Delayed antigen-specific CD4 + T-cell induction correlates with impaired immune responses to SARS-COV-2 mRNA vaccination in the elderly

  1. Norihide Jo
  2. Yu Hidaka
  3. Osamu Kikuchi
  4. Masaru Fukahori
  5. Takeshi Sawada
  6. Masahiko Aoki
  7. Masaki Yamamoto
  8. Miki Nagao
  9. Satoshi Morita
  10. Takako E Nakajima
  11. Manabu Muto
  12. Yoko Hamazaki

Reviewed by

Read the full article

Listed in

Log in to save this article

Abstract

Despite the clinical efficacy of coronavirus disease 2019 mRNA vaccines, the elderly demonstrate lower IgG levels and neutralizing titers and a higher risk of severe diseases. CD4 + T cells play a central role in regulating antigen-specific antibody and CD8 + T-cell responses; however, because their composition and functionality change significantly with age, relationships between age-associated defects in T cells and the immunogenicity of or reactogenicity to mRNA vaccines are unclear. Using a vaccine cohort ( n = 216), we found that the elderly (aged ≥65 years) showed delayed induction and early contraction of vaccine-specific CD4 + T cells, and that the compromised C–X–C motif chemokine receptor 3 + circulating T follicular helper cell response after the first dose was associated with the lower IgG levels. Additionally, the elderly experienced significantly fewer systemic adverse effects (AEs) after the second dose, with those exhibiting few AEs showing lower cytokine + CD4 + T cells after the first dose and lower antibody levels after the second dose. Furthermore, T helper 1 cells in the elderly expressed higher levels of programmed cell death protein-1, a negative regulator of the T-cell response, which was associated with less production of vaccine-specific CD4 + T cells and impaired CD8 + T-cell expansion. Thus, efficient induction of vaccine-specific effector/memory CD4 + T cells after the first dose may trigger robust cytokine production after the second dose, leading to effective vaccine responses and higher systemic reactogenicity. These results suggested that an enhanced CD4 + T-cell response after the first dose is key to improved vaccination efficacy in the elderly.

One Sentence Summary

We compared immunogenicity and reactogenicity to COVID-19 mRNA vaccine in 107 adults (aged <65 years) and 109 elderly (aged ≥65) individuals.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2022.05.10.490700: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Study design: This longitudinal study was reviewed and approved by the Kyoto University Graduate School and Faculty of Medicine, Ethics Committee (R0418).
    Consent: At the time of enrollment, all donors provided written informed consent, in accordance with the Declaration of Helsinki.
    Sex as a biological variablenot detected.
    RandomizationThe parameters used were as follows: opt-SNE: max iterations = 1000, opt-SNE end = 5000, perplexity = 30, theta = 0.5, components = 2, random seed = 6925, verbosity = 25; FlowSOM: xdim = 10, ydim = 10, rien =10, comma-separated k values = 20, 25, and random seed = 6793.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Activation-induced marker (AIM) assay: PBMCs were cultured in 100 µL of X-VIVO15 medium supplemented with 5% human AB serum for 23 h at 37 ℃ in the presence of SARS-CoV-2 peptide pools (0.6 nmol/mL) and CD40 blocking antibody (0.5 µg/mL, Miltenyi Biotech) in 96-well U-bottom plates at 1×106 PBMCs per well.
    CD40
    suggested: (Cell Sciences Cat# CMC106, RRID:AB_10101897)
    Software and Algorithms
    SentencesResources
    Blood samples were collected at the Ki-CONNECT and Clinical BioResource Center (CBRC) at Kyoto University Hospital.
    Clinical BioResource Center
    suggested: None
    RBD IgM and IgG levels were measured at LSI Medience (Tokyo, Japan) using ARCHITECT SARS-CoV-2 IgM and ARCHITECT SARS-CoV-2 IgG II Quant (Abbott), respectively
    Abbott
    suggested: (Abbott, RRID:SCR_010477)
    FCS 3.0 data files were exported and analyzed using FlowJo software version 10.8.1.
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    The markers applied to the opt-SNE and FlowSOM are described in the figure legends.
    FlowSOM
    suggested: (FlowSOM, RRID:SCR_016899)
    Statistical analyses: Statistical analyses were performed using GraphPad Prism 9.0.
    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:
    This study has several limitations. We compared the T-cell response and humoral immunity to mRNA vaccines between adults and the elderly. Although individuals ≥65 years of age are commonly defined as the elderly, there is no clear medical or biological evidence to support this definition. Second, vaccination could affect various immune cell subsets other than T cells, and we did not analyze other immune cell types that are critical for vaccine-induced immunity, including antigen-presenting cells and B cells. Moreover, we only investigated the frequencies and cytokine production of vaccine-specific T cells in peripheral blood; therefore, it remains unclear whether other immune cell types or T cells in secondary lymphoid organs, where actual immune responses occur, differ between the two groups and how the difference affects vaccine-induced immune responses. Third, we evaluated only anti-RBD antibody titer but not neutralizing activity, in which cTfh cells play an important role (38), although previous studies report that these two parameters are highly correlated (29, 58). Finally, we provided evidence only of a correlation between T-cell responses after the first dose with antibody responses in the elderly, as well as AEs irrespective of age. Further studies are needed to investigate causal relationships among these parameters. In conclusion, we demonstrated the characteristics of immune responses to the mRNA vaccine BNT162b2 in the elderly, revealing a delayed induction and ...

    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 10.1101/2022.05.10.490700v1 on bioRxiv