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Cited by 831SARS-CoV-2 and COVID-19 ResearchImmune responses and vaccinationsT-cell and B-cell Immunology

SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses

Open access
Turner, Jackson S., O’Halloran, Jane A., Kalaidina, Elizaveta, Kim, Wooseob, Schmitz, Aaron J., Zhou, Julian Q., Lei, Tingting, Thapa, Mahima +15 more·2021·Nature
DOI 10.1038/s41586-021-03738-2PMC PMC8935394

Published version of a preprint

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Abstract

SARS-CoV-2 mRNA-based vaccines are about 95% effective in preventing COVID-19 1-5. The dynamics of antibody-secreting plasmablasts and germinal centre B cells induced by these vaccines in humans remain unclear. Here we examined antigen-specific B cell responses in peripheral blood (n = 41) and draining lymph nodes in 14 individuals who had received 2 doses of BNT162b2, an mRNA-based vaccine that encodes the full-length SARS-CoV-2 spike (S) gene 1. Circulating IgG- and IgA-secreting plasmablasts that target the S protein peaked one week after the second immunization and then declined, becoming undetectable three weeks later. These plasmablast responses preceded maximal levels of serum anti-S binding and neutralizing antibodies to an early circulating SARS-CoV-2 strain as well as emerging variants, especially in individuals who had previously been infected with SARS-CoV-2 (who produced the most robust serological responses). By examining fine needle aspirates of draining axillary lymph nodes, we identified germinal centre B cells that bound S protein in all participants who were sampled after primary immunization. High frequencies of S-binding germinal centre B cells and plasmablasts were sustained in these draining lymph nodes for at least 12 weeks after the booster immunization. S-binding monoclonal antibodies derived from germinal centre B cells predominantly targeted the receptor-binding domain of the S protein, and fewer clones bound to the N-terminal domain or to epitopes shared with the S proteins of the human betacoronaviruses OC43 and HKU1. These latter cross-reactive B cell clones had higher levels of somatic hypermutation as compared to those that recognized only the SARS-CoV-2 S protein, which suggests a memory B cell origin. Our studies demonstrate that SARS-CoV-2 mRNA-based vaccination of humans induces a persistent germinal centre B cell response, which enables the generation of robust humoral immunity.

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Crossref · 10.1038/s41586-021-03738-2

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 28 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    S-binding plasmablasts were detected in FNA samples at 5, 7 and 15 weeks after immunization, when they had become undetectable in blood from all participants in the cohort.

    “S-binding plasmablasts were detected in FNA samples at 5, 7 and 15 weeks after immunization, when they had become undetectable in blood from all participants in the cohort.”
    Quote in the paperSubstantial claim
  • Findingown data

    ELISpot detected SARS-CoV-2 S-specific IgG- and IgA-secreting plasmablasts 3 weeks after primary immunization in 24 of 33 participants without prior infection, but in 0 of 8 previously infected participants.

    “We detected SARS-CoV-2-S-specfic IgG- and IgA-secreting plasmablasts 3 weeks after primary immunization in 24 of 33 participants with no history of SARS-CoV-2 infection, but in 0 of 8 participants who had previously been infected with SARS-CoV-2.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Clones related to S-binding monoclonal antibodies had significantly increased mutation frequencies in IGHV genes compared to previously published naive B cells, particularly those related to cross-reactive monoclonal antibodies.

    “Clones related to S-binding monoclonal antibodies had significantly increased mutation frequencies in their immunoglobulin heavy chain variable region (IGHV) genes compared to previously published naive B cells19, particularly those related to monoclonal antibodies that cross-reacted with seasonal betacoronaviruses”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Turner, J. S. et al. Human germinal centres engage memory and naive B cells after influenza vaccination. Nature 586, 127–132 (2020). source

      Not checked in the free run.

  • Findingown data

    The vaccine induced a strong IgG-dominated plasmablast response in blood that peaked one week after the booster immunization.

    “The vaccine induced a strong IgG-dominated plasmablast response in blood that peaked one week after the booster immunization.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Robust plasmablast responses were detected in the draining lymph nodes of all 14 participants in the FNA cohort.

    “we detected robust plasmablast responses in the draining lymph nodes of all 14 participants in the FNA cohort.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 20
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Findingown data

    Serum neutralizing titres increased markedly in participants without prior infection after boosting, with geometric mean neutralization titres against WA1/2020 D614G of 58 at 3 weeks after primary immunization and 572 at 2 or 4 weeks after boost.

