mRNA prime-boost vaccination promotes clonal continuity in germinal center reactions and broadens SARS-CoV-2 variant coverage.

mRNA- and adenovirus-based (rAd) SARS-CoV-2 vaccines have been widely used in various homologous and heterologous prime-boost combinations. It remains unknown, however, which vaccination regimens effectively promote B cell clonal continuity (i.e., the participation of individual B cell clones in durable GC reactions to prime and subsequent boost). Here, we characterize SARS-CoV-2-specific GC B cell dynamics in vaccinated mice. While rAd/mRNA prime-boost elicited SARS-CoV-2-neutralizing antibody (nAb) titers equivalent to those induced by mRNA/mRNA, the latter provided broader nAb coverage of variants of concern. B cell fate-mapping experiments revealed that mRNA/mRNA afforded higher clonal continuity between primary and secondary GC reactions than rAd/mRNA, which was associated with similarly sized but more durable GC responses upon mRNA prime. Homologous rAd/rAd prime-boost resulted in vector backbone-biased antibody responses and limited clonal continuity of SARS-CoV-2-specific B cells. Our study suggests that high clonal continuity as observed during mRNA homologous prime-boost is key for vaccination regimens against rapidly evolving pathogens.