Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)–Specific T Cells and Antibodies in Coronavirus Disease 2019 (COVID-19) Protection: A Prospective Study

  1. Ivan A Molodtsov
  2. Evgenii Kegeles
  3. Alexander N Mitin
  4. Olga Mityaeva
  5. Oksana E Musatova
  6. Anna E Panova
  7. Mikhail V Pashenkov
  8. Iuliia O Peshkova
  9. Almaqdad Alsalloum
  10. Walaa Asaad
  11. Anna S Budikhina
  12. Alexander S Deryabin
  13. Inna V Dolzhikova
  14. Ioanna N Filimonova
  15. Alexandra N Gracheva
  16. Oxana I Ivanova
  17. Anastasia Kizilova
  18. Viktoria V Komogorova
  19. Anastasia Komova
  20. Natalia I Kompantseva
  21. Ekaterina Kucheryavykh
  22. Denis А Lagutkin
  23. Yakov A Lomakin
  24. Alexandra V Maleeva
  25. Elena V Maryukhnich
  26. Afraa Mohammad
  27. Vladimir V Murugin
  28. Nina E Murugina
  29. Anna Navoikova
  30. Margarita F Nikonova
  31. Leyla A Ovchinnikova
  32. Yana Panarina
  33. Natalia V Pinegina
  34. Daria M Potashnikova
  35. Elizaveta V Romanova
  36. Aleena A Saidova
  37. Nawar Sakr
  38. Anastasia G Samoilova
  39. Yana Serdyuk
  40. Naina T Shakirova
  41. Nina I Sharova
  42. Saveliy A Sheetikov
  43. Anastasia F Shemetova
  44. Liudmila V Shevkova
  45. Alexander V Shpektor
  46. Anna Trufanova
  47. Anna V Tvorogova
  48. Valeria M Ukrainskaya
  49. Anatoliy S Vinokurov
  50. Daria A Vorobyeva
  51. Ksenia V Zornikova
  52. Grigory A Efimov
  53. Musa R Khaitov
  54. Ilya A Kofiadi
  55. Alexey A Komissarov
  56. Denis Y Logunov
  57. Nelli B Naigovzina
  58. Yury P Rubtsov
  59. Irina A Vasilyeva
  60. Pavel Volchkov
  61. Elena Vasilieva

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Abstract

Background

During the ongoing coronavirus disease 2019 (COVID-19) pandemic, many individuals were infected with and have cleared the virus, developing virus-specific antibodies and effector/memory T cells. An important unanswered question is what levels of T-cell and antibody responses are sufficient to protect from the infection.

Methods

In 5340 Moscow residents, we evaluated anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin M (IgM)/immunoglobulin G (IgG) titers and frequencies of the T cells specific to the membrane, nucleocapsid, and spike proteins of SARS-CoV-2, using interferon gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay. Additionally, we evaluated the fractions of virus-specific CD4+ and CD8+ T cells using intracellular staining of IFN-γ and interleukin 2 followed by flow cytometry. We analyzed the COVID-19 rates as a function of the assessed antibody and T-cell responses, using the Kaplan–Meier estimator method, for up to 300 days postinclusion.

Results

We showed that T-cell and antibody responses are closely interconnected and are commonly induced concurrently. Magnitudes of both responses inversely correlated with infection probability. Individuals positive for both responses demonstrated the highest levels of protectivity against the SARS-CoV-2 infection. A comparable level of protection was found in individuals with antibody response only, whereas the T-cell response by itself granted only intermediate protection.

Conclusions

We found that the contribution of the virus-specific antibodies to protection against SARS-CoV-2 infection is more pronounced than that of the T cells. The data on the virus-specific IgG titers may be instructive for making decisions in personalized healthcare and public anti–COVID-19 policies.

Clinical Trials Registration. NCT04898140.

