Robust and Persistent B- and T-Cell Responses after COVID-19 in Immunocompetent and Solid Organ Transplant Recipient Patients
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Subjects
2.2. Antibody Assays
2.3. Protein Peptide Pools
2.4. PBMC Isolation
2.5. Activation Induction Marker Assay
2.6. Antigen-Specific Cytokine Production
2.7. Detection of Antigen-Specific CD4+and CD8+ T-Cell Proliferative Response
2.8. Statistical Analysis
3. Results
3.1. Characteristics of the Patients Analysed
3.2. Antigen-Specific Antibody Response in Convalescent COVID-19 IC and TX Patients
3.3. Effector and Memory T-Cell Responses in IC and TX Patients after COVID-19
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Chan, J.F.; Yuan, S.; Kok, K.H.; Kai-Wang To, K.; Chu, H.; Yang, J.; Xing, F.; Liu, J.; Chik-Yan Yip, C.; Wing-Shan Poon, R.; et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster. Lancet 2020, 395, 514–523. [Google Scholar] [CrossRef] [Green Version]
- Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506. [Google Scholar] [CrossRef] [Green Version]
- Chen, G.; Wu, D.; Guo, W.; Cao, Y.; Huang, D.; Wang, H.; Wang, T.; Zhang, X.; Chen, H.; Yu, H.; et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Investig. 2020, 130, 2620–2629. [Google Scholar] [CrossRef] [Green Version]
- Candel González, F.J.; Viñuela-Prieto, J.M.; Del Castillo, J.G.; García, P.B.; Saavedra, M.F.; Píriz, A.H.; Jiménez Virumbrales, D.; Canora Lebrato, J.; García de Casasola, G.; Gil Prieto, R.; et al. Utility of lateral flow tests in SARS-CoV-2 infection monitorization. Rev. Esp. Quimioter. 2020, 33, 258. [Google Scholar] [CrossRef]
- Carsetti, R.; Zaffina, S.; Mortari, E.P.; Terreri, S.; Corrente, F.; Capponi, C.; Palomba, P.; Mirabella, M.; Cascioli, S.; Palange, P.; et al. Different innate and adaptive immune response to SARS-CoV-2 infection of asymptomatic, mild and severe cases. Front. Immunol. 2020, 11, 610300. [Google Scholar] [CrossRef] [PubMed]
- Borremans, B.; Gamble, A.; Prager, K.; Helman, S.; McClain, A.; Cox, C.; Savage, V.; Lloyd-Smith, J.O. Quantifying antibody kinetics and RNA shedding during early-phase SARS-CoV-2 infection by time since symptom onset. eLife 2020, 9, e60122. [Google Scholar] [CrossRef] [PubMed]
- Ou, J.; Tan, M.; He, H.; Tan, H.; Mai, J.; Long, Y.; Jiang, X.; He, Q.; Huang, Y.; Li, Y.; et al. Study on the expression levels of antibodies against SARS-CoV-2 at different period of disease and its related factors in 192 cases of COVID-19 patients. MedRxiv 2020. [Google Scholar] [CrossRef]
- Qin, C.; Zhou, L.; Hu, Z.; Zhang, S.; Yang, S.; Tao, Y.; Xie, C.; Ma, K.; Shang, K.; Wang, W.; et al. Dysregulation of immune response in patients with (COVID-19) in Wuhan, China. Clin. Infect. Dis. 2020, 71, 762–768. [Google Scholar] [CrossRef] [PubMed]
- Huang, A.T.; Garcia-Carreras, B.; Hitchings, M.D.T.; Yang, B.; Katzelnick, L.; Rattigan, S.M.; Borgert, B.A.; Moreno, C.A.; Solomon, B.D.; Rodriguez-Barraquer, I.; et al. A systematic review of antibody mediated immunity to coronaviruses: Antibody kinetics, correlates of protection, and association of antibody responses with severity of disease. Nat. Commun. 2020, 11, 4704. [Google Scholar] [CrossRef]
- Zhang, J.; Qu, X.; Liu, Z.; Wang, Q.; Wu, J.; Hu, Y.; Bai, T.; Xie, T.; Huang, M.; Wu, T.; et al. Spike-specific circulating T follicular helper cell and cross-neutralizing antibody responses in COVID-19 convalescent individuals. Nat. Microbiol. 2021, 6, 51–58. [Google Scholar] [CrossRef]