    “Serum neutralizing titres increased markedly in participants without a history of SARS-CoV-2 infection after boosting, with geometric mean neutralization titres against WA1/2020 D614G of 58 at 3 weeks after primary immunization and 572 at 2 or 4 weeks after boost (5 or 7 weeks after primary immunization).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    S-binding germinal centre B cell frequencies increased at least transiently in all participants after boosting and persisted at high frequency in most individuals for at least 7 weeks.

    “S-binding germinal centre B cell frequencies increased at least transiently in all participants after boosting and persisted at high frequency in most individuals for at least 7 weeks.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Plasma IgG anti-S titres increased in all participants, reached peak geometric mean half-maximal binding titres of 5,567 and 15,850 at 5 weeks in participants without and with prior infection, and declined by 15 weeks.

    “plasma IgG antibody titres against S, measured by enzyme-linked immunosorbent assay (ELISA), increased in all participants over time, and reached peak geometric mean half-maximal binding titres of 5,567 and 15,850 at 5 weeks after immunization among participants without and with history of SARS-CoV-2 infection, respectively, with a subsequent decline by 15 weeks after immunization.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Anti-S IgA and anti-RBD IgG showed similar kinetics, with peak geometric mean half-maximal binding titres of 172 and 739 for anti-S IgA and 4,501 and 7,965 for anti-RBD IgG among participants without and with prior infection, before declining.

    “Anti-S IgA titres and IgG titres against the receptor-binding domain (RBD) of S showed similar kinetics, and reached peak geometric mean half-maximal binding titres of 172 and 739 for anti-S IgA and 4,501 and 7,965 for anti-RBD IgG among participants without and with history of SARS-CoV-2 infection, respectively, before declining.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Plasmablasts peaked in blood during the first week after boosting, with frequencies ranging from 3 to 4,100 S-binding plasmablasts per 10^6 PBMCs.

    “Plasmablasts peaked in blood during the first week after boosting (week 4 after primary immunization), with frequencies that varied widely from 3 to 4,100 S-binding plasmablasts per 106 peripheral blood mononuclear cells (PBMCs)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The vast majority of S-binding lymph node plasmablasts were isotype-switched at 4 weeks after primary immunization, and IgA-switched cells accounted for 25% or more of the plasmablasts in 6 of 14 participants.

    “The vast majority of S-binding lymph node plasmablasts were isotype-switched at 4 weeks after primary immunization, and IgA-switched cells accounted for 25% or more of the plasmablasts in 6 out of 14 participants”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    S-binding plasmablasts were detected in all lymph nodes sampled and increased in frequency after boosting.

    “S-binding plasmablasts (defined as CD19+CD3−IgDlowCD20lowCD38+CD71+BLIMP1+ lymphocytes) were detected in all of the lymph nodes that we sampled, and increased in frequency after boosting”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IgM responses were weaker and more transient, peaking 4 weeks after immunization in participants without prior infection with a geometric mean half-maximal binding titre of 78, and were undetectable in all but 2 previously infected participants.

    “IgM responses were weaker and more transient, peaking 4 weeks after immunization among participants without history of SARS-CoV-2 infection with a geometric mean half-maximal binding titre of 78 and were undetectable in all but 2 previously infected participants”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Neutralizing titres against B.1.1.7 and B.1.351 were lower than against WA1/2020 D614G, with geometric mean neutralization titres of 49 and 373 against B.1.1.7 and 36 and 137 against B.1.351 after primary and secondary immunization.

    “Neutralizing titres against the B.1.1.7 and B.1.351 variants were lower, with geometric mean neutralization titres of 49 and 373 against B.1.1.7 and 36 and 137 against B.1.351 after primary and secondary immunization, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    These geometric mean neutralization titres were 78-, 73- and 53-fold higher after primary immunization and 16-, 25- and 20-fold higher after boosting against WA1/2020 D614G, B.1.1.7 and B.1.351, respectively, than in participants without prior infection.

    “These geometric mean neutralization titres were 78-, 73- and 53-fold higher after primary immunization and 16-, 25- and 20-fold higher after boosting against WA1/2020 D614G, B.1.1.7 and B.1.351, respectively, than in participants without a history of SARS-CoV-2 infection”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    These responses were detectable after the first immunization but greatly expanded after the booster injection.

