Monocytic reactive oxygen species–induced T-cell apoptosis impairs cellular immune response to SARS-CoV-2 mRNA vaccine

Abstract

Background: We have recently shown that during acute severe coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein induces a cascade of events resulting in T-cell apoptosis. Indeed, by neutralizing the protease activity of its receptor, angiotensin-converting enzyme 2, S protein 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: We used ELISA to quantify the presence of RBD and AngII in peripheral blood of participants and the presence of IFN-γ in the supernatant of PBMCs exposed to S protein. Monocytic ROS production, T-cell apoptosis, and S protein–induced T-lymphocyte proliferation were measured by flow cytometry, and DNA damage was measured by immunofluorescence. Results: In most vaccinees, we observed that the presence of circulating RBD peaked on day 14 and was linked to an increase in AngII plasma levels with a peak on day 28. This increase correlated with the ability of monocytes to produce ROS and to induce ROS-mediated DNA damage in neighboring cells, including PBMCs; CD4+ and CD8+ T-lymphocyte apoptosis; and a poor response to protein S in vitro from both CD4+ and CD8+ T cells. Conclusions: 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. Clinical trial registration: ClinicalTrials.gov Identifier: NCT05655351.