Abstract
Recent reports of rare ChAdOx1-S vaccine-related venous thrombosis led to the suspension of its usage in several countries. Vaccine-induced thrombotic thrombocytopenia (VITT) is characterized by thrombocytopenia and thrombosis in association with anti-platelet factor 4 (PF4) antibodies. Herein, we propose five potential anionic substances of the ChAdOx1-S vaccine that can combine with PF4 and trigger VITT, including (1) the proteins on the surface of adenovirus, e.g., negative charged glycoprotein, (2) the adjuvant components of the vaccine, e.g., Tween 80, (3) the DNA of adenovirus, (4) the S protein antigen expressed by the vaccine, and (5) the negatively charged impurity proteins expressed by the vaccine, e.g., adenovirus skeleton proteins. After analysis of each case, we consider the most possible trigger to be the negatively charged impurity proteins expressed by the vaccine. Then, we display the possible extravascular route and intravascular route of the formation of PF4 autoantibodies triggered by the negatively charged impurity proteins, which is accordant with the clinical situation. Accordingly, the susceptible individuals of VITT after ChAdOx1-S vaccination may be people who express negatively charged impurity proteins and reach a certain high titer.
Highlights
Due to severe thrombotic adverse events named vaccine-induced thrombotic thrombocytopenia (VITT) [1, 2] reported in Denmark, Norway, Germany, Austria, and the United Kingdom, the usage of AstraZeneca recombinant adenoviral ChAdOx1-S was limited in several countries [3]
According to the related reports, we suggest five potential anionic substances of the ChAdOx1-S vaccine that can combine with platelet factor 4 (PF4) as follows: 1. The proteins on the surface of adenovirus, for example, negatively charged glycoprotein
(2) The intravascular route (Figure 1): after the intramuscular injection of the ChAdOx1-S vaccine, the adenovirus leaks into the blood circulation, travels to distant and different tissues, and infects a range of permissive cells, which confer susceptibility, such as epithelial and endothelial cells, etc., that secret the adenovirus vector proteins along with copious SARS-CoV-2 spike proteins, and the adenovirus vector proteins bind to PF4, and trigger the VITT process
Summary
Due to severe thrombotic adverse events named vaccine-induced thrombotic thrombocytopenia (VITT) [1, 2] reported in Denmark, Norway, Germany, Austria, and the United Kingdom, the usage of AstraZeneca recombinant adenoviral ChAdOx1-S was limited in several countries [3]. Greinacher et al [15] found that antibodies tested against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, which indicates that the SARSCoV-2 spike protein may not be a trigger of VITT From another perspective, the above four anionic substances are common in other adenovirus-based vaccines, for example, the Ad26.COV2.S vaccine, if they are plausible, which means that the Ad26.COV2.S vaccine would cause the same incidence and severity of VITT as the ChAdOx1-S vaccine, but that is apparently not the situation [18]. (2) The intravascular route (Figure 1): after the intramuscular injection of the ChAdOx1-S vaccine, the adenovirus leaks into the blood circulation, travels to distant and different tissues, and infects a range of permissive cells, which confer susceptibility, such as epithelial and endothelial cells, etc., that secret the adenovirus vector proteins along with copious SARS-CoV-2 spike proteins, and the adenovirus vector proteins bind to PF4, and trigger the VITT process. Young women have a more intense immune response than men and the elderly, so they are more prone to the above immune response routes
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