TY - JOUR
T1 - SARS-CoV-2 Omicron boosting induces de novo B cell response in humans
AU - Alsoussi, Wafaa B.
AU - Malladi, Sameer Kumar
AU - Zhou, Julian Q.
AU - Liu, Zhuoming
AU - Ying, Baoling
AU - Kim, Wooseob
AU - Schmitz, Aaron J.
AU - Lei, Tingting
AU - Horvath, Stephen C.
AU - Sturtz, Alexandria J.
AU - McIntire, Katherine M.
AU - Evavold, Birk
AU - Han, Fangjie
AU - Scheaffer, Suzanne M.
AU - Fox, Isabella F.
AU - Mirza, Senaa F.
AU - Parra-Rodriguez, Luis
AU - Nachbagauer, Raffael
AU - Nestorova, Biliana
AU - Chalkias, Spyros
AU - Farnsworth, Christopher W.
AU - Klebert, Michael K.
AU - Pusic, Iskra
AU - Strnad, Benjamin S.
AU - Middleton, William D.
AU - Teefey, Sharlene A.
AU - Whelan, Sean P.J.
AU - Diamond, Michael S.
AU - Paris, Robert
AU - O’Halloran, Jane A.
AU - Presti, Rachel M.
AU - Turner, Jackson S.
AU - Ellebedy, Ali H.
N1 - Funding Information:
The authors thank all the donors for generously providing precious specimens; L. Kessels and the Washington University School of Medicine 382 Study Team (study coordinators A. Haile, R. Thompson, D. Carani, K. Gray and C. Ayres; pharmacists M. Royal and J. Tran; and laboratory technicians L. Blair, A. Afghanzada and N. Schodl) for assistance with scheduling participants and sample collection; P. Woodard, B. Thomas, M. Harrod, R. Hamlin, M. Rohn; the staff of the Center for Clinical Research Imaging at Washington University School of Medicine for assistance with sample collection; and C. Dalton and B. Roemmich for performing the nucleocapsid binding assay. The WU382 study was reviewed and approved by the Washington University Institutional Review Board (approval no. 202109021). This work was supported in part with funding from the US National Institutes of Health (NIH) and Moderna. The Ellebedy laboratory was supported by NIH grants U01AI141990, 1U01AI150747, 5U01AI144616-02 and R01AI168178-01. The Diamond laboratory was supported by NIH grant R01 AI157155. The Whelan laboratory was supported by NIH grant R01 AI163019. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official view of NIAID or NIH.
Funding Information:
The Ellebedy laboratory and Infectious Disease Clinical Research Unit has received funding under sponsored research agreements from Moderna related to the data presented in the current study. The Ellebedy laboratory received funding from Emergent BioSolutions and AbbVie that are unrelated to the data presented in the current study. A.H.E. has received consulting and speaking fees from InBios International, Fimbrion Therapeutics, RGAX, Mubadala Investment Company, Moderna, Pfizer, GSK, Danaher, Third Rock Ventures, Goldman Sachs and Morgan Stanley and is the founder of ImmuneBio Consulting. W.B.A., A. J. Schmitz, S.P.J.W., M.S.D., J.S.T. and A.H.E. are recipients of a licensing agreement with Abbvie that is unrelated to the data presented in the current study. M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, Moderna, Sterne-Kessler and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Emergent BioSolutions and Moderna. S.P.J.W. is a consultant for Thylacine Bio. S.P.J.W. is a recipient of a licensing agreement with Vir Biotechnology and Merck. The Whelan laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology. R.P., B.N., S.C. and R.N. are employees of and shareholders in Moderna. The other authors declare no competing interests.
Funding Information:
The authors thank all the donors for generously providing precious specimens; L. Kessels and the Washington University School of Medicine 382 Study Team (study coordinators A. Haile, R. Thompson, D. Carani, K. Gray and C. Ayres; pharmacists M. Royal and J. Tran; and laboratory technicians L. Blair, A. Afghanzada and N. Schodl) for assistance with scheduling participants and sample collection; P. Woodard, B. Thomas, M. Harrod, R. Hamlin, M. Rohn; the staff of the Center for Clinical Research Imaging at Washington University School of Medicine for assistance with sample collection; and C. Dalton and B. Roemmich for performing the nucleocapsid binding assay. The WU382 study was reviewed and approved by the Washington University Institutional Review Board (approval no. 202109021). This work was supported in part with funding from the US National Institutes of Health (NIH) and Moderna. The Ellebedy laboratory was supported by NIH grants U01AI141990, 1U01AI150747, 5U01AI144616-02 and R01AI168178-01. The Diamond laboratory was supported by NIH grant R01 AI157155. The Whelan laboratory was supported by NIH grant R01 AI163019. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official view of NIAID or NIH.
Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/5/18
Y1 - 2023/5/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85156269927&partnerID=8YFLogxK
U2 - 10.1038/s41586-023-06025-4
DO - 10.1038/s41586-023-06025-4
M3 - Article
C2 - 37011668
AN - SCOPUS:85156269927
SN - 0028-0836
VL - 617
SP - 592
EP - 598
JO - Nature
JF - Nature
IS - 7961
ER -