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Significance The most promising target for a universal influenza A vaccine is the conserved hemagglutinin (HA) stem domain. However, in infected or immunized individuals, the response to HA stem is limited due to HA head immunodominance. To understand factors hampering the development of stem B cells, we have immunized mice with full-length HA and HA stem alone or in different combinations and shown that physical attachment of HA head to stem severely hinders stem responses. By increasing local antigen concentration of full-length HA, we were able to rescue stem-specific B cells and serum antibodies. Our results provide a template for improving vaccination by overcoming immunodominance.

Outflanking immunodominance to target subdominant broadly neutralizing epitopes