Temporal single-cell landscape suggests infection-induced IgM plasma cells as a correlate of durable influenza...

While influenza vaccines prevent disease, their protection is short-lived compared to natural infection. However, a comprehensive single-cell comparison of B cell responses between infection and vaccination is lacking.

We generated a single-cell transcriptome and BCR dataset of 150,131 B cells from 7 individuals (3 natural H3N2 infections, 4 quadrivalent vaccine vaccinees). We identify four key descriptive findings: (1) Natural infection, but not vaccination, induces a sustained population of IgM⁺ plasma cells with high HLA-II expression, suggestive of prolonged antigen presentation; (2) natural infection strongly induces interferon-stimulated gene (ISG) expression in B cells, which peaks in early infection (1-2 days postsymptom onset) and correlates with antiviral responses-this ISG signature is barely detectable in vaccinated individuals; (3) vaccination skews memory B cells toward restricted IGHV3-23 and IGHV3-33 usage, while infection shows broader clonal diversity; (4) temporal dynamics reveal that infection-associated B cell profiles peak later but persist longer than those induced by vaccination.

We identify an infection-induced IgM⁺ plasma cell population with sustained HLA-II expression, absent after vaccination. These cells may contribute to long-lived immunity and represent a potential target for improving vaccine durability.