Ota Nakao, Itani Masahiko, Aoki Tomohiro, Sakurai Aki, Fujisawa Takashi, Okada Yasuaki, Noda Kosumo, Arakawa Yoshiki, Tokuda Sadahisa, Tanikawa Rokuya
Stroke Center, Department of Neurosurgery, Sapporo Teishinkai Hospital, Sapporo, Japan.
Department of Pharmacology, The Jikei University School of Medicine, Tokyo, Japan; Department of Neurosurgery, Kyoto University School of Medicine, Kyoto, Japan.
J Clin Neurosci. 2025 Jun;136:111223. doi: 10.1016/j.jocn.2025.111223. Epub 2025 Apr 3.
The rapid deployment of mRNA vaccines for SARS-CoV-2, such as BNT162b2 (BioNTech-Pfizer) and mRNA-1273 (Moderna), provided a critical tool in combating the COVID-19 pandemic. While their short-term safety and efficacy were demonstrated in clinical trials, rare adverse events, including hemorrhagic strokes, have been reported after widespread use. However, the long-term biodistribution and effects of mRNA vaccines remain underexplored. This study aimed to investigate the long-term presence of SARS-CoV-2 spike protein in brain tissues of patients with hemorrhagic strokes, examining its potential association with mRNA vaccination.
A total of 19 cases of hemorrhagic stroke from 2023 to 2024 were retrospectively analyzed. Immunohistochemical staining for SARS-CoV-2 spike protein and nucleocapsid protein was performed on tissue samples. In situ hybridization was conducted in selected cases to confirm the origin of spike protein expression (vaccine or viral infection). Vaccination history and SARS-CoV-2 infection status were documented for all cases.
Spike protein expression was detected in 43.8 % of vaccinated patients, predominantly localized to the intima of cerebral arteries, even up to 17 months post-vaccination. While no active inflammatory changes were identified, infiltration of CD4-, CD8- and CD68- positive cells was observed in the spike protein positive vessels. In situ hybridization confirmed the presence of both vaccine-derived mRNA and SARS-CoV-2 virus-derived mRNA, which encode the spike protein, in select cases. Notably, spike protein positivity was observed exclusively in female patients (P = 0.015). None of the cases showed nucleocapsid protein positivity, supporting the absence of active viral infection.
Although the possibility of spike protein expression due to asymptomatic SARS-CoV-2 infection cannot be entirely excluded, this study demonstrated prolonged presence of SARS-CoV-2 spike protein in the cerebral arteries following mRNA vaccination. Additionally, some inflammatory cell infiltration was observed in spike-positive vessels. These findings raise significant concerns regarding the biodistribution of lipid nanoparticle-based vaccines and their long-term safety. Global replication studies are urgently required to validate these findings and ensure comprehensive safety evaluations of mRNA vaccines.
BNT162b2（BioNTech-辉瑞）和mRNA-1273（莫德纳）等针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的信使核糖核酸（mRNA）疫苗的迅速推广，为抗击2019冠状病毒病（COVID-19）大流行提供了关键工具。虽然它们的短期安全性和有效性在临床试验中得到了证实，但在广泛使用后，包括出血性中风在内的罕见不良事件也有报道。然而，mRNA疫苗的长期生物分布和影响仍未得到充分研究。本研究旨在调查出血性中风患者脑组织中SARS-CoV-2刺突蛋白的长期存在情况，研究其与mRNA疫苗接种的潜在关联。
回顾性分析了来自2023年至2024年的19例出血性中风病例。对组织样本进行了SARS-CoV-2刺突蛋白和核衣壳蛋白的免疫组织化学染色。在选定病例中进行原位杂交，以确认刺突蛋白表达的来源（疫苗或病毒感染）。记录了所有病例的疫苗接种史和SARS-CoV-2感染状况。
在43.8%的接种疫苗患者中检测到刺突蛋白表达，主要定位于脑动脉内膜，甚至在接种疫苗后17个月仍有表达。虽然未发现活跃的炎症变化，但在刺突蛋白阳性血管中观察到CD4、CD8和CD68阳性细胞浸润。原位杂交在部分病例中证实了编码刺突蛋白的疫苗衍生mRNA和SARS-CoV-2病毒衍生mRNA的存在。值得注意的是，仅在女性患者中观察到刺突蛋白阳性（P = 0.015）。所有病例均未显示核衣壳蛋白阳性，支持无活跃病毒感染。
尽管不能完全排除无症状SARS-CoV-2感染导致刺突蛋白表达的可能性，但本研究表明mRNA疫苗接种后，SARS-CoV-2刺突蛋白在脑动脉中持续存在。此外，在刺突阳性血管中观察到一些炎症细胞浸润。这些发现引发了对基于脂质纳米颗粒的疫苗生物分布及其长期安全性的重大担忧。迫切需要开展全球范围的重复研究以验证这些发现，并确保对mRNA疫苗进行全面的安全性评估。
