The novel coronavirus SARS-CoV-2 has resulted in a global pandemic with worldwide 6-digital infection rates and thousands death tolls daily. Enormeous effords are undertaken to achieve high coverage of immunization in order to reach herd immunity to
stop spreading of SARS-CoV-2 infection. Several SARS-CoV-2 vaccines, based either on mRNA, viral vectors, or inactivated SARS-CoV-2 virus have been approved and are being applied worldwide. However, recently increased numbers of normally very rare types of thromboses associated with thrombocytopenia have been reported in particular in the context of the adenoviral vector vaccine ChAdOx1 nCoV-19 from Astra Zeneca. While statistical prevalence of these side effects seem to correlate with this particular vaccine type, i.e. adenonoviral vector based vaccines, the exact molecular mechanisms are still not clear. The present review summarizes current data and hypotheses for molecular and cellular mechanisms into one integrated hypothesis indicating that coagulopathies, including thromboses, thrombocytopenia and other related side effects are correlated to an interplay of the two components in the vaccine, i.e. the spike antigen and the adenoviral vector, with the innate and immune system which under certain circumstances can imitate the picture of a limited COVID-19 pathological picture.
Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure and death. Data from patients with severe clinical manifes
tations compared to patients with mild symptoms indicate that highly dysregulated exuberant inflammatory responses correlate with severity of disease and lethality. Significantly elevated cytokine levels, i.e. cytokine storm, seem to play a central role in severity and lethality in COVID-19. We have previously shown that excessive cytokine release induced by highly pathogenic avian H5N1 influenza A virus was reduced by application of proteasome inhibitors. In the present study we present experimental data of a central cellular pro-inflammatory signal pathways, NF-kappaB, in the context of published clinical data from COVID-19 patients and develop a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro-inflammatory cytokines and chemokines via blocking the nuclear translocation of NF-kappaB by proteasome inhibitors. The simultaneous inhibition of multiple cytokines/chemokines using clinically approved proteasome inhibitors is expected to have a higher therapeutic potential compared to single target approaches to prevent cascade (i.e. triggering, synergistic, and redundant) effects of multiple induced cytokines and may provide an additional therapeutic option to be explored for treatment of critical stage COVID-19 patients.
