NOSIMMUNE

The primary goal of this research project is to build and evaluate a new vaccinal protein vector optimized for intranasal vaccination against respiratory infections. This new, bi-functional vector is purposed: (i) To bind and cross the nasal epithelium in the Nasal Associated Lymphoid Tissue (NALT). This will be achieved by including a Fc portion (CH2 and CH3 domains of immunoglobulins) targeting the transcytosis-competent FcRn receptor. (ii) To bind and deliver antigens in the endocytic pathway of migratory dendritic cells for efficient antigen presentation to CD8+ and CD4+ T cells by MHCI and MHCII. This will be achieved through a VHH nanobody raised against C-type lectin expressed in migratory DCs. Our project aims at delivering an in vivo pre-clinical proof-of-principle for this new intranasal vaccine approach. In a first step, we will produce recombinant proteins carrying influenza A virus (IAV) CD4+ and CD8+ T cell epitopes. We will evaluate if those vaccines ensure the induction of local, long-lasting, broadly reactive T cell responses and protection against infectious challenge using multiple viral strains. Using a collection of mutant vectors (targeting epithelial cells, dendritic cells, both or none), we will determine experimentally which targeting moieties actually contribute to the immunogenicity of the vector. In a second step, we will evaluate if the principle of mono or bi-specific targeting (epithelial cells and dendritic cells) can be also applied to deliver nanoparticle containing mRNA encoding full-length antigens in vivo to ensure local T cell and IgA responses. Altogether, this project intends to explore a new approach to deliver antigens to the immune system of the nose using tractable, receptor ligands interactions to induce local and persisting immunity against respiratory infections.