    “These responses were detectable after the first immunization but greatly expanded after the booster injection.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    S-binding germinal centre B cells and plasmablasts persisted in draining lymph nodes for at least 12 weeks after booster immunization (15 weeks after first immunization), remaining at or near peak frequency in 8 of 10 participants sampled at 15 weeks.

    “High frequencies of S-binding germinal centre B cells and plasmablasts were sustained in these draining lymph nodes for at least 12 weeks after the booster immunization.”
    • Also stated in: § Abstract · plain
      “S-binding germinal centre B cells remained at or near their peak frequency 15 weeks after immunization in 8 of the 10 participants sampled at that time point”
    • Also stated in: § Abstract · plain
      “S-binding germinal centre B cells and plasmablasts persisted for at least 15 weeks after the first immunization (12 weeks after secondary immunization) in 8 of the 10 participants who were sampled at that time point.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Circulating IgG- and IgA-secreting plasmablasts specific for SARS-CoV-2 S peaked one week after the second immunization and then declined, becoming undetectable three weeks later.

    “Circulating IgG- and IgA-secreting plasmablasts that target the S protein peaked one week after the second immunization and then declined, becoming undetectable three weeks later.”
    • Also stated in: § Abstract · plain
      “Plasmablasts peaked in blood during the first week after boosting (week 4 after primary immunization)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In previously infected participants, neutralizing titres increased more rapidly and to higher levels after immunization, with geometric mean neutralization titres after primary immunization of 4,544, 3,584 and 1,897 and after secondary immunization of 9,381, 9,351 and 2,749 against WA1/2020 D614G, B.1.1.7 and B.1.351.

    “In these participants, neutralizing titres increased more rapidly and to higher levels after immunization, with geometric mean neutralization titres of 4,544, 3,584 and 1,897 against WA1/2020 D614G, B.1.1.7 and B.1.351, respectively, after primary immunization, and 9,381, 9,351 and 2,749 against WA1/2020 D614G, B.1.1.7 and B.1.351, respectively, after secondary immunization.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Cross-reactive clones were not identified in all individuals and comprised a small fraction of responding B cells, consistent with a similar analysis of SARS-CoV-2 mRNA vaccine-induced plasmablasts.

    “However, these cross-reactive clones were not identified in all individuals and comprised a small fraction of responding B cells, consistent with a similar analysis of SARS-CoV-2 mRNA vaccine-induced plasmablasts37.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Amanat, F. et al. SARS-CoV-2 mRNA vaccination induces functionally diverse antibodies to NTD, RBD and S2. Cell https://doi.org/10.1016/j.cell.2021.06.005 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Germinal centre responses induced by more robust adjuvants such as sheep red blood cells, complete Freund's adjuvant or saponin-based adjuvants tend to peak at 2-4 weeks after vaccination and can persist at low frequencies for several months.

    “Germinal centre responses induced by immunization with more robust adjuvants such as sheep red blood cells, complete Freund’s adjuvant or saponin-based adjuvants tend to peak slightly later, at 2–4 weeks after vaccination, and can persist at low frequencies for several months27–33.”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [27] Bachmann, M. F., Odermatt, B., Hengartner, H. & Zinkernagel, R. M. Induction of long-lived germinal centers associated with persisting antigen after viral infection. J. Exp. Med. 183, 2259–2269 (1996). source

      Not checked in the free run.

    • cites [28] Dogan, I. et al. Multiple layers of B cell memory with different effector functions. Nat. Immunol. 10, 1292–1299 (2009). source

      Not checked in the free run.

    • cites [29] Rothaeusler, K. & Baumgarth, N. B-cell fate decisions following influenza virus infection. Eur. J. Immunol. 40, 366–377 (2010). source

      Not checked in the free run.

    • cites [30] Pape, K. A., Taylor, J. J., Maul, R. W., Gearhart, P. J. & Jenkins, M. K. Different B cell populations mediate early and late memory during an endogenous immune response. Science 331, 1203–1207 (2011). source

      Not checked in the free run.

    • cites [31] Turner, J. S., Benet, Z. L. & Grigorova, I. Transiently antigen primed B cells can generate multiple subsets of memory cells. PLoS ONE 12, e0183877 (2017). source

      Not checked in the free run.

