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.
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).
- Rolf Marschalek
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Saskia Middeldorp, Radboud University Nijmegen, Netherlands
© 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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