Cytokine release syndrome-like serum responses after COVID-19 vaccination are frequent and clinically inapparent under cancer immunotherapy

  1. Thomas Walle
  2. Sunanjay Bajaj
  3. Joscha A. Kraske
  4. Thomas Rösner
  5. Christiane S. Cussigh
  6. Katharina A. Kälber
  7. Lisa Jasmin Müller
  8. Sophia Boyoung Strobel
  9. Jana Burghaus
  10. Stefan M. Kallenberger
  11. Christoph K. Stein-Thöringer
  12. Maximilian Jenzer
  13. Antonia Schubert
  14. Steffen Kahle
  15. Anja Williams
  16. Birgit Hoyler
  17. Lin Zielske
  18. Renate Skatula
  19. Stefanie Sawall
  20. Mathias F. Leber
  21. Russell Z. Kunes
  22. Johannes Krisam
  23. Carlo Fremd
  24. Andreas Schneeweiss
  25. Jürgen Krauss
  26. Leonidas Apostolidis
  27. Anne Katrin Berger
  28. Georg M. Haag
  29. Stefanie Zschäbitz
  30. Niels Halama
  31. Christoph Springfeld
  32. Romy Kirsten
  33. Jessica C. Hassel
  34. Dirk Jäger
  35. NCT ANTICIPATE Investigators
  36. Christiane S. Cussigh
  37. Katharina A. Kälber
  38. Omar Abdelrahim
  39. Elena Busch
  40. Patrick Derigs
  41. Katharina Dischinger
  42. Fouad Mitri
  43. Kerstin Schmidt
  44. Irfan A. Bhatti
  45. Barbara Grün
  46. Nicolas Hohmann
  47. Lena Woydack
  48. Xin-Wen Zhang
  49. Dyke Ferber
  50. Andreas Mock
  51. Tillmann Pompecki
  52. Timo Schank
  53. Carlo Fremd
  54. Georg M. Haag
  55. Niels Halama
  56. Romy Kirsten
  57. Jessica C. Hassel
  58. Dirk Jäger
  59. Guy Ungerechts

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Abstract

Patients with cancer frequently receive immune-checkpoint inhibitors (ICIs), which may modulate immune responses to COVID-19 vaccines. Recently, cytokine release syndrome (CRS) was observed in a patient with cancer who received BTN162b2 vaccination under ICI treatment. Here, we analyzed adverse events and serum cytokines in patients with 23 different tumors undergoing ( n  = 64) or not undergoing ( n  = 26) COVID-19 vaccination under ICI therapy in a prospectively planned German single-center cohort study ( n  = 220). We did not observe clinically relevant CRS (≥grade 2) after vaccination (95% CI 0–5.6%; Common Terminology of Adverse Events v.5.0) in this small cohort. Within 4 weeks after vaccination, serious adverse events occurred in eight patients (12.5% 95% CI 5.6–23%): six patients were hospitalized due to events common under cancer therapy including immune related adverse events and two patients died due to conditions present before vaccination. Despite absence of CRS symptoms, a set of pairwise-correlated CRS-associated cytokines, including CXCL8 and interleukin-6 was >1.5-fold upregulated in 40% (95% CI 23.9–57.9%) of patients after vaccination. Hence, elevated cytokine levels are common and not sufficient to establish CRS diagnosis.

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  1. Version published to 10.1038/s43018-022-00398-7
  2. ScreenIT

    SciScore for 10.1101/2021.12.08.21267430: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Informed consent, hemoglobin levels ≥8g/dl when additional blood samples were obtained and measurable disease according to RECIST 1.1 were obligatory requirements for inclusion.
    IRB: The trial received institutional ethics review board approval at Ethics Commission I Medical Faculty Heidelberg, Heidelberg University (S-373/2020, S-207/2005,) and Ethics Commission II Medical Faculty Mannheim, Heidelberg University (
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    BlindingThe acquisition and processing of the raw data was performed by a clinician scientist who was blinded to the patients’ identity and metadata and who was not involved in downstream data analysis.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Serum samples were thawed and immediately analyzed in duplicates using the Legendplex Cytokine Storm Panel 1 (741091, Biolegend, CA, USA), Cytokine Storm Panel 2 (741142, Biolegend, CA, USA) or SARS-CoV-2 Neutralizing Antibody Assay (741127, Biolegend, CA, USA) according to manufacturer’s instructions and analyzed on a BD FACS Canto II flow cytometer (BD, NJ, USA)
    SARS-CoV-2 Neutralizing Antibody Assay ( 741127
    suggested: None
    Software and Algorithms
    SentencesResources
    Pre-existing health conditions were obtained from electronic patient records and defined according to the Side Effect Resource (SIDER v4.1, http://sideeffects.embl.de).
    SIDER
    suggested: (SIDER, RRID:SCR_004321)
    General data analysis: All data analysis was performed using Python 3 in a Jupyter notebook or Graph Pad Prism 9.2.0 (
    Python
    suggested: (IPython, RRID:SCR_001658)
    GraphPad Software Inc, CA, U.S.A.).
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Plotting was done using the Matplotlib (3.4.3) and Seaborn (0.11.2) packages.
    Matplotlib
    suggested: (MatPlotLib, RRID:SCR_008624)
    Plots were arranged using Adobe Illustrator 2021 (25.2.2
    Adobe Illustrator
    suggested: (Adobe Illustrator, RRID:SCR_010279)
    We calculated pairwise Euclidian distances using scipy’s (1.7.2) scipy.spatial.distance.pdist function.
    scipy
    suggested: (SciPy, RRID:SCR_008058)
    Using scipy’s scipy.cluster.hierarchy.linkage function with the UPGMA method, we obtained the row and column linkages from the untransposed and transposed Euclidian distance matrix respectively and transformed these into flat clusters by applying scipy.cluster.hierarchy.fcluster function using a cophenetic distance of 1.6.
    scipy’s
    suggested: None
    For categorical data/contingency tables we used Fisher’s exact test (GraphPad Prism 9.2.0).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: Thank you for sharing your code.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Despite these important insights, our study also has several limitations which should be considered in its interpretation. Adverse events under SARS-CoV-2 vaccination were not the primary endpoint of this study. Therefore, sample size was not optimized for this endpoint and our trial is not powered to estimate the exact frequency of rare AE under ICT and COVID-19 vaccination. Moreover, AE were assessed upon presentation at our day clinic every 1-6 weeks and not at a standardized early timepoint as performed for randomized controlled vaccination trials (Polack et al., 2020). While serious AEs were generally reported instantly, lower grade AEs may be underreported due to recall bias. Finally, all serum cytokine and antibody titer analyses are research grade and absolute concentrations from this study should not be used to establish clinical diagnoses. Strengths of our analysis include the prospective design, prospective recruitment of most patients, long-term follow-up, broad array of cancer types and combination ICTs. In summary, induction of CRS-related cytokines after COVID-19 vaccination is common in ICT-treated cancer patients, but generally clinically inapparent and hence not sufficient to define CRS. Our study supports current clinical practice of COVID-19 vaccination in cancer patients under ICT.

    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 10.1101/2021.12.08.21267430v1 on medRxiv