Robust T Cell Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19
Takuya Sekine, André Perez-Potti, Olga Rivera-Ballesteros, Kristoffer Strålin, Jean-Baptiste Gorin, Annika Olsson, Sian Llewellyn-Lacey, Habiba Kamal, Gordana Bogdanovic, Sandra Muschiol, David J Wullimann, Tobias Kammann, Johanna Emgård, Tiphaine Parrot, Elin Folkesson, Karolinska COVID-19 Study Group, Olav Rooyackers, Lars I Eriksson, Jan-Inge Henter, Anders Sönnerborg, Tobias Allander, Jan Albert, Morten Nielsen, Jonas Klingström, Sara Gredmark-Russ, Niklas K Björkström, Johan K Sandberg, David A Price, Hans-Gustaf Ljunggren, Soo Aleman, Marcus Buggert, Mira Akber, Lena Berglin, Helena Bergsten, Susanna Brighenti, Demi Brownlie, Marta Butrym, Benedict Chambers, Puran Chen, Martin Cornillet Jeannin, Jonathan Grip, Angelica Cuapio Gomez, Lena Dillner, Isabel Diaz Lozano, Majda Dzidic, Malin Flodström Tullberg, Anna Färnert, Hedvig Glans, Alvaro Haroun-Izquierdo, Elizabeth Henriksson, Laura Hertwig, Sadaf Kalsum, Efthymia Kokkinou, Egle Kvedaraite, Marco Loreti, Magalini Lourda, Kimia Maleki, Karl-Johan Malmberg, Nicole Marquardt, Christopher Maucourant, Jakob Michaelsson, Jenny Mjösberg, Kirsten Moll, Jagadees Muva, Johan Mårtensson, Pontus Nauclér, Anna Norrby-Teglund, Laura Palma Medina, Björn Persson, Lena Radler, Emma Ringqvist, John Tyler Sandberg, Ebba Sohlberg, Tea Soini, Mattias Svensson, Janne Tynell, Renata Varnaite, Andreas Von Kries, Christian Unge, Takuya Sekine, André Perez-Potti, Olga Rivera-Ballesteros, Kristoffer Strålin, Jean-Baptiste Gorin, Annika Olsson, Sian Llewellyn-Lacey, Habiba Kamal, Gordana Bogdanovic, Sandra Muschiol, David J Wullimann, Tobias Kammann, Johanna Emgård, Tiphaine Parrot, Elin Folkesson, Karolinska COVID-19 Study Group, Olav Rooyackers, Lars I Eriksson, Jan-Inge Henter, Anders Sönnerborg, Tobias Allander, Jan Albert, Morten Nielsen, Jonas Klingström, Sara Gredmark-Russ, Niklas K Björkström, Johan K Sandberg, David A Price, Hans-Gustaf Ljunggren, Soo Aleman, Marcus Buggert, Mira Akber, Lena Berglin, Helena Bergsten, Susanna Brighenti, Demi Brownlie, Marta Butrym, Benedict Chambers, Puran Chen, Martin Cornillet Jeannin, Jonathan Grip, Angelica Cuapio Gomez, Lena Dillner, Isabel Diaz Lozano, Majda Dzidic, Malin Flodström Tullberg, Anna Färnert, Hedvig Glans, Alvaro Haroun-Izquierdo, Elizabeth Henriksson, Laura Hertwig, Sadaf Kalsum, Efthymia Kokkinou, Egle Kvedaraite, Marco Loreti, Magalini Lourda, Kimia Maleki, Karl-Johan Malmberg, Nicole Marquardt, Christopher Maucourant, Jakob Michaelsson, Jenny Mjösberg, Kirsten Moll, Jagadees Muva, Johan Mårtensson, Pontus Nauclér, Anna Norrby-Teglund, Laura Palma Medina, Björn Persson, Lena Radler, Emma Ringqvist, John Tyler Sandberg, Ebba Sohlberg, Tea Soini, Mattias Svensson, Janne Tynell, Renata Varnaite, Andreas Von Kries, Christian Unge
Abstract
SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. Here, we systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in unexposed individuals, exposed family members, and individuals with acute or convalescent COVID-19. Acute-phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent-phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative exposed family members and convalescent individuals with a history of asymptomatic and mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits broadly directed and functionally replete memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19.
Conflict of interest statement
Declaration of Interests The authors declare no competing interests.
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
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References
- Alshukairi A.N., Khalid I., Ahmed W.A., Dada A.M., Bayumi D.T., Malic L.S., Althawadi S., Ignacio K., Alsalmi H.S., Al-Abdely H.M. Antibody Response and Disease Severity in Healthcare Worker MERS Survivors. Emerg. Infect. Dis. 2016;22:1113–1115.
