Abstract
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 of these vaccines and the development of new variant-derived ones1–4. SARS-CoV-2 booster immunizations in humans primarily recruit pre-existing memory B cells (MBCs)5–9. It remains unclear, however, whether the additional doses induce germinal centre (GC) reactions where reengaged B cells can further mature and whether variant-derived vaccines can elicit responses to novel epitopes specific to such variants. Here, we show that boosting with the original SARS- CoV-2 spike vaccine (mRNA-1273) or a B.1.351/B.1.617.2 (Beta/Delta) bivalent vaccine (mRNA-1273.213) induces robust spike-specific GC B cell responses in humans. The GC response persisted for at least eight weeks, leading to significantly more mutated antigen-specific MBC and bone marrow plasma cell compartments. Interrogation of MBC-derived spike-binding monoclonal antibodies (mAbs) isolated from individuals boosted with either mRNA-1273, mRNA-1273.213, or a monovalent Omicron BA.1-based vaccine (mRNA-1273.529) revealed a striking imprinting effect by the primary vaccination series, with all mAbs (n=769) recognizing the original SARS-CoV-2 spike protein. Nonetheless, using a more targeted approach, we isolated mAbs that recognized the spike protein of the SARS-CoV-2 Omicron (BA.1) but not the original SARS-CoV-2 spike from the mRNA-1273.529 boosted individuals. The latter mAbs were less mutated and recognized novel epitopes within the spike protein, suggesting a naïve B cell origin. Thus, SARS-CoV-2 boosting in humans induce robust GC B cell responses, and immunization with an antigenically distant spike can overcome the antigenic imprinting by the primary vaccination series.
Competing Interest Statement
The Ellebedy laboratory and Infectious Disease Clinical Research Unit 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. AHE is a consultant for Mubadala Investment Company and the founder of ImmuneBio Consulting. WBA, AJSchmitz, SPJW, MSD, JST, and AHE are recipients of a licensing agreement with Abbvie that is unrelated to the data presented in the current study. MSD 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. SPJW is a consultant for Thylacine Bio. SPJW 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. RP, BN, SC, and RN are employees of and shareholders in Moderna, Inc. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official view of NIAID or NIH.