- Fafi-Kremer, S.; Bruel, T.; Madec, Y.; Grant, R.; Tondeur, L.; Grzelak, L.; Staropoli, I.; Anna, F.; Souque, P.; Fernandes-Pellerin, S.; et al. Serologic responses to SARSCoV-2 infection among hospital staff with mild disease in eastern France. medRxiv 2020. [Google Scholar] [CrossRef]
- Brochot, E.; Demey, B.; Touze, A.; Belouzard, S.; Dubuisson, J.; Schmit, J.L.; Duverlie, G.; Francois, C.; Castelain, S.; Helle, F.; et al. Anti-Spike anti-Nucleocapsid and neutralizing antibodies in SARS-CoV-2 inpatients and asymptomatic individuals. Front. Microbiol. 2020, 11, 584251. [Google Scholar] [CrossRef]
- Wang, X.; Guo, X.; Xin, Q.; Pan, Y.; Hu, Y.; Li, J.; Chu, Y.; Feng, Y.; Wang, Q. Neutralizing Antibody Responses to Severe Acute Respiratory Syndrome Coronavirus 2 in Coronavirus Disease 2019 Inpatients and Convalescent Patients. Clin. Infect. Dis. 2020, 71, 2688–2694. [Google Scholar] [CrossRef] [PubMed]
- Wang, P.; Liu, L.; Nair, M.S.; Yin, M.T.; Luo, Y.; Wang, Q.; Yuan, T.; Mori, K.; Guzman Solis, A.; Yamashita, M.; et al. SARS-CoV-2 neutralizing antibody responses are more robust in patients with severe disease. Emerg. Microbes Infect. 2020, 9, 2091–2093. [Google Scholar] [CrossRef]
- Thieme, C.J.; Anft, M.; Paniskaki, K.; Blazquez-Navarro, A.; Doevelaar, A.; Seiberto, F.S.; Hoelzer, B.; Konik, M.J.; Moritz Berger, M.; Brenner, T.; et al. Robust T cell response towards spike, membrane, and nucleocapsid SARS-CoV-2proteins is not associated with recovery in critical COVID-19 patients. Cell Rep. Med. 2020, 1, 100092. [Google Scholar] [CrossRef]
- Weiskopf, D.; Schmitz, K.S.; Raadsen, M.P.; Grifoni, A.; Okba, N.M.A.; Henrik Endeman, H.; van den Akker, J.P.C.; Molenkamp, R.; Koopmans, M.P.G.; van Gorp, E.C.M.; et al. Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome. Sci. Immunol. 2020, 5, eabd2071. [Google Scholar] [CrossRef]
- Grifoni, A.; Weiskopf, D.; Ramirez, S.I.; Mateus, J.; Dan, J.M.; Rydyznski Moderbacher, C.; Rawlings, S.A.; Sutherland, A.; Premkumar, L.; Jadi, R.S.; et al. 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. [Google Scholar] [CrossRef] [PubMed]
- Dan, J.M.; Mateus, J.; Kato, Y.; Hastie, K.M.; Yu, E.D.; Faliti, C.E.; Grifoni, A.; Ramirez, S.I.; Haupt, S.; Frazier, A.; et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 2021, 371, eabf4063. [Google Scholar] [CrossRef] [PubMed]
- Caballero-Marcos, A.; Salcedo, M.; Alonso-Fernández, R.; Rodríguez-Perálvarez, M.; Olmedo, M.; Graus Morales, J.; Cuervas-Mons, V.; Cachero, A.; Loinaz-Segurola, C.; Iñarrairaegui, M.; et al. Changes in humoral immune response after SARS-CoV-2 infection in liver transplant recipients compared to immunocompetent patients. Am. J. Transplant. 2021, 21, 2876–2884. [Google Scholar] [CrossRef] [PubMed]
- Thieme, C.J.; Anft, M.; Paniskaki, K.; Blazquez-Navarro, A.; Doevelaar, A.; Seibert, F.S.; Hoelzer, B.; Konik, M.J.; Meister, T.L.; Pfaender, S.; et al. The Magnitude and Functionality of SARS-CoV-2 Reactive Cellular and Humoral Immunity in Transplant Population Is Similar to the General Population Despite Immunosuppression. Transplantation 2021, 105, 2156. [Google Scholar] [CrossRef]
- Percivalle, E.; Cambiè, G.; Cassaniti, I.; Vecchio Nepita, E.; Maserati, R.; Ferrari, A.; Di Martino, R.; Isernia, P.; Mojoli, F.; Bruno, R.; et al. Prevalence of SARS-CoV-2 specific neutralising antibodies in blood donors from the Lodi Red Zone in Lombardy, Italy, as at 06 April 2020. Eurosurveill 2020, 25, 2001031. [Google Scholar] [CrossRef] [PubMed]
