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Cited by 751SARS-CoV-2 and COVID-19 ResearchImmune responses and vaccinationsCOVID-19 Clinical Research Studies

Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2

Open access
Collier, Dami A., Ferreira, Isabella A. T. M., Kotagiri, Prasanti, Datir, Rawlings P., Lim, Eleanor Y., Touizer, Emma, Meng, Bo, Abdullahi, Adam +160 more·2021·Nature
DOI 10.1038/s41586-021-03739-1PMC PMC8373615

Published version of a preprint

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Abstract

Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age 1 . Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine 2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating.

AI snapshot

Written from the paper’s full text.

TL;DR

In 140 BNT162b2 vaccine recipients, older age—especially ≥80 years—was associated with lower serum neutralization, binding IgG/IgA, memory B cell and T cell responses after the first dose, and reduced neutralization against variants of concern. The second dose restored detectable neutralization across age groups, but the authors conclude that elderly individuals are a high-risk population requiring measures to boost vaccine responses.

Key findings

  • After the first dose, geometric mean neutralization titre was lower in participants aged ≥80 years than in younger individuals: 48.2 (95% CI 34.6–67.1) versus 104.1 (95% CI 69.7–155.2), P = 0.004; around half of those ≥80 showed no evidence of neutralization.
  • Sera from participants above 80 had lower neutralization potency against B.1.1.7 (Alpha), B.1.351 (Beta) and P.1 (Gamma) than against wild-type virus and were more likely to lack any neutralization against VOCs after the first dose; after the second dose, neutralization against VOCs was detectable regardless of age.
  • The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders than non-responders after the first dose; elderly participants showed lower somatic hypermutation in class-switched BCRs, driven by the IgA1/2 isotype, and lower convergence with public SARS-CoV-2-associated clones.
  • IFNγ and IL-2 production by SARS-CoV-2 spike-specific T cells was lower in older participants and both cytokines were secreted primarily by CD4 T cells; among 101 participants, 8 had anti-MPO autoantibodies, 2 anti-fibrillarin and 1 anti-cardiolipin, with all but one anti-MPO-positive participant over 80 years old.

Methods

  • Observational cohort of 140 participants who received at least one BNT162b2 dose between 14 December 2020 and 10 February 2021 at Addenbrooke’s Hospital; median age 72 years (IQR 44–83), 51% female; blood samples were taken 3–12 weeks after the first dose and 3 weeks after the second dose.
  • Immune assays included pseudotyped virus neutralization against wild-type D614G and VOC spike proteins (ID50 cutoff 20), multiplex particle-based flow cytometry for binding IgG/IgA, BCR repertoire sequencing, flow cytometry, IFNγ/IL-2 FluoroSpot T cell assays, and serum autoantibody/cytokine panels.
  • Analyses used logistic regression for age group and neutralization adjusted for sex and sampling interval, linear regression for continuous age and log-transformed ID50/antibody/T cell responses, and Wilcoxon/Mann-Whitney, Chi-square and correlation tests with multiple-comparison adjustment.

Limitations

  • The paper states that further work is needed to understand the effect of age on the durability of immune responses following vaccination.
  • The paper states that the trend towards reduced anti-spike IgG and neutralization in participants with autoantibodies did not reach statistical significance, probably owing to small sample size.
  • Evident from the text: this was a non-intervention observational study without randomization, it reports immune correlates rather than clinical efficacy or protection outcomes, and several analyses—including autoantibodies and BCR repertoire—were exploratory with small subsets.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41586-021-03739-1

Cites

Statistics

Nothing to recompute.

Claims the paper makes

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

  • Findingown data

    There was no association between any of the measured serum cytokines or chemokines and the ability of sera to neutralize SARS-CoV-2 PVs.

    “PIDF, a known senescence-associated secretory phenotype (SASP) molecule, was the only molecule that was enriched in sera from participants aged over 80 years, and there was no association between any of these molecules and the ability of sera to neutralize SARS-CoV-2 PVs (Extended Data Fig. 7).”
    Quote in the paperNot a substantial claim
  • Findingown data

    After the first BNT162b2 dose, levels of binding IgG or IgA were lower in older individuals than in younger individuals.

