CEA CHRU

CNRS

CPU INRA

INRIA INSERM

INSTITUT PASTEUR

IRD

1CEA CHRU

CNRS

CPU INRA

INRIA INSERM

INSTITUT PASTEUR

IRD

Skin targeting for vaccine efficacy

Laboratory of « Immunity and Infection »INSERMParis, France

Behazine COMBADIERE, PhDDirector of research INSERM

CEA CHRU

CNRS

CPU INRA

INRIA INSERM

INSTITUT PASTEUR

IRD

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

CEA CHRU

CNRS

CPU INRA

INRIA INSERM

INSTITUT PASTEUR

IRD

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 DC

Lymph nodeMicro-

environments

Lymph nodeMicro-

environments

CEA CHRU

CNRS

CPU INRA

INRIA INSERM

INSTITUT PASTEUR

IRD

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

CEA CHRU

CNRS

CPU INRA

INRIA INSERM

INSTITUT PASTEUR

IRD

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

CEA CHRU

CNRS

CPU INRA

INRIA INSERM

INSTITUT PASTEUR

IRD

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 route

IM route

Hair follicle Langerhans cells favors CD8 responses

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

Human skin Explants

Human immune cells

Immunodeficient mice

CLINICAL TRIALSPre-clinical modelsHumanized 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