Targeting the “universal” Influenza A vaccine candidate M2e to Clec9A-expressing Dendritic Cells
Kavishna Ranmali1,2, Emily Ang1,2, Anna Ker1,2, Hae-Young Park3,4, Irina Caminschi3,, Ken Shortman4, Mireille H. Lahoud3, and Sylvie Alonso1,2
1Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore; 2Immunology Programme, Life Sciences Institute, National University of Singapore; 3Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia; 4The Walter and Eliza Hall Institute, Melbourne, Australia
Over the past century there have been at least four devastating pandemics caused by Influenza A that took the lives of millions, and the threat of the next great pandemic remains a top global health concern today. Currently available vaccines need to be annually reviewed and updated to match circulating strains, and are accompanied by long and complicated production cycles with limited production capacity. In response to these limitations, increasing efforts have been devoted to develop “universal” flu vaccine candidates that would provide broad, cross-clade protection against all influenza A strains. Such candidate is the highly conserved non-glycosylated 24-amino acid ectodomain of M2 protein (M2e). However, its low immunogenicity has slowed down its clinical development and novel vaccine approaches are needed to improve the protective potential of M2e. Our strategy is to target M2e to a specific sub-population of dendritic cells (CD8+ DCs) as a way to boost the immunogenicity of M2e. This is achieved by engineering a chimeric anti-Clec9A monoclonal antibody fused at its heavy chains with three copies of M2e antigen. In this presentation, we will show the immunogenicity and protective efficacy upon a single dose administration of the Clec9A-M2e construct combined with different adjuvants. Furthermore, a dose response study and the long-term anti-M2e antibody response will be featured. Our data support that the Clec9A targeting strategy represents a promising approach to boost the immunogenicity of M2e with the additional benefit of dose and antigen sparing. Since the equivalent DC sub-population exists in humans (CD141+ DCs), translation to human should be possible.