- 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. T cell responses to whole SARS coronavirus in humans. J. Immunol. 2008, 181, 5490–5500. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Favà, A.; Donadeu, L.; Sabé, N.; Pernin, V.; González-Costello, J.; Lladó, L.; Meneghini, M.; Charmetant, X.; García-Romero, E.; Cachero, A.; et al. SARS-CoV-2-Specific serological and functional T cell immune responses during acute and early COVID-19 convalescence in solid organ transplant patients. Am. J. Transplant. 2021, 21, 2749–2761. [Google Scholar] [CrossRef] [PubMed]
- Williamson, E.J.; Walker, A.J.; Bhaskaran, K.; Bacon, S.; Bates, C.; Morton, C.E.; Curtis, H.J.; Mehrkar, A.; Evans, D.; Inglesby, P.; et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020, 584, 430–436. [Google Scholar] [CrossRef] [PubMed]
- Favà, A.; Cucchiari, D.; Montero, N.; Toapanta, N.; Centellas, F.J.; Vila-Santandreu, A.; Coloma, A.; Meneghini, M.; Manonelles, A.; Sellarés, J.; et al. Clinical characteristics and risk factors for severe COVID-19 in hospitalized kidney transplant recipients: A multicentric cohort study. Am. J. Transplant. 2020, 20, 3030–3041. [Google Scholar] [CrossRef] [PubMed]
- Alberici, F.; Delbarba, E.; Manenti, C.; Econimo, L.; Francesca Valerio, F.; Pola, A.; Maffei, C.; Possenti, S.; Zambetti, N.; Moscato, M.; et al. A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia. Kidney Int. 2020, 97, 1083–1088. [Google Scholar] [CrossRef]
- Coll, E.; Fernandez-Ruiz, M.; Padilla, M.; Moreso, F.; Hernández-Vicente, A.; Yañez, I.; Molina, M.; Vázquez-Sánchez, T.; Crespo, M.; Facund, C.; et al. COVID-19 in Solid Organ Transplant Recipients in Spain throughout 2020: Catching the Wave? Transplantation 2021, 105, 2146. [Google Scholar] [CrossRef]
- Grupper, A.; Rabinowich, L.; Schwartz, D.; Schwartz, I.F.; Ben-Yehoyada, M.; Shashar, M.; Katchman, E.; Halperin, T.; Turner, D.; Goykhman, Y.; et al. Reduced humoral response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus. Am. J. Transplant. 2021, 21, 2719–2726. [Google Scholar] [CrossRef]
- Marinaki, S.; Adamopoulos, S.; Degiannis, D.; Roussos, S.; Pavlopoulou, I.D.; Hatzakis, A.; Boletis, I.N. Immunogenicity of SARS-CoV-2 BNT162b2 vaccine in solid organ transplant recipients. Am. J. Transplant. 2021. [Google Scholar] [CrossRef]
- Bertrand, D.; Hamzaoui, M.; Lemée, V.; Lamulle, J.; Hanoy, M.; Laurent, C.; Lebourg, L.; Etienne, I.; Lemoine, M.; Le Roy, F.; et al. Antibody and T Cell Response to SARS-CoV-2 Messenger RNA BNT162b2 Vaccine in Kidney Transplant Recipients and Hemodialysis Patients. J. Am. Soc. Nephrol. 2021, 32, 2147–2152. [Google Scholar] [CrossRef]
- Kamar, N.; Abravanel, F.; Marion, O.; Couat, C.; Izopet, J.; Del Bello, A. Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients. N. Engl. J. Med. 2021, 385, 661–662. [Google Scholar] [CrossRef] [PubMed]
- Stumpf, J.; Tonnus, W.; Paliege, A.; Rettig, R.; Steglich, A.; Gembardt, F.; Kessel, F.; Kröger, H.; Arndt, P.; Sradnick, J.; et al. Cellular and Humoral Immune Responses after Three Doses of BNT162b2 mRNA SARS-Cov-2 Vaccine in Kidney Transplant. Transplantation 2021, 105, e267–e269. [Google Scholar] [CrossRef] [PubMed]
- Cavagna, L.; Seminare, E.; Zanframundo, G.; Gregorini, M.; Di Matteo, A.; Rampino, T.; Montecucco, C.; Pelenghi, S.; Cattadori, B.; Pattonieri, E.F.; et al. Calcineurin Inhibitor-Based Immunosuppression and COVID-19: Results from a Multidisciplinary Cohort of Patients in Northern Italy. Microorganisms 2020, 8, 977. [Google Scholar] [CrossRef] [PubMed]