    “Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old.”
    • Also stated in: § B cell responses to mRNA vaccination · plain
      “Like the neutralization titres, levels of IgG against spike declined with age (Fig. 2b, Extended Data Fig. 3).”
    • Also stated in: § B cell responses to mRNA vaccination · plain
      “The concentrations of total and subclass anti-spike IgGs were significantly lower in participants aged 80 or older than in the younger group (Fig. 2d).”
    Quote in the paperSubstantial claim
  • Findingown data

    IFNγ spike-specific T cell responses were significantly larger in immunized individuals below 80 years of age than in an unexposed population of the same age.

    “However, IFNγ spike-specific T cell responses were significantly larger in immunized individuals below 80 years of age than in an unexposed population of the same age (Fig. 4c).”
    Quote in the paperSubstantial claim
  • Findingown data

    In participants who had suboptimal or no neutralization after dose 1 and who subsequently received the second dose within the study period, all but two elderly participants responded with an increase in neutralization activity.

    “In participants who had suboptimal or no neutralization after dose 1, and who subsequently received the second dose within the study period (Fig. 1c), all but two elderly participants responded with an increase in neutralization activity (Extended Data Table 1, Fig. 1b).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Concentrations of total and subclass anti-spike IgGs were significantly lower in participants aged 80 or older than in the younger group.

    “The concentrations of total and subclass anti-spike IgGs were significantly lower in participants aged 80 or older than in the younger group (Fig. 2d).”
    Quote in the paperSubstantial claim
  • May combine two claims. 19
  • Classified as probably not a substantial claim. 22
  • The quote only partly states this claim. 3

  • May combine two claims.

    Findingown data

    There was an increase in usage of the IGHV4 family in the older age group, with increased proportion of IGHV4.34, IGHV4.39, IGHV4.59 and IGHV4.61, whereas in the younger age group there was an increase in usage of the IGHV1 family, with increases in IGHV1.18 and IGHV1.69D.

    “We found an increase in usage of the immunoglobulin heavy variable 4 (IGHV4) family in the older age group, with an increased proportion of IGHV4.34,IGHV4.39,IGHV4.59 and IGHV4.61,whereas in the younger age group there was an increase in usage of the IGHV1 family, with increases in IGHV1.18 and IGHV1.69D(Fig. 3b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After the first BNT162b2 dose, serum neutralization was lower in older individuals than in younger individuals, with a marked drop in participants over 80 years old.

    “Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old.”
    • Also stated in: § Neutralization following immunization · plain
      “This analysis showed a nonlinear relationship with a marked drop around the age of 80 years (Fig. 1a).”
    • Also stated in: § Neutralization following immunization · plain
      “Geometric mean neutralization titre (GMT) was lower in participants aged 80 years or more than in younger individuals (48.2 (95% confidence interval (CI) 34.6-67.1)versus 104.1 (95% CI 69.7-155.2),P = 0.004; Extended Data Table 1, Fig. 1b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Following the first dose, the frequency of IFNγ-secreting T cells against a CEF+ peptide pool did not differ by age category and was similar to healthy SARS-CoV-2 unexposed controls.

    “Following the first dose of vaccine, the frequency of IFNγ-secreting T cells against a CEF+ peptide pool that included cytomegalovirus (CMV)-, Epstein-Barr virus (EBV)-and influenza-specific peptides did not differ by age category and was similar to healthy SARS-CoV-2 unexposed controls (Extended Data Fig. 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Eight participants had autoantibodies against myeloperoxidase, two against fibrillarin and one against cardiolipin.

    “Eight participants had autoantibodies against myeloperoxidase (anti-MPO), two against fibrillarin and one against cardiolipin (Extended Data Fig. 7).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CMV-positive individuals in the older age group had significantly higher IFNγ, but not IL-2, responses to SARS-CoV-2 spike peptides than CMV-negative individuals in the same age group.

