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

Nature. 2023 May;617(7961):592-598. doi: 10.1038/s41586-023-06025-4. Epub 2023 Apr 3.


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 vaccines aimed at the new variants1-4. SARS-CoV-2 booster immunizations in humans primarily recruit pre-existing memory B cells5-9. However, it remains unclear whether the additional doses induce germinal centre reactions whereby re-engaged B cells can further mature, and whether variant-derived vaccines can elicit responses to variant-specific epitopes. Here we show that boosting with an mRNA vaccine against the original monovalent SARS-CoV-2 mRNA vaccine or the bivalent B.1.351 and B.1.617.2 (Beta/Delta) mRNA vaccine induced robust spike-specific germinal centre B cell responses in humans. The germinal centre response persisted for at least eight weeks, leading to significantly more mutated antigen-specific bone marrow plasma cell and memory B cell compartments. Spike-binding monoclonal antibodies derived from memory B cells isolated from individuals boosted with either the original SARS-CoV-2 spike protein, bivalent Beta/Delta vaccine or a monovalent Omicron BA.1-based vaccine predominantly recognized the original SARS-CoV-2 spike protein. Nonetheless, using a more targeted sorting approach, we isolated monoclonal antibodies that recognized the BA.1 spike protein but not the original SARS-CoV-2 spike protein from individuals who received the mRNA-1273.529 booster; these antibodies were less mutated and recognized novel epitopes within the spike protein, suggesting that they originated from naive B cells. Thus, SARS-CoV-2 booster immunizations in humans induce robust germinal centre B cell responses and can generate de novo B cell responses targeting variant-specific epitopes.

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology
  • B-Lymphocytes* / cytology
  • B-Lymphocytes* / immunology
  • COVID-19 Vaccines* / administration & dosage
  • COVID-19 Vaccines* / immunology
  • COVID-19* / immunology
  • COVID-19* / prevention & control
  • COVID-19* / virology
  • Epitopes, B-Lymphocyte / genetics
  • Epitopes, B-Lymphocyte / immunology
  • Germinal Center* / cytology
  • Germinal Center* / immunology
  • Humans
  • Immunization, Secondary*
  • Memory B Cells / cytology
  • Memory B Cells / immunology
  • Plasma Cells / cytology
  • Plasma Cells / immunology
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / immunology
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / immunology


  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • COVID-19 Vaccines
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Epitopes, B-Lymphocyte

Supplementary concepts

  • SARS-CoV-2 variants
  • COVID-19 vaccine booster shot