Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade

Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination

Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade.

Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination.This work was funded by the UK Medical Research Council (project number MC_UU_00025/12), the Medical Research Foundation (MRF-057-0002-RG-THAV-C0798) and The Evelyn Trust (grant number 20/40) to JEDT. NJM was supported by the MRC (TSF ref. MR/T032413/1), NHSBT (grant ref. WPA15-02) and Addenbrooke’s Charitable Trust (grant ref. 900239). MAC was supported by the Medical Research Council (project number MC_UU_00025/10). KRP was supported by the Medical Research Council (project number MC_UU_00025/11). KF held an MRC studentship with support from the Cambridge European Trust and St. John’s College. KW has received funding by the Deutsche Forschungsgemeinschaft (WA 1597/6-1 and WA 1597/7-1). KW and BK received support by the German Federal Ministry of Education and Research (BMBF) through a grant to the German genetic multi-organ Auto-Immunity Network (GAIN), grant code 01GM2206A. FH is an ERC Advanced Investigator (695669). We thank Carola G. Vinuesa for helpful discussion. The authors also thank the Flow Cytometry Facilities at the MRC-Toxicology Unit, University of Cambridge; Katarzyna Kania from CRUK-CI-Genomics, Cambridge UK for advice on single cell RNA sequencing experiments; and Rosalind Kieran from the Department of Oncology, Cambridge University NHS Hospitals Foundation Trust, Cambridge UK, for contributions for patient recruitment and data collection