    “The rate of CMV IgG positivity was higher in the older age group (Extended Data Fig. 6); unexpectedly, though, CMV-positive individuals in this group had significantly higher IFNγ, but not IL-2, responses to SARS-CoV-2 spike peptides than CMV-negative individuals in the same age group (Extended Data Fig. 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There were no differences in isotype proportions between the two age groups, or by neutralization.

    “There were no differences in isotype proportions between the two age groups (Extended Data Fig. 5), or by neutralization (Fig. 3a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In a cohort of 140 individuals, there is an inverse relationship between age and neutralizing responses following the first dose of BNT162b2, with a more precipitous decline around the age of 80 years.

    “Here, in a cohort of 140 individuals, we have shown not only an inverse relationship between age and neutralizing responses following the first dose of BNT162b2, but also a more precipitous decline around the age of 80 years.”
    Quote in the paperSubstantial claim

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

    Findingown data

    In two individuals (ID 4 and ID 8), serum neutralization was lower after the first dose and increased after the second dose of BNT162b2 against pseudovirus expressing wild-type spike protein (D614G).

    “Neutralization curves for serum from two individuals (ID 4 and ID 8) with lower responses after the first dose (blue) and increased neutralization activity after the second dose (red) of BNT162b2 against pseudovirus expressing wild-type spike protein (D614G).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Around half of those above the age of 80 have a suboptimal neutralizing antibody response after the first dose of BNT162b2, accompanied by lower T cell responses compared to younger individuals.

    “We found that around half of those above the age of 80 have a suboptimal neutralizing antibody response after the first dose of BNT162b2, accompanied by lower T cell responses compared to younger individuals.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Study design and conductown data

    The pseudotyped virus system used to investigate neutralization was validated by a high correlation between PVs expressing Wuhan-1 D614G spike and a B.1 lineage live virus isolate using sera from thirteen individuals after two vaccine doses.

    “We first validated the use of a pseudotyped virus (PV) system to investigate neutralization, by comparing geometric mean titres (GMTs) between PVs expressing the Wuhan-1 D614G spike (referred to here as wild-type) and a B.1 lineage live virus isolate, using sera isolated from thirteen individuals after two vaccine doses (Extended Data Fig. 2).”
    • Also stated in: § Neutralization following immunization · plain
      “We observed a high correlation between the two approaches, consistent with other findings 11 , and proceeded with the PV system.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Schmidt, F. et al. Measuring SARS-CoV-2 neutralizing antibody activity using pseudotyped and chimeric viruses. J. Exp. Med. 217, e20201181 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    A clinically accredited assay for N antibodies showed evidence that five individuals in each group had previously been infected with SARS-CoV-2, and this was adjusted for in multivariable analyses.

    “A clinically accredited assay for N antibodies 9 showed evidence that five individuals in each group had previously been infected with SARS-CoV-2 (Extended Data Table 1), and we adjusted for this in multivariable analyses (Extended Data Tables 2, 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Collier, D. A. et al. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies. Nature 593, 136–141 (2021). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Neutralizing antibodies dominate protection against initial infection.

    “Although it is increasingly recognized that neutralizing antibodies dominate protection against initial infection 4,13 , T cells might limit disease progression 5 when neutralizing antibody titres are low 14 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Khoury, D. S. et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat. Med. https://doi.org/10.1038/s41591-021-01377-8 (2021). source

      Not checked in the free run.

    • cites [13] Mercado, N. B. et al. Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques. Nature 586, 583–588 (2020). 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

    Experiments were performed in technical duplicates and repeated.

    “Experiments were done in technical duplicates and a repeat was done.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Individuals aged 80 or more were prioritized for vaccination in the UK and elsewhere, as they represented the group at greatest risk of severe COVID-19.

