PT  - JOURNAL ARTICLE
AU  - Wooseob Kim
AU  - Julian Q. Zhou
AU  - Alexandria J. Sturtz
AU  - Stephen C. Horvath
AU  - Aaron J. Schmitz
AU  - Tingting Lei
AU  - Elizaveta Kalaidina
AU  - Mahima Thapa
AU  - Wafaa B. Alsoussi
AU  - Alem Haile
AU  - Michael K. Klebert
AU  - Teresa Suessen
AU  - Luis Parra-Rodriguez
AU  - Philip A. Mudd
AU  - William D. Middleton
AU  - Sharlene A. Teefey
AU  - Iskra Pusic
AU  - Jane A. O’Halloran
AU  - Rachel M. Presti
AU  - Jackson S. Turner
AU  - Ali H. Ellebedy
TI  - Germinal centre-driven maturation of B cell response to SARS-CoV-2 vaccination
AID  - 10.1101/2021.10.31.466651
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.10.31.466651
4099  - http://biorxiv.org/content/early/2021/11/02/2021.10.31.466651.short
4100  - http://biorxiv.org/content/early/2021/11/02/2021.10.31.466651.full
AB  - Germinal centres (GC) are lymphoid structures where vaccine-responding B cells acquire affinity-enhancing somatic hypermutations (SHM), with surviving clones differentiating into memory B cells (MBCs) and long-lived bone marrow plasma cells (BMPCs)1–4. Induction of the latter is a hallmark of durable immunity after vaccination5. SARS-CoV-2 mRNA vaccination induces a robust GC response in humans6–8, but the maturation dynamics of GC B cells and propagation of their progeny throughout the B cell diaspora have not been elucidated. Here we show that anti-SARS-CoV-2 spike (S)-binding GC B cells were detectable in draining lymph nodes for at least six months in 10 out of 15 individuals who had received two doses of BNT162b2, a SARS-CoV-2 mRNA vaccine. Six months after vaccination, circulating S-binding MBCs were detected in all participants (n=42) and S-specific IgG-secreting BMPCs were detected in 9 out of 11 participants. Using a combined approach of single-cell RNA sequencing of responding blood and lymph node B cells from eight participants and expression of the corresponding monoclonal antibodies, we tracked the evolution of 1540 S-specific B cell clones. SHM accumulated along the B cell differentiation trajectory, with early blood plasmablasts showing the lowest frequencies, followed by MBCs and lymph node plasma cells whose SHM largely overlapped with GC B cells. By three months after vaccination, the frequency of SHM within GC B cells had doubled. Strikingly, S+ BMPCs detected six months after vaccination accumulated the highest level of SHM, corresponding with significantly enhanced anti-S polyclonal antibody avidity in blood at that time point. This study documents the induction of affinity-matured BMPCs after two doses of SARS-CoV-2 mRNA vaccination in humans, providing a foundation for the sustained high efficacy observed with these vaccines.Competing Interest StatementThe Ellebedy laboratory received funding under sponsored research agreements that are unrelated to the data presented in the current study from Emergent BioSolutions and from AbbVie. A.H.E. is a consultant for Mubadala Investment Company and the founder of ImmuneBio Consulting. J.S.T. is a consultant for Gerson Lehrman Group. J.S.T., A.J.Schmitz., and A.H.E. are recipients of a licensing agreement with Abbvie that is unrelated to the data presented in the current study. A patent application related to this work has been filed by Washington University School of Medicine. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official view of NIAID or NIH.