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Introduction: Acute COVID-19 infection causes significant alterations in the innate and adaptive immune systems. While most individuals recover naturally, some develop long COVID (LC) syndrome, marked by persistent or new symptoms weeks to months after SARS-CoV-2 infection. Despite its prevalence, there are no clinical tests to distinguish LC patients from those fully recovered. Understanding the immunological basis of LC is essential for improving diagnostic and treatment approaches. Methods: We performed deep immunophenotyping and functional assays to examine the immunological profiles of LC patients, individuals with active COVID-19, recovered patients, and healthy donors. This analysis assessed both innate and adaptive immune features, identifying potential biomarkers for LC syndrome. A Binomial Generalized Linear Model (BGLM) was used to pinpoint immune features characterizing LC. Results: COVID-19 patients exhibited depletion of innate immune cell subsets, including plasmacytoid and conventional dendritic cells, classical, non-classical, and intermediate monocytes, and monocyte-derived inflammatory dendritic cells. Elevated basal inflammation was observed in COVID-19 patients compared to LC patients, whose immune profiles were closer to those of healthy donors and recovered individuals. However, LC patients displayed persistent immune alterations, including reduced T cell subsets (CD4, CD8, Tregs) and switched memory B cells, similar to COVID-19 patients. Through BGLM, a unique adaptive immune signature for LC was identified, featuring memory CD8 and gd T cells with low proliferative capacity and diminished expression of activation and homing receptors. Discussion: The findings highlight a unique immunological signature associated with LC syndrome, characterized by persistent adaptive immune dysregulation. While LC patients displayed recovery in innate immune profiles comparable to healthy and Recovered individuals, deficits in T cell and memory B cell populations were evident, differentiating LC from full recovery. These findings provide insights into LC pathogenesis and may support the development of diagnostic tools and targeted therapies. [ABSTRACT FROM AUTHOR]

Introduction: Assessing the response to vaccinations is one of the diagnostic criteria for Common Variable Immune Deficiencies (CVIDs). Vaccination against SARS-CoV-2 offered the unique opportunity to analyze the immune response to a novel antigen. We identify four CVIDs phenotype clusters by the integration of immune parameters after BTN162b2 boosters. Methods: We performed a longitudinal study on 47 CVIDs patients who received the 3rd and 4th vaccine dose of the BNT162b2 vaccine measuring the generation of immunological memory. We analyzed specific and neutralizing antibodies, spike-specific memory B cells, and functional T cells. Results: We found that, depending on the readout of vaccine efficacy, the frequency of responders changes. Although 63.8% of the patients have specific antibodies in the serum, only 30% have high-affinity specific memory B cells and generate recall responses. Discussion: Thanks to the integration of our data, we identified four functional groups of CVIDs patients with different B cell phenotypes, T cell functions, and clinical diseases. The presence of antibodies alone is not sufficient to demonstrate the establishment of immune memory and the measurement of the in-vivo response to vaccination distinguishes patients with different immunological defects and clinical diseases. [ABSTRACT FROM AUTHOR]