Long-Term Accuracy of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Interferon-γ Release Assay and Its Application in Household Investigation

  1. Kanagavel Murugesan
  2. Prasanna Jagannathan
  3. Jonathan Altamirano
  4. Yvonne A Maldonado
  5. Hector F Bonilla
  6. Karen B Jacobson
  7. Julie Parsonnet
  8. Jason R Andrews
  9. Run Zhang Shi
  10. Scott Boyd
  11. Benjamin A Pinsky
  12. Upinder Singh
  13. Niaz Banaei

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Abstract

Background

An immunodiagnostic assay that sensitively detects a cell-mediated immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed for epidemiological investigation and for clinical assessment of T- cell-mediated immune response to vaccines, particularly in the context of emerging variants that might escape antibody responses.

Methods

The performance of a whole blood interferon-gamma (IFN-γ) release assay (IGRA) for the detection of SARS-CoV-2 antigen-specific T cells was evaluated in coronavirus disease 2019 (COVID-19) convalescents tested serially up to 10 months post-infection and in healthy blood donors. SARS-CoV-2 IGRA was applied in contacts of households with index cases. Freshly collected blood in the lithium heparin tube was left unstimulated, stimulated with a SARS-CoV-2 peptide pool, and stimulated with mitogen.

Results

The overall sensitivity and specificity of IGRA were 84.5% (153/181; 95% confidence interval [CI]: 79.0–89.0) and 86.6% (123/142; 95% CI: 80.0–91.2), respectively. The sensitivity declined from 100% (16/16; 95% CI: 80.6–100) at 0.5-month post-infection to 79.5% (31/39; 95% CI: 64.4–89.2) at 10 months post-infection (P < .01). The IFN-γ response remained relatively robust at 10 months post-infection (3.8 vs 1.3 IU/mL, respectively). In 14 households, IGRA showed a positivity rate of 100% (12/12) and 65.2% (15/23), and IgG of 50.0% (6/12) and 43.5% (10/23) in index cases and contacts, respectively, exhibiting a difference of + 50% (95% CI: +25.4 to +74.6) and +21.7% (95% CI: +9.23 to +42.3), respectively. Either IGRA or IgG was positive in 100% (12/12) of index cases and 73.9% (17/23) of contacts.

Conclusions

The SARS-CoV-2 IGRA is a useful clinical diagnostic tool for assessing cell-mediated immune response to SARS-CoV-2.

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  1. Version published to 10.1093/cid/ciac045
  2. ScreenIT

    SciScore for 10.1101/2021.09.20.21263527: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Ethics: The two-parent studies which collected blood from infected and exposed individuals were approved by the Stanford University Institutional Review Board.
    Consent: Informed consent was obtained before blood collection.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The anti-SARS-CoV-2 IgG antibody level was reported as the ratio of optical density (OD) of the sample over the OD of the calibrator.
    anti-SARS-CoV-2 IgG
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical analysis was done with GraphPad Prism 8.0.1 software (San Diego, CA, USA).
    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:
    Although the findings are promising, this study has several limitations. First, the whole blood SARS-CoV-2 IGRA did not distinguish between CD4 and CD8 T cell responses. Prior studies in convalescents have shown that IFN-γ response in IGRA is predominantly CD4 T cell-derived [12, 26]. However, a more complex assay design that allows measurement of CD4 and CD8 T cells response is possible if clinically indicated. Second, given that healthy blood donors were recruited during the pandemic, we would not know whether the 16% positivity rate with SARS-CoV-2 IGRA in this group was due to true-positive results due to past SARS-CoV-2 infection, false-positive results, or cross-reactivity due to past infection with seasonal CoV [7, 27, 28]. Third, the IgG response in this study was not further assessed for its ability to neutralize the virus. Such characterization was not relevant in the context of investigating IGRA accuracy. Forth, SARS-CoV-2 IGRA was not applied to the investigation of vaccine response in this study. Studies are underway to measure the vaccine response with IGRA in immunocompromised patients. Lastly, the household study lacked multiple time points to more accurately assess the performance of IGRA vs IgG, and we did not perform risk assessment in household contacts to correlate IGRA positivity with exposure risk. In summary, the whole blood SARS-CoV-2 IGRA was shown to maintain sensitivity in convalescents up to 10 months post-infection and was shown to have a higher...

    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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  3. Version published to 10.1101/2021.09.20.21263527 on medRxiv