Journal Article

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

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

2022

Overview

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 cells 1 – 5 (BMPCs). SARS-CoV-2 mRNA vaccination induces a persistent GC response that lasts for at least six months in humans 6 – 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. Sequencing of B cell receptors and expression of the corresponding monoclonal antibodies is used to characterize the evolution of the long-term B cell response to SARS-CoV-2 mRNA vaccination.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/31 / 631/250/1619/40/1742 / 631/250/2152/2040 / 631/250/2152/2153/1291 / 631/250/2152/2153/1982 / Affinity / Antibodies, Monoclonal / Antibodies, Viral / Avidity / B-Lymphocytes - cytology / B-Lymphocytes - immunology / Blood / BNT162 Vaccine - administration & dosage / BNT162 Vaccine - immunology / Bone marrow / Cell differentiation / COVID-19 / COVID-19 - immunology / COVID-19 - prevention & control / COVID-19 - virology / Diphtheria / Enzymes / Germinal Center - cytology / Germinal Center - immunology / Germinal centers / Humanities and Social Sciences / Humans / Immunoglobulin G / Immunological memory / Infections / Influenza / Libraries / Long bone / Lymph nodes / Lymphatic system / Lymphocytes B / Memory cells / Monoclonal antibodies / mRNA / mRNA vaccines / multidisciplinary / Neutralization / Plasma / Plasma cells / Proteins / RNA, Messenger - genetics / SARS-CoV-2 - genetics / SARS-CoV-2 - immunology / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Spike Glycoprotein, Coronavirus - immunology / Spike protein / Tetanus / Vaccination