. D. M. E., & Rimmelzwaan, G. F. (2006) · Vaccine · doi:10.1016/j.vaccine.2006.08.036 · Cited by 229 · see citing works
Efficient lysis of human immunodeficiency virus type 1-infected cells by cytotoxic T lymphocytes
Yang, O. O., Kalams, S. A., Rosenzweig, M., Piechocka‐Trocha, A., Jones, N. G., Koziel, M. J., Walker, B. D., & Johnson, R. P. (1996) · Journal of Virology · doi:10.1128/jvi.70.9.5799-5806.1996 · Cited by 217 · see citing works
Lin, H., Rathmell, J. C., Gray, G. S., Thompson, C. B., Leiden, J. M., & Alegre, M. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.1.199 · Cited by 182 · see citing works
Healthy Human Subjects Have CD4+ T Cells Directed against H5N1 Influenza Virus
Roti, M., Yang, J., Berger, D., Huston, L., James, E. A., & Kwok, W. W. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.3.1758 · Cited by 130 · see citing works
van de Berg, P. J., van Leeuwen, E. M. M., ten Berge, I. J. M., & van Lier, R. A. W. (2008) · Current Opinion in Immunology · doi:10.1016/j.coi.2008.03.007 · Cited by 129 · see citing works
Riley, S., Kwok, K. O., Wu, K. M., Ning, D. Y., Cowling, B. J., Wu, J. T. K., Ho, L., Tsang, T., Lo, S., Chu, D. K. W., et al. (2011) · PLoS Medicine · doi:10.1371/journal.pmed.1000442 · Cited by 108 · see citing works
Li, I. W. S., Hung, I. F., To, K. K., Chan, K., Wong, S. S. Y., Chan, J. F., Cheng, V. C., Tsang, O. T.-Y., Lai, S.-T., Lau, Y., et al. (2010) · CHEST Journal · doi:10.1378/chest.09-3072 · Cited by 105 · see citing works
Ge, X., Tan, V., Bollyky, P. L., Standifer, N. E., James, E. A., & Kwok, W. W. (2010) · Journal of Virology · doi:10.1128/jvi.02226-09 · Cited by 101 · see citing works
Richards, K. A., Topham, D. J., Chaves, F. A., & Sant, A. J. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1001395 · Cited by 79 · see citing works
Hallmarks of CD4 T cell immunity against influenza
McKinstry, K. K., Strutt, T. M., & Swain, S. L. (2011) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2011.02367.x · Cited by 79 · see citing works
Correlates of protection: Novel generations of influenza vaccines
Rimmelzwaan, G. F., & McElhaney, J. E. (2008) · Vaccine · doi:10.1016/j.vaccine.2008.07.043 · Cited by 78 · see citing works
An overview of serum antibody responses to influenza virus antigens.
Couch, R. B. (2003) · PubMed · Cited by 68 · see citing works
Stambas, J., Guillonneau, C., Kedzierska, K., Mintern, J., Doherty, P., & Gruta, N. L. L. (2008) · Pharmacology and Therapeutics · doi:10.1016/j.pharmthera.2008.08.007 · Cited by 46 · see citing works
Reassortment between human A(H3N2) viruses is an important evolutionary mechanism
Schweiger, B., Bruns, L., & Meixenberger, K. (2006) · Vaccine · doi:10.1016/j.vaccine.2006.05.105 · Cited by 44 · see citing works
Memory T-Cell Response to Rotavirus Detected with a Gamma Interferon Enzyme-Linked Immunospot Assay
Kaufhold, R. M., Field, J. A., Caulfield, M. J., Wang, S., Joseph, H., Wooters, M. A., Green, T., Clark, H. F., Krah, D. L., & Smith, J. G. (2005) · Journal of Virology · doi:10.1128/jvi.79.9.5684-5694.2005 · Cited by 36 · see citing works
Surveillance and impact of influenza in Europe
Aymard, M., Valette, M., Lina, B., & Thouvenot, D. (1999) · Vaccine · doi:10.1016/s0264-410x(99)00103-6 · Cited by 23 · see citing works
Epidemiology and Virology of Influenza Illness
Monto, A. S. (2000) · The American Journal of Managed Care · Cited by 22 · see citing works
Clinical and laboratory diagnosis of influenza virus infections.
