These thromboembolic events in combination with thrombocytopenia share similarities with another condition, ‘heparin-induced thrombocytopenia’ (HIT). TTS has been observed for these four vaccines in 36, 5, 200, and 24 patients, indicating a relative risk of 0.4, 0.5, 15.7, and 6.9 cases per Mio injections. This indicates that thromboembolic events associated with case mortality were in the range of 21.4–52% (see Table 1). Thrombosis-related death cases for these four vaccines were 74, 6, 81, and 12, respectively. Thrombocytopenia and immunothrombocytopenia (ITP) have been observed in 314 cases after 96.6 Mio vaccination doses with Comirnaty (3.3 cases per Mio injections), in 28 cases with Spikevax after 10.5 Mio vaccination doses with Comirnaty (2.6 cases per Mio injections), in 269 with Vaxzevria after 12.7 Mio vaccination doses cases (21.2 cases per Mio injections), and in 23 cases with after 3.4 Mio vaccination doses cases (6.6 cases per Mio injections).

The latest data from the security surveillance of the Paul-Ehrlich-Institute in Germany (report dated from Decem) revealed still a significant risk increase for the AstraZeneca vaccine compared to the other vaccines (see Table 1). The higher than expected occurrence of CVST led to a rapid suspension of the Vaxzevria vaccination campaign in several European countries (March 11–14, 2021: Denmark, several northern European countries, Thailand, Ireland March 15, 2021: Germany, Italy, France, and Spain). The most severe side effects entailed rare events of thrombocytopenia combined with cerebral venous sinus thrombosis (CVST). While vaccination with BioNTech and Moderna mostly causes only mild and typical immediate vaccination side effects, severe side effects thromboses (ITP) or thrombosis with thrombocytopenia syndrome (TTS) were first observed with Vaxzevria in Europe (in March 2021). All four vaccines encode slightly different forms of the SARS-CoV-2 Spike glycoprotein, which mediates virus binding to the host cell membrane and entry via ACE2 and TMPRSS2, respectively ( Hoffmann et al., 2020).

The world has faced the fastest development and production of vaccines ever, resulting in a total of four vaccines that have received conditional market authorizations by the regulatory bodies: the mRNA vaccines from BioNTech/Pfizer (BTN162b2/Comirnaty EMA: 21.12.20) and Moderna (mRNA-1273/Spikevax EMA: 6.1.21), as well as the adenoviral vector-based vaccines from AstraZeneca (AZD1222/ChAdOx1-S/Vaxzevria EMA: 29.1.21) and Janssen ( EMA: 11.3.21). The COVID-19 pandemic, starting in the last months of 2019 in Wuhan (China) and caused by the RNA virus SARS-CoV-2, so far (January 4, 2022) has resulted in more than 293.0 million (Mio) infections and more than 5.46 Mio deaths (data source: ). Avoiding such splicing events should become part of a rational vaccine design to increase safety of prospective vaccines. Secreted Spike variants could potentially initiate severe side effects when binding to cells via the ACE2 receptor. 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.

Here, we describe an unexpected mechanism that could explain thromboembolic events occurring with DNA-based but not with RNA-based vaccines. Meanwhile, scientists have proposed an immune-based pathomechanism and the condition has been coined vaccine-induced immune thrombotic thrombocytopenia (VITT). These events only occurred following vaccination with adenoviral vector-based vaccines but not following vaccination with mRNA-based vaccines. Besides CVST, splanchnic vein thromboses (SVT) and other thromboembolic events have been observed. In some rare cases, cerebral venous sinus thromboses (CVST) have been reported as a severe side effect occurring 4–14 days after the first vaccination and were often accompanied by thrombocytopenia. 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.

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