    • cites [32] Havenar-Daughton, C. et al. Rapid germinal center and antibody responses in non-human primates after a single nanoparticle vaccine immunization. Cell Rep. 29, 1756–1766.e8 (2019). source

      Not checked in the free run.

    • cites [33] Cirelli, K. M. et al. Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance. Cell 177, 1153–1171.e28 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    SARS-CoV-2 mRNA-based vaccination of humans induces a persistent germinal centre B cell response that enables robust humoral immunity.

    “Our studies demonstrate that SARS-CoV-2 mRNA-based vaccination of humans induces a persistent germinal centre B cell response, which enables the generation of robust humoral immunity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Responses to mRNA vaccination are superior to those seen after seasonal influenza virus vaccination in humans, in whom haemagglutinin-binding germinal centre B cells were detected in only three out of eight participants.

    “These responses to mRNA vaccination are superior to those seen after seasonal influenza virus vaccination in humans19, in whom haemagglutinin-binding germinal centre B cells were detected in only three out of eight participants.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Turner, J. S. et al. Human germinal centres engage memory and naive B cells after influenza vaccination. Nature 586, 127–132 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    BNT162b2 is an mRNA vaccine that encodes the full-length SARS-CoV-2 spike gene.

    “an mRNA-based vaccine that encodes the full-length SARS-CoV-2 spike (S) gene1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Mulligan, M. J. et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 586, 589–593 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Somatic hypermutation frequency was computed by counting nucleotide mismatches from the germline sequence in the heavy chain variable segment up to the CDR3, excluding the first 18 positions that could be error-prone because of the primers used for monoclonal antibody generation.

    “Mutation frequency was calculated by counting the number of nucleotide mismatches from the germline sequence in the observed heavy chain variable segment leading up to the CDR3, while excluding the first 18 positions that could be error-prone owing to the primers used for generating the monoclonal antibody sequences.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Duplicate consensus sequences were collapsed into unique sequences, except when they had different isotype assignments.

    “Duplicate consensus sequences, except those with different isotype assignments, were collapsed into unique sequences.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The results shown in Extended Data Fig. 1 come from one experiment performed in duplicate.

    “Results are from one experiment performed in duplicate.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Sequences identified by IgBLAST as non-productively rearranged were excluded from further analysis.

    “Sequences annotated as non-productively rearranged by IgBLAST were removed from further analysis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Quality control required fewer than 10 non-informative positions per sequence.

    “Quality control was performed, requiring each sequence to have non-empty V and J gene annotations; exhibit chain consistency in all annotations; bear fewer than 10 non-informative (non-A/T/G/C, such as N or –) positions; and carry a CDR3 with no N and a nucleotide length that is a multiple of 3.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The 0.15 normalized Hamming distance threshold for clonal clustering was chosen by manual inspection and kernel density estimation to find the local minimum between the two modes of the within-participant distance-to-nearest distribution.

    “This distance threshold was determined by manual inspection in conjunction with kernel density estimates to identify the local minimum between the two modes of the within-participant bimodal distance-to-nearest distribution (Extended Data Fig. 3a).”
    • Also stated in: § Extended Data · plain
      “A clustering threshold of 0.15 (dashed black line) was chosen via manual inspection and kernel density estimate (dashed purple line) to separate the two modes of the within-participant distance distribution representing, respectively, sequences that were probably clonally related and unrelated.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Sequences whose isotype assignment conflicted with constant region primer alignment were removed.

    “Sequences with inconsistent isotype assignment and constant region primer alignment were removed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    No statistical methods were used to predetermine sample size.

    “No statistical methods were used to predetermine sample size.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A robust T follicular helper response sustains the germinal centre reaction.

    “A robust T follicular helper response sustains the germinal centre reaction34,35.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Qi, H., Cannons, J. L., Klauschen, F., Schwartzberg, P. L. & Germain, R. N. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature 455, 764–769 (2008). source

      Not checked in the free run.

    • cites [35] Johnston, R. J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006–1010 (2009). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Quality control required each BCR sequence to have non-empty V and J gene annotations.

