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Skin targeting for vaccine efficacy

Laboratory of « Immunity and Infection »INSERMParis, France

Behazine COMBADIERE, PhDDirector of research INSERM

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FONDAMENTAL QUESTIONS AND NEW HOPES FOR VACCINATION

B cells

CD4 T cells

CD8 T cells

Dendritic cells

Intensity

Quality(T cells: cytokine released,

cytotoxicity, B cells: IgG, IgA)

Persistence of Memory

Localization (mucosa, skin, liver)

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

3- How?Adapting the route of immunization bio-diversity of antigen-presenting cells (AP Skin, Mucosa sites

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SKIN TARGETING OF APC DICTATES IMMUNOLOGICAL OUTCOMES

B cells

CD4 T cells

CD8 T cells

Dendritic cells

Lymph nodesStratum corneum

Epidermis

Dermis

Hypodermis

Lymphatic and blood capillary vessels

Dermal-epidermal junction

HAIR FOLLICLE

Blood vessels

Leukocytes recruitment(neutrophils,

monocytes, pDC)

Lymphatic vessels

Differential targeting of antigen-presenting cells dictates the immunological outcomes

(intensity, quality, localization)

Langerhans cells

Dermal DCLymph node

Micro- environments

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HAIR FOLLICLE TARGETING OF COMPOUNDS TO LANGERHANS CELLS

Stratum corneum

Hair fibre

Follicular cast

+ cyanoacrylate glue + follicular casts+ ca. 30% of stratum corneum

Vogt et al. J Invest Dermatology 2006 and Mahe J Invest Dermatology 2008

Stratum corneum

Epidermis

Dermis

Hypodermis

Lymphatic and blood capillary vessels

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SUITABLE SIZE OF VACCINE COMPOUNDS INTO FOLLICULAR DUCTS

5

37°C

Skin purified human CD1a+ cells (+40nm)

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

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Influenza-specific CD8

PROOF OF CONCEPT: PHASE I TRIAL OF AN INFLUENZA VACCINE

Influenza-specific CD4

Vogt et al. J Immunol 2008 and Combadiere et al Plos One 2010 TC routeIM route

Hair follicle Langerhans cells favors CD8 responses and also mucosal immunity but not IgG responses

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FROM HUMANIZED MICE TO CLINICAL TRIALS

“tailor-cut” immunization strategies could be proposed for infectious diseases: HIV, Malaria, Tuberculosis, emerging diseases and cancerEU-FP7 large-scale coordination : CUT’HIVAC project 2010-2014

Human skin Explants

Human immune cells

Immunodeficient mice

CLINICAL TRIALSPre-clinical modelsHumanized mice

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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