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BACKGROUND: Whereas several studies have demonstrated the long-term immunogenicity of BNT162b2 vaccine in healthy adults, little evidence was provided in vulnerable populations (VPs) with generally low ability to respond to immunizations. We aimed to identify pre-vaccination immune phenotype and transcriptional signatures in B and T-cell subsets associated with immune response and long-term maintenance upon SARS-CoV-2 vaccination in VPs.METHODS: A cohort of VPs (N = 169) including solid organ transplant recipients (SOT; N = 35), Inflammatory Bowel Disease (N = 31), Down Syndrome (N = 42), people living with HIV (N = 36), primary immune deficiencies (N = 25) and healthy controls (N = 37) were enrolled in the CONVERS Study. SARS-CoV-2 Vaccine responsiveness was evaluated by SARS-CoV-2-specific Ab and SARS-CoV-2-specific CD4+ T cells in VPs naive to infection or vaccination. Based on the humoral response at T28, individuals were classified as Protected (P: anti-spike antibody [anti-S] titer ≥0.8) and Not-Protected (NP: anti-S titer <0.8). Peripheral blood mononuclear cells, after SARS-CoV-2 Prot-S peptides stimulation were sort-purified in four cell subsets and analyzed by multiplexed RT-PCR (Fluidigm, Biomark).RESULTS: SOT presented a significantly lower serological immunogenicity with 31 % of individuals being NP at T28 whereas only 1 out of the remaining 119 resulted Ab negative at T28. At T0, NP individuals showed a lower increase of Ag specific CD40L+ T cells and lower switched memory B cells compared to P patients. Gene-expression analysis revealed distinct signatures at baseline between P and NP individuals with 63 and 49 DEGs identified in two experimental conditions, respectively unstimulated and stimulated.CONCLUSIONS: Pre-vaccination B and T-cell characteristics at both phenotypic and gene- expression level correlate with short- and long- term memory maintenance in VPs with lower immunogenicity upon BNT162b2 vaccine. Such signatures need to be validated in larger cohorts and may provide a predictive score to inform personalized and more effective vaccine interventions.