Profiling B cell immunodominance after SARS-CoV-2 infection reveals antibody evolution to non-neutralizing viral targets

Dissecting the evolution of memory B cells (MBCs) against SARS-CoV-2 is critical for understanding antibody recallupon secondary exposure. Here, we usedsingle-cell sequencing to profile SARS-CoV-2-reactive B cells in 38 COVID-19 patients. Using oligo-tagged antigen baits, we isolated B cells specific to the SARS-CoV-2 spike, nucleoprotein (NP), open reading frame 8 (ORF8), and endemic human coronavirus (HCoV) spike proteins. SARS-CoV-2 spike-specific cells were enriched in the memory compartment of acutely infected and convalescent patients several months post symptom onset. With severe acute infection, substantial populations of endemic HCoV-reactive antibody-secreting cells were identified and possessed highlymutated variable genes, signifying preexisting immunity. Finally, MBCs exhibited pronounced maturation to NP and ORF8 over time, especially in older patients. Monoclonal antibodies against these targets were non-neutralizing and non-protective in vivo. These findings reveal antibody adaptation to non-neutralizing intracellular antigens during infection, emphasizing the importance of vaccination for inducing neutralizing spike-specific MBCs.

Automated summary

Analyzing the evolution of memory B cells (MBCs) against SARS-CoV-2 is crucial for understanding antibody recall upon secondary exposure. Single-cell sequencing was used to profile SARS-CoV-2-reactive B cells in COVID-19 patients, revealing enrichment of SARS-CoV-2 spike-specific cells in the memory compartment and highly mutated variable genes in endemic HCoV-reactive antibody-secreting cells. Additionally, MBCs exhibited pronounced maturation to NP and ORF8 over time.