Newton, D. W., Treanor, J. J., & Menegus, M. A. (2000) · PubMed · Cited by 21 · see citing works
Identification of T-Cell Epitopes Using ELISpot and Peptide Pool Arrays
Tobery, T. W., & Caulfield, M. J. (2004) · Humana Press eBooks · doi:10.1385/1-59259-679-7:121 · Cited by 20 · see citing works
Safety and efficacy of live attenuated, cold-adapted, influenza vaccine-trivalent
Belshe, R. B., & Mendelman, P. M. (2003) · Immunology and Allergy Clinics of North America · doi:10.1016/s0889-8561(03)00098-5 · Cited by 19 · see citing works
Intraseasonal Dynamics and Dominant Sequences in H3N2 Influenza
Creanza, N., Schwarz, J. S., & Cohen, J. E. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008544 · Cited by 12 · see citing works
Plaque Formation with Influenza Viruses in Dog Kidney Cells
Ho, P. P. K., Young, A. L., & Truehaft, M. (1976) · Journal of General Virology · doi:10.1099/0022-1317-33-1-143 · Cited by 10 · see citing works
Would you volunteer to be quarantined and infected with influenza virus?
OXFORD, J. S., Gelder, C. M., & Lambkin‐Williams, R. (2005) · Expert Review of Anti-infective Therapy · doi:10.1586/14787210.3.1.1 · Cited by 9 · see citing works
Self-citationEpidemiology and virology of influenza illness. Based on a presentation by Arnold S. Monto, MD.
(2000) · PubMed · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Grifoni, A., Weiskopf, D., Ramirez, S. I., Mateus, J., Dan, J. M., Moderbacher, C. R., Rawlings, S. A., Sutherland, A., Premkumar, L., Jadi, R. S., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.015 · Cited by 3,595 · see citing works
Adaptive immunity to SARS-CoV-2 and COVID-19
Sette, A., & Crotty, S. (2021) · Cell · doi:10.1016/j.cell.2021.01.007 · Cited by 1,860 · see citing works
Robust T Cell Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19
Sekine, T., Perez-Potti, A., Rivera-Ballesteros, O., Strålin, K., Gorin, J.-B., Olsson, A., Llewellyn-Lacey, S., Kamal, H., Bogdanovic, G., Muschiol, S., et al. (2020) · Cell · doi:10.1016/j.cell.2020.08.017 · Cited by 1,788 · see citing works
Krammer, F., Smith, G. J. D., Fouchier, R. A. M., Peiris, M. J. S., Kedzierska, K., Doherty, P. C., Palese, P., Shaw, M. L., Treanor, J. J., Webster, R. G., et al. (2018) · Nature Reviews Disease Primers · doi:10.1038/s41572-018-0002-y · Cited by 1,589 · see citing works
Mathew, D., Giles, J. R., Baxter, A. E., Oldridge, D. A., Greenplate, A. R., Wu, J. E., Alanio, C., Kuri-Cervantes, L., Pampena, M. B., D’Andrea, K., et al. (2020) · Science · doi:10.1126/science.abc8511 · Cited by 1,509 · see citing works
Self-citationThe T cell immune response against SARS-CoV-2
Moss, P. A. H. (2022) · Nature Immunology · doi:10.1038/s41590-021-01122-w · Cited by 1,205 · see citing works
Peng, Y., Mentzer, A. J., Liu, G., Yao, X., Yin, Z., Dong, D., Dejnirattisai, W., Rostron, T., Supasa, P., Liu, C., et al. (2020) · Nature Immunology · doi:10.1038/s41590-020-0782-6 · Cited by 1,179 · see citing works
Self-citationSun, L., Su, Y., Jiao, A., Wang, X., & Zhang, B. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01471-y · Cited by 1,057 · see citing works
Lin, L., Lu, L., Cao, W., & Li, T. (2020) · Emerging Microbes & Infections · doi:10.1080/22221751.2020.1746199 · Cited by 909 · see citing works
Human memory T cells: generation, compartmentalization and homeostasis
Farber, D. L., Yudanin, N. A., & Restifo, N. P. (2014) · Nature Reviews Immunology · doi:10.1038/nri3567 · Cited by 897 · see citing works
