Influenza viruses remain a severe threat to public health. Since currently licensed vaccines mediate insufficient protection, novel vaccine approaches that elicit broad protection are being developed. A candidate universal vaccine based on chimeric hemagglutinins (HA) was recently tested in a phase I trial. To dissect the B cell immune responses elicited by this vaccine, we used a “Total-seq HA array”, which revealed the transcriptome and antibody specificity of individual HA-reactive memory B cells after vaccination. Our analyses revealed previously unknown transcriptional heterogeneity within the antigen-specific memory B cell population in response to chimeric HA vaccination, representing seemingly functionally distinct cell subsets. In addition, we provide evidence that the chimeric HA-based universal influenza vaccine induces HA stalk-reactive memory B cells, with B cell clones shared by multiple subjects (public clones). Furthermore, we identified a surprising antigen-specific B cell subset expressing IgD and IgM with low mutation rates. In summary, this study provides an in-depth analysis of the B cell responses elicited by a novel universal influenza virus vaccine candidate and could inform strategies to further optimize future vaccine designs.



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