    “Quality control was performed, requiring each sequence to have non-empty V and J gene annotations; exhibit chain consistency in all annotations; bear fewer than 10 non-informative (non-A/T/G/C, such as N or –) positions; and carry a CDR3 with no N and a nucleotide length that is a multiple of 3.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The control tonsillectomy sample with a high frequency of germinal centre B cells, collected before the COVID-19 pandemic from an unrelated donor, was stained as a negative control.

    “A control tonsillectomy sample with a high frequency of germinal centre B cells that was collected before the COV1D-19 pandemic from an unrelated donor was stained as a negative control.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Quality control required chain consistency across all annotations.

    “Quality control was performed, requiring each sequence to have non-empty V and J gene annotations; exhibit chain consistency in all annotations; bear fewer than 10 non-informative (non-A/T/G/C, such as N or –) positions; and carry a CDR3 with no N and a nucleotide length that is a multiple of 3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The induced germinal centre reaction recruited cross-reactive memory B cells as well as newly engaged clones that target unique epitopes within SARS-CoV-2 S protein.

    “The induced germinal centre reaction recruited cross-reactive memory B cells as well as newly engaged clones that target unique epitopes within SARS-CoV-2 S protein.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Antigen-specific germinal centre B cells have been found to persist for at least one year, albeit at very low levels.

    “antigen-specific germinal centre B cells have been found to persist for at least one year, albeit at very low levels28,30.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Dogan, I. et al. Multiple layers of B cell memory with different effector functions. Nat. Immunol. 10, 1292–1299 (2009). source

      Not checked in the free run.

    • cites [30] Pape, K. A., Taylor, J. J., Maul, R. W., Gearhart, P. J. & Jenkins, M. K. Different B cell populations mediate early and late memory during an endogenous immune response. Science 331, 1203–1207 (2011). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Only unique consensus sequences supported by at least two reads were used in subsequent analyses.

    “Only unique consensus sequences with at least two contributing reads were used subsequently (Extended Data Table 6).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Viruses were passaged once in Vero-hACE2-TMPRSS2 cells and deep sequenced after RNA extraction to confirm the introduction and stability of substitutions.

    “All viruses were passaged once in Vero-hACE2-TMPRSS2 cells and subjected to deep sequencing after RNA extraction to confirm the introduction and stability of substitutions17.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Chen, R. E. et al. Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies. Nat. Med. 27, 717–726 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Quality control required a CDR3 with no N and a nucleotide length divisible by 3.

    “Quality control was performed, requiring each sequence to have non-empty V and J gene annotations; exhibit chain consistency in all annotations; bear fewer than 10 non-informative (non-A/T/G/C, such as N or –) positions; and carry a CDR3 with no N and a nucleotide length that is a multiple of 3.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Within each clone, duplicate IMGT-aligned V(D)J sequences from bulk sequencing were collapsed, except for duplicates from different B cell compartments or isotypes.

    “Within each clone, duplicate IMGT-aligned V(D)J sequences from bulk sequencing were collapsed with the exception of duplicates derived from different B cell compartments or isotypes.”
    Quote in the paperNot a substantial claim
37 of 37

  • The paper relies on this without support.

    Robust and persistent germinal centre reactions are critical for generating high-affinity and durable antibody responses.

    “Whether these vaccines induce the robust and persistent germinal centre reactions that are critical for generating high-affinity and durable antibody responses has not been examined in humans.”

  • The paper relies on this without support.

    Elicitation of high affinity and durable protective antibody responses is a hallmark of a successful humoral immune response to vaccination.

    “Elicitation of high affinity and durable protective antibody responses is a hallmark of a successful humoral immune response to vaccination.”

  • The paper relies on this without support.

    The BNT162b2 vaccine is injected into the deltoid muscle, which drains primarily to the lateral axillary lymph nodes.

    “The BNT162b2 vaccine is injected into the deltoid muscle, which drains primarily to the lateral axillary lymph nodes.”

  • The paper relies on this without support.

    Participants classified as having no history of SARS-CoV-2 infection were truly uninfected.

    “Fine needle aspirates (FNAs) of the draining axillary lymph nodes were collected from 14 participants (none with history of SARS-CoV-2 infection)”
    “None of the 14 participants in our study who underwent FNA of draining lymph nodes had a history of SARS-CoV-2 infection.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • mRNA vaccines induce robust protection against SARS-CoV-2.

    “mRNA vaccines are promising candidates for future vaccine approaches, based on their demonstrated ability to induce robust protection against SARS-CoV-28.”