- Beigel J.H., Tomashek K.M., Dodd L.E., Mehta A.K., Zingman B.S., Kalil A.C., Hohmann E., Chu H.Y., Luetkemeyer A., Kline S. Remdesivir for the Treatment of Covid-19— Preliminary Report. N Engl J Med. 2020 doi: 10.1056/NEJMoa2007764. Published online May 22, 2020.
- Betts M.R., Nason M.C., West S.M., De Rosa S.C., Migueles S.A., Abraham J., Lederman M.M., Benito J.M., Goepfert P.A., Connors M. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood. 2006;107:4781–4789.
- Blom K., Braun M., Ivarsson M.A., Gonzalez V.D., Falconer K., Moll M., Ljunggren H.G., Michaëlsson J., Sandberg J.K. Temporal dynamics of the primary human T cell response to yellow fever virus 17D as it matures from an effector- to a memory-type response. J. Immunol. 2013;190:2150–2158.
- Braun J., Loyal L., Frentsch M., Wendisch D., Georg P., Kurth F., Hippenstiel S., Dingeldey M., Kruse B., Fauchere F. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature. 2020 doi: 10.1038/s41586-020-2598-9. Published online July 29, 2020.
- Buggert M., Norström M.M., Salemi M., Hecht F.M., Karlsson A.C. Functional avidity and IL-2/perforin production is linked to the emergence of mutations within HLA-B∗5701-restricted epitopes and HIV-1 disease progression. J. Immunol. 2014;192:4685–4696.
- Buggert M., Nguyen S., Salgado-Montes de Oca G., Bengsch B., Darko S., Ransier A., Roberts E.R., Del Alcazar D., Brody I.B., Vella L.A. Identification and characterization of HIV-specific resident memory CD8+ T cells in human lymphoid tissue. Sci. Immunol. 2018;3 eaar4526.
- Callow K.A., Parry H.F., Sergeant M., Tyrrell D.A. The time course of the immune response to experimental coronavirus infection of man. Epidemiol. Infect. 1990;105:435–446.
- Chandrashekar A., Liu J., Martinot A.J., McMahan K., Mercado N.B., Peter L., Tostanoski L.H., Yu J., Maliga Z., Nekorchuk M. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science. 2020;369:812–817.
- Channappanavar R., Fett C., Zhao J., Meyerholz D.K., Perlman S. Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection. J. Virol. 2014;88:11034–11044.
- Demkowicz W.E., Jr., Littaua R.A., Wang J., Ennis F.A. Human cytotoxic T-cell memory: long-lived responses to vaccinia virus. J. Virol. 1996;70:2627–2631.
- Fuertes Marraco S.A., Soneson C., Cagnon L., Gannon P.O., Allard M., Abed Maillard S., Montandon N., Rufer N., Waldvogel S., Delorenzi M., Speiser D.E. Long-lasting stem cell-like memory CD8+ T cells with a naïve-like profile upon yellow fever vaccination. Sci. Transl. Med. 2015;7:282ra48.
- 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. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell. 2020;181:1489–1501.e15.
- Guan W.J., Ni Z.Y., Hu Y., Liang W.H., Ou C.Q., He J.X., Liu L., Shan H., Lei C.L., Hui D.S.C., China Medical Treatment Expert Group for Covid-19 Clinical Characteristics of Coronavirus Disease 2019 in China. N. Engl. J. Med. 2020;382:1708–1720.
- Habib H. Has Sweden’s controversial covid-19 strategy been successful? BMJ. 2020;369:m2376.
- He R., Lu Z., Zhang L., Fan T., Xiong R., Shen X., Feng H., Meng H., Lin W., Jiang W., Geng Q. The clinical course and its correlated immune status in COVID-19 pneumonia. J. Clin. Virol. 2020;127:104361.
- He X., Lau E.H.Y., Wu P., Deng X., Wang J., Hao X., Lau Y.C., Wong J.Y., Guan Y., Tan X. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat. Med. 2020;26:672–675.
- Hotez P.J., Corry D.B., Strych U., Bottazzi M.E. COVID-19 vaccines: neutralizing antibodies and the alum advantage. Nat. Rev. Immunol. 2020;20:399–400.
- Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., Zhang L., Fan G., Xu J., Gu X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.
