Vaccine serologic responses among transplant patients associate with COVID-19 infection and T peripheral helper cells

  1. Jacob E. Lemieux
  2. Amy Li
  3. Matteo Gentili
  4. Cory A. Perugino
  5. Zoe F. Weiss
  6. Kathryn Bowman
  7. Pierre Ankomah
  8. Hang Liu
  9. Gregory D. Lewis
  10. Natasha Bitar
  11. Taryn Lipiner
  12. Nir Hacohen
  13. Shiv S. Pillai
  14. Marcia B. Goldberg

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Abstract

Background

Therapeutically immunosuppressed transplant recipients exhibit attenuated responses to COVID-19 vaccines. To better understand the immune alterations that determined poor vaccine response, we correlated quantities of circulating T and B cell subsets at baseline with longitudinal serologic responses to SARS-CoV-2 mRNA vaccination in heart and lung transplant recipients.

Methods

Samples at baseline and at approximately 8 and 30 days after each vaccine dose for 22 heart and lung transplant recipients with no history of COVID-19, four heart and lung transplant recipients with prior COVID-19 infection, and 12 healthy controls undergoing vaccination were analyzed. Anti-spike protein receptor binding domain (RBD) IgG and pseudovirus neutralization activity were measured. Proportions of B and T cell subsets at baseline were comprehensively quantitated.

Results

At 8-30 days post vaccination, healthy controls displayed robust anti-RBD IgG responses, whereas heart and lung transplant recipients showed minimally increased responses. A parallel absence of activity was observed in pseudovirus neutralization. In contrast, three of four (75%) transplant recipients with prior COVID-19 infection displayed robust responses at levels comparable to controls. Baseline levels of activated PD-1 + HLA-DR + CXCR5 - CD4 + T cells (also known as T peripheral helper [T PH ] cells) and CD4+ T cells strongly predicted the ability to mount a response.

Conclusions

Immunosuppressed patients have defective vaccine responses but can be induced to generate neutralizing antibodies after SARS-CoV-2 infection. Strong correlations of vaccine responsiveness with baseline T PH and CD4 + T cell numbers highlights a role for T helper activity in B cell differentiation into antibody secreting cells during vaccine response.

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  1. ScreenIT

    SciScore for 10.1101/2021.07.11.21260338: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Study approval: All study procedures involving human subjects were approved by the Mass General Brigham Human Research Committee, the governing institutional review board at Massachusetts General Hospital.
    Consent: Informed consent was received from participants prior to inclusion in the study, either in writing or by institutional review board-established verbal consent procedures employed during the COVID-19 pandemic.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    ELISA and neutralizing antibody assays: Purified SARS-CoV-2 D614G spike protein receptor binding domain (RBD) and whole spike protein were generously provided by Aaron Schmidt.
    D614G spike protein receptor binding domain ( RBD )
    suggested: None
    The following antibody panel was used to quantitate B and T cell subsets: anti-human HLA-DR-BUV395 (BD Biosciences, Clone Tu39, 1:400)
    anti-human HLA-DR-BUV395
    suggested: None
    Recombinant DNA
    SentencesResources
    pCMV-SARS2SΔC D614G-gp41 was generated by PCR mutagenesis from pCMV-SARS2SΔC-gp41 and Gibson assembly.
    pCMV-SARS2SΔC-gp41
    suggested: None
    pCMV-SARS2SΔC N501Y/D614G-gp41 and pCMV-SARS2SΔC E484K/N501Y/D614G-gp41 were obtained by Gibson assembly of the respective gBlocks (IDT) in pCMV-SARS2SΔC D614G-gp41.
    pCMV-SARS2SΔC N501Y/D614G-gp41
    suggested: None
    pCMV-SARS2SΔC
    suggested: None
    pCMV-SARS2SΔC D614G-gp41
    suggested: None
    Software and Algorithms
    SentencesResources
    FCS files were analyzed using FlowJo software (version 10.7.2).
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)

    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 limitation of our analysis is that pre-vaccine measurements were available only for 3 transplant patients and our “baseline” populations among transplant patients were mixtures of pre-vaccine and 9 days post the first vaccine dose timepoints; however, in the three subjects in whom both pre-vaccine and 9 days post the first vaccine dose timepoints were measured, the responses at the two timepoints were strongly correlated (r = 0.97, >0.99, and >0.99, Fig. S7A), and no trends were observed that would suggest that the observed differences in CD4+ populations between transplant and control were artifactual (Fig. S7B). It remains unclear why natural infection is able to overcome the reduction in baseline CD4+ T cells in many transplant patients (3 of 4 in our study); moreover, in our study, two uninfected transplant patients demonstrated an antibody response, albeit delayed (Fig. 3A and 3C). Delayed responses to SARS-CoV-2 vaccination have also been reported in kidney transplant and chronic dialysis patients (20, 36). The association between IgG responses and TPH cells may offer a clue, as these cells have been implicated in extrafollicular B cell differentiation and maintenance (37) and COVID-19 infection induces expansion of TPH cells (38) and increases in non-germinal center B cell responses (39). Based on data in humans and monkeys, anti-spike protein IgG and anti-RBD IgG are strong immune correlates of protection to COVID-19 infection (40–42). The weakness of this response ...

    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

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  2. Version published to 10.1101/2021.07.11.21260338v1 on medRxiv