Temporary antimetabolite treatment hold boosts SARS-CoV-2 vaccination–specific humoral and cellular immunity in kidney transplant recipients

  1. Eva Schrezenmeier
  2. Hector Rincon-Arevalo
  3. Annika Jens
  4. Ana-Luisa Stefanski
  5. Charlotte Hammett
  6. Bilgin Osmanodja
  7. Nadine Koch
  8. Bianca Zukunft
  9. Julia Beck
  10. Michael Oellerich
  11. Vanessa Proß
  12. Carolin Stahl
  13. Mira Choi
  14. Friederike Bachmann
  15. Lutz Liefeldt
  16. Petra Glander
  17. Ekkehard Schütz
  18. Kirsten Bornemann-Kolatzki
  19. Covadonga López del Moral
  20. Hubert Schrezenmeier
  21. Carolin Ludwig
  22. Bernd Jahrsdörfer
  23. Kai-Uwe Eckardt
  24. Nils Lachmann
  25. Katja Kotsch
  26. Thomas Dörner
  27. Fabian Halleck
  28. Arne Sattler
  29. Klemens Budde

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Abstract

Transplant recipients exhibit an impaired protective immunity after SARS-CoV-2 vaccination, potentially caused by mycophenolate (MPA) immunosuppression. Recent data from patients with autoimmune disorders suggest that temporary MPA hold might greatly improve booster vaccination outcomes. We applied a fourth dose of SARS-CoV-2 vaccine to 29 kidney transplant recipients during a temporary (5 weeks) MPA/azathioprine hold, who had not mounted a humoral immune response to previous vaccinations. Seroconversion until day 32 after vaccination was observed in 76% of patients, associated with acquisition of virus-neutralizing capacity. Interestingly, 21/25 (84%) calcineurin inhibitor–treated patients responded, but only 1/4 belatacept-treated patients responded. In line with humoral responses, counts and relative frequencies of spike receptor binding domain–specific (RBD-specific) B cells were markedly increased on day 7 after vaccination, with an increase in RBD-specific CD27 ++ CD38 + plasmablasts. Whereas overall proportions of spike-reactive CD4 + T cells remained unaltered after the fourth dose, frequencies were positively correlated with specific IgG levels. Importantly, antigen-specific proliferating Ki67 + and in vivo–activated programmed cell death 1–positive T cells significantly increased after revaccination during MPA hold, whereas cytokine production and memory differentiation remained unaffected. In summary, antimetabolite hold augmented all arms of immunity during booster vaccination. These data suggest further studies of antimetabolite hold in kidney transplant recipients.

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  1. Version published to 10.1172/jci.insight.157836
  2. ScreenIT

    SciScore for 10.1101/2022.01.05.21268478: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: Study protocol and participants: All participants gave written informed consent for sample collection according to the approval of the ethics committees of the Charité-Universitätsmedizin Berlin (EA2/010/21, EA4/188/20).
    IRB: Study protocol and participants: All participants gave written informed consent for sample collection according to the approval of the ethics committees of the Charité-Universitätsmedizin Berlin (EA2/010/21, EA4/188/20).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    For flow cytometric analysis, the following fluorochrome-labeled antibodies were used: CD14 (M5E2, BD Biosciences, Franklin Lakes, NJ, USA), CD3 (UCHT1, BD), CD27 (L128, BD), CD19 (SJ25C1, BD), CD24 (ML5, BD), IgD (IA6-2, BioLegend, San Diego, CA, USA), CD38 (clone HIT2, BioLegend).
    CD14
    suggested: None
    CD3
    suggested: (BioLegend Cat# 391501, RRID:AB_2616702)
    CD27
    suggested: None
    CD19
    suggested: (Agilent Cat# TC67401, RRID:AB_579635)
    CD24
    suggested: None
    IA6-2
    suggested: None
    CD38
    suggested: None
    For labelling of surface markers, antibodies against CD3 (SK7, Biolegend), CD4 (SK3, BD), CD8 (SK1, Ebioscience, San Diego, CA, USA), CD45RO (UCHL1, BioLegend), CD62L (DREG-56, BioLegend) and PD1 (EH12.1, Becton Dickinson) were used.
    CD4
    suggested: (Cell Sciences Cat# 873.019.050, RRID:AB_10048825)
    CD8
    suggested: (Bethyl Cat# A810-007, RRID:AB_2891978)
    CD45RO
    suggested: None
    UCHL1
    suggested: None
    CD62L
    suggested: None
    DREG-56
    suggested: None
    PD1
    suggested: None
    Software and Algorithms
    SentencesResources
    Co-expression of cytokines was quantified by Boolean gating in Flowjo.
    Flowjo
    suggested: (FlowJo, RRID:SCR_008520)
    Statistical analysis and graph preparation was conducted in GraphPad Prism 8 (GraphPad, La Jolla, CA, USA).
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    As an obvious limitation of our approach, a subgroup of patients with previous or ongoing Belatacept treatment did not benefit from MPA hold. Although patient numbers were small, our data support the notion that Belatacept efficiently inhibits vaccine responses (38) irrespective of the presence of anti-metabolites, suggesting that other approaches are needed for Belatacept-treated patients. In summary our data provide evidence that temporal hold of MPA for 5 weeks in patients under previous CNI, MPA ± CS is a viable option to accelerate and increase vaccine efficacy in KTR, particularly given that graft function remained stable and no rejection episodes or increases in anti-HLA antibodies and dd-cfDNA plasma concentrations were observed. Our study thus highlights a potential rapid vaccination strategy for at-risk patients under standard CNI-based immunosuppression that warrants testing in larger cohorts.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2022.01.05.21268478 on medRxiv