Monocytic reactive oxygen species–induced T-cell apoptosis impairs cellular immune response to SARS-CoV-2 mRNA vaccine - 31/01/25

Doi : 10.1016/j.jaci.2025.01.003

Sandrine Gimenez, BASc ^a, Emna Hamrouni, PharmD ^a, Sonia André, PhD ^b, Morgane Picard, PhD ^b, Calayselvy Soundaramourty, BASc ^b, Claire Lozano, PharmD, PhD ^c, Thierry Vincent, MD, PhD ^c,^d, Tu-Anh Tran, MD, PhD ^d,^e, Lucy Kundura, PhD ^a,^{^{∗
These authors contributed equally to this work.}}, Jérôme Estaquier, PhD ^b,^f,^⁎^{^{∗
These authors contributed equally to this work.}} , Pierre Corbeau, MD, PhD ^a,^d,^g,^⁎^{^{∗
These authors contributed equally to this work.}}
^a Institute of Human Genetics, Molecular Bases of Human Diseases, UMR9002, CNRS and Montpellier University, Montpellier, France
^b Université de Paris, INSERM U1124, Mort Cellulaire dans les Interactions Hôte-Pathogène, Paris, France
^c Immunology Department, University Hospital, Montpellier, France
^d Montpellier University, Montpellier, France
^e Pediatrics Department, University Hospital, Nîmes, France
^f CHU de Québec–Université Laval Research Center, Department of Microbiology and Immunology, Québec City, Québec, Canada
^g Immunology Department, University Hospital, Nîmes, France

^∗Corresponding author: Jérôme Estaquier, PhD, Research Center du CHU de Quebec, Laval University, 2705 Boulevard Laurier, Québec, QC G1V 4G2, Canada.Research Center du CHU de QuebecLaval University2705 Boulevard LaurierQuébecQCG1V 4G2Canada^∗Pierre Corbeau, MD, PhD, Institute of Human Genetics, 141 rue de la Cardonille, 34396 Montpellier cedex 5, France.Institute of Human Genetics141 rue de la Cardonille34396cedex 5MontpellierFrance

connectez-vous ou créez un compte

Bienvenue sur EM-consulte, la référence des professionnels de santé.
Article gratuit.

Connectez-vous pour en bénéficier!

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Friday 31 January 2025
Cet article a été publié dans un numéro de la revue, cliquez ici pour y accéder

Graphical abstract

Le texte complet de cet article est disponible en PDF.

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.