SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best

  1. Ane Fernandez Salinas
  2. Eva Piano Mortari
  3. Sara Terreri
  4. Concetta Quintarelli
  5. Federica Pulvirenti
  6. Stefano Di Cecca
  7. Marika Guercio
  8. Cinzia Milito
  9. Livia Bonanni
  10. Stefania Auria
  11. Laura Romaggioli
  12. Giuseppina Cusano
  13. Christian Albano
  14. Salvatore Zaffina
  15. Carlo Federico Perno
  16. Giuseppe Spadaro
  17. Franco Locatelli
  18. Rita Carsetti
  19. Isabella Quinti

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Abstract

Background

Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization.

Methods

Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine.

Results

The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only.

Conclusion

In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected.

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  1. Version published to 10.1007/s10875-021-01133-0
  2. ScreenIT

    SciScore for 10.1101/2021.06.24.21259130: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Eligible patients were informed on the study, including its safety profile and supply procedures, and signed the informed consents for vaccination and for the immunological study.
    IRB: The study was approved the Ethical Committee of the Sapienza University of Rome (Prot. 0521/2020, July 13, 2020).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The study was performed in accordance with the Good Clinical Practice guidelines, the International Conference on Harmonization guidelines, and the most recent version of the Declaration of Helsinki. Methods for identify anti-Spike and anti-Receptor Binding Domain (RBD) antibodies and Spike-specific B- and T-cell responses are summarized in the Online Repository.
    anti-Spike
    suggested: None
    anti-Receptor Binding Domain (RBD)
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical Package for Social Sciences version 15 (SPSS Inc., 233 South Wacker Drive, 11th Floor, Chicago) will be used for the analysis.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    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:
    However, the discrepancy between this clinical evidence and the lack of antibodies underlines the limitations of this correlate of protection against the severe forms of COVID-19 and requires in depth studies on SARS-CoV-2 specific B- and T-cells function in PAD. However, data on immunogenicity of SARS-CoV-2 vaccine in patients with inborn errors of immunity are few and limited to anecdotal cases or heterogeneous cohort [31]. Although the natural course of COVID-19 is primarily characterized by the function of the innate immune system, with a secondary involvement of T- and B-cells, vaccines are designed to force the adaptive immune system to generate neutralizing antibodies and memory B- and T-cells that effectively protect from COVID-19. Here we showed that while HD produced specific antibodies and generate high affinity MBCs and activated MBCs that significantly increased after immunization, these responses are lacking in all XLA and severely impaired in CVID patients after SARS-CoV-2 immunization, suggesting an incomplete protection. However, in five out of seven CVID patients who were previously infected with SARS-CoV-2, IgG were detectable at the time of vaccination administered at least three months after SARS-CoV-2 infection recovery, suggesting that if IgG were produced, they might persist after the primary infection. Moreover, in these previously infected CVID patients, IgG response was boosted by the subsequent immunization. Interestingly, in all CVID patients, vac...

    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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  3. Version published to 10.1101/2021.06.24.21259130v1 on medRxiv