    “Individuals aged 80 or more were prioritized for vaccination in the UK and elsewhere, as they represented the group at greatest risk of severe COVID-19 22 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Docherty, A. B. et al. Features of 20 133 UK patients in hospital with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. Br. Med. J. 369, m1985 (2020) source

      Not checked in the free run.

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

    Premisecitation

    Responses to the ChAdOx1 nCov-19 (AZD-1222) vaccine were lower in older than in younger mice, and the difference was overcome by booster dosing.

    “These data reflect the finding that responses to the ChAdOx1 nCov-19 (AZD-1222) vaccine were lower in older than in younger mice, and the difference was overcome by booster dosing 21 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Silva-Cayetano, A. et al. A booster dose enhances immunogenicity of the COVID-19 vaccine candidate ChAdOx1 nCoV-19 in aged mice. Med 2, 243–262 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    No commonly misidentified cell lines were used in this study.

    “No commonly misidentified lines were used in this study.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study was approved by the East of England -Cambridge Central Research Ethics Committee (17/EE/0025).

    “The study was approved by the East of England -Cambridge Central Research Ethics Committee (17/EE/0025).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Bonferroni adjustment was made for multiple comparisons in the linear correlation analyses between binding antibody levels, ID50, age and T cell responses.

    “Bonferroni adjustment was made for multiple comparisons in the linear correlation analyses between binding antibody levels, ID50, age and T cell responses.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Bonferroni adjustment was made for multiple comparisons in linear regression analyses.

    “Bonferroni adjustment was made for multiple comparisons in linear regression.”
    • Also stated in: § Extended Data · plain
      “Bonferroni adjustment was made for multiple comparisons.”
    • Also stated in: § Extended Data · plain
      “Bonferroni adjustment was made for multiple comparisons.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Autoantibodies and inflammatory cytokines or chemokines are associated with immune senescence.

    “Autoantibodies and inflammatory cytokines or chemokines are associated with immune senescence 17 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Ray, D. & Yung, R. Immune senescence, epigenetics and autoimmunity. Clin. Immunol. 196, 59–63 (2018). 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

    Participants were recruited consecutively with no exclusion criteria.

    “Consecutively presenting participants were recruited with no exclusion.”
    • Also stated in: § Additional information · plain
      “Community participants or health care workers receiving the first dose of the BNT162b2 vaccine between the 14th of December 2020 to the 10th of February 2021 were consecutively recruited.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All cell lines used were tested by PCR and were mycoplasma free.

    “All cell lines used were tested (by PCR) and were mycoplasma free.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The emergence of new variants with increased transmissibility and reduced sensitivity to vaccine-elicited antibodies, and for which vaccines are less able to prevent infection, has raised fears for vulnerable groups in whom the magnitude and quality of immune responses may be suboptimal.

    “In addition, the emergence of new variants with increased transmissibility 8 and reduced sensitivity to vaccine-elicited antibodies 9 , and for which vaccines are less able to prevent infection 10 , has raised fears for vulnerable groups in whom the magnitude and quality of immune responses may be suboptimal.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] Volz, E. et al. Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England. Nature 593, 266–269 (2021). source

      Not checked in the free run.

    • cites [9] Collier, D. A. et al. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies. Nature 593, 136–141 (2021). source

      Not checked in the free run.

    • cites [10] Madhi, S. A. et al. Efficacy of the ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant. N. Engl. J. Med. 384, 1885–1898 (2021). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    There is increasing evidence that neutralizing responses are a correlate of protection.

    “There is increasing evidence that neutralizing responses are a correlate of protection [4][5][6] .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] Khoury, D. S. et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat. Med. https://doi.org/10.1038/s41591-021-01377-8 (2021). source

      Not checked in the free run.

    • cites [5] Israelow, B. et al. Adaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2. Preprint at https://doi.org/10.1101/2021.05.19.444825 (2021). source

      Not checked in the free run.

    • cites [6] Feng, S. et al. Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection. Preprint at https://doi.org/10.1101/2021.06.21.21258528 (2021). source

      Not checked in the free run.

