Vaccination boosts protective responses and counters SARS-CoV-2-induced pathogenic memory B cells

  1. Pankaj Kumar Mishra
  2. Natalie Bruiners
  3. Rahul Ukey
  4. Pratik Datta
  5. Alberta Onyuka
  6. Deborah Handler
  7. Sabiha Hussain
  8. William Honnen
  9. Sukhwinder Singh
  10. Valentina Guerrini
  11. Yue Yin
  12. Hannah Dewald
  13. Alok Choudhary
  14. Daniel B. Horton
  15. Emily S. Barrett
  16. Jason Roy
  17. Stanley H. Weiss
  18. Patricia Fitzgerald-Bocarsly
  19. Martin J. Blaser
  20. Jeffrey L. Carson
  21. Reynold A. Panettieri
  22. Alfred Lardizabal
  23. Theresa Li-Yun Chang
  24. Abraham Pinter
  25. Maria Laura Gennaro

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Abstract

Much is to be learned about the interface between immune responses to SARS-CoV-2 infection and vaccination. We monitored immune responses specific to SARS-CoV-2 Spike Receptor-Binding-Domain (RBD) in convalescent individuals for eight months after infection diagnosis and following vaccination. Over time, neutralizing antibody responses, which are predominantly RBD specific, generally decreased, while RBD-specific memory B cells persisted. RBD-specific antibody and B cell responses to vaccination were more vigorous than those elicited by infection in the same subjects or by vaccination in infection-naïve comparators. Notably, the frequencies of double negative B memory cells, which are dysfunctional and potentially pathogenic, increased in the convalescent subjects over time. Unexpectedly, this effect was reversed by vaccination. Our work identifies a novel aspect of immune dysfunction in mild/moderate COVID-19, supports the practice of offering SARS-CoV-2 vaccination regardless of infection history, and provides a potential mechanistic explanation for the vaccination-induced reduction of “Long-COVID” symptoms.

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  1. Version published to 10.1101/2021.04.11.21255153v2 on medRxiv
  2. ScreenIT

    SciScore for 10.1101/2021.04.11.21255153: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIACUC: All work involving blood products from SARS-CoV-2-infected subjects were performed in a biosafety level 2+ (BSL-2+) laboratory utilizing protocols approved by the Rutgers Institutional Biosafety Committee.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    As negative control for SARS-CoV-2 antibody testing, we used 104 stored serum/plasma samples collected prior to the COVID-19 pandemic (Institutional review board of the Rutgers New Jersey Medical School, Pro0119980237 and Pro20150001314) and 103 serum samples obtained during the pandemic from subjects that remained SARS-CoV-2 PCR-negative and seronegative for at least 16 weeks following the test blood draw (43) (ClinicalTrials.gov registration number NCT04336215).
    SARS-CoV-2
    suggested: None
    To monitor depletion of antigen-specific antibodies, RBD- and N-specific IgG titers of untreated and absorbed samples were determined as described above, prior to use in neutralization assays.
    antigen-specific
    suggested: None
    For the detection of antigen-specific B cells, PBMCs were incubated with the RBD tetramer and antibodies to CD19-BV700 (HIB19, BioLegend), CD20-PE-CF594
    HIB19
    suggested: None
    Additionally, cells were stained with APC-labelled antibodies against CD3 (UCHT1, Thermo Fisher Scientific), CD4 (OKT4, Thermo Fisher Scientific), CD14 (C1D3, Thermo Fisher Scientific), and CD16 (CB16, Thermo Fisher Scientific) to eliminate non-B cells.
    CD3
    suggested: None
    UCHT1
    suggested: None
    CD4
    suggested: (BioLegend Cat# 391503, RRID:AB_2721611)
    OKT4
    suggested: None
    CD14
    suggested: (BioLegend Cat# 348805, RRID:AB_2889063)
    CD16
    suggested: None
    CB16
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Manassas VA) and HeLa cells stably expressing ACE2 (HeLa-ACE2) were obtained from Dennis Burton at the Scripps Research Institute (21)
    HeLa
    suggested: CLS Cat# 300194/p772_HeLa, RRID:CVCL_0030)
    The virus titers were determined by standard plaque assay utilizing Vero E6 cells (45) and recorded as plaque forming units per milliliter (PFU/mL).
    Vero E6
    suggested: RRID:CVCL_XD71)
    neutralization assay: HeLa-Ace2 cells were seeded in 96-well black optical-bottom plates at a density of 1 × 104 cells/well in FluoroBrite DMEM (Thermo Fisher Scientific) containing 4% FBS (Seradigm)
    HeLa-Ace2
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical Analysis: All flow cytometry data were analyzed with FlowJo v12 software (FlowJo LLC, Ashland OR).
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Statistical analysis was performed with GraphPad Prism 8.4 (Graph Pad Software Inc.,
    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04336215RecruitingRutgers COVID-19 Cohort Study

    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.

    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 10.1101/2021.04.11.21255153v1 on medRxiv