Cellular immune correlates of protection against symptomatic pandemic influenza
Sridhar, S., Begom, S., Bermingham, A., Hoschler, K., Adamson, W., Carman, W., Bean, T., Barclay, W., Deeks, J. J., & Lalvani, A. (2013) · Nature Medicine · doi:10.1038/nm.3350 · Cited by 862 · see citing works
Tarke, A., Sidney, J., Methot, N., Yu, E. D., Zhang, Y., Dan, J. M., Goodwin, B., Rubiro, P., Sutherland, A., Wang, E., et al. (2021) · Cell Reports Medicine · doi:10.1016/j.xcrm.2021.100355 · Cited by 706 · see citing works
SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition
Nelde, A., Bilich, T., Heitmann, J. S., Maringer, Y., Salih, H. R., Roerden, M., Lübke, M., Bauer, J., Rieth, J., Wacker, M., et al. (2021) · Nature Immunology · doi:10.1038/s41590-020-00808-x · Cited by 582 · see citing works
Airway Memory CD4+ T Cells Mediate Protective Immunity against Emerging Respiratory Coronaviruses
Zhao, J., Zhao, J., Mangalam, A. K., Channappanavar, R., Fett, C., Meyerholz, D. K., Agnihothram, S., Baric, R. S., David, C. S., & Perlman, S. (2016) · Immunity · doi:10.1016/j.immuni.2016.05.006 · Cited by 496 · see citing works
COVID-19 Coronavirus Vaccine Design Using Reverse Vaccinology and Machine Learning
Ong, E., Wong, M. U., Huffman, A., & He, Y. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01581 · Cited by 499 · see citing works
Potent protection against H5N1 and H7N9 influenza via childhood hemagglutinin imprinting
Gostic, K. M., Ambrose, M. R., Worobey, M., & Lloyd‐Smith, J. O. (2016) · Science · doi:10.1126/science.aag1322 · Cited by 464 · see citing works
Petsch, B., Schnee, M., Vogel, A. B., Lange, E., Hoffmann, B., Voss, D., Schlake, T., Thess, A., Kallen, K.-J., Stitz, L., et al. (2012) · Nature Biotechnology · doi:10.1038/nbt.2436 · Cited by 461 · see citing works
Programs for the persistence, vigilance and control of human CD8+ lung-resident memory T cells
Hombrink, P., Helbig, C., Backer, R. A., Piet, B., Oja, A. E., Stark, R., Brasser, G., Jongejan, A., Jonkers, R. E., Nota, B., et al. (2016) · Nature Immunology · doi:10.1038/ni.3589 · Cited by 455 · see citing works
Zens, K. D., Chen, J. K., & Färber, D. L. (2016) · JCI Insight · doi:10.1172/jci.insight.85832 · Cited by 415 · see citing works
Influenza Virus: Dealing with a Drifting and Shifting Pathogen
Kim, H., Webster, R. G., & Webby, R. J. (2018) · Viral Immunology · doi:10.1089/vim.2017.0141 · Cited by 423 · see citing works
Zhao, Y., Qin, L., Zhang, P., Li, K., Liang, L., Sun, J., Xu, B., Dai, Y., Li, X., Zhang, C., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.139834 · Cited by 402 · see citing works
Self-citationInfection fatality rate of SARS-CoV2 in a super-spreading event in Germany
Streeck, H., Schulte, B., Kümmerer, B. M., Richter, E., Höller, T., Fuhrmann, C., Bartok, E., Dolscheid‐Pommerich, R., Berger, M., Wessendorf, L., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19509-y · Cited by 391 · see citing works
Yang, Z., Liu, J., Zhou, Y., Zhao, Q., Zhao, Q., & Liu, J. (2020) · Journal of Infection · doi:10.1016/j.jinf.2020.03.062 · Cited by 361 · see citing works
Heterogeneity of Human CD4 <sup>+</sup> T Cells Against Microbes
Sallusto, F. (2016) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032414-112056 · Cited by 336 · see citing works
Next-generation influenza vaccines: opportunities and challenges
Wei, C., Crank, M. C., Shiver, J. W., Graham, B. S., Mascola, J. R., & Nabel, G. J. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0056-x · Cited by 333 · see citing works
