Boosting Compromised SARS-CoV-2-specific Immunity with MRNA Vaccination in Liver Transplant Recipients

Overview

Journal J Hepatol

Publisher Elsevier

Specialty Gastroenterology

Date 2023 Feb 22

PMID 36804404

Authors

Hendrik Luxenburger

David B Reeg

Julia Lang-Meli

Matthias Reinscheid

Miriam Eisner

Dominik Bettinger

Valerie Oberhardt

Elahe Salimi Alizei

Katharina Wild

Anne Graeser

Vivien Karl

Sagar

Florian Emmerich

Florian Klein

Marcus Panning

Daniela Huzly

Bertram Bengsch

Tobias Boettler

Roland Elling

Robert Thimme

Maike Hofmann

Christoph Neumann-Haefelin

Affiliations

Soon will be listed here.

Abstract

Background & Aims: Liver transplant recipients (LTRs) demonstrate a reduced response to COVID-19 mRNA vaccination; however, a detailed understanding of the interplay between humoral and cellular immunity, especially after a third (and fourth) vaccine dose, is lacking.

Methods: We longitudinally compared the humoral, as well as CD4+ and CD8+ T-cell, responses between LTRs (n = 24) and healthy controls (n = 19) after three (LTRs: n = 9 to 16; healthy controls: n = 9 to 14 per experiment) to four (LTRs: n = 4; healthy controls: n = 4) vaccine doses, including in-depth phenotypical and functional characterization.

Results: Compared to healthy controls, development of high antibody titers required a third vaccine dose in most LTRs, while spike-specific CD8+ T cells with robust recall capacity plateaued after the second vaccine dose, albeit with a reduced frequency and epitope repertoire compared to healthy controls. This overall attenuated vaccine response was linked to a reduced frequency of spike-reactive follicular T helper cells in LTRs.

Conclusion: Three doses of a COVID-19 mRNA vaccine induce an overall robust humoral and cellular memory response in most LTRs. Decisions regarding additional booster doses may thus be based on individual vaccine responses as well as evolution of novel variants of concern.

Impact And Implications: Due to immunosuppressive medication, liver transplant recipients (LTR) display reduced antibody titers upon COVID-19 mRNA vaccination, but the impact on long-term immune memory is not clear. Herein, we demonstrate that after three vaccine doses, the majority of LTRs not only exhibit substantial antibody titers, but also a robust memory T-cell response. Additional booster vaccine doses may be of special benefit for a small subset of LTRs with inferior vaccine response and may provide superior protection against evolving novel viral variants. These findings will help physicians to guide LTRs regarding the benefit of booster vaccinations.

Citing Articles

Impaired SARS-CoV-2-Specific CD8+ T Cells After Infection or Vaccination but Robust Hybrid T Cell Immunity in Patients with Multiple Myeloma.

Shoumariyeh K, Csernalabics B, Salimi Alizei E, Reinscheid M, Giese S, Ciminski K Vaccines (Basel). 2024; 12(11).

PMID: 39591152 PMC: 11598869. DOI: 10.3390/vaccines12111249.

Distinct T cell responsiveness to different COVID-19 vaccines and cross-reactivity to SARS-CoV-2 variants with age and CMV status.

Brummelman J, Suarez-Hernandez S, de Rond L, Bogaard-van Maurik M, Molenaar P, van Wijlen E Front Immunol. 2024; 15:1392477.

PMID: 38774878 PMC: 11106399. DOI: 10.3389/fimmu.2024.1392477.

When Cell-Mediated Immunity after Vaccination Is Important.

Paganelli R Pathogens. 2024; 13(1).

PMID: 38251372 PMC: 10819879. DOI: 10.3390/pathogens13010065.

Safety and Efficacy of a Third Dose of the BNT162b2 Vaccine in Liver-Transplanted and Healthy Adolescents.

Sintusek P, Buranapraditkun S, Khunsri S, Thongmee T, Vichaiwattana P, Polsawat W JPGN Rep. 2023; 4(4):e373.

PMID: 38034438 PMC: 10684171. DOI: 10.1097/PG9.0000000000000373.

Evaluation of Humoral Response following SARS-CoV-2 mRNA-Based Vaccination in Liver Transplant Recipients Receiving Tailored Immunosuppressive Therapy.

Manzia T, Sensi B, Conte L, Siragusa L, Angelico R, Frongillo F J Clin Med. 2023; 12(21).

PMID: 37959382 PMC: 10650358. DOI: 10.3390/jcm12216913.

References

Lang-Meli J, Luxenburger H, Wild K, Karl V, Oberhardt V, Salimi Alizei E . SARS-CoV-2-specific T-cell epitope repertoire in convalescent and mRNA-vaccinated individuals. Nat Microbiol. 2022; 7(5):675-679. PMC: 9064790. DOI: 10.1038/s41564-022-01106-y. View

Ruether D, Schaub G, Duengelhoef P, Haag F, Brehm T, Fathi A . SARS-CoV2-specific Humoral and T-cell Immune Response After Second Vaccination in Liver Cirrhosis and Transplant Patients. Clin Gastroenterol Hepatol. 2021; 20(1):162-172.e9. PMC: 8427908. DOI: 10.1016/j.cgh.2021.09.003. View

Caballero-Marcos A, Salcedo M, Alonso-Fernandez R, Rodriguez-Peralvarez M, Olmedo M, Graus Morales J . Changes in humoral immune response after SARS-CoV-2 infection in liver transplant recipients compared to immunocompetent patients. Am J Transplant. 2021; 21(8):2876-2884. PMC: 8251470. DOI: 10.1111/ajt.16599. View

