Variant-specific spike conformational dynamics shape memory B cell selection during recall

Abstract

Immune imprinting profoundly shapes antibody responses to breakthrough infections and vaccination against evolving endemic viruses. Current vaccine design primarily focuses on antigen sequence and variant mutations but rarely consider the structural context in which these antigens are being recognized. In this study, we make use of the longitudinal analysis of memory B cell (MBC) responses in boosted individuals enrolled in the COVIBOOST clinical trial to provide a proof of principle that variant-specific conformational dynamics can impact MBC recruitment and protective antibody responses, independently of epitope conservation. Combining functional characterization of MBC-derived monoclonal antibodies, repertoire analysis, epitope mapping and in silico structural modeling of epitope accessibility, we found that the adjuvanted B.1.351 spike vaccine preferentially recalled MBCs targeting exposed receptor-binding domain neutralizing epitopes. This preferential recruitment arises from the more restricted conformational dynamics of the B.1.351 spike compared to the ancestral Hu-1 spike, leading to increased masking of class 4 and 5 cryptic RBD epitopes. These findings demonstrate that antigen conformational dynamics can be leveraged to redirect pre-existing immunity toward neutralizing epitopes upon boost immunization.