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Skin targeting for vaccine efficacy Laboratory of « Immunity and Infection » INSERM Paris, France

Skin targeting for vaccine efficacy Laboratory of « Immunity and Infection » INSERM Paris, France Behazine COMBADIERE, PhD Director of research INSERM. Fondamental questions and New hopes for vaccination. 1- Vaccination for whom ? Defining the target population

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Skin targeting for vaccine efficacy Laboratory of « Immunity and Infection » INSERM Paris, France

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  1. Skin targeting for vaccine efficacy Laboratory of « Immunity and Infection » INSERM Paris, France Behazine COMBADIERE, PhD Director of research INSERM

  2. Fondamental questions and New hopes for vaccination • 1- Vaccination for whom? • Defining the target population • History of infection and multiplicity of vaccination • Otherdiseases in the population • 2- What type of immunity ? • Defining the correlates of protection • differsdepending of the pathogens • 3- How? • Adapting the route of immunization • bio-diversity of antigen-presentingcells (AP • Skin, Mucosa sites Intensity Quality (T cells: cytokine released, cytotoxicity, B cells: IgG, IgA) Persistence of Memory Localization (mucosa, skin, liver) CD4 T cells Dendritic cells B cells CD8 T cells

  3. SKIN TARGETING OF APC DICTATES IMMUNOLOGICAL OUTCOMES Lymph nodes HAIR FOLLICLE Stratum corneum Langerhans cells Lymph node Micro- environments Epidermis Lymphatic vessels Dermal- epidermal junction Dermal DC Dermis Differential targeting of antigen-presenting cells dictates the immunological outcomes (intensity, quality, localization) Lymphatic and blood capillary vessels Hypodermis Leukocytes recruitment(neutrophils, monocytes, pDC) CD4 T cells Dendritic cells B cells CD8 T cells Blood vessels

  4. Stratum corneum Follicular cast Hair fibre + cyanoacrylate glue + follicular casts+ ca. 30% of stratum corneum HAIR FOLLICLE TARGETING OF COMPOUNDS TO LANGERHANS CELLS Stratum corneum Epidermis Dermis Lymphatic and blood capillary vessels Hypodermis Vogt et al. J Invest Dermatology 2006 and Mahe J Invest Dermatology 2008

  5. Suitable size of vaccine compounds intofollicularducts 1500-700 nm   200 nm   40 nm Suitable size for Langerhans cells up-take of vaccine : biodegradable or solid nanoparticles, virus like particles, small viruses, DNA, protein/peptide-carrier 37°C Skin purified human CD1a+ cells (+40nm)

  6. PROOF OF CONCEPT: PHASE I TRIAL OF AN INFLUENZA VACCINE Influenza-specific CD8 TC route Vogt et al. J Immunol 2008 and Combadiere et al Plos One 2010 IM route Hair follicle Langerhans cells favors CD8 responses and also mucosal immunity but not IgG responses Influenza-specific CD4

  7. FROM HUMANIZED MICE TO CLINICAL TRIALS “tailor-cut” immunization strategies could be proposed for infectious diseases: HIV, Malaria, Tuberculosis, emerging diseases and cancer EU-FP7 large-scale coordination : CUT’HIVAC project 2010-2014 Pre-clinical models Humanized mice CLINICAL TRIALS Human skin Explants Human immune cells Immunodeficient mice

  8. PERSPECTIVES • Alternative methods of vaccination against infectious diseases to increase vaccine efficacy and allow a “tailor-cut” immune response • Understanding skin immunological role for initiation and maintenance of immunity to infectious diseases • Translation of basic research using innovative preclinical modelsinto clinical trials • 5 Phase I/II/IIa clinical trials are planned for 2011-2014: • Preventive and therapeutic HIV vaccine (3 trials): DNA-GTU® technology (FIT-Biotech) by TC, ID, IM or combined routes • Influenza vaccination in adults and in elderly (2 trials) : trivalent influenza vaccine by TC, ID and IM routes

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