Restricted immune responses to SARS-CoV-2 mRNA vaccination have been observed frequently in individuals suffering from various immunodeficiencies. With increased antibody evasion properties of rising Omicron subvariants, there is a need to assess if other components of adaptive immunity generate resilient responses against SARS-CoV-2 across immunodeficient states. Here we assessed T cell responses of n=279 individuals covering five different immunodeficiencies and healthy controls before and after booster vaccination and - in a subset of patients - additional Omicron infection. We observed significantly increased Omicron-reactive T cell responses upon booster vaccination, particularly in initial poor responders, across all patient groups. Overall T cell composition shifted towards an increased CD8/CD4-ratio, which was accompanied by a more pronounced cytotoxic profile. Moreover, Omicron-reactive T cell responses showed signs of longevity represented by a novel T EMRAsubpopulation with stem-cell-like characteristics and increased proliferative capacity. Regardless of underlying immunodeficiency, booster-vaccinated and Omicron-infected individuals were protected against severe disease and exhibited ameliorated and diversified T cell responses directed explicitly against Omicron, despite a solid immunological imprint of multiple wildtype Wuhan-based vaccine doses.

Supported by grants from SciLifeLab National COVID-19 Research Program and financed by the Knut and Alice Wallenberg Foundation, the Swedish Research Council, Nordstjernan AB, Region Stockholm (Clinical research position-, ALF-, and CIMEDgrants). TRM is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, project: 496946670).

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