- Ibarrondo F.J., Fulcher J.A., Goodman-Meza D., Elliott J., Hofmann C., Hausner M.A., Ferbas K.G., Tobin N.H., Aldrovandi G.M., Yang O.O. Rapid Decay of Anti-SARS-CoV-2 Antibodies in Persons with Mild Covid-19. N. Engl. J. Med. 2020 doi: 10.1056/NEJMc2025179. Published online July 21, 2020.
- Juno J.A., Tan H.X., Lee W.S., Reynaldi A., Kelly H.G., Wragg K., Esterbauer R., Kent H.E., Batten C.J., Mordant F.L. Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19. Nat. Med. 2020 doi: 10.1038/s41591-020-0995-0. Published online July 13, 2020.
- Kirkcaldy R.D., King B.A., Brooks J.T. COVID-19 and Postinfection Immunity: Limited Evidence, Many Remaining Questions. JAMA. 2020 doi: 10.1001/jama.2020.7869. Published online May 11, 2020.
- Le Bert N., Tan A.T., Kunasegaran K., Tham C.Y.L., Hafezi M., Chia A., Chng M.H.Y., Lin M., Tan N., Linster M. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature. 2020 doi: 10.1038/s41586-020-2550-z. Published online July 15, 2020.
- Li C.K., Wu H., Yan H., Ma S., Wang L., Zhang M., Tang X., Temperton N.J., Weiss R.A., Brenchley J.M. T cell responses to whole SARS coronavirus in humans. J. Immunol. 2008;181:5490–5500.
- Liu J., Li S., Liu J., Liang B., Wang X., Wang H., Li W., Tong Q., Yi J., Zhao L. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine. 2020;55:102763.
- Long Q.X., Tang X.J., Shi Q.L., Li Q., Deng H.J., Yuan J., Hu J.L., Xu W., Zhang Y., Lv F.J. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat. Med. 2020;26:1200–1204.
- Mallapaty S. Will antibody tests for the coronavirus really change everything? Nature. 2020;580:571–572.
- Mateus J., Grifoni A., Tarke A., Sidney J., Ramirez S.I., Dan J.M., Burger Z.C., Rawlings S.A., Smith D.M., Phillips E. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science. 2020 doi: 10.1126/science.abd3871. Published online August 4, 2020.
- Miller J.D., van der Most R.G., Akondy R.S., Glidewell J.T., Albott S., Masopust D., Murali-Krishna K., Mahar P.L., Edupuganti S., Lalor S. Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity. 2008;28:710–722.
- Ni L., Ye F., Cheng M.L., Feng Y., Deng Y.Q., Zhao H., Wei P., Ge J., Gou M., Li X. Detection of SARS-CoV-2-Specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals. Immunity. 2020;52:971–977.e3.
- Owen R.E., Sinclair E., Emu B., Heitman J.W., Hirschkorn D.F., Epling C.L., Tan Q.X., Custer B., Harris J.M., Jacobson M.A. Loss of T cell responses following long-term cryopreservation. J. Immunol. Methods. 2007;326:93–115.
- Plebani M., Padoan A., Negrini D., Carpinteri B., Sciacovelli L. Diagnostic performances and thresholds: The key to harmonization in serological SARS-CoV-2 assays? Clin. Chim. Acta. 2020;509:1–7.
- Precopio M.L., Betts M.R., Parrino J., Price D.A., Gostick E., Ambrozak D.R., Asher T.E., Douek D.C., Harari A., Pantaleo G. Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responses. J. Exp. Med. 2007;204:1405–1416.
- Price D.A., Brenchley J.M., Ruff L.E., Betts M.R., Hill B.J., Roederer M., Koup R.A., Migueles S.A., Gostick E., Wooldridge L. Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses. J Exp Med. 2005;202:1349–1361.
- Reynisson B., Alvarez B., Paul S., Peters B., Nielsen M. NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data. Nucleic Acids Res. 2020;48:W449–W454.
- Robbiani D.F., Gaebler C., Muecksch F., Lorenzi J.C.C., Wang Z., Cho A., Agudelo M., Barnes C.O., Gazumyan A., Finkin S. Convergent Antibody Responses to SARS-CoV-2 Infection in Convalescent Individuals. bioRxiv. 2020 doi: 10.1101/2020.05.13.092619.
- Seydoux E., Homad L.J., MacCamy A.J., Parks K.R., Hurlburt N.K., Jennewein M.F., Akins N.R., Stuart A.B., Wan Y.H., Feng J. Characterization of neutralizing antibodies from a SARS-CoV-2 infected individual. bioRxiv. 2020 doi: 10.1101/2020.05.12.091298.
