Rapid Hypermutation B Cell Trajectory Recruits Previously Primed B Cells Upon Third SARS-Cov-2 mRNA Vaccination

The COVID-19 pandemic shows that vaccination strategies building on an ancestral viral strain need to be optimized for the control of potentially emerging viral variants. Therefore, aiming at strong B cell somatic hypermutation to increase antibody affinity to the ancestral strain - not only at high antibody titers - is a priority when utilizing vaccines that are not targeted at individual variants since high affinity may offer some flexibility to compensate for strain-individual mutations. Here, we developed a next-generation sequencing based SARS-CoV-2 B cell tracking protocol to rapidly determine the level of immunoglobulin somatic hypermutation at distinct points during the immunization period. The percentage of somatically hypermutated B cells in the SARS-CoV-2 specific repertoire was low after the primary vaccination series, evolved further over months and increased steeply after boosting. The third vaccination mobilized not only naive, but also antigen-experienced B cell clones into further rapid somatic hypermutation trajectories indicating increased affinity. Together, the strongly mutated post-booster repertoires and antibodies deriving from this may explain why the third, but not the primary vaccination series, offers some protection against immune-escape variants such as Omicron B.1.1.529.

Automated summary

The COVID-19 pandemic highlights the importance of optimizing vaccination strategies for potential viral variants. Researchers have developed a sequencing-based protocol to track B cells and determine the level of immunoglobulin somatic hypermutation during the immunization period. The findings suggest that increasing antibody affinity to the ancestral strain is a priority when using vaccines not targeted at individual variants, as it may provide flexibility to compensate for strain-specific mutations. The study also shows that the third vaccine dose induces a rapid increase in somatic hypermutation, indicating increased affinity and potential protection against immune-escape variants.