Significance
Although the need for a universal influenza vaccine has long been recognized, only a handful of candidates have been identified so far, with even fewer advancing in the clinical pipeline. The 24–amino acid ectodomain of M2 protein (M2e) has been developed over the past two decades. However, M2e-based vaccine candidates have shortcomings, including the need for several administrations and the lack of sustained antibody titers over time. We report here a vaccine targeting strategy that has the potential to confer sustained and strong protection upon a single shot of a small amount of M2e antigen. The current COVID-19 pandemic has highlighted the importance of developing versatile, powerful platforms for the rapid deployment of vaccines against any incoming threat.
Abstract
Influenza, commonly referred to as “flu,” is a major global public health concern and a huge economic burden to societies. Current influenza vaccines need to be updated annually to match circulating strains, resulting in low take-up rates and poor coverage due to inaccurate prediction. Broadly protective universal flu vaccines that do not need to be updated annually have therefore been pursued. The highly conserved 24–amino acid ectodomain of M2 protein (M2e) is a leading candidate, but its poor immunogenicity 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 2 µg of the Clec9A–M2e construct triggered an exceptionally sustained anti-M2e antibody response and resulted in a 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.
