BNT162b2 induces robust cross-variant SARS-CoV-2 immunity in children

  1. Yannic C Bartsch
  2. Jessica W Chen
  3. Jaewon Kang
  4. Madeline D Burns
  5. Kerri J St Denis
  6. Maegan L Sheehan
  7. Jameson P Davis
  8. Alejandro B Balazs
  9. Lael M Yonker
  10. Galit Alter

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Abstract

Currently available mRNA vaccines are extremely safe and effective to prevent severe SARS-CoV-2 infections. However, the emergence of novel variants of concerns has highlighted the importance of high population-based vaccine rates to effectively suppress viral transmission and breakthrough infections. While initially left out from vaccine efforts, children have become one of the most affected age groups and are key targets to stop community and household spread. Antibodies are central for vaccine induced protection and emerging data points to the importance of additional Fc effector functions like opsononophagocytosis or cytotoxicity, particularly in the context of variants of concern that escape neutralizing antibodies. Here, we observed delayed induction and reduced magnitude of vaccine induced antibody titers in children 5-11 years receiving two doses of the age recommended 10 μg dose of the Pfizer SARS-CoV-2 BNT162b2 vaccine compared to adolescents (12-15 years) or adults receiving the 30 μg dose. Conversely, children mounted equivalent or more robust neutralization and opsonophagocytic functions at peak immunogenicity, pointing to a qualitatively more robust humoral functional response in children. Moreover, broad cross-variants of concern responses were observed across children, with enhanced IgM and parallel IgG cross-reactivity to variants of concern (VOCs) in children compared to adults. Collectively, these data argue that despite the lower magnitude of the BNT162b2 induced antibody response in children, vaccine induced immunity in children target VOCs broadly and exhibit enhanced functionality that may contribute to attenuation of disease.

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  1. ScreenIT

    SciScore for 10.1101/2022.05.18.22275283: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: All individuals or their legal guardian gave informed consent prior to enrollment.
    IRB: This study was overseen and approved by the MassGeneralBrigham Institutional Review Board (
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Primary natural killer cells for the antibody-dependent natural killer activation (ADNKA) assays were isolated from buffy coats from health donors using the RosetteSep NK cell enrichment kit (STEMCELL Technologies).
    antibody-dependent natural killer activation ( ADNKA
    suggested: None
    Antibody Isotype and Fc Receptor Binding: Antigen-specific antibody isotype, subclass, and Fc receptor binding profiles were analyzed using a custom multiplex Luminex assay as previously described 35.
    Antigen-specific antibody isotype , subclass ,
    suggested: None
    Following overnight incubation, non-specific antibodies were washed off and the immune complexes were incubated with Ig isotypes or subclasses with a 1:100 diluted PE-conjugated secondary antibody for IgG1 (clone: HP6001), IgG2 (clone: 31-7-4), IgG3 (clone: HP6050), IgG4 (clone: HP6025), IgM (clone: SA-DA4), IgA1 (clone: B3506B4), or IgA2 (clone: A9604D2) (all Southern Biotech).
    IgG1
    suggested: None
    IgG2
    suggested: None
    IgG3
    suggested: None
    IgG4
    suggested: None
    IgA1
    suggested: None
    IgA2
    suggested: None
    Following incubation, excessive antibodies were washed off and relative antigen-specific antibody levels were determined on an iQue analyzer (Intellicyt)
    antigen-specific
    suggested: None
    C3 deposited on beads were stained with anti-guinea pig C3-FITC antibody (MP Biomedicals, 1:100
    anti-guinea pig C3-FITC
    suggested: None
    Antibody-Dependent Neutrophil Phagocytosis (ADNP) Assays: ADNP assays were performed as previously described 37.
    Antibody-Dependent Neutrophil Phagocytosis ( ADNP
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Cell Lines and Primary Cells: THP-1 cells, a human leukemia monocyte cell line, were maintained in RPMI-1640 Medium (Sigma-Aldrich) with 10% fetal bovine serum (FBS, Sigma-Aldrich), 1% L-glutamine (Corning), 2% of 5000 IU/mL of Penicillin and 5,000 ug/ml of Streptomycin Solution (Pen-Strep, Corning), 1% of 1M HEPES (Corning), and 5mM 2-Mercaptoethanol (Gibco).
    THP-1
    suggested: None
    Human embryonic kidney (HEK) 293T cells expressing ACE2 for neutralization assays were maintained in Dulbecco’s Modified Eagle’s Medium (DMEM, Corning) with 10% FBS (VWR) and 1% Pen-Strep (Corning) and incubated in 37°C with 5% CO2.
    HEK
    suggested: None
    293T
    suggested: None
    Three-fold serial dilutions of plasma samples starting at 1:12 or 1:30 were performed before adding pseudovirus expressing either SARS-CoV-2 wild-type spike or omicron variant spike to HEK293T expressing ACE-2 cells for 1 hour.
    HEK293T
    suggested: RRID:CVCL_HA71)
    ACE-2
    suggested: None
    Software and Algorithms
    SentencesResources
    Primary neutrophils for antibody-dependent neutrophil phagocytosis (ADNP) assays were isolated from whole blood from healthy donors using Ammonium-Chloride-Potassium (ACK) Lysing Buffer (Quality Biological) followed by centrifugation and multiple wash steps prior to assay usage.
    Quality Biological
    suggested: None
    Data Analysis and Statistics: Data analysis was performed on GraphPad Prism (v.9.3) and RStudio (v.1.3).
    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: 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: 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.

  2. Version published to 10.1101/2022.05.18.22275283v1 on medRxiv