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

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Abstract Age-associated B cells (ABCs) accumulate with age, as well as in individuals with a range of immunological dyscrasias. These include patients with cancer treated with immune checkpoint blockade and patients with inborn errors of immunity. In this study, we sought to determine whether ABCs found in all these conditions are similar, and whether they enhance or detract from the response to COVID-19 vaccination. We use single cell RNA sequencing to show that ABCs arising from distinct aetiologies have common transcriptional profiles and may be subdivided according to the expression of genes associated with different immune functions, such as the autoimmune regulator (AIRE). Next, we perform detailed longitudinal profiling of the COVID-19 vaccination response in patients and controls. We show that high pre-vaccination ABC frequency correlates with decreased levels of antigen-specific memory B cells, and reduced magnitude and longevity of neutralising capacity against SARS-CoV-2 virus. Potentially contributing to this, ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes. This could contribute to diminished vaccine responses either directly as result of inhibitory signalling or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may therefore serve as a biomarker identifying individuals at risk of a suboptimal response to COVID-19 vaccination.

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