The history of MF59 ® adjuvant: a phoenix that arose from the ashes
O’Hagan, D. T., Ott, G. S., Nest, G. V., Rappuoli, R., & Giudice, G. D. (2012) · Expert Review of Vaccines · doi:10.1586/erv.12.140 · Cited by 318 · see citing works
Barrett, J. R., Belij-Rammerstorfer, S., Dold, C., Ewer, K. J., Folegatti, P. M., Gilbride, C., Halkerston, R., Hill, J., Jenkin, D., Stockdale, L., et al. (2021) · Nature Medicine · doi:10.1038/s41591-020-01179-4 · Cited by 315 · see citing works
Current and next generation influenza vaccines: Formulation and production strategies
Soema, P. C., Kompier, R., Amorij, J., & Kersten, G. F. A. (2015) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2015.05.023 · Cited by 315 · see citing works
Jóźwik, A., Habibi, M. S., Paras, A., Zhu, J., Guvenel, A., Dhariwal, J., Almond, M., Wong, E., Sykes, A., Maybeno, M., et al. (2015) · Nature Communications · doi:10.1038/ncomms10224 · Cited by 303 · see citing works
Integrative Physiology of Pneumonia
Quinton, L. J., Walkey, A. J., & Mizgerd, J. P. (2018) · Physiological Reviews · doi:10.1152/physrev.00032.2017 · Cited by 308 · see citing works
Correlates of protection against SARS‐CoV‐2 infection and COVID‐19 disease
Goldblatt, D., Alter, G., Crotty, S., & Plotkin, S. A. (2022) · Immunological Reviews · doi:10.1111/imr.13091 · Cited by 300 · see citing works
Lynn, D. J., Benson, S. C., Lynn, M. A., & Pulendran, B. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00554-7 · Cited by 300 · see citing works
Mucosal immune responses to infection and vaccination in the respiratory tract
Mettelman, R. C., Allen, E. K., & Thomas, P. G. (2022) · Immunity · doi:10.1016/j.immuni.2022.04.013 · Cited by 272 · see citing works
Immunological memory to SARS‐CoV ‐2 infection and COVID ‐19 vaccines
Sette, A., & Crotty, S. (2022) · Immunological Reviews · doi:10.1111/imr.13089 · Cited by 266 · see citing works
Hayward, A. C., Wang, L., Goonetilleke, N. P., Fragaszy, E., Bermingham, A., Copas, A. J., Dukes, O., Millett, E. R. C., Nazareth, I., Nguyen‐Van‐Tam, J. S., et al. (2015) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201411-1988oc · Cited by 266 · see citing works
Self-citationTregoning, J. S., Russell, R. F., & Kinnear, E. (2018) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2017.1415684 · Cited by 263 · see citing works
Wang, Z., Wan, Y., Qiu, C., Quiñones‐Parra, S. M., Zhu, Z., Loh, L., Tian, D., Ren, Y., Hu, Y., Zhang, X., et al. (2015) · Nature Communications · doi:10.1038/ncomms7833 · Cited by 262 · see citing works
Cross-reactive memory T cells and herd immunity to SARS-CoV-2
Lipsitch, M., Grad, Y. H., Sette, A., & Crotty, S. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-00460-4 · Cited by 260 · see citing works
Immunosenescence: influenza vaccination and the elderly
Haq, K., & McElhaney, J. E. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.03.008 · Cited by 256 · see citing works
Evasion of Influenza A Viruses from Innate and Adaptive Immune Responses
van de Sandt, C. E., Kreijtz, J. H. C. M., & Rimmelzwaan, G. F. (2012) · Viruses · doi:10.3390/v4091438 · Cited by 242 · see citing works
Complex Correlates of Protection After Vaccination
Plotkin, S. A. (2013) · Clinical Infectious Diseases · doi:10.1093/cid/cit048 · Cited by 239 · see citing works
Knudsen, N. P. H., Olsen, A. W., Buonsanti, C., Follmann, F., Zhang, Y., Coler, R. N., Fox, C. B., Meinke, A. L., D’Oro, U., Casini, D., et al. (2016) · Scientific Reports · doi:10.1038/srep19570 · Cited by 234 · see citing works
