TY - JOUR
T1 - Germinal centre-driven maturation of B cell response to mRNA vaccination
AU - Kim, Wooseob
AU - Zhou, Julian Q.
AU - Horvath, Stephen C.
AU - Schmitz, Aaron J.
AU - Sturtz, Alexandria J.
AU - Lei, Tingting
AU - Liu, Zhuoming
AU - Kalaidina, Elizaveta
AU - Thapa, Mahima
AU - Alsoussi, Wafaa B.
AU - Haile, Alem
AU - Klebert, Michael K.
AU - Suessen, Teresa
AU - Parra-Rodriguez, Luis
AU - Mudd, Philip A.
AU - Whelan, Sean P.J.
AU - Middleton, William D.
AU - Teefey, Sharlene A.
AU - Pusic, Iskra
AU - O’Halloran, Jane A.
AU - Presti, Rachel M.
AU - Turner, Jackson S.
AU - Ellebedy, Ali H.
N1 - Funding Information:
The Ellebedy laboratory received funding under sponsored research agreements from Emergent BioSolutions and from AbbVie. J.S.T. is a consultant for Gerson Lehrman Group.
Funding Information:
We thank the study participants for providing these specimens. We thank B. J. Laidlaw for critical reading of the manuscript and C. A. Nelson for help with the binding affinity analyses. The Ellebedy laboratory was supported by National Institute of Allergy and Infectious Diseases (NIAID) grants U01AI141990 and 1U01AI150747, NIAID Centers of Excellence for Influenza Research and Surveillance contract HHSN272201400006C and HHSN272201400008C, and NIAID Collaborative Influenza Vaccine Innovation Centers contract 75N93019C00051. W.K. was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2021R1A6A3A03041509). J.S.T. was supported by NIAID 5T32CA009547. This study used samples obtained from the Washington University School of Medicine’s COVID-19 biorepository supported by the NIH/National Center for Advancing Translational Sciences, grant number UL1 TR002345. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official view of NIAID or NIH. The WU353 and WU368 studies were reviewed and approved by the Washington University Institutional Review Board (approval numbers 202003186 and 202012081, respectively).
Funding Information:
We thank the study participants for providing these specimens. We thank B. J. Laidlaw for critical reading of the manuscript and C. A. Nelson for help with the binding affinity analyses. The Ellebedy laboratory was supported by National Institute of Allergy and Infectious Diseases (NIAID) grants U01AI141990 and 1U01AI150747, NIAID Centers of Excellence for Influenza Research and Surveillance contract HHSN272201400006C and HHSN272201400008C, and NIAID Collaborative Influenza Vaccine Innovation Centers contract 75N93019C00051. W.K. was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2021R1A6A3A03041509). J.S.T. was supported by NIAID 5T32CA009547. This study used samples obtained from the Washington University School of Medicine?s COVID-19 biorepository supported by the NIH/National Center for Advancing Translational Sciences, grant number UL1 TR002345. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official view of NIAID or NIH. The WU353 and WU368 studies were reviewed and approved by the Washington University Institutional Review Board (approval numbers 202003186 and 202012081, respectively).
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/4/7
Y1 - 2022/4/7
N2 - Germinal centres (GC) are lymphoid structures in which B cells acquire affinity-enhancing somatic hypermutations (SHM), with surviving clones differentiating into memory B cells (MBCs) and long-lived bone marrow plasma cells1–5 (BMPCs). SARS-CoV-2 mRNA vaccination induces a persistent GC response that lasts for at least six months in humans6–8. The fate of responding GC B cells as well as the functional consequences of such persistence remain unknown. Here, we detected SARS-CoV-2 spike protein-specific MBCs in 42 individuals who had received two doses of the SARS-CoV-2 mRNA vaccine BNT162b2 six month earlier. Spike-specific IgG-secreting BMPCs were detected in 9 out of 11 participants. Using a combined approach of sequencing the B cell receptors of responding blood plasmablasts and MBCs, lymph node GC B cells and plasma cells and BMPCs from eight individuals and expression of the corresponding monoclonal antibodies, we tracked the evolution of 1,540 spike-specific B cell clones. On average, early blood spike-specific plasmablasts exhibited the lowest SHM frequencies. By contrast, SHM frequencies of spike-specific GC B cells increased by 3.5-fold within six months after vaccination. Spike-specific MBCs and BMPCs accumulated high levels of SHM, which corresponded with enhanced anti-spike antibody avidity in blood and enhanced affinity as well as neutralization capacity of BMPC-derived monoclonal antibodies. We report how the notable persistence of the GC reaction induced by SARS-CoV-2 mRNA vaccination in humans culminates in affinity-matured long-term antibody responses that potently neutralize the virus.
AB - Germinal centres (GC) are lymphoid structures in which B cells acquire affinity-enhancing somatic hypermutations (SHM), with surviving clones differentiating into memory B cells (MBCs) and long-lived bone marrow plasma cells1–5 (BMPCs). SARS-CoV-2 mRNA vaccination induces a persistent GC response that lasts for at least six months in humans6–8. The fate of responding GC B cells as well as the functional consequences of such persistence remain unknown. Here, we detected SARS-CoV-2 spike protein-specific MBCs in 42 individuals who had received two doses of the SARS-CoV-2 mRNA vaccine BNT162b2 six month earlier. Spike-specific IgG-secreting BMPCs were detected in 9 out of 11 participants. Using a combined approach of sequencing the B cell receptors of responding blood plasmablasts and MBCs, lymph node GC B cells and plasma cells and BMPCs from eight individuals and expression of the corresponding monoclonal antibodies, we tracked the evolution of 1,540 spike-specific B cell clones. On average, early blood spike-specific plasmablasts exhibited the lowest SHM frequencies. By contrast, SHM frequencies of spike-specific GC B cells increased by 3.5-fold within six months after vaccination. Spike-specific MBCs and BMPCs accumulated high levels of SHM, which corresponded with enhanced anti-spike antibody avidity in blood and enhanced affinity as well as neutralization capacity of BMPC-derived monoclonal antibodies. We report how the notable persistence of the GC reaction induced by SARS-CoV-2 mRNA vaccination in humans culminates in affinity-matured long-term antibody responses that potently neutralize the virus.
UR - http://www.scopus.com/inward/record.url?scp=85127418875&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-04527-1
DO - 10.1038/s41586-022-04527-1
M3 - Article
C2 - 35168246
AN - SCOPUS:85127418875
SN - 0028-0836
VL - 604
SP - 141
EP - 145
JO - Nature
JF - Nature
IS - 7904
ER -