Germline based SARS-CoV-2 specific B cell repertoire motif identified with novel sequence based bioinformatic...

Human antibody diversification, achieved through gene selection and somatic hypermutation (SHM), is critical for protecting against diverse pathogens. This study investigates whether specific immune responses possess distinct receptor sequence patterns that differentiate them from the general immune repertoire. Utilizing data from an anti-SARS-CoV-2 vaccination study, we analyzed two properties of SARS-CoV-2 specific memory B-cells and compared them to the background immune repertoire. Driven by somatic hypermutation (SHM), B cells exhibit a highly dynamic nature. Consequently, groups sharing a direct lineage from a common progenitor are defined as B-cell clones. First, we studied substitution survival - the number of clones to survive amino acid substitutions across the variable region of the B cell receptor (BCR). Second, we analyzed clonal amino acid trimer usage patterns across the BCR gene to gain insight into prevalent genomic motifs found in different immune sub-repertoires. We demonstrated that these two metrics can effectively cluster and distinguish SARS-CoV-2 specific B cell responses. Furthermore, we observed that SARS-CoV-2-specific B-cells show an increased tendency to utilize and conserve a specific CDR2 motif derived from the VH3-30 gene and its alleles. Beyond identifying a specific germline motif related to SARS-CoV-2-specific B-cells response, our findings demonstrate that our novel analysis pipeline can successfully identify signatures of specific immune responses. We therefore suggest that using the methods described here could be key for the study of the substrate of B-cell selection and protective immunity in other vaccine and pathogen responses.