Abstract

To fight the Covid-19 pandemic caused by the RNA virus SARS-CoV-2 a global vaccination campaign is in progress to achieve the immunization of billions of people mainly with adenoviral vector- or mRNA-based vaccines, all of which encode the SARS-CoV-2 Spike protein. In some rare cases, cerebral venous sinus thromboses (CVST) have been reported as a severe side effect occurring 4 to 14 days after the first vaccination and were often accompanied by thrombocytopenia. Besides CVST, splanchnic vein thromboses (SVT) and other thromboembolic events have been observed. These events only occurred following vaccination with adenoviral vector-based vaccines but not following vaccination with mRNA-based vaccines. Meanwhile, scientists have proposed an immune-based pathomechanism and the condition has been coined Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT). Here, we describe an unexpected mechanism that could explain thromboembolic events occurring with DNA-based but not with RNA-based vaccines. We show that DNA-encoded mRNA coding for Spike protein can be spliced in a way that the transmembrane anchor of Spike is lost, so that nearly full-length Spike is secreted from cells. Secreted Spike variants could potentially initiate severe side effects when binding to cells via the ACE2 receptor. Avoiding such splicing events should become part of a rational vaccine design to increase safety of prospective vaccines.

Data availability

The original WUHAN SARS-CoV-2 sequence is available in the NCBI database (NCBI Reference Sequence: NC_045512.2); the adenoviral and codon-optimized Spike sequence data have a protected intellectual property by the companies. The primary sequence of Ad5.S, designed and used by the colleagues in Ulm, can be retrieved upon request (contact Prof. Stefan Kochanek).

The following previously published data sets were used

Article and author information

Author details

  1. Eric Kowarz

    Institute of Pharmaceutical Biology, Goethe-University, Frankfurt/Main, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Lea Krutzke

    Department of Gene Therapy, University of Ulm, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4092-4131
  3. Marius Külp

    Institute of Pharmaceutical Biology, Goethe-University, Frankfurt/Main, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Patrick Streb

    Institute of Pharmaceutical Biology, Goethe-University, Frankfurt/Main, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Patrizia Larghero

    Institute of Pharmaceutical Biology, Goethe-University, Frankfurt/Main, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Jennifer Reis

    Institute of Pharmaceutical Biology, Goethe-University, Frankfurt/Main, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Silvia Bracharz

    Institute of Pharmaceutical Biology, Goethe-University, Frankfurt/Main, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Tatjana Engler

    Department of Gene Therapy, University of Ulm, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Stefan Kochanek

    Department of Gene Therapy, University of Ulm, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Rolf Marschalek

    Institute of Pharmaceutical Biology, Goethe-University, Frankfurt/Main, Germany
    For correspondence
    Rolf.Marschalek@em.uni-frankfurt.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4870-3445

Funding

Goethe University Corona Task Force

  • Rolf Marschalek

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Saskia Middeldorp, Radboud University Nijmegen, Netherlands

Publication history

  1. Preprint posted: May 26, 2021 (view preprint)
  2. Received: October 25, 2021
  3. Accepted: January 21, 2022
  4. Accepted Manuscript published: January 27, 2022 (version 1)
  5. Version of Record published: February 15, 2022 (version 2)

Copyright

© 2022, Kowarz et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Eric Kowarz
  2. Lea Krutzke
  3. Marius Külp
  4. Patrick Streb
  5. Patrizia Larghero
  6. Jennifer Reis
  7. Silvia Bracharz
  8. Tatjana Engler
  9. Stefan Kochanek
  10. Rolf Marschalek
(2022)
Vaccine-induced COVID-19 mimicry syndrome
eLife 11:e74974.
https://doi.org/10.7554/eLife.74974
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