Abstract Background Dysregulation of the innate immune response to SARS-CoV-2 has been linked to poor outcomes in COVID-19. Neutrophils are key players in this response, displaying distinct functional profiles associated with disease severity. This study investigates how neutrophil phenotypes, and their mediators are modulated in severe COVID-19 following vaccination. Methods and Results We conducted an observational case-control study using clinical data, serum samples, and circulating neutrophils from patients hospitalized with severe COVID-19. Neutrophils from vaccinated patients exhibited increased expression of surface markers including TREM-1, CD182, HLA-DR, and PD-L1, alongside higher HLA-DR mean fluorescence intensity (MFI). These cells also showed a higher proportion of inflammatory (CD16⁺CD182⁺TREM-1⁺) and immunoregulatory (HLA-DR⁺PD-L1⁺) subsets compared to non-vaccinated individuals. Exploratory principal component analysis (PCA) revealed a trend toward separation of vaccinated and non-vaccinated groups, suggestively driven by inflammatory cytokines (IL-6, TNF-α, GM-CSF, IL-18) and neutrophil surface markers (HLA-DR, PD-L1, TREM-1, CD16). Conclusions These findings suggest that prior COVID-19 vaccination is associated with a distinct neutrophil activation profile in patients with severe disease, characterized by the concomitant expression of pro-inflammatory and immunoregulatory markers. This immune phenotype may reflect a more balanced inflammatory response during severe SARS-CoV-2 infection. These findings open avenues for future studies incorporating functional assays and larger, independent cohorts to confirm and extend the biological and clinical relevance of these observations.
Oliveira et al. (Sat,) studied this question.