Saini, S. K., Hersby, D. S., Tamhane, T., Povlsen, H. R., Hernandez, S. P. A., Nielsen, M., Gang, A. O., & Hadrup, S. R. (2021) · Science Immunology · doi:10.1126/sciimmunol.abf7550 · Cited by 222 · see citing works
Slütter, B., Pewe, L. L., Kaech, S. M., & Harty, J. T. (2013) · Immunity · doi:10.1016/j.immuni.2013.09.013 · Cited by 228 · see citing works
Memory CD4+ T cells protect against influenza through multiple synergizing mechanisms
McKinstry, K. K., Strutt, T. M., Kuang, Y., Brown, D. M., Sell, S., Dutton, R. W., & Swain, S. L. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63689 · Cited by 223 · see citing works
Jóźwik, A., Habibi, M. S., Paras, A., Zhu, J., Guvenel, A., Dhariwal, J., Almond, M., Wong, E., Sykes, A., Maybeno, M., et al. (2016) · Nature Communications · doi:10.1038/ncomms11011 · Cited by 223 · see citing works
T Cell Responses to Viral Infections – Opportunities for Peptide Vaccination
Huber, S. K. R., van Beek, J., de Jonge, J., Luytjes, W., & van Baarle, D. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00171 · Cited by 221 · see citing works
(2021) · doi:10.1038/s41467-021-25167-5 · Cited by 216 · see citing works
Self-citationSkelly, D. T., Harding, A. C., Gilbert-Jaramillo, J., Knight, M. L., Longet, S., Brown, A., Adele, S., Adland, E., Brown, H., Team, M. L., et al. (2021) · doi:10.21203/rs.3.rs-226857/v2 · Cited by 216 · see citing works
Son, Y. M., Cheon, I. S., Wu, Y., Li, C., Wang, Z., Gao, X., Chen, Y., Takahashi, Y., Fu, Y., Dent, A. L., et al. (2021) · Science Immunology · doi:10.1126/sciimmunol.abb6852 · Cited by 210 · see citing works
Self-citationCorrelates of protection to influenza virus, where do we go from here?
Cox, R. J. (2013) · Human Vaccines & Immunotherapeutics · doi:10.4161/hv.22908 · Cited by 209 · see citing works
Influenza Vaccination Strategies: Comparing Inactivated and Live Attenuated Influenza Vaccines
Sridhar, S., Brokstad, K. A., & Cox, R. J. (2015) · Vaccines · doi:10.3390/vaccines3020373 · Cited by 209 · see citing works
Cytotoxic CD4 T Cells—Friend or Foe during Viral Infection?
Juno, J. A., van Bockel, D., Kent, S. J., Kelleher, A. D., Zaunders, J. J., & Munier, C. M. L. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00019 · Cited by 195 · see citing works
COVID-19 vaccines in patients with cancer: immunogenicity, efficacy and safety
Fendler, A., de Vries, E. G. E., GeurtsvanKessel, C. H., Haanen, J. B. A. G., Wormann, B. J., Turajlic, S., & von Lilienfeld‐Toal, M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00610-8 · Cited by 205 · see citing works
Immunology and efficacy of MF59-adjuvanted vaccines
Ko, E., & Kang, S. (2018) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2018.1495301 · Cited by 198 · see citing works
Antrobus, R., Coughlan, L., Berthoud, T. K., Dicks, M. D. J., Hill, A. V. S., Lambe, T., & Gilbert, S. C. (2013) · Molecular Therapy · doi:10.1038/mt.2013.284 · Cited by 197 · see citing works
Ward, B. J., Makarkov, A. I., Séguin, A., Pillet, S., Trépanier, S., Dhaliwall, J. K., Libman, M., Vesikari, T., & Landry, N. (2020) · The Lancet · doi:10.1016/s0140-6736(20)32014-6 · Cited by 192 · see citing works
Paich, H. A., Sheridan, P. A., Handy, J., Karlsson, E. A., Schultz-Cherry, S., Hudgens, M. G., Noah, T. L., Weir, S. S., & Beck, M. A. (2013) · Obesity · doi:10.1002/oby.20383 · Cited by 184 · see citing works
T Cell Responses to SARS-CoV-2
