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

• Published in: Nature (London) Vol. 617; no. 7961; pp. 592 - 598
• Main Authors: Alsoussi, Wafaa B., Malladi, Sameer Kumar, Zhou, Julian Q., Liu, Zhuoming, Ying, Baoling, Kim, Wooseob, Schmitz, Aaron J., Lei, Tingting, Horvath, Stephen C., Sturtz, Alexandria J., McIntire, Katherine M., Evavold, Birk, Han, Fangjie, Scheaffer, Suzanne M., Fox, Isabella F., Mirza, Senaa F., Parra-Rodriguez, Luis, Nachbagauer, Raffael, Nestorova, Biliana, Chalkias, Spyros, Farnsworth, Christopher W., Klebert, Michael K., Pusic, Iskra, Strnad, Benjamin S., Middleton, William D., Teefey, Sharlene A., Whelan, Sean P. J., Diamond, Michael S., Paris, Robert, O’Halloran, Jane A., Presti, Rachel M., Turner, Jackson S., Ellebedy, Ali H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.05.2023; Nature Publishing Group
• Subjects: 13; 13/109; 13/31; 14; 14/1; 38; 38/39; 38/77; 38/91; 631/250/1619/40/2508; 631/250/2152/2153/1291; 631/250/2152/2153/1982; 631/250/590/2293; Antibodies, Monoclonal - immunology; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Antigens; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Bone marrow; COVID-19; COVID-19 - immunology; COVID-19 - prevention & control; COVID-19 - virology; COVID-19 Vaccines - administration & dosage; COVID-19 Vaccines - immunology; Enzymes; Epitopes; Epitopes, B-Lymphocyte - genetics; Epitopes, B-Lymphocyte - immunology; Germinal Center - cytology; Germinal Center - immunology; Humanities and Social Sciences; Humans; Immunization; Immunization, Secondary; Immunogenicity; Immunological memory; Lymphatic system; Lymphocytes B; Memory B Cells - cytology; Memory B Cells - immunology; Memory cells; Monoclonal antibodies; mRNA; mRNA vaccines; multidisciplinary; Plasma; Plasma Cells - cytology; Plasma Cells - immunology; Proteins; Robustness; SARS-CoV-2 - genetics; SARS-CoV-2 - immunology; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; Spike protein; Vaccines
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-06025-4

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 variants 1 – 4 . SARS-CoV-2 booster immunizations in humans primarily recruit pre-existing memory B cells 5 – 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. COVID-19 booster immunizations aimed at spike protein from new SARS-CoV-2 variants induce robust germinal centre B cell responses against the original spike protein, as well as de novo B cell responses against the variant spike protein.