"Abstract
Background: ... 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.
Methods: 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.
Results: 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.
Conclusions: Although the possibility of spike protein expression due to asymptomatic SARS-CoV-2 infection cannot be entirely excluded, this study demonstrated that mRNA vaccines for SARS-CoV-2 can result in prolonged spike protein expression within the intima of cerebral arteries, persisting for months after vaccination. This raises significant concerns regarding the biodistribution of lipid nanoparticle-encapsulated mRNA and the potential for long-term, yet rare, adverse events. Additionally, the notable presence of spike protein in vaccinated individuals and some inflammatory cell infiltration was observed in spike-positive vessels—particularly women—highlights potential sex-based differences in vaccine response. These results underscore the urgent global studies to replicate and expand upon these findings, ensuring a more comprehensive understanding of the long-term safety profile of mRNA vaccines."
© 2025 The Author(s). Published by Elsevier Ltd.
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