Dynamic immune dysregulation in severe mental illness: Exaggerated innate and attenuated adaptive immune responses following SARS-CoV-2 vaccination.

Background: Immune dysregulation in severe mental illness (SMI) is usually characterised using static measurements. As such, how the immune system of SMI patients responds to real-world challenges remains largely unknown. Prior studies suggest that patients may exhibit an exaggerated innate and attenuated adaptive immune response, but in vivo studies are lacking. Objectives: This study aimed to assess immune responses to SARS-CoV-2 vaccination in SMI patients compared to non-psychiatric controls (NPCs). We investigated post-vaccination changes in cytokine and antibody levels, their associations, and secondary measures including tryptophan-kynurenine pathway metabolites and psychiatric symptoms. Methods: We collected blood samples of 72 SMI patients and 127 NPCs before and after the first and second vaccine dose administrations to quantify cytokines (IL1β, IL6, IL8, IL10) and anti-SARS-CoV-2 antibodies (Spike, S1, S2, S1RBD, Nucleocapsid). We used linear mixed models to assess whether post-vaccination changes in biomarker levels differ between SMI patients and NPCs, and to evaluate associations among biomarkers. Results: SMI patients showed significantly greater increases in IL1β (F(394.3) = 30.03, Conclusion: Our findings provide in vivo evidence for exaggerated innate and attenuated adaptive immune responses to vaccination in SMI patients. The study underscores the need for longitudinal, experimental approaches in immunopsychiatry to better characterise the dynamic dysregulation of both the innate and the adaptive immune system in this population.