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Introduction: Considering the reported efficacy of monoclonal antibodies (mAbs) directed against the Spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in reducing disease severity, the aim of this study was to investigate the innate immune response before and after mAbs treatment in 72 vaccinated and 31 unvaccinated SARS‐CoV‐2 patients. Methods: The mRNA levels of IFN‐I, IFN‐related genes and cytokines were evaluated using RT/real‐time quantitative PCR. Results: Vaccinated patients showed increased rate of negative SARS‐CoV‐2 PCR tests on nasopharyngeal swab compared with unvaccinated ones after mAbs treatment (p =.002). Unvaccinated patients had lower IFN‐α/ω and higher IFN‐related genes (IFNAR1, IFNAR2, IRF9, ISG15, ISG56 and IFI27) and cytokines (IL‐6, IL‐10 and TGF‐β) mRNA levels compared to vaccinated individuals before mAbs (p <.05 for all genes). Increased IFN‐α/ω, IFNAR1, IFNAR2 and IRF9 levels were observed in unvaccinated patients after mAbs treatment, while the mRNA expression ISGs and IL‐10 were reduced in all patients. Conclusion: These data suggest that anti‐S vaccinated patients have increased levels of innate immune genes compared to unvaccinated ones. Also, gene expression changes in IFN genes after mAbs administration are different according to the vaccination status of patients. [ABSTRACT FROM AUTHOR]