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

    Study design and conductnone given

    The study was approved by the East of England - Cambridge Central Research Ethics Committee.

    “The study was approved by the East of England -Cambridge Central Research Ethics Committee.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    None of the cell lines used were authenticated.

    “None of the cell lines used were authenticated.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. The quote only partly states this claim.

    Study design and conductown data

    The study adjusted for sex and time interval from vaccination to sampling as confounders in logistic regression modeling the association between age group and neutralization after the first dose.

    “The effects of sex and time interval from vaccination to sampling as confounders were adjusted for.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Neutralization data are representative of two independent experiments each with two technical repeats.

    “GMT ± s.d. are representative of two independent experiments each with two technical repeats.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    A sample size of 50 per group (1:1 ratio) was required for 90% power at alpha 0.05.

    “Using an alpha of 0.05 and power of 90% required a sample size of 50 with a 1:1 ratio in each group.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The risk ratio of non-neutralisation in the ≥80 years group compared with the <80 years group was assumed to be 5.

  • May combine two claims.

    Interpretationreasoning

    Possible explanations for poorer neutralizing responses in the elderly include lower concentrations of antibodies (quantity) and/or lower-affinity antibodies (quality) resulting from B cell selection, reduced CD4+ T cell help, or a combination of both.

    “Therefore, possible explanations for their poorer neutralizing responses include lower concentrations of antibodies (quantity) and/or lower-affinity antibodies (quality) resulting from B cell selection, reduced CD4 + T cell help, or a combination of both.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    mRNA vaccines have shown excellent efficacy when administered as two doses separated by a three-or four-week gap.

    “In particular, mRNA vaccines have shown excellent efficacy when administered as two doses separated by a three-or four-week gap 2,3 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020). source

      Not checked in the free run.

    • cites [3] Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. The quote only partly states this claim.

    Study design and conductown data

    In the analysis of the association between age group and neutralisation after the first dose, sex and time interval from vaccination to sampling were adjusted for as confounders.

    “The effect of sex and time interval from vaccination to sampling as confounders were adjusted for.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a study of the Moderna 1273 mRNA vaccine in individuals above 55 years of age, neutralization was detectable only after the second dose, whereas binding antibodies were detectable after both doses.

    “Furthermore, in a study of the Moderna 1273 mRNA vaccine in individuals above 55 years of age, neutralization was detectable only after the second dose, whereas binding antibodies were detectable after both doses 19 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Anderson, E. J. et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N. Engl. J. Med. 383, 2427–2438 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Elderly individuals are likely to be at greater risk from VOCs, as a greater proportion of individuals in the over-80 age group showed no neutralizing activity to P.1 and B.1.1.7 after the first dose.

    “Critically, we show that elderly individuals are likely to be at greater risk from VOCs, as a greater proportion of individuals in the over-80 age group showed no neutralizing activity to P.1 and B.1.1.7 after the first dose.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    T cells might limit disease progression when neutralizing antibody titres are low.

    “Although it is increasingly recognized that neutralizing antibodies dominate protection against initial infection 4,13 , T cells might limit disease progression 5 when neutralizing antibody titres are low 14 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Israelow, B. et al. Adaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2. Preprint at https://doi.org/10.1101/2021.05.19.444825 (2021). source

      Not checked in the free run.

    • cites [14] McMahan, K. et al. Correlates of protection against SARS-CoV-2 in rhesus macaques. Nature 590, 630–634 (2021). source

      Not checked in the free run.

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

    Premisecitation

    CMV serostatus has been associated with poorer responses to vaccination and infections.

    “CMV serostatus has been associated with poorer responses to vaccination and infections 15,16 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Merani, S., Pawelec, G., Kuchel, G. A. & McElhaney, J. E. Impact of aging and cytomegalovirus on immunological response to influenza vaccination and infection. Front. Immunol. 8, 784 (2017). source

      Not checked in the free run.

