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Vaccination with an mRNA COVID-19 vaccine determines not only a consistent reduction in the risk of SARS-CoV-2 infection but also contributes to disease attenuation in infected people. Of note, hyperinflammation and damage-associated molecular patterns (DAMPs) have been clearly associated with severe illness and poor prognosis in COVID-19 patients. In this report, we revealed a significant reduction in the levels of IL-1ss and DAMPs molecules, as S100A8 and High Mobility Group Protein B1 (HMGB1), in vaccinated patients as compared to non-vaccinated ones. COVID-19 vaccination indeed prevents severe clinical manifestations in patients and limits the release of systemic danger signals in SARS-CoV-2 infected people.