mRNA-based influenza vaccine expands the breadth of the B cell response in humans

Eliciting durable antibody responses against rapidly evolving pathogens such as the influenza virus remains a formidable challenge. Conventional influenza virus vaccines are poorly immunogenic and induce antibody responses of limited breadth. Germinal center (GC) reactions in draining lymph nodes are key sites for antibody diversification and affinity maturation following vaccination. Whether an mRNA-based influenza virus vaccine can induce a superior GC response in humans compared to conventional vaccines remains unclear. We assessed B cell responses in an observational study of cohorts of healthy young adults receiving a licensed, split-virion or an investigative mRNA-based quadrivalent seasonal influenza virus vaccine over two consecutive seasons. mRNA-based vaccines consistently elicited higher antibody titers and frequencies of memory B cells. In the draining lymph nodes, mRNA vaccination stimulated sustained GC reactions that persisted for at least 26 weeks post vaccination in five of thirteen participants across the two seasons. To understand how sustained GC activity shapes the secreted serum IgG repertoire, we performed proteomic analysis of serum IgG repertoire. mRNA vaccination increased the number of vaccine-elicited serum IgG clonotypes and promoted intraclonal expansion within pre-existing clonotypes. B cell lineage analyses further indicated that expanded serum clonotypes map to GC B cell-associated subbranches, consistent with ongoing GC-driven evolution underlying intraclonal expansion. This repertoire remodeling was accompanied by increased binding breadth against antigenically divergent influenza viruses. These findings reveal a key role for persistent GC responses in broadening the repertoire of vaccine-induced antibodies.