Germinal centre-driven maturation of B cell response to mRNA vaccination

Wooseob Kim, Julian Q. Zhou, Stephen C. Horvath, Aaron J. Schmitz, Alexandria J. Sturtz, Tingting Lei, Zhuoming Liu, Elizaveta Kalaidina, Mahima Thapa, Wafaa B. Alsoussi, Alem Haile, Michael K. Klebert, Teresa Suessen, Luis Parra-Rodriguez, Philip A. Mudd, Sean P. J. Whelan, William D. Middleton, Sharlene A. Teefey, Iskra Pusic, Jane A. O’Halloran, Rachel M. Presti, Jackson S. Turner and Ali H. Ellebedy ()
Additional contact information
Wooseob Kim: Washington University School of Medicine
Julian Q. Zhou: Washington University School of Medicine
Stephen C. Horvath: Washington University School of Medicine
Aaron J. Schmitz: Washington University School of Medicine
Alexandria J. Sturtz: Washington University School of Medicine
Tingting Lei: Washington University School of Medicine
Zhuoming Liu: Washington University School of Medicine
Elizaveta Kalaidina: Washington University School of Medicine
Mahima Thapa: Washington University School of Medicine
Wafaa B. Alsoussi: Washington University School of Medicine
Alem Haile: Washington University School of Medicine
Michael K. Klebert: Washington University School of Medicine
Teresa Suessen: Washington University School of Medicine
Luis Parra-Rodriguez: Washington University School of Medicine
Philip A. Mudd: Washington University School of Medicine
Sean P. J. Whelan: Washington University School of Medicine
William D. Middleton: Washington University School of Medicine
Sharlene A. Teefey: Washington University School of Medicine
Iskra Pusic: Washington University School of Medicine
Jane A. O’Halloran: Washington University School of Medicine
Rachel M. Presti: Washington University School of Medicine
Jackson S. Turner: Washington University School of Medicine
Ali H. Ellebedy: Washington University School of Medicine

Nature, 2022, vol. 604, issue 7904, 141-145

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-04527-1

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