    • cites [16] Kadambari, S., Klenerman, P. & Pollard, A. J. Why the elderly appear to be more severely affected by COVID-19: the potential role of immunosenescence and CMV. Rev. Med. Virol. 30, e2144 (2020). source

      Not checked in the free run.

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  • The authors state this as an assumption.

    The risk ratio of non-neutralisation in the ≥80 years group compared with the <80 years group was assumed to be 5.

    “We assumed a risk ratio of non-neutralisation in the ≥80 years group compared with <80 years group of 5.”
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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?

  • Regardless of the vaccine received, reductions in vaccine-elicited humoral immunity is likely to be clinically significant for persons with impaired immunity as a result of underlying disease, immunosuppressive drugs or older age.

    “Moreover, regardless of the vaccine received, reductions in vaccine-elicited humoral immunity is likely to be clinically significant for persons with impaired immunity as a result of underlying disease, immunosuppressive drugs or older age [241][242][243][244] .”

    From The biological and clinical significance of emerging SARS-CoV-2 variants (2021) · cites this paper as [241]

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • EDTA concentration differs by a factor of one million

    Minor

    The Methods specify 2 mM EDTA for staining PBMCs, whereas the reporting summary specifies 2nM for the same staining step.

  • Memory B-cell result cites the BCR-clone panel

    Minor

    The text assigns the spike-specific memory B-cell result to Fig. 3e, but that panel is described as a comparison of BCR clones, not memory B cells.

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References 65 · Cited by 751