Sette, A., Sidney, J., & Crotty, S. (2023) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101721-061120 · Cited by 181 · see citing works
Ip, D., Lau, L. L., Leung, N., Fang, V. J., Chan, K., Chu, D. K. W., Leung, G. M., Peiris, M. J. S., Uyeki, T. M., & Cowling, B. J. (2016) · Clinical Infectious Diseases · doi:10.1093/cid/ciw841 · Cited by 186 · see citing works
Jegaskanda, S., Weinfurter, J. T., Friedrich, T. C., & Kent, S. J. (2013) · Journal of Virology · doi:10.1128/jvi.03030-12 · Cited by 184 · see citing works
Woods, C. W., McClain, M. T., Chen, M., Zaas, A. K., Nicholson, B. P., Varkey, J. B., Veldman, T., Kingsmore, S. F., Huang, Y., Lambkin‐Williams, R., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0052198 · Cited by 185 · see citing works
Self-citationRevealing the role of CD4+ T cells in viral immunity
Sant, A. J., & McMichael, A. J. (2012) · The Journal of Experimental Medicine · doi:10.1084/jem.20121517 · Cited by 181 · see citing works
Self-citationImmune responses after live attenuated influenza vaccination
Mohn, K. G.-I., Smith, I., Sjursen, H., & Cox, R. J. (2017) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2017.1377376 · Cited by 179 · see citing works
Oshansky, C. M., Gartland, A. J., Wong, S., Jeevan, T., Wang, D., Roddam, P. L., Caniza, M. A., Hertz, T., DeVincenzo, J. P., Webby, R. J., et al. (2014) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201309-1616oc · Cited by 173 · see citing works
Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly
Pereira, B. I., Xu, X., & Akbar, A. N. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.583019 · Cited by 182 · see citing works
Self-citationTang, B. M. P., Shojaei, M., Teoh, S., Meyers, A. F. A., Ho, J., Ball, T. B., Keynan, Y., Pisipati, A., Kumar, A., Eisen, D. P., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11249-y · Cited by 176 · see citing works
Experimental infection of human volunteers
Roestenberg, M., Hoogerwerf, M.-A., Ferreira, D. M., Mordmüller, B. G., & Yazdanbakhsh, M. (2018) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(18)30177-4 · Cited by 167 · see citing works
Pathogenicity and virulence of influenza
Liang, Y. (2023) · Virulence · doi:10.1080/21505594.2023.2223057 · Cited by 187 · see citing works
Influenza virus-specific CD4+ and CD8+ T cell-mediated immunity induced by infection and vaccination
Jansen, J. M., Gerlach, T. H., Elbahesh, H., Rimmelzwaan, G. F., & Saletti, G. (2019) · Journal of Clinical Virology · doi:10.1016/j.jcv.2019.08.009 · Cited by 168 · see citing works
Herati, R. S., Muselman, A., Vella, L., Bengsch, B., Parkhouse, K., Del Alcazar, D., Kotzin, J., Doyle, S. A., Tebas, P., Hensley, S. E., et al. (2017) · Science Immunology · doi:10.1126/sciimmunol.aag2152 · Cited by 167 · see citing works
The immune response to influenza in older humans: beyond immune senescence
McElhaney, J. E., Verschoor, C. P., Andrew, M. K., Haynes, L., Kuchel, G. A., & Pawelec, G. (2020) · Immunity & Ageing · doi:10.1186/s12979-020-00181-1 · Cited by 168 · see citing works
The Era of Cytotoxic CD4 T Cells
Cenerenti, M., Saillard, M., Romero, P. J., & Jandus, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.867189 · Cited by 167 · see citing works
Updates on immunologic correlates of vaccine-induced protection
Plotkin, S. A. (2020) · Vaccine · doi:10.1016/j.vaccine.2019.10.046 · Cited by 165 · see citing works
T cell mediated immunity to influenza: mechanisms of viral control
