Is the vaccination-induced B cell receptor repertoire predictable?

Vaccines trigger an immune response that results in a population of memory cells that can quickly respond to subsequent antigen re-encounters. Most vaccines are designed to induce memory B cells with vaccine-specific B cell receptors (BCRs). Post-vaccination, clonal expansion of B cells results in measurably expanded vaccine-specific BCR clonotypes. We set out to determine to what extent it is predictable which specific BCR clonotypes are vaccine-induced in an individual. We sequenced the BCR heavy chain repertoire in a cohort of 19 individuals prior- and 7 days post Tdap booster vaccination. We tested two modalities to predict which clonotypes were expanded post-vaccination: first, we utilized a small database of monoclonal antibodies with known specificity to Tdap vaccine antigens and tested various sequence look-up methods, identifying clonal look-up as the best method. We then utilized a leave-one-out approach in which expanded clonotypes in one individual were predicted using data from other members of the cohort. The second approach significantly outperformed the first, indicating that BCR clonotype expansion can be learned across subjects. These results support the utility of systematically collecting BCR specificity data through efforts like the Immune Epitope database and highlight the limitations on general prediction approaches resulting from relatively small dataset sizes for BCRs with known specificities. Additionally, our study provides 1) a comparison of several BCR specificity prediction methods, 2) a dataset that can be used for benchmarking of subsequent methods, and 3) a methodological framework for comparing BCR repertoires pre- and post-vaccination.