Gimenez Sandrine, Hamrouni Emna, André Sonia, Picard Morgane, Soundaramourty Calayselvy, Lozano Claire, Vincent Thierry, Tran Tu-Anh, Kundura Lucy, Estaquier Jérôme, Corbeau Pierre
Institute of Human Genetics, Molecular Bases of Human Diseases, UMR9002, CNRS and Montpellier University, Montpellier, France.
Université de Paris, INSERM U1124, Mort Cellulaire dans les Interactions Hôte-Pathogène, Paris, France.
J Allergy Clin Immunol. 2025 May;155(5):1635-1646. doi: 10.1016/j.jaci.2025.01.003. Epub 2025 Jan 10.
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.
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.
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.
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.
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.
ClinicalTrials.gov Identifier: NCT05655351.
我们最近发现，在2019年冠状病毒病急性重症期间，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突（S）蛋白会引发一系列事件，导致T细胞凋亡。实际上，S蛋白通过中和其受体血管紧张素转换酶2的蛋白酶活性，诱导循环中的血管紧张素II（AngII）增加，从而导致单核细胞释放活性氧（ROS）并引发程序性T细胞死亡。
在此，我们测试了已知会导致疫苗抗原S蛋白受体结合域（RBD）循环的SARS-CoV-2 mRNA疫苗是否会引发相同的级联反应。
我们使用酶联免疫吸附测定（ELISA）来定量参与者外周血中RBD和AngII的存在，以及暴露于S蛋白的外周血单核细胞（PBMC）上清液中γ干扰素（IFN-γ）的存在。通过流式细胞术测量单核细胞ROS生成、T细胞凋亡以及S蛋白诱导的T淋巴细胞增殖，并通过免疫荧光测量DNA损伤。
在大多数接种疫苗者中，我们观察到循环RBD在第14天达到峰值，并且与第28天血浆AngII水平升高有关。这种升高与单核细胞产生ROS以及诱导包括PBMC在内的邻近细胞中ROS介导的DNA损伤的能力相关；CD4和CD8 T淋巴细胞凋亡；以及CD4和CD8 T细胞对体外S蛋白的反应不佳。
我们观察到疫苗抗原引发的级联反应与SARS-CoV-2感染引发的相同。这种级联反应可能解释了SARS-CoV-2 mRNA疫苗在预防感染方面效率欠佳、疫苗记忆有限以及某些副作用的原因。在此模型中，AngII受体拮抗剂和/或抗氧化剂可能会改善SARS-CoV-2疫苗的性能。
ClinicalTrials.gov标识符：NCT05655351。
