Appearance of IgG to SARS-CoV-2 in saliva effectively indicates seroconversion in mRNA vaccinated immunocompromised individuals

  1. Katie Healy
  2. Elisa Pin
  3. Puran Chen
  4. Gunnar Söderdahl
  5. Piotr Nowak
  6. Stephan Mielke
  7. Lotta Hansson
  8. Peter Bergman
  9. C. I. Edvard Smith
  10. Per Ljungman
  11. Davide Valentini
  12. Ola Blennow
  13. Anders Österborg
  14. Giorgio Gabarrini
  15. Khaled Al-Manei
  16. Hassan Alkharaan
  17. Michal Jacek Sobkowiak
  18. Xinling Xu
  19. Mira Akber
  20. Karin Loré
  21. Cecilia Hellström
  22. Sandra Muschiol
  23. Gordana Bogdanovic
  24. Marcus Buggert
  25. Hans-Gustaf Ljunggren
  26. Sophia Hober
  27. Peter Nilsson
  28. Soo Aleman
  29. Margaret Sällberg Chen

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Abstract

Background

Immunocompromised individuals are highly susceptible to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Whether vaccine-induced immunity in these individuals involves the oral cavity, a primary site of infection, is presently unknown.

Methods

Immunocompromised individuals (n=404) and healthy controls (n=82) participated in a prospective clinical trial encompassing two doses of the mRNA BNT162b2 vaccine. Immunocompromised individuals included primary immunodeficiencies (PID) and secondary immunodeficiencies caused by human immunodeficiency virus (HIV) infection, allogeneic hematopoietic stem cell transplantation (HSCT)/chimeric antigen receptor T cell therapy (CAR-T), solid organ transplantation (SOT), and chronic lymphocytic leukemia (CLL). Saliva and serum samples were collected at four time points from the first vaccine dose until 2 weeks after second dose. SARS-CoV-2 spike specific immunoglobulin G (IgG) responses were quantified by a multiplex bead-based assay in saliva and correlated to paired serum IgG titers determined by Elecsys® Anti-SARS-CoV-2 S assay.

Results

IgG responses to the SARS-CoV-2 spike full-length trimeric glycoprotein (Spike-f) and S1 subunit in saliva in the HIV and HSCT/CAR-T groups were comparable to healthy controls. In contrast, PID, SOT, and CLL patients all displayed weaker responses which were mainly influenced by disease parameters or immunosuppressants. Salivary IgG levels strongly correlated with serum IgG titers on days 21 and 35 (rho=0.8079 and 0.7768, p=<0.0001). Receiver operating characteristic curve analysis for the predictive power of salivary IgG yielded AUC=0.95, PPV=90.7% for the entire cohort on D35.

Conclusions

Saliva conveys humoral responses induced by BNT162b2 vaccination. The predictive power makes it highly suitable for screening low responding/vulnerable groups for revaccination.

Trial Registration

ClinicalTrials.gov Identifier: NCT04780659

Funding

Knut and Alice Wallenberg Foundation, Erling Perssons family foundation, Region Stockholm, Swedish Research Council, Karolinska Institutet, The Swedish Blood Cancer Foundation and the organization for PID patient group in Sweden, and Nordstjernan AB. Center for Medical Innovation (CIMED), the Swedish Medical Research Council and the Stockholm County Council (ALF).

GRAPHIC ABSTRACT

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  1. ScreenIT

    SciScore for 10.1101/2021.09.30.21264377: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: All participants provided written informed consent.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Sample collection and SARS-CoV-2 antibody detection in saliva: All saliva samples were processed by a standardized protocol in the same laboratory.
    SARS-CoV-2
    suggested: None
    After cross-linking of the antibody-antigen complexes, a R-phycoerithryne-conjugated anti-human IgG antibody (H10104, Invitrogen) was applied for detection of IgG bound to spike.
    anti-human IgG
    suggested: (Thermo Fisher Scientific Cat# H10104, RRID:AB_2536546)
    Sample collection and SARS-CoV-2 antibody detection in serum: Serum samples were analyzed for detection of antibodies to SARS-CoV-2 spike protein receptor binding domain (RBD), using the quantitative Elecsys® Anti-SARS-CoV-2 S test (Roche Diagnostics) (29) on the Cobas 8000 e801pro.
    SARS-CoV-2 spike protein receptor binding domain (RBD)
    suggested: None
    Data analysis and statistics: The salivary antibody data were acquired as median fluorescence intensities (MFI) for each sample and antigen.
    antigen.
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical analysis was performed using R and R studio (40) for correlation analyses and logistic regression analyses and Prism software v.9 (Graphpad) for all other comparisons.
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    Graphpad
    suggested: (GraphPad, RRID:SCR_000306)

    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:
    Limitations of our study include the lack of antibody isotype analysis and virus neutralizing capacity. The antibody durability in saliva and exploration of local memory B and T cell immunity remain to be investigated. Vaccines other than BNT162b2 also remain to be compared in similar cohorts. Although our data in saliva in consistent with Sahin et al. (35), that after full vaccination healthy volunteers showed a 10-fold increase in producing spike-binding IgG, the present data suggests that the vast majority of HIV and HSCT patients also displayed similar levels as healthy controls. We did not measure IgA, as it had already been shown that the BNT162b2 vaccine elicits mainly IgG and less IgA in saliva in healthcare workers (30). Mucosal antibodies specific to SARS-CoV-2 are considered important in reducing transmission potential in vaccinated individuals (36). The magnitude of anti-spike IgG responses in the saliva of vaccinated individuals, which exceeded those seen in mild convalescent individuals, is encouraging as it indicates that vaccination might confer a sterilizing immune response in the oral cavity and thereby lower virus transmission. The observation that vaccine-induced IgG efficiently translocates into saliva, with high predictive values of BNT162b2-induced seroconversion, is beneficial for immune surveys. Many risk groups are vulnerable to SARS-CoV-2 infection and need regular monitoring. Therefore, saliva and home sampling represent a safe and convenient alter...

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

    IdentifierStatusTitle
    NCT04780659Active, not recruitingCOVID-19 Vaccination of Immunodeficient Persons (COVAXID)

    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 10.1101/2021.09.30.21264377 on medRxiv