TARGETING THE 'UNIVERSAL' INFLUENZA A VACCINE CANDIDATE M2E TO CLEC9A - EXPRESSING DENDRITIC CELLS

Abstract

Influenza, commonly referred to as “flu”, is a top global public health concern with up to 100 million individuals infected each year, and between 300,000-600,000 deaths worldwide. Currently available influenza vaccines need to be reviewed and updated annually to match circulating strains. However, the lack of accurate predictive tools often leads to less than optimal overall vaccine efficacies. Therefore, broadly protective “universal” flu vaccines have been actively pursued. Such a candidate is the highly conserved 24-amino acid ectodomain of M2 protein (M2e), 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 sub-population of dendritic cells (cDC1) by engineering a chimeric anti-Clec9A monoclonal antibody fused with three copies of M2e at each of its heavy chains. We show that single administration of just 2µg of this construct triggered a long-lasting anti-M2e antibody response, and resulted in strong anamnestic protective response upon lethal influenza challenge. Furthermore, Clec9A-M2e immunization significantly boosted existing anti-M2e titers from prior flu exposure, to levels expected to confer robust protection in both young adult and old mice. Our data thus support that the Clec9A targeting strategy has the potential to address the shortcomings faced with current M2e vaccine candidates, with the unique added benefits of antigen and dose sparing. Since the equivalent DC sub-population exists in humans (CD141+ DCs), translation to human is a realistic and exciting avenue.