Gruta, N. L. L., & Turner, S. J. (2014) · Trends in Immunology · doi:10.1016/j.it.2014.06.004 · Cited by 164 · see citing works
Rajão, D. S., & Perez, D. R. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.00123 · Cited by 160 · see citing works
SP-A and SP-D: Dual Functioning Immune Molecules With Antiviral and Immunomodulatory Properties
Watson, A., Madsen, J., & Clark, H. W. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.622598 · Cited by 159 · see citing works
Immunological assessment of influenza vaccines and immune correlates of protection
Reber, A., & Katz, J. M. (2013) · Expert Review of Vaccines · doi:10.1586/erv.13.35 · Cited by 157 · see citing works
Bilich, T., Nelde, A., Heitmann, J. S., Maringer, Y., Roerden, M., Bauer, J., Rieth, J., Wacker, M., Peter, A., Hörber, S., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abf7517 · Cited by 147 · see citing works
Brazzoli, M., Magini, D., Bonci, A., Buccato, S., Giovani, C., Kratzer, R., Zurli, V., Mangiavacchi, S., Casini, D., Brito, L. M., et al. (2016) · Journal of Virology · doi:10.1128/jvi.01786-15 · Cited by 154 · see citing works
Memoli, M. J., Czajkowski, L. M., Reed, S., Athota, R., Bristol, T., Proudfoot, K., Fargis, S., Stein, M. K., Dunfee, R. L., Shaw, P. A., et al. (2014) · Clinical Infectious Diseases · doi:10.1093/cid/ciu924 · Cited by 153 · see citing works
Antiviral B cell and T cell immunity in the lungs
Chiu, C., & Openshaw, P. (2014) · Nature Immunology · doi:10.1038/ni.3056 · Cited by 151 · see citing works
The impact of CMV infection on survival in older humans
Pawelec, G., McElhaney, J. E., Aiello, A. E., & Derhovanessian, E. (2012) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.04.002 · Cited by 145 · see citing works
Laidlaw, B. J., Decman, V., Ali, M. A., Abt, M. C., Wolf, A. I., Monticelli, L. A., Mozdzanowska, K., Angelosanto, J., Artis, D., Erikson, J., et al. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003207 · Cited by 141 · see citing works
Pillet, S., Aubin, É., Trépanier, S., Bussière, D., Dargis, M., Poulin, J., Yassine‐Diab, B., Ward, B. J., & Landry, N. (2016) · Clinical Immunology · doi:10.1016/j.clim.2016.03.008 · Cited by 144 · see citing works
McKendry, R., Spalluto, C. M., Burke, H., Nicholas, B., Cellura, D., Al‐Shamkhani, A., Staples, K. J., & Wilkinson, T. M. A. (2015) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201504-0782oc · Cited by 144 · see citing works
Self-citationBetter influenza vaccines: an industry perspective
Chen, J.-R., Liu, Y.-M., Tseng, Y.-C., & Ma, C. (2020) · Journal of Biomedical Science · doi:10.1186/s12929-020-0626-6 · Cited by 143 · see citing works
Pachnio, A., Ciaúrriz, M., Begum, J., Lal, N., Zuo, J., Beggs, A. D., & Moss, P. A. H. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005832 · Cited by 141 · see citing works
Virus-specific T cells as correlate of (cross-)protective immunity against influenza
Altenburg, A. F., Rimmelzwaan, G. F., & de Vries, R. D. (2014) · Vaccine · doi:10.1016/j.vaccine.2014.11.054 · Cited by 140 · see citing works
Human SARS-CoV-2 challenge uncovers local and systemic response dynamics
Lindeboom, R. G. H., Worlock, K. B., Dratva, L. M., Yoshida, M., Scobie, D., Wagstaffe, H. R., Richardson, L., Wilbrey-Clark, A., Barnes, J. L., Kretschmer, L., et al. (2024) · Nature · doi:10.1038/s41586-024-07575-x · Cited by 143 · see citing works
McElhaney, J. E., Kuchel, G. A., Zhou, X., Swain, S. L., & Haynes, L. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00041 · Cited by 138 · see citing works
