IL-6 and IL-8 elevations after co-administration of COVID-19 and influenza vaccines are associated with lower anti-spike IgG titers at three and six months post-vaccination

The early innate immune response to vaccination plays a crucial role in shaping adaptive immunity and long-term protection. In this study, we investigated the early cytokine response to COVID-19 and flu vaccination and its association with mid-term humoral immunity. Twenty-nine healthcare workers (HCWs) who received the monovalent SARS-CoV-2 XBB.1.5 mRNA vaccine along with the seasonal quadrivalent inactivated influenza vaccine were enrolled. Serum samples were collected at baseline (T0), five days (T1), three months (T2), and six months (T3) post-vaccination. The levels of seven innate cytokines and chemokines were quantified at T0 and T1, while anti-trimeric spike (S) IgG titers were measured at T0, T2 and T3. Our analysis revealed a significant increase in CXCL10, TNF-α, and IL-6 at T1, whereas CCL3 and IL-8 mean levels remained unchanged. Spearman's correlation analysis showed a coordinated activation of inflammatory mediators, with IL-6 and IL-8 exhibiting the strongest correlation. Notably, early cytokine responses were associated with humoral immunity, as IL-6 and IL-8 levels at T1 were negatively correlated with anti-trimeric S IgG titers at T2 and T3. These findings suggest that early inflammatory cytokine increases may limit the persistence of vaccine-induced antibody response.