Beatrice Bernocchi

Inserm

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Didier Betbeder

Lille Inflammation Research International Center

Rodolphe Carpentier

Lille Inflammation Research International Center

Isabelle Dimier‐Poisson

Université de Tours

Nils Lycke

University of Gothenburg

Peter Staeheli

University Medical Center Freiburg

Corinne Ducournau

Institut de Biologie Structurale

Ajibola Omokanye

European Centre for Disease Prevention and Control

Isabelle Lantier

Université de Tours

Minh Quan Lê

Lille Inflammation Research International Center

Valentina Bernasconi

Coalition for Epidemic Preparedness Innovations

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University of Gothenburg

Université de Tours

Infectiologie Animale et Santé Publique

Lille Inflammation Research International Center

Université de Lille

Inserm

Centre Hospitalier Universitaire de Lille

Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement

Institut National de la Recherche Agronomique

Institute for Biomedicine

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Mechanisms allowing protein delivery in nasal mucosa using NPL nanoparticles

Journal of Controlled Release (2016)

Beatrice Bernocchi Rodolphe Carpentier Isabelle Lantier Corinne Ducournau Isabelle Dimier‐Poisson

The intranasal administration of proteins using nanoparticles is a promising approach for several applications, especially for mucosal vaccines. Delivery of protein within the epithelial barrier is a key point to elicit an immune response and nano-carrier has to show no toxicity. The aim of this work was to elucidate the interactions of cationic porous nanoparticles loaded with protein delivery for antigen delivery in the nose. We investigated the loading, the cellular delivery and the epithelial transcytosis of proteins associated to these nanoparticles containing an anionic lipid in their core (NPL). NPL were highly endocytosed by airway epithelial cells and significantly improved the protein delivery into the cell. In vitro transcytosis studies showed that NPL did not modify the in vitro epithelial permeability suggesting no toxicity of these carriers. Moreover protein and NPL did not translocate the epithelial barrier. In vivo studies demonstrated that NPL prolonged the nasal residence time of the protein and no NPL were found beyond the epithelial barrier in vivo , precluding a negative side effect. All together these results establish the NPL as a bio-eliminable and optimal vaccine carrier. After nasal administration, NPL deliver antigens in airway epithelial cells without crossing the epithelial barrier.

Transcytosis

10.1016/j.jconrel.2016.04.014

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Porous Nanoparticles With Self-Adjuvanting M2e-Fusion Protein and Recombinant Hemagglutinin Provide Strong and Broadly Protective Immunity Against Influenza Virus Infections

Frontiers in Immunology (2018)

Valentina Bernasconi Beatrice Bernocchi Liang Ye Minh Quan Lê Ajibola Omokanye

Due to the high risk of an outbreak of pandemic influenza, the development of a broadly protective universal influenza vaccine is highly warranted. The design of such a vaccine has attracted attention and much focus has been given to nanoparticle-based influenza vaccines which can be administered intranasally. This is particularly interesting since, contrary to injectable vaccines, mucosal vaccines elicit local IgA and lung resident T cell immunity, which have been found to correlate with stronger protection in experimental models of influenza virus infections. Also, studies in human volunteers have indicated that pre-existing CD4+ T cells correlate well to increased resistance against infection. We have previously developed a fusion protein with 3 copies of the ectodomain of matrix protein 2 (M2e), which is one of the most explored conserved influenza A virus antigen for a broadly protective vaccine known today. To improve the protective ability of the self-adjuvanting fusion protein, CTA1-3M2e-DD, we incorporated it into porous maltodextrin nanoparticles (NPLs). This proof-of-principle study demonstrates that the combined vaccine vector given intranasally enhanced immune protection against a live challenge infection and reduced the risk of virus transmission between immunized and unimmunized individuals. Most importantly, immune responses to NPLs that also contained recombinant hemagglutinin (HA) were strongly enhanced in a CTA1-enzyme dependent manner and we achieved broadly protective immunity against a lethal infection with heterosubtypic influenza virus. Immune protection was mediated by enhanced levels of lung resident CD4+ T cells as well as anti-HA and -M2e serum IgG and local IgA antibodies.

10.3389/fimmu.2018.02060