- Shin H.S., Kim Y., Kim G., Lee J.Y., Jeong I., Joh J.S., Kim H., Chang E., Sim S.Y., Park J.S., Lim D.G. Immune Responses to Middle East Respiratory Syndrome Coronavirus During the Acute and Convalescent Phases of Human Infection. Clin. Infect. Dis. 2019;68:984–992.
- Singer M., Deustchman C.S., Seymour C.W., Shankar-Hari M., Annane D., Bauer M., Bellomo R., Bernard G.R., Chiche J.D., Coopersmith C.M. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315:801–810.
- Sridhar S., Begom S., Bermingham A., Hoschler K., Adamson W., Carman W., Bean T., Barclay W., Deeks J.J., Lalvani A. Cellular immune correlates of protection against symptomatic pandemic influenza. Nat. Med. 2013;19:1305–1312.
- Tang F., Quan Y., Xin Z.T., Wrammert J., Ma M.J., Lv H., Wang T.B., Yang H., Richardus J.H., Liu W., Cao W.C. Lack of peripheral memory B cell responses in recovered patients with severe acute respiratory syndrome: a six-year follow-up study. J. Immunol. 2011;186:7264–7268.
- Thevarajan I., Nguyen T.H.O., Koutsakos M., Druce J., Caly L., van de Sandt C.E., Jia X., Nicholson S., Catton M., Cowie B. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat. Med. 2020;26:453–455.
- Wang C., Li W., Drabek D., Okba N.M.A., van Haperen R., Osterhaus A.D.M.E., van Kuppeveld F.J.M., Haagmans B.L., Grosveld F., Bosch B.J. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat. Commun. 2020;11:2251.
- Wei W.E., Li Z., Chiew C.J., Yong S.E., Toh M.P., Lee V.J. Presymptomatic Transmission of SARS-CoV-2 — Singapore, January 23-March 16, 2020. MMWR Morb. Mortal. Wkly. Rep. 2020;69:411–415.
- Wilk A.J., Rustagi A., Zhao N.Q., Roque J., Martinez-Colon G.J., McKechnie J.L., Ivison G.T., Ranganath T., Vergara R., Hollis T. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat. Med. 2020;26:1070–1076.
- Wilkinson T.M., Li C.K., Chui C.S., Huang A.K., Perkins M., Liebner J.C., Lambkin-Williams R., Gilbert A., Oxford J., Nicholas B. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat. Med. 2012;18:274–280.
- Wolfel R., Corman V.M., Guggemos W., Seilmaier M., Zange S., Muller M.A., Niemeyer D., Jones T.C., Vollmar P., Rothe C. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020;581:465–469.
- Woloshin S., Patel N., Kesselheim A.S. False Negative Tests for SARS-CoV-2 Infection — Challenges and Implications. N. Engl. J. Med. 2020;383:e38.
- Wu Z., McGoogan J.M. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020 doi: 10.1001/jama.2020.2648. Published online February 24, 2020.
- Yang L.T., Peng H., Zhu Z.L., Li G., Huang Z.T., Zhao Z.X., Koup R.A., Bailer R.T., Wu C.Y. Long-lived effector/central memory T-cell responses to severe acute respiratory syndrome coronavirus (SARS-CoV) S antigen in recovered SARS patients. Clin. Immunol. 2006;120:171–178.
- Yang R., Gui X., Xiong Y. Comparison of Clinical Characteristics of Patients with Asymptomatic vs Symptomatic Coronavirus Disease 2019 in Wuhan, China. JAMA Netw. Open. 2020;3:e2010182.
- Zhao J., Zhao J., Mangalam A.K., Channappanavar R., Fett C., Meyerholz D.K., Agnihothram S., Baric R.S., David C.S., Perlman S. Airway Memory CD4+ T Cells Mediate Protective Immunity against Emerging Respiratory Coronaviruses. Immunity. 2016;44:1379–1391.
- Zhao J., Alshukairi A.N., Baharoon S.A., Ahmed W.A., Bokhari A.A., Nehdi A.M., Layqah L.A., Alghamdi M.G., Al Gethamy M.M., Dada A.M. Recovery from the Middle East respiratory syndrome is associated with antibody and T-cell responses. Sci. Immunol. 2017;2 eaan5393.
- Zheng H.Y., Zhang M., Yang C.X., Zhang N., Wang X.C., Yang X.P., Dong X.Q., Zheng Y.T. Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients. Cell. Mol. Immunol. 2020;17:541–543.
- Zheng M., Gao Y., Wang G., Song G., Liu S., Sun D., Xu Y., Tian Z. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell. Mol. Immunol. 2020;17:533–535.
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