Research works printed but not linked: 15

  1. Walsh, E. E. et al. Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N. Engl. J. Med. 383, 2439–2450 (2020). · DOI · Paper page
  2. Khoury, D. S. et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat. Med. https://doi.org/10.1038/s41591-021-01377-8 (2021). · DOI · Paper page
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Authors
Collier, D. A., Ferreira, I. A. T. M., Kotagiri, P., Datir, R. P., Lim, E. Y., Touizer, E., Meng, B., Abdullahi, A., The CITIID-NIHR BioResource COVID-19 Collaboration, Principal Investigators, Baker, S., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P. A., Matheson, N. J., Owehand, W. H., Saunders, C., Summers, C., Thaventhiran, J. E. D., Toshner, M., Weekes, M. P., Maxwell, P., Shaw, A., Nurses, C. A. V. R., Bucke, A., Calder, J., Canna, L., Domingo, J., Elmer, A., Fuller, S., Harris, J., Hewitt, S., Kennet, J., Jose, S., Kourampa, J., Meadows, A., O’Brien, C., Price, J., Publico, C., Rastall, R., Ribeiro, C., Rowlands, J., Ruffolo, V., Tordesillas, H., Logistics, S., Bullman, B., Dunmore, B. J., Fawke, S., Gräf, S., Hodgson, J., Huang, C., Hunter, K., Jones, E., Legchenko, E., Matara, C., Martin, J., Mescia, F., O’Donnell, C., Pointon, L., Pond, N., Shih, J., Sutcliffe, R., Tilly, T., Treacy, C., Tong, Z., Wood, J., Wylot, M., Acquisition, S. P. A. D., Bergamaschi, L., Betancourt, A., Bower, G., Cossetti, C., De Sa, A., Epping, M., Fawke, S., Gleadall, N., Grenfell, R., Hinch, A., Huhn, O., Jackson, S., Jarvis, I., Krishna, B., Lewis, D., Marsden, J., Nice, F., Okecha, G., Omarjee, O., Perera, M., Potts, M., Richoz, N., Romashova, V., Yarkoni, N. S., Sharma, R., Stefanucci, L., Stephens, J., Strezlecki, M., Turner, L., Collection, C. D., D. D. De Bie, E. M., Bunclark, K., Josipovic, M., Mackay, M., Michael, A., Rossi, S., Selvan, M., Spencer, S., Yong, C., Royal Papworth Hospital, I. C. U., Ansaripour, A., Michael, A., Mwaura, L., Patterson, C., Polwarth, G., Addenbrooke’s Hospital, I. C. U., Polgarova, P., di Stefano, G., Cambridge and Peterborough Foundation Trust, Fahey, C., Michel, R., ANPC and Centre for Molecular Medicine and Innovative Therapeutics, Bong, S.-H., Coudert, J. D., Holmes, E., BioResource4, N., Allison, J., Butcher, H., Caputo, D., Clapham-Riley, D., Dewhurst, E., Furlong, A., Graves, B., Gray, J., Ivers, T., Kasanicki, M., Le Gresley, E., Linger, R., Meloy, S., Muldoon, F., Ovington, N., Papadia, S., Phelan, I., Stark, H., Stirrups, K. E., Townsend, P., Walker, N., Webster, J., Elmer, A., Kingston, N., Graves, B., Le Gresley, E., Caputo, D., Bergamaschi, L., Smith, K. G. C., Bradley, J. R., Ceron-Gutierrez, L., Cortes-Acevedo, P., Barcenas-Morales, G., Linterman, M. A., McCoy, L. E., Davis, C., Thomson, E., Lyons, P. A., McKinney, E., Doffinger, R., Wills, M., & Gupta, R. K.
Affiliations
  • University of Cambridge (GB)
  • University College London (GB)
  • University of Basel (CH)
  • Cambridge University Hospitals NHS Foundation Trust (GB)
  • Addenbrooke's Hospital (GB)
  • Papworth Hospital NHS Foundation Trust (GB)
  • Hycult Biotech (Netherlands) (NL)
  • Fulbourn Hospital (GB)
  • Murdoch University (AU)
  • NIHR BioResource (GB)
  • Facultad de Estudios Superiores Cuautitlán (MX)
  • Babraham Institute (GB)
  • MRC University of Glasgow Centre for Virus Research (GB)
Corresponding author
  • McKinney, Eoin
  • Wills, Mark
  • Gupta, Ravindra K.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-06-30
Volume
596
Issue
7872
Pages
417-422
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03739-1
PMC
PMC8373615
OpenAlex
W3176552995
Cited by
751
References
65
Citations by year
2026: 44 · 2025: 72 · 2024: 105 · 2023: 156 · 2022: 267 · 2021: 106
FWCI
50.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, cc-by-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
  • Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion, other-oa)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
  • HAL (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo
  • Apollo (cc-by)
  • ETH Zürich Research Collection (cc-by)
Funders
  • Wellcome Trust (200871, 200871/Z/16/Z, WT108082AIA, DEL-15-006, 104064/Z/14/Z)
  • UK Research and Innovation
  • National Institute for Health and Care Research (NF-SI-0514-10109)
  • Department of Health and Social Care
  • University of Cambridge
  • Royal Australasian College of Physicians
  • Cambridge University Hospitals (BRC 2012-2017)
  • Evelyn Trust (20/75)
  • Directorate for Biological Sciences
  • NIHR BioResource
  • Medical Research Council (MR/S00081X/1, 2249900, MR/R008698/1)
  • Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0428, BBS/E/B/000COV01, BBS/E/B/000C0427)
  • NIHR Cambridge Biomedical Research Centre
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Keywords
BNT162b2 mRNA vaccine, SARS-CoV-2, vaccine response heterogeneity, older adults, variants of concern, neutralizing antibodies, somatic hypermutation, interferon-gamma, interleukin-2, vaccine non-responders, booster vaccination
MeSH terms
SARS-CoV-2, COVID-19 Vaccines, mRNA Vaccines, BNT162 Vaccine, Adult, Aged, Aged, 80 and over, Aging, Antibodies, Viral, Autoantibodies, B-Lymphocytes, Female, Health Personnel, Humans, Immunoglobulin A, Immunoglobulin G, Immunity, Immunization, Secondary, Immunologic Memory, Inflammation, Interferon-gamma, Interleukin-2, Male, Middle Aged, T-Lymphocytes, Vaccination, Vaccines, Synthetic, Immunoglobulin Class Switching, Somatic Hypermutation, Immunoglobulin, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus

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