Novel mRNA-based vaccines have been proven powerful tools to combat the global pandemic caused by SARS-CoV2 with BNT162b2 (trade name: Comirnaty) efficiently protecting individuals from COVID-19 across a broad age range. Still, it remains largely unknown how renal insufficiency and immunosuppressive medication affect development of vaccine induced immunity. We therefore comprehensively analyzed humoral and cellular responses in kidney transplant recipients after the standard second vaccination dose. As opposed to all healthy vaccinees and the majority of hemodialysis patients, only 4/39 and 1/39 transplanted individuals showed IgA and IgG seroconversion at day 8±1 after booster immunization with minor changes until day 23±5, respectively. Although most transplanted patients mounted spike-specific T helper cell responses, frequencies were significantly reduced compared to controls and dialysis patients, accompanied by a broad impairment in effector cytokine production, memory differentiation and activation-related signatures. Spike-specific CD8 + T cell responses were less abundant than their CD4 + counterparts in healthy controls and hemodialysis patients and almost undetectable in transplant patients. Promotion of anti-HLA antibodies or acute rejection was not detected after vaccination. In summary, our data strongly suggest revised vaccination approaches in immunosuppressed patients, including individual immune monitoring for protection of this vulnerable group at risk to develop severe COVID-19.

Background: Tissue-resident memory (TRM) T cells are known to be important for the first line of defense in mucosa-associated tissues. However, the composition, localization, effector function, and specificity of TRM T cells in the human kidney and their relevance for renal pathology have not been investigated. Methods: Lymphocytes derived from blood, renal peri-tumor samples, and tumor samples were phenotypically and functionally assessed by applying flow cytometry and highly advanced histology (Multi-Epitope Ligand Cartography) methods. Results: CD69+CD103+CD8+ TRM T cells in kidneys display an inflammatory profile reflected by enhanced IL-2, IL-17, and TNFα production, and their frequencies correlate with increasing age and kidney function. We further identified mucosa-associated invariant T (MAIT) and CD56dim and CD56bright Natural Killer (NK) cells likewise expressing CD69 and CD103, the latter significantly enriched in renal tumor tissues. CD8+ TRM cell frequencies were not elevated in kidney tumor tissue, but co-expressed PD-1 and TOX and produced granzyme B. Tumor-derived CD8+ TRM cells from patients with metastases were functionally impaired. Both CD69+CD103- CD4+ and CD69+CD103-CD8+ TRM T cells form distinct clusters in tumor tissues in proximity to antigen-presenting cells. Finally, EBV, CMV, BKV, and influenza antigen-specific CD8+ T cells were enriched in the effector memory T cell population in the kidney. Conclusion: Our data provide an extensive overview of TRM cells' phenotypes and functions in the human kidney for the first time, pointing towards their potential relevance in kidney transplantation and renal disease.

Novel mRNA-based vaccines have been proven powerful tools to combat the global pandemic caused by SARS-CoV2 with BNT162b2 efficiently protecting individuals from COVID-19 across a broad age range. Still, it remains largely unknown how renal insufficiency and immunosuppressive medication affect development of vaccine induced immunity. We therefore comprehensively analyzed humoral and cellular responses in kidney transplant recipients after prime-boost vaccination with BNT162b2. As opposed to all healthy vaccinees and the majority of hemodialysis patients, only 4/39 and 1/39 transplanted individuals showed IgA and IgG seroconversion at day 8±1 after booster immunization with minor changes until day 23±5, respectively. Although most transplanted patients mounted spike-specific T helper cell responses, frequencies were significantly reduced compared to controls and dialysis patients, accompanied by a broad impairment in effector cytokine production, memory differentiation and activation-related signatures. Spike-specific CD8+ T cell responses were less abundant than their CD4+ counterparts in healthy controls and hemodialysis patients and almost undetectable in transplant patients. Signs of alloreactivity promoted by BNT162b2 were not documented within the observation period. In summary, our data strongly suggest revised vaccination approaches in immunosuppressed patients, including individual immune monitoring for protection of this vulnerable group at risk to develop severe COVID-19.