P308

SARS-CoV-2 induced B cells generate an anticipatory memory against new virus variants and re-engage in COVID-19 vaccine responses

BRUHN M. ¹, OBARA M. ¹, CHIYYEADU A. ², COSTA B. ¹, SALAM A. ¹, ZIEGLER A. ¹, WALTL I. ¹, PAVLOU A. ¹, BONIFACIUS A. ³, HOFFMANN M. ^4,5, GRAALMANN T. ^6,7,9, PÖHLMANN S. ^4,5, EIZ-VESPER B. ³, SCHAMBACH A. ^2,8, KALINKE U. ^1,10

¹ Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany, Hannover, Germany; ² Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany, Hannover, Germany; ³ Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany, Hannover, Germany; ⁴ Infection Biology Unit, German Primate Center, Göttingen, Germany , Göttingen, Germany; ⁵ Faculty of Biology, Georg-August-University Göttingen, Göttingen, Germany, Göttingen, Germany; ⁶ Department for Rheumatology and Immunology, Hannover Medical School, Hannover, Germany, Hannover, Germany; ⁷ Junior Research Group for Translational Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany, Hannover, Germany; ⁸ Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA, Boston, United States; ⁹ Biomedical Research in End-Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany; ¹⁰ Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany, Hannover, Germany

Background: During the COVID-19 pandemic, numerous new SARS-CoV-2 variants of concern (VOC) evolved, many of which escape from antibody responses. Vaccination of COVID-19 convalescent individuals induces antibody responses of superior quantity and quality, which may even neutralize new VOC. We aimed to understand how memory B cell (MBC) maturation ultimately leads to an increased neutralization breadth.
Methods: We studied the B-cell response of a convalescent individual, who received additional COVID-19 vaccination after recovery. Spike-specific B cells were sorted before and at different time points after vaccination and were analyzed by single-cell RNA sequencing. V(D)J sequences of single B cells were deciphered and used to produce recombinant monoclonal antibodies.
Results: MBC that originated from the initial SARS-CoV-2 infection re-entered the vaccine response. The activated MBC shifted to an atypical state. Infection-induced MBC substantially contributed to a secondary plasmablast response. A few dominant clonotypes that used characteristic VH gene segments and that diversified through somatic hypermutation (SHM) constituted a large fraction of the responding B cells. Analysis of functional consequences allowed to trace back the neutralization of VOC to specific SHM in the mAb heavy chain.
Conclusion: MBC mature in times of convalescence and provide a diversified repertoire for recall responses. In doing so, SHM contribute to the formation of an anticipatory memory that is suitable to neutralize virus variants that might emerge in the future. The concept can be exploited for the design of virus-neutralizing antibodies that can be adapted to upcoming immune-escape variants.