Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for millions of infections and hundreds of thousands of deaths globally. There are no widely available licensed therapeutics against SARS-CoV-2, highlighting an urgent need for effective interventions. The virus enters host cells through binding of a receptor-binding domain within its trimeric spike glycoprotein to human angiotensin-converting enzyme 2. In this article, we describe the generation and characterization of a panel of murine mAbs directed against the receptor-binding domain. One mAb, 2B04, neutralized wild-type SARS-CoV-2 in vitro with remarkable potency (half-maximal inhibitory concentration of <2 ng/ml). In a murine model of SARS-CoV-2 infection, 2B04 protected challenged animals from weight loss, reduced lung viral load, and blocked systemic dissemination. Thus, 2B04 is a promising candidate for an effective antiviral that can be used to prevent SARS-CoV-2 infection.

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.