Chimeric hemagglutinin influenza virus vaccine constructs elicit broadly protective stalk-specific antibodies

Current influenza virus vaccine strategies stimulate immune responses toward the globular head domain of the hemagglutininprotein in order to inhibit key steps of the virus life cycle. Because this domain is highly variable across strains, new vaccineformulations are required in most years. Here we demonstrate a novel vaccine strategy that generates immunity to the highlyconserved stalk domain by using chimeric hemagglutinin constructs that express unique head and stalk combinations. By repeatedlyimmunizing mice with constructs that expressed the same stalk but an irrelevant head, we specifically stimulated astalk-directed response that provided broad-based heterologous and heterosubtypic immunity in mice. Notably, our vaccinationscheme provides a universal vaccine approach that protects against challenge with an H5 subtype virus. Furthermore, through invivo studies using passively transferred antibodies or depletion of CD8⁺T cells, we demonstrated the critical role that humoralmechanisms of immunity play in the protection observed. The present data suggest that a vaccine strategy based on the stalk domainof the hemagglutinin protein could be used in humans to broadly protect against a variety of influenza virus subtypes.