SARS-CoV-2-specific memory B cells can persist in the elderly despite loss of neutralising antibodies

  1. Anna Jeffery-Smith
  2. Alice R Burton
  3. Sabela Lens
  4. Chloe Rees-Spear
  5. Monika Patel
  6. Robin Gopal
  7. Luke Muir
  8. Felicity Aiano
  9. Katie J Doores
  10. J. Yimmy Chow
  11. Shamez N Ladhani
  12. Maria Zambon
  13. Laura E McCoy
  14. Mala K Maini

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Abstract

Memory B cells (MBC) can provide a recall response able to supplement waning antibodies with an affinity-matured response better able to neutralise variant viruses. We studied a cohort of vulnerable elderly care home residents and younger staff, a high proportion of whom had lost neutralising antibodies (nAb), to investigate their reserve immunity from SARS-CoV-2-specific MBC. Class-switched spike and RBD-tetramer-binding MBC with a classical phenotype persisted five months post-mild/asymptomatic SARS-CoV-2 infection, irrespective of age. Spike/RBD-specific MBC remained detectable in the majority who had lost nAb, although at lower frequencies and with a reduced IgG/IgA isotype ratio. Functional spike/S1/RBD-specific recall was also detectable by ELISpot in some who had lost nAb, but was significantly impaired in the elderly, particularly to RBD. Our findings demonstrate persistence of SARS-CoV-2-specific MBC beyond loss of nAb, but highlight the need for careful monitoring of functional defects in RBD-specific B cell immunity in the elderly.

One sentence summary

Circulating class-switched spike and RBD-specific memory B cells can outlast detectable neutralising antibodies but are functionally constrained in the elderly.

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  1. ScreenIT

    SciScore for 10.1101/2021.05.30.446322: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Written information regarding the study was provided to all participants; verbal consent for testing was obtained by care home managers from staff members and residents or their next of kin as appropriate.
    IRB: Stored pre-pandemic samples from seven healthy individuals were used as controls, recruited under ethics number 11/LO/0421 approved by the ‘South East Coast - Brighton and Sussex Research Ethics Committee.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Two panels (surface and intranuclear) of monoclonal antibodies (mAbs) were used to phenotype global and antigen specific subsets (Table S2)
    antigen specific subsets ( Table S2
    suggested: None
    The following day, ELISpot plates were washed in filtered PBS supplemented with 0.5% Tween 20 (Merck) and incubated for four hours in the dark at room temperature with 1ug/ml goat anti-human IgG horse radish peroxidase antibody (Jackson Immunoresearch).
    anti-human IgG
    suggested: None
    Recombinant DNA
    SentencesResources
    15 Briefly, spike glycoprotein trimer (uncleaved spike stabilised in the prefusion conformation (GGGG substitution at furin cleavage site and 2P mutation)64 and RBD protein12 were cloned into a pHLsec vector containing Avi and 6xHis tags.
    pHLsec
    suggested: None
    28,30 Briefly, codon-optimised DNA fragments were cloned into mammalian expression vector pQ-3C-2xStrep to create plasmids, which were then transfected into Expi293F cells growing at 37 in 5% CO2 atmosphere using ExpiFectamine reagent (Thermofisher Scientific).
    pQ-3C-2xStrep
    suggested: None
    Software and Algorithms
    SentencesResources
    All samples were acquired on a Fortessa-X20 (BD Biosciences) and analysed using FlowJo (TreeStar)
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Data analysis and statistics: Data were analysed using GraphPad Prism.
    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:
    A caveat to our study is that we were only able to study circulating B cells, whilst additional recall responses may be compartmentalised within the mucosa. A recent study suggested mild infection can stimulate mucosal SARS-CoV-2-specific IgA secretion in the absence of circulating antibodies.58 The bias towards the retention of IgA+ spike/RBD-specific MBC in those who had lost all detectable serum nAb to live virus could therefore be reflective of a stronger mucosal response in these individuals. An increase in mucosal-homing IgA responses has been described as a feature of the ageing immune response,59 consistent with the older composition of our cohort. Alternatively, the relative preservation of IgA rather than IgG spike/RBD-specific MBC in those with the fastest waning nAb may simply reflect the recent observations that IgA dominates the early nAb response to SARS-CoV-2 infection,56 and may not decline as fast as the IgG response.9,60 Since our ELISpot assays did not measure the function of IgA isotype B cells, we may have under-estimated the full extent of residual SARS-CoV-2-specific responses, particularly in those with a more IgA-skewed response. In addition, several studies have shown that the magnitude of the MBC response to SARS-CoV-2 continues to increase beyond six months,9,23,50,61 again implying that we may have under-estimated the extent of recall potential in our cohort at five months. Future studies should also examine the preservation of non-spike-specific...

    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.

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  2. Version published to 10.1101/2021.05.30.446322v1 on bioRxiv