Background: We have recently shown that, during acute severe COVID-19, SARS-CoV-2 spike protein (S) induces a cascade of events resulting in T cell apoptosis. Indeed, by neutralizing the protease activity of its receptor, ACE2, S induces an increase in circulating Angiotensin II (AngII), resulting in monocytic release of reactive oxygen species (ROS) and programmed T cell death.
Objective: Here, we tested whether SARS-CoV-2 mRNA vaccines, known to cause the circulation of the vaccine antigen, S-protein receptor binding domain (RBD), might trigger the same cascade.
Methods: To this aim, we used ELISA to quantify the presence of RBD and AngII in participants' peripheral blood as well as the presence of interferon-γ in the supernatant of peripheral blood mononuclear cells (PBMCs) exposed to S. Monocytic ROS production, T cell apoptosis, and S-induced T lymphocyte proliferation were measured by flow cytometry, and DNA damage by immunofluorescence.
Results: In most vaccinees, we observed the presence of circulating RBD peaking on Day 14, and linked to an increase in AngII plasma levels with a peak on Day 28. This increase correlated with i) the ability of monocytes to produce ROS and to induce ROS-mediated DNA damage in neighboring cells, including PBMCs, ii) CD4+ and CD8+ T lymphocyte apoptosis, and iii) a poor response to S in vitro from both CD4+ and CD8+ T cells.
Clinical implications: We observed the same cascade of events triggered by the vaccinal antigen as by SARS-CoV-2 infection. This cascade may account for the suboptimal efficiency of mRNA SARS-CoV-2 vaccines in preventing the infection, the limited vaccine memory, and certain side-effects. In this model, AngII receptor antagonists and/or antioxidants might improve the performance of the SARS-CoV-2 vaccine.
Keywords: DNA damage; SARS-CoV-2 spike; T cell response; oxidative stress; programmed T cell death.
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