Distinct intrathecal inflammatory signatures following relapse and anti- COVID-19 mRNA vaccination in Multiple Sclerosis. A cross-sectional study.

Abstract Background: The role of off-target inflammatory response to vaccination in exacerbating multiple sclerosis (MS) is a matter of debate. Methods: In this cross-sectional study, we compared the CSF cytokine profiles associated with MS relapses and anti-COVID-19 mRNA vaccinations in patients with relapsing-remitting MS (RRMS). We also compared central inflammatory responses between RRMS patients and individuals without neuroinflammatory disorders. All patients were recruited in the Neuromed Research Institute, Pozzilli (IS). Results: We enrolled 97 consecutives unvaccinated RRMS patients with a clinical relapse occurring within 100 days from the diagnostic lumbar puncture (LP), 29 consecutive RRMS in clinical remission, and 24 consecutive controls. The latter groups of patients received anti-COVID-19 mRNA vaccine within 100 days from LP. In the first group, we observed a significant negative correlation between relapse distance and CSF concentrations of IL-2 (Spearman’s rho= -0.305, p = 0.002), IL-6 (Spearman’s rho= -0.291, p= 0.004), and IL-17 (Spearman’s rho= -0.275, p = 0.006). Linear regression confirmed a significant association for IL-2 (beta = -0.265, 95% CI -0.004 - 0, p = 0.016), IL-6 (beta = -0.284, 95% CI -0.005 - -0.001, p = 0.01), and IL-17 (beta = -0.224, 95% CI -0.004 - 0, p = 0.044), considering possible confounders (age, sex, OCB presence, EDSS). In the second group, distance from vaccination was positively correlated with CSF levels of IL-12 (Spearman’s rho = 0.539, p= 0.003), IL-13 (Spearman’s rho = 0.512, p = 0.005), IL-1ra (Spearman’s rho = 0.481, p = 0.008), MIP-1a (Spearman’s rho = -0.371, p = 0.047). Linear regression confirmed a significant association for IL-12 (beta = 0.536, 95%CI 0.004-0.016, p = 0.004), IL-13 (beta = 0.416, 95%CI 0.001-0.02, p = 0.035), and IL-1ra (beta = 0.506, 95%CI 0.259-2.344, p = 0.016), also considering the effect of other possible confounders (age, sex). No significant associations between vaccine distance and CSF cytokines levels emerged in the control group. Conclusion: Our results indicate that COVID-19 vaccination causes in RRMS patients a central inflammatory response significantly different from that associated with disease relapses. The lack of central inflammatory response observed in control patients indicates that MS patients are suscptible to the central inflammatory effects of vaccination.