Coughlan, L., Sridhar, S., Payne, R., Edmans, M. D., Milicic, A., Venkatraman, N., Lugonja, B., Clifton, L., Qi, C., Folegatti, P. M., et al. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.02.011 · Cited by 138 · see citing works
Assessment of Influenza Virus Hemagglutinin Stalk-Based Immunity in Ferrets
Krammer, F., Hai, R., Yondola, M. A., Tan, G. S., Leyva-Grado, V. H., Ryder, A. B., Miller, M. S., Rose, J. K., Palese, P., García‐Sastre, A., et al. (2014) · Journal of Virology · doi:10.1128/jvi.03004-13 · Cited by 134 · see citing works
Exploiting Mucosal Immunity for Antiviral Vaccines
Iwasaki, A. (2016) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032414-112315 · Cited by 132 · see citing works
Design, recruitment, and microbiological considerations in human challenge studies
Darton, T. C., Blohmke, C. J., Moorthy, V. S., Altmann, D. M., Hayden, F. G., Clutterbuck, E. A., Levine, M. M., Hill, A. V. S., & Pollard, A. J. (2015) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(15)00068-7 · Cited by 130 · see citing works
Altenburg, A. F., Kreijtz, J. H. C. M., de Vries, R. D., Song, F., Fux, R., Rimmelzwaan, G. F., Sutter, G., & Volz, A. (2014) · Viruses · doi:10.3390/v6072735 · Cited by 126 · see citing works
Chen, J., Wang, P., Yuan, L., Zhang, L., Zhang, L., Zhao, H. J., Chen, C., Chen, Y., Han, J., Jia, J., et al. (2022) · 中国科学通报:英文版 · doi:10.1016/j.scib.2022.05.018 · Cited by 130 · see citing works
Self-citationGreen, C., Scarselli, E., Sande, C., Thompson, A., de Lara, C. M., Taylor, K., Haworth, K., Sorbo, M. D., Angus, B., Siani, L., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aac5745 · Cited by 129 · see citing works
Lee, J. K. H., Lam, G., Shin, T., Samson, S., Greenberg, D. P., & Chit, A. (2021) · Vaccine · doi:10.1016/j.vaccine.2020.09.004 · Cited by 129 · see citing works
Gray, J. I., Westerhof, L. M., & MacLeod, M. K. L. (2018) · Immunology · doi:10.1111/imm.12929 · Cited by 128 · see citing works
- Authors
- Wilkinson, T. M., Li, C. K. F., Chui, C. S. C., Huang, A. K. Y., Perkins, M., Liebner, J. C., Lambkin-Williams, R., Gilbert, A., Oxford, J., Nicholas, B., Staples, K. J., Dong, T., Douek, D. C., McMichael, A. J., & Xu, X.-N.
- Affiliations
- University of Southampton (GB)
- University of Oxford (GB)
- National Institutes of Health (US)
- Corresponding author
- Wilkinson, Tom M
- Xu, Xiao-Ning
- ORCID
- Venue
- Nature Medicine
- Published
- 2012-01-29
- Volume
- 18
- Issue
- 2
- Pages
- 274-280
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2036182565
- Cited by
- 974
- References
- 43
- Citations by year
- 2026: 23 · 2025: 55 · 2024: 45 · 2023: 77 · 2022: 62 · 2021: 73 · 2020: 79 · 2019: 71 · 2018: 70 · 2017: 59 · 2016: 95 · 2015: 72 · 2014: 69 · 2013: 72 · 2012: 51
- FWCI
- 62.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- National Institutes of Health
- Medical Research Council
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- influenza, CD4+ T cells, cytotoxic T lymphocytes, pandemic H1N1, H3N2, H1N1, viral shedding, disease severity, influenza vaccine design
- MeSH terms
- Adolescent, Adult, Antibodies, Viral, Female, Humans, Immunity, Cellular, Influenza, Human, Male, Middle Aged, Severity of Illness Index, Time Factors, CD4-Positive T-Lymphocytes, Virus Shedding, CD8-Positive T-Lymphocytes, Influenza A Virus, H1N1 Subtype, Influenza A Virus, H3N2 Subtype, Young Adult, Immunity, Humoral
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