Influenza, commonly referred to as“flu,”is a major global public health concern and ahuge economic burden to societies. Current influenza vaccines need to be updatedannually to match circulating strains, resulting in low take-up rates and poor coveragedue to inaccurate prediction. Broadly protective universalflu vaccines that do not needto be updated annually have therefore been pursued. 

The highly conserved 24–aminoacid ectodomain of M2 protein (M2e) is a leading candidate, but its poor immunoge-nicity has been a major roadblock in its clinical development. Here, we report a targeting strategy that shuttles M2e to a specific dendritic cell subset (cDC1) by engineering a recombinant anti-Clec9A monoclonal antibody fused at each of its heavy chains with three copies of M2e. 

Single administration in mice of 2μg of the Clec9A–M2e construct triggered an exceptionally sustained anti-M2e antibody response and resulted ina strong anamnestic protective response upon influenza challenge. Furthermore, and importantly, Clec9A–M2e immunization significantly boosted preexisting anti-M2e titers from prior flu exposure. Thus, the Clec9A-targeting strategy allows antigen and dose sparing, addressing the shortcomings of current M2e vaccine candidates. As the cDC1 subset exists in humans, translation to humans is an exciting and realistic avenue.