Poor neutralization and rapid decay of antibodies to SARS-CoV-2 variants in vaccinated dialysis patients

  1. Jessica Bassi
  2. Olivier Giannini
  3. Chiara Silacci-Fregni
  4. Laura Pertusini
  5. Paolo Hitz
  6. Tatiana Terrot
  7. Yves Franzosi
  8. Francesco Muoio
  9. Christian Saliba
  10. Marcel Meury
  11. Exequiel A. Dellota
  12. Josh R. Dillen
  13. Patrick Hernandez
  14. Nadine Czudnochowski
  15. Elisabetta Cameroni
  16. Nicola Beria
  17. Mariangela Ventresca
  18. Alberto Badellino
  19. Soraya Lavorato-Hadjeres
  20. Elisabetta Lecchi
  21. Tecla Bonora
  22. Matteo Mattiolo
  23. Guido Trinci
  24. Daniela Garzoni
  25. Giuseppe Bonforte
  26. Valentina Forni-Ogna
  27. Davide Giunzioni
  28. Lorenzo Berwert
  29. Ravindra K. Gupta
  30. Paolo Ferrari
  31. Alessandro Ceschi
  32. Pietro Cippà
  33. Davide Corti
  34. Antonio Lanzavecchia
  35. Luca Piccoli

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Abstract

Patients on dialysis are at risk of severe course of SARS-CoV-2 infection. Understanding the neutralizing activity and coverage of SARS-CoV-2 variants of vaccine-elicited antibodies is required to guide prophylactic and therapeutic COVID-19 interventions in this frail population. By analyzing plasma samples from 130 hemodialysis and 13 peritoneal dialysis patients after two doses of BNT162b2 or mRNA-1273 vaccines, we found that 35% of the patients had low-level or undetectable IgG antibodies to SARS-CoV-2 Spike (S). Neutralizing antibodies against the vaccine-matched SARS-CoV-2 and Delta variant were low or undetectable in 49% and 77% of patients, respectively, and were further reduced against other emerging variants. The fraction of non-responding patients was higher in SARS-CoV-2-naïve hemodialysis patients immunized with BNT162b2 (66%) than those immunized with mRNA-1273 (23%). The reduced neutralizing activity correlated with low antibody avidity. Patients followed up to 7 months after vaccination showed a rapid decay of the antibody response with an average 21- and 10-fold reduction of neutralizing antibodies to vaccine-matched SARS-CoV-2 and Delta variant, which increased the fraction of non-responders to 84% and 90%, respectively. These data indicate that dialysis patients should be prioritized for additional vaccination boosts. Nevertheless, their antibody response to SARS-CoV-2 must be continuously monitored to adopt the best prophylactic and therapeutic strategy.

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  3. Version published to 10.1371/journal.pone.0263328
  4. Version published to 10.1101/2021.10.05.21264054v2 on medRxiv
  5. ScreenIT

    SciScore for 10.1101/2021.10.05.21264054: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Study participants and ethics statement: Blood samples were obtained from 143 dialysis patients and 48 healthcare workers under study protocols approved by the local Institutional Review Boards (Canton Ticino Ethics Committee, Switzerland).
    Consent: All subjects provided written informed consent for the use of blood and blood components (such as PBMCs, sera or plasma).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power AnalysisStatistical analysis: The study was designed to have 80% power to detect a minimum 25% difference in total incidence of cases with poor neutralizing antibody response (i.e., low or undetectable plasma antibody titers) or in average neutralizing titers between dialysis patients and healthy controls as well as within the HD subgroups.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Cell lines: Cell lines used in this study were obtained from ATCC (Vero E6 TMPRSS2) or ThermoFisher Scientific (Expi CHO cells, Expi293F™ and FreeStyle 293 cells)
    CHO
    suggested: None
    Vero E6 TMPRSS2 cells were grown in DMEM supplemented with 10% HyClone (FBS)
    Vero E6 TMPRSS2
    suggested: JCRB Cat# JCRB1819, RRID:CVCL_YQ49)
    Plasma pseudovirus neutralization assay: Vero E6-TMPRSS2 were grown in DMEM supplemented with 10% FBS and seeded into white bottom 96 well plates (PerkinElmer, 6005688), as previously described35.
    Vero E6-TMPRSS2
    suggested: None
    Recombinant DNA
    SentencesResources
    Production of recombinant glycoproteins: The SARS-CoV-2 RBD WT construct was synthesized by GenScript into phCMV1, with a sequence encoding an N-terminal mu-phosphatase signal peptide, an ‘ETGT’ linker, SARS-CoV-2 S residues 328-531, a linker sequence, an Avi tag, a twin Strep tag and a 8xHis-tag.
    phCMV1
    suggested: None
    The SARS-CoV-2 stabilized Spike WT (D614G) construct was synthesized by GenScript into pCDNA with an N-terminal mu-phosphatase signal peptide, 2P stabilizing mutation28,29, a TEV cleavage site and a C-terminal foldon, 8x His-tag, Avi tag and C-tag30 and expressed in FreeStyle 293 cells following manufacturer’s instructions.
    pCDNA
    suggested: RRID:Addgene_105932)
    Amino acid substitutions were introduced into the D614G pCDNA_SARS-CoV-2_S plasmid as previously described31.
    pCDNA_SARS-CoV-2_S
    suggested: None
    Software and Algorithms
    SentencesResources
    Data were analyzed and visualized with Prism (Version 9.1.0).
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    Data were plotted and analyzed with GraphPad Prism software (version 9.1.0).
    GraphPad Prism
    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:
    Our study has some limitations including a missing control group of patients matched by age, gender and comorbidities, without ESKD, while our control group was composed by younger individuals with few or no comorbidities. Another limitation was the low number of PD patients that did not allow to make subgroup analyses of risk factors of defective response. In addition, our patients were unbalanced in terms of type of mRNA vaccine received (BNT162b2 or mRNA-1273), although we had sufficient statistical power to make a comparison, even in a subgroup of patients matched by age, gender and comorbidity index. In conclusion, our study demonstrates, at the functional level, that mRNA vaccines induce a defective neutralizing antibody response against SARS-CoV-2 variants in dialysis patients, in particular in naïve HD patients immunized with BNT162b2. Our findings support the need of an additional boost, preferentially with a high-dose mRNA vaccine, in this population58-60, which, however, need to be continuously monitored with proper serological tests that measure not only the serum antibody levels, but also their neutralizing activity, either directly or indirectly through an avidity test. Finally, our data suggest that some patients may not respond efficiently even after an additional boost and, therefore, in case of SARS-CoV-2 infection, they should be considered for other therapeutic strategies, including early immunotherapy with monoclonal antibodies.

    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.

  6. Version published to 10.1101/2021.10.05.21264054v1 on medRxiv