    From Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models (2023) · cites this paper as [8]

  • mRNA vaccines induce robust germinal center responses in humans, resulting in memory B cells specific for full-length spike and RBD.

    “mRNA vaccines induce robust germinal center responses in humans (14, 15), which result in memory B cells that are specific for both the full-length SARS-CoV-2 spike protein and the spike receptor-binding domain (RBD) (16–18).”

    From mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern (2021) · cites this paper as [14]

  • Prolonged germinal center reactions continue to generate circulating memory B cells for at least several months after vaccination.

    “suggests that prolonged germinal center reactions (14) continue to generate circulating memory B cells for at least several months after vaccination.”

    From mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern (2021) · cites this paper as [14]

  • The levels of neutralizing mAbs elicited by the mRNA vaccines has been high and in most persons are likely to be maintained for many months above the levels required for protection against even the most resistant circulating variants.

    “The levels of neutralizing mAbs elicited by the mRNA vaccines has been high and in most persons are likely to be maintained for many months above the levels required for protection against even the most resistant circulating variants 164,239,240 .”

    From The biological and clinical significance of emerging SARS-CoV-2 variants (2021) · cites this paper as [240]

  • The mRNA vaccines appear to often elicit memory B cells that undergo somatic hypermutation, which should broaden the response to viruses with variant spike proteins.

    “In addition, the mRNA vaccines appear to often elicit memory B cells that undergo somatic hypermutation, which should broaden the response to viruses with variant spike proteins 239,240 .”

    From The biological and clinical significance of emerging SARS-CoV-2 variants (2021) · cites this paper as [240]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Second-dose sweating percentage does not match the cohort size

    Minor

    Two of 41 participants is approximately 4.9%, not the reported 4.8% to one decimal place.

    Reported 4.8 · recomputed 4.878049

1 of 1

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References 75 · Cited by 831

Research works printed but not linked: 1

  1. Csardi, G. & Nepusz, T. The igraph software package for complex network research. InterJournal Complex Syst. 1695, 1–9 (2006).

Authors
Turner, J. S., O’Halloran, J. A., Kalaidina, E., Kim, W., Schmitz, A. J., Zhou, J. Q., Lei, T., Thapa, M., Chen, R. E., Case, J. B., Amanat, F., Rauseo, A. M., Haile, A., Xie, X., Klebert, M. K., Suessen, T., Middleton, W. D., Shi, P.-Y., Krammer, F., Teefey, S. A., Diamond, M. S., Presti, R. M., & Ellebedy, A. H.
Affiliations
  • Washington University in St. Louis (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • The University of Texas Medical Branch at Galveston (US)
Corresponding author
  • Presti, Rachel M.
  • Ellebedy, Ali H.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-06-28
Volume
596
Issue
7870
Pages
109-113
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03738-2
PMC
PMC8935394
OpenAlex
W3177181935
Cited by
831
References
75
Citations by year
2026: 78 · 2025: 84 · 2024: 119 · 2023: 145 · 2022: 285 · 2021: 119
FWCI
53.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Amon G. Carter Foundation
  • John S. Dunn Foundation
  • Washington University in St. Louis
  • Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation (AI134907)
  • National Institutes of Health (HHSN272201400006C, 75N93019C00051, HHSN272201400008C, UL1TR002345, UL1TR001439)
  • National Cancer Institute (T32CA009547)
  • National Institute of Allergy and Infectious Diseases (HHSN272201400008C), R01AI157155, R01AI134907, contract HHSN272201400006C, 75N93019C00051, AI134907, AI157155, U01AI150747, U01AI141990, HHSN 272201400006C)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
SARS-CoV-2, mRNA vaccines, BNT162b2, germinal center B cells, plasmablasts, humoral immunity, SARS-CoV-2 spike protein, receptor binding domain, somatic hypermutation, memory B cells, axillary lymph nodes, vaccine-induced antibody response, prior SARS-CoV-2 infection
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Vaccines, mRNA Vaccines, BNT162 Vaccine, Adult, Aged, Animals, Antibodies, Viral, Chlorocebus aethiops, Clone Cells, Humans, Middle Aged, Plasma Cells, Time Factors, Vaccines, Synthetic, Vero Cells, Germinal Center, Healthy Volunteers

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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