Oberhardt V, Luxenburger H, Kemming J, Schulien I, Ciminski K, Giese S . Rapid and stable mobilization of CD8 T cells by SARS-CoV-2 mRNA vaccine. Nature. 2021; 597(7875):268-273. PMC: 8426185. DOI: 10.1038/s41586-021-03841-4. View

Toniutto P, Cussigh A, Cmet S, Bitetto D, Fornasiere E, Fumolo E . Immunogenicity and safety of a third dose of anti-SARS-CoV-2 BNT16b2 vaccine in liver transplant recipients. Liver Int. 2022; 43(2):452-461. PMC: 9348042. DOI: 10.1111/liv.15331. View

Nelson R, Chen Y, Venezia O, Majerus R, Shin D, Carrington M . SARS-CoV-2 epitope-specific CD4 memory T cell responses across COVID-19 disease severity and antibody durability. Sci Immunol. 2022; 7(73):eabl9464. PMC: 9097883. DOI: 10.1126/sciimmunol.abl9464. View

Toniutto P, Falleti E, Cmet S, Cussigh A, Veneto L, Bitetto D . Past COVID-19 and immunosuppressive regimens affect the long-term response to anti-SARS-CoV-2 vaccination in liver transplant recipients. J Hepatol. 2022; 77(1):152-162. PMC: 8908852. DOI: 10.1016/j.jhep.2022.02.015. View

Dumortier J, Duvoux C, Roux O, Altieri M, Barraud H, Besch C . Covid-19 in liver transplant recipients: the French SOT COVID registry. Clin Res Hepatol Gastroenterol. 2021; 45(4):101639. PMC: 7843027. DOI: 10.1016/j.clinre.2021.101639. View

Cornberg M, Buti M, Eberhardt C, Grossi P, Shouval D . EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients. J Hepatol. 2021; 74(4):944-951. PMC: 7867401. DOI: 10.1016/j.jhep.2021.01.032. View

10.

Sahin U, Muik A, Vogler I, Derhovanessian E, Kranz L, Vormehr M . BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans. Nature. 2021; 595(7868):572-577. DOI: 10.1038/s41586-021-03653-6. View

11.

Reinscheid M, Luxenburger H, Karl V, Graeser A, Giese S, Ciminski K . COVID-19 mRNA booster vaccine induces transient CD8+ T effector cell responses while conserving the memory pool for subsequent reactivation. Nat Commun. 2022; 13(1):4631. PMC: 9358914. DOI: 10.1038/s41467-022-32324-x. View

12.

Wieland D, Kemming J, Schuch A, Emmerich F, Knolle P, Neumann-Haefelin C . TCF1 hepatitis C virus-specific CD8 T cells are maintained after cessation of chronic antigen stimulation. Nat Commun. 2017; 8:15050. PMC: 5418623. DOI: 10.1038/ncomms15050. View

13.

Kalimuddin S, Tham C, Qui M, de Alwis R, Sim J, Lim J . Early T cell and binding antibody responses are associated with COVID-19 RNA vaccine efficacy onset. Med. 2021; 2(6):682-688.e4. PMC: 8030737. DOI: 10.1016/j.medj.2021.04.003. View

14.

Zander R, Kasmani M, Chen Y, Topchyan P, Shen J, Zheng S . Tfh-cell-derived interleukin 21 sustains effector CD8 T cell responses during chronic viral infection. Immunity. 2022; 55(3):475-493.e5. PMC: 8916994. DOI: 10.1016/j.immuni.2022.01.018. View

15.

Painter M, Mathew D, Goel R, Apostolidis S, Pattekar A, Kuthuru O . Rapid induction of antigen-specific CD4 T cells is associated with coordinated humoral and cellular immunity to SARS-CoV-2 mRNA vaccination. Immunity. 2021; 54(9):2133-2142.e3. PMC: 8361141. DOI: 10.1016/j.immuni.2021.08.001. View

16.

Guarino M, Cossiga V, Esposito I, Furno A, Morisco F . Effectiveness of SARS-CoV-2 vaccination in liver transplanted patients: The debate is open!. J Hepatol. 2021; 76(1):237-239. PMC: 8330141. DOI: 10.1016/j.jhep.2021.07.034. View

17.

Davidov Y, Indenbaum V, Tsaraf K, Cohen-Ezra O, Likhter M, Ben Yakov G . A third dose of the BNT162b2 mRNA vaccine significantly improves immune responses among liver transplant recipients. J Hepatol. 2022; 77(3):702-709. PMC: 9015954. DOI: 10.1016/j.jhep.2022.03.042. View

18.

Cui C, Wang J, Fagerberg E, Chen P, Connolly K, Damo M . Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses. Cell. 2021; 184(25):6101-6118.e13. PMC: 8671355. DOI: 10.1016/j.cell.2021.11.007. View

19.

Harberts A, Schaub G, Ruether D, Duengelhoef P, Brehm T, Karsten H . Humoral and Cellular Immune Response After Third and Fourth SARS-CoV-2 mRNA Vaccination in Liver Transplant Recipients. Clin Gastroenterol Hepatol. 2022; 20(11):2558-2566.e5. PMC: 9287575. DOI: 10.1016/j.cgh.2022.06.028. View

20.

Guarino M, Cossiga V, Loperto I, Esposito I, Ortolani R, Fiorentino A . COVID-19 in liver transplant recipients: incidence, hospitalization and outcome in an Italian prospective double-centre study. Sci Rep. 2022; 12(1):4831. PMC: 8940902. DOI: 10.1038/s41598-022-08947-x. View