- Rovida, F.; Cassaniti, I.; Percivalle, E.; Sarasini, A.; Paolucci, S.; Klersy, C.; Cutti, S.; Novelli, V.; Marena, C.; Luzzaro, F.; et al. Incidence of SARS-CoV-2 infection in health care workers from Northern Italy based on antibody status: Immune protection from secondary infection—A retrospective observational case-control study. Int. J. Infect. Dis. 2021, 109, 199–202. [Google Scholar] [CrossRef]
- OMurchu, E.; Byrne, P.; Carty, P.G.; De Gascun, C.; Keogan, M.; O’Neill, M.; Harrington, P.; Ryan, M. Quantifying the risk of SARS-CoV-2 reinfection over time. Rev. Med. Virol. 2021, e2260. [Google Scholar] [CrossRef]
Immunocompetent (IC) (n = 57) | p Value | Transplanted (TX) (n = 15) | p Value | p Value IC vs. TX | |||
---|---|---|---|---|---|---|---|
Pneumonia | Mild | Pneumonia | Mild | ||||
Subjects % (n) | 53% (30) | 47% (27) | 60% (9) | 40% (6) | |||
Transplanted Organ: | |||||||
Kidney % (n) | na | na | 78% (7) | 33% (2) | |||
Heart % (n) | na | na | 11% (1) | 33% (2) | |||
Lung % (n) | na | na | 11% (1) | 33% (2) | |||
Time After Transplant, Median [range] months | na | na | 89 [3–288] | 20 [1–43] | |||
Age, Median [range] | 62 [44–81] | 45 [21–61] | p < 0.001 | 58 [48–71] | 59 [39–65] | p = 0.556 | p = 0.119 |
Sex, M/F % (n) | 63% (19)/37% (11) | 48% (13)/52% (14) | p = 0.358 | 78% (7)/22% (2) | 83% (5)/18% (1) | p = 1 | p = 0.079 |
Symptoms: | |||||||
Fever % (n) | 90% (27) | 70% (19) | 100% (9) | 33% (2) | |||
Rhinitis %(n) | 0 | 24% (8) | 0 | 0 | |||
Cough % (n) | 43% (13) | 26% (7) | 50% (4) | 33% (2) | |||
Sore Throat % (n) | 0 | 11% (3) | 13% (1) | 0 | |||
Conjunctivitis % (n) | 0 | 0 | 13% (1) | 0 | |||
Ageusia % (n) | 7% (2) | 56% (15) | 0 | 33% (2) | |||
Anosmia % (n) | 3% (1) | 56% (15) | 0 | 0 | |||
Gastrointestinal % (n) | 17% (5) | 19% (5) | 50% (4) | 50% (3) | |||
Headache % (n) | 3% (1) | 44% (12) | 13% (1) | 33% (2) | |||
O2 supply, % patients (n): | |||||||
no | 3% (1) | 100% (27) | 56% (5) | 100% (6) | |||
<5 mL/min | 27% (8) | 0 | 33% (3) | 0 | |||
≥5 mL/min | 70% (21) | 0 | 11% (1) | 0 | p < 0.001 | ||
Duration of SARS-CoV-2 infection, Median [range] Days | 20 [4–38] | 20 [12–29] | 17 [10–36] | 7 [4–25] | p = 0.773 | ||
Outcome: | |||||||
Live % (n) | 100% (30) | 100% (27) | 100% (9) | 83% (5) |
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Zavaglio, F.; Frangipane, V.; Morosini, M.; Gabanti, E.; Zelini, P.; Sammartino, J.C.; Ferrari, A.; Gregorini, M.; Rampino, T.; Asti, A.; et al. Robust and Persistent B- and T-Cell Responses after COVID-19 in Immunocompetent and Solid Organ Transplant Recipient Patients. Viruses 2021, 13, 2261. https://doi.org/10.3390/v13112261
Zavaglio F, Frangipane V, Morosini M, Gabanti E, Zelini P, Sammartino JC, Ferrari A, Gregorini M, Rampino T, Asti A, et al. Robust and Persistent B- and T-Cell Responses after COVID-19 in Immunocompetent and Solid Organ Transplant Recipient Patients. Viruses. 2021; 13(11):2261. https://doi.org/10.3390/v13112261
Chicago/Turabian StyleZavaglio, Federica, Vanessa Frangipane, Monica Morosini, Elisa Gabanti, Paola Zelini, Josè Camilla Sammartino, Alessandro Ferrari, Marilena Gregorini, Teresa Rampino, Annalia Asti, and et al. 2021. "Robust and Persistent B- and T-Cell Responses after COVID-19 in Immunocompetent and Solid Organ Transplant Recipient Patients" Viruses 13, no. 11: 2261. https://doi.org/10.3390/v13112261