SARS-CoV-2 Omicron boosting induces de novo B cell response in humans.

The primary two-dose SARS-CoV-2 mRNA vaccine series are strongly immunogenic in humans, but the emergence of highly infectious variants necessitated additional doses and the development of new variant-derived vaccines 1-4 . SARS-CoV-2 booster immunizations in humans primarily recruit pre-existing memory B cells (MBCs) 5-9 . It remains unclear, however, whether the additional doses induce germinal centre (GC) reactions where reengaged B cells can further mature and whether variant-derived vaccines can elicit responses to variant-specific epitopes. Here, we show that boosting with either the original monovalent SARS-CoV-2 or bivalent B.1.351/B.1.617.2 (Beta/Delta) mRNA vaccines induces robust spike-specific GC B cell responses in humans. The GC response persisted for at least eight weeks, leading to significantly more mutated antigen-specific bone marrow plasma cell and MBC compartments. All MBC-derived spike-binding monoclonal antibodies (mAbs, n=766) isolated from individuals boosted with either the original SARS-CoV-2 spike, bivalent Beta/Delta, or a monovalent Omicron BA.1-based vaccine recognized the original SARS-CoV-2 spike protein. Nonetheless, by using a more targeted sorting approach we isolated mAbs that recognized the BA.1 spike protein but not the original SARS-CoV-2 spike from the mRNA-1273.529 boosted individuals. The latter mAbs were less mutated and recognized novel epitopes within the spike protein, suggesting a naïve B cell origin. Thus, SARS-CoV-2 booster immunizations in humans induce robust GC B cell responses and can generate de novo B cell responses targeting variant-specific epitopes.