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.