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  1. Version published to 10.1093/cid/ciac278
  2. ScreenIT

    SciScore for 10.1101/2021.08.19.21262278: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Ethics: This study was approved by the Moscow City Ethics Committee of the Research Institute of the Organization of Health and Healthcare Management and performed according to the Helsinki Declaration.
    Consent: All participants provided their written informed consent.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Participant inclusion: The study cohort consists of individuals above 18 years old who had voluntarily come to one of four Moscow City Clinics for routine testing for COVID-19 antibodies and agreed to participate in the study.
    COVID-19
    suggested: None
    SARS-CoV-2–specific antibodies and virus-neutralizing activity of plasma: We evaluated the titers of the virus-specific IgM and IgG antibodies in blood serum using an automated CL-series chemiluminescent immunoassay analyzer with compatible reagent kits (Mindray, China); here and below ‘IgG’ and ‘IgM’ refer to results obtained with this method, if not mentioned otherwise.
    IgG
    suggested: None
    For a separate representative group of participants, we measured antibodies specific to SARS-CoV-2 spike (S) and nucleocapsid (N) proteins using the SARS-CoV-2-IgG-EIA-BEST ELISA kit (Vector-Best, Russia) and the automated ARCHITECT i1000SR analyzer with compatible reagent kit (Abbott, USA), respectively, according to the manufacturer’s standard protocol; additionally, we measured the virus-neutralizing activity of plasma by microneutralization assay using SARS-CoV-2 (hCoV-19/Russia/Moscow_PMVL-1/2020) in a 96-well plate and a 50% tissue culture infective dose (TCID50) of 100 as described in 4, with plasma dilutions of 10, 20, 40, 80, 160, 320, 640, and 1,280 times.
    Vector-Best, Russia
    suggested: None
    Software and Algorithms
    SentencesResources
    For a separate representative group of participants, we measured antibodies specific to SARS-CoV-2 spike (S) and nucleocapsid (N) proteins using the SARS-CoV-2-IgG-EIA-BEST ELISA kit (Vector-Best, Russia) and the automated ARCHITECT i1000SR analyzer with compatible reagent kit (Abbott, USA), respectively, according to the manufacturer’s standard protocol; additionally, we measured the virus-neutralizing activity of plasma by microneutralization assay using SARS-CoV-2 (hCoV-19/Russia/Moscow_PMVL-1/2020) in a 96-well plate and a 50% tissue culture infective dose (TCID50) of 100 as described in 4, with plasma dilutions of 10, 20, 40, 80, 160, 320, 640, and 1,280 times.
    Abbott
    suggested: (Abbott, RRID:SCR_010477)
    Flow cytometry: PBMC were plated into 96-well U-bottom plates at a concentration of 1×106 cells per well in 100 µL of serum-free AIM-V medium (ThermoFisher Scientific; USA) supplemented with 1X AlbuMAX (ThermoFisher Scientific; USA), 2 mM L-glutamine, 50 μg/mL streptomycin, and 10 μg/mL gentamicin.
    ThermoFisher Scientific
    suggested: None
    We analyzed data using FlowJo software (BD Biosciences, USA).
    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:
    Our study has several limitations: (i) the cohort analyzed is likely to be non-representative and includes only individuals who have visited outpatient clinics to voluntarily undertake tests for COVID-19 antibodies levels and who agreed to participate in the study; (ii) only a limited fraction of cases were reported to the city registry of COVID-19 cases, so some patients who indeed had COVID-19 after inclusion remained unreported; and (iii) we evaluated contributions of systemic antibody and T cell responses to the infectivity probabilities, whereas their local role in lungs, where the critical events of the SARS-CoV-2 infection occur, may be different. However, peripheral blood collection is a much less invasive intervention than bronchoscopy and therefore is more suitable for massive testing of the population in order to predict COVID-19 rates. It should be noted that the results reported are applicable only to infection with alpha SARS-Cov-2, which was dominant in Moscow during the time of study. Further research is needed to understand whether the results obtained hold for the new Delta variant. Taken together, our data suggest the advantage of serology testing over the analysis of T cell responses for the prediction of SARS-CoV-2 infection rates on a population level. According to our results, the calculated probabilities of infection depending on the specific IgG titers may be instructive for making decisions in personalized healthcare, as well as for the development o...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04898140RecruitingThe Evaluation of Cellular and Humoral Immunity to COVID-19 …

    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.

  3. Version published to 10.1101/2021.08.19.21262278 on medRxiv