The coronavirus spike glycoprotein attaches to host receptors and mediates viral fusion. Using a broad screening approach, we isolated seven monoclonal antibodies (mAbs) that bind to all human-infecting coronavirus spike proteins from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune donors. These mAbs recognize the fusion peptide and acquire affinity and breadth through somatic mutations. Despite targeting a conserved motif, only some mAbs show broad neutralizing activity in vitro against alpha- and betacoronaviruses, including animal coronaviruses WIV-1 and PDF-2180. Two selected mAbs also neutralize Omicron BA.1 and BA.2 authentic viruses and reduce viral burden and pathology in vivo. Structural and functional analyses showed that the fusion peptide–specific mAbs bound with different modalities to a cryptic epitope hidden in prefusion stabilized spike, which became exposed upon binding of angiotensin-converting enzyme 2 (ACE2) or ACE2-mimicking mAbs.

Probing CD4 T cell immunity to SARS-CoV-2: A better understanding of CD4 ⁺ T cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to the design of effective next-generation vaccines. Low et al. defined and estimated the CD4 ⁺ T cell repertoire of convalescent COVID-19 patients. After sorting various CD4 ⁺ T cell subsets, they generated numerous T cell clones that reacted to the SARS-CoV-2 spike protein. A large number of T cell clones from almost all individuals recognized a small conserved immunodominant region within the spike protein receptor-binding domain (RBD). The researchers isolated T cell clones that broadly reacted to the spike protein of other coronaviruses, providing evidence for the recall of preexisting cross-reactive memory T cells after SARS-CoV-2 infection. Science , abg8985, this issue p. 1336

Memory B cells persist for a lifetime and rapidly differentiate into antibody-producing plasmablasts and plasma cells upon antigen re-encounter. The clonal relationship and evolution of memory B cells and circulating plasmablasts is not well understood. Using single-cell sequencing combined with isolation of specific antibodies, we found that in two healthy donors, the memory B cell repertoire was dominated by large IgM, IgA and IgG2 clonal families, whereas IgG1 families, including those specific for recall antigens, were of small size. Analysis of multiyear samples demonstrated stability of memory B cell clonal families and revealed that a large fraction of recently generated plasmablasts was derived from long-term memory B cell families and was found recurrently. Collectively, this study provides a systematic description of the structure, stability and dynamics of the human memory B cell pool and suggests that memory B cells may be active at any time point in the generation of plasmablasts.