Cross-neutralization activity against SARS-CoV-2 is present in currently available intravenous immunoglobulins

  1. José-María Díez
  2. Carolina Romero
  3. Júlia Vergara-Alert
  4. Melissa Belló-Perez
  5. Jordi Rodon
  6. José Manuel Honrubia
  7. Joaquim Segalés
  8. Isabel Sola
  9. Luis Enjuanes
  10. Rodrigo Gajardo

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Abstract

Background

There is a crucial need for effective therapies that are immediately available to counteract COVID-19 disease. Recently, ELISA binding cross-reactivity against components of human epidemic coronaviruses with currently available intravenous immunoglobulins (IVIG) Gamunex-C and Flebogamma DIF (5% and 10%) have been reported. In this study, the same products were tested for neutralization activity against SARS-CoV-2, SARS-CoV and MERS-CoV and their potential as an antiviral therapy.

Methods

The neutralization capacity of six selected lots of IVIG was assessed against SARS-CoV-2 (two different isolates), SARS-CoV and MERS-CoV in cell cultures. Infectivity neutralization was measured by determining the percent reduction in plaque-forming units (PFU) and by cytopathic effects for two IVIG lots in one of the SARS-CoV-2 isolates. Neutralization was quantified using the plaque reduction neutralization test 50 (PRNT 50 ) in the PFU assay and the half maximal inhibitory concentration (IC 50 ) in the cytopathic/cytotoxic method (calculated as the minus log 10 dilution which reduced the viral titer by 50%).

Results

All IVIG preparations showed neutralization of both SARS-CoV-2 isolates, ranging from 79 to 89.5% with PRNT 50 titers from 4.5 to >5 for the PFU method and ranging from 47.0%-64.7% with an IC 50 ~1 for the cytopathic method. All IVIG lots produced neutralization of SARS-CoV ranging from 39.5 to 55.1 % and PRNT 50 values ranging from 2.0 to 3.3. No IVIG preparation showed significant neutralizing activity against MERS-CoV.

Conclusion

In cell culture neutralization assays, the tested IVIG products contain antibodies with significant cross-neutralization capacity against SARS-CoV-2 and SARS-CoV. However, no neutralization capacity was demonstrated against MERS-CoV. These preparations are currently available and may be immediately useful for COVID-19 management.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2020.06.19.160879: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The following kits were used for the qualitative determination of IgG class antibodies in the experimental IVIG lots: SARS Coronavirus IgG ELISA kit (Creative Diagnostics, Shirley, NY, USA), against virus lysate; Human Anti-SARS-CoV-2 Virus Spike 1 [S1] IgG ELISA Kit (Alpha Diagnostic Intl. Inc., San Antonio, TX, USA), against S1 subunit spike protein; RV-402100-1, Human Anti-MERS-NP IgG ELISA Kit (Alpha Diagnostic Intl. Inc.), against N protein; RV-402400-1, Human Anti-MERS-RBD IgG ELISA Kit (Alpha Diagnostic Intl. Inc.), against receptor-binding domain (RBD) of S1 subunit spike protein (S1/RBD); RV-402300-1, Human Anti-MERS-S2 IgG ELISA Kit (Alpha Diagnostic Intl. Inc.), against S2 subunit spike protein; RV-405200 (formerly RV-404100-1).
    Anti-SARS-CoV-2 Virus Spike 1
    suggested: None
    S1
    suggested: None
    Anti-MERS-NP IgG
    suggested: None
    Anti-MERS-RBD IgG ELISA Kit (Alpha Diagnostic Intl. Inc.), against receptor-binding domain (RBD
    suggested: None
    Anti-MERS-S2 IgG
    suggested: None
    S2
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Huh7 is composed of epithelial-like cells susceptible to infection by MERS-CoV 24.
    Huh7
    suggested: None
    Vero E6 is composed of epithelial-like cells susceptible to infection by SARS-CoV and SARS-CoV-2 25.
    Vero E6
    suggested: RRID:CVCL_XD71)

    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:
    Despite the limitations of the in vitro nature of this study, the clinical implications of the findings are encouraging. Although IVIG are considered a therapeutic option for hyperinflammation in patients with severe COVID-19 30, the results of this study may support the use of high dose IVIG as a therapy for COVID-19. Positive results have already been reported for IVIG in case studies 31,32. IVIG is being tested in an ongoing clinical trial 33. Further studies looking at the functionality of these antibodies could improve our understanding the human coronavirus acquired immunity. This could pave the way for IVIG (and other IgG products such as intramuscular or subcutaneous preparations) as a potential therapeutic/prophylactic approach to fight future epidemics by emerging human coronaviruses. In conclusion, under the experimental conditions of this study, IVIG (Flebogamma DIF and Gamunex-C) contained antibodies with significant neutralization capacity against SARS-CoV and SARS-CoV-2, but not against MERS-CoV. Additional research is warranted to advance IVIG towards clinical use for COVID-19.

    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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    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 10.1101/2020.06.19.160879 on bioRxiv