Transcript 1 - Ariis
Skin targeting for vaccine efficacy Laboratory of « Immunity and Infection » INSERM Paris, France Behazine COMBADIERE, PhD Director of research INSERM CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD 1 FONDAMENTAL QUESTIONS AND NEW HOPES FOR VACCINATION 1- Vaccination for whom? Defining the target population History of infection and multiplicity of vaccination Other diseases in the population 2- What type of immunity ? Defining the correlates of protection differs depending of the pathogens Intensity CD4 T cells Quality 3- How? Adapting the route of immunization bio-diversity of antigen-presenting cells (AP Skin, Mucosa sites CEA CHRU CNRS CPU INRA INRIA (T cells: cytokine released, Dendritic cells cytotoxicity, B cells: IgG, IgA) B cells Persistence of Memory CD8 T cells Localization INSERM (mucosa, skin, liver) INSTITUT PASTEUR IRD SKIN TARGETING OF APC DICTATES IMMUNOLOGICAL OUTCOMES HAIR FOLLICLE Lymph nodes Stratum corneum Langerhans cells Epidermis Dermalepidermal junction Lymph node Microenvironments Dermal DC Dermis Lymphatic vessels Differential targeting of antigen-presenting cells Lymphatic and blood capillary vessels dictates the immunological outcomes (intensity, quality, localization) Hypodermis Leukocytes recruitment(neutrophils, monocytes, pDC) CD4 T cells Dendritic cells CEA CHRU CNRS Blood CPU vessels INRA INRIA INSERM INSTITUT PASTEUR B cells CD8 T cellsIRD HAIR FOLLICLE TARGETING OF COMPOUNDS TO LANGERHANS CELLS Stratum corneum Follicular cast Hair fibre Stratum corneum Epidermis + cyanoacrylate glue + follicular casts + ca. 30% of stratum corneum Dermis Lymphatic and blood capillary vessels Hypodermis Vogt et al. J Invest Dermatology 2006 and Mahe J Invest Dermatology 2008 CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD SUITABLE SIZE OF VACCINE COMPOUNDS INTO FOLLICULAR DUCTS 1500-700 nm 200 nm 40 nm Suitable size for Langerhans cells up-take of 37°C vaccine : biodegradable or solid nanoparticles, virus like particles, small viruses, DNA, protein/peptide-carrier Skin purified human CD1a+ cells (+40nm) CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD 5 PROOF OF CONCEPT: PHASE I TRIAL OF AN INFLUENZA VACCINE Influenza-specific CD8 Vogt et al. J Immunol 2008 and Combadiere et al Plos One 2010 TC route IM route Hair follicle Langerhans cells favors CD8 responses Influenza-specific CD4 and also mucosal immunity but not IgG responses CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD 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 CLINICAL TRIALS Pre-clinical models Humanized mice Human skin Explants Human immune cells Immunodeficient mice CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD 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 models into clinical trials 5 Phase I/II/IIa clinical trials are planned for 2011-2014: o Preventive and therapeutic HIV vaccine (3 trials): DNA-GTU® technology (FIT-Biotech) by TC, ID, IM or combined routes o Influenza vaccination in adults and in elderly (2 trials) : trivalent influenza vaccine by TC, ID and IM routes CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD