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Data on the effect of booster SARS‐CoV‐2 vaccination are mainly focused on humoral immunogenicity, while the kinetics of vaccine‐induced cellular response and its correlation with effectiveness in hematologic patients are less explored. Our aim was to evaluate the longitudinal cellular and humoral immunogenicity induced by two and three doses of the mRNA‐1273 SARS‐CoV‐2 vaccine in 270 patients with hematologic malignancies, and its relationship with the severity of breakthrough SARS‐CoV‐2 infection. Results indicate that at 23 weeks after the second dose, the seroconversion rate declined from 68.5% to 59.3%, with a reduction in median anti‐S titers from 1577 to 456 BAU/mL, mainly in patients over 65 years of age or chronic lymphocytic leukemia (CLL) patients undergoing active therapy. Cellular immunogenicity, however, remained positive in 84.4% of cases. A third vaccine dose seroconverted 42.7% (41/96) and triggered cellular response in 36.7% (11/30) of previously negative patients. Notably, only 7.2% (15/209) of patients failed to develop both humoral and cellular response. Active therapy, anti‐CD20 antibodies, lymphopenia, hypogammaglobulinemia, and low CD19+ cell count were associated with poor humoral response, while active disease, GvHD immunosuppressive therapy, lymphopenia, and low CD3+, CD4+, CD56+ cell count determined an impaired cellular response. After 13.8 months of follow‐up, the incidence of SARS‐CoV‐2 infection was 24.8% (67/270), including 6 (9%) severe/critical cases associated with a weaker cellular (median interferon gamma (IFN‐γ) 0.19 vs. 0.35 IU/mL) and humoral response (median anti‐S titer <4.81 vs. 788 BAU/mL) than asymptomatic/mild cases. In conclusion, SARS‐CoV‐2 booster vaccination improves humoral response and COVID‐19 severity is associated with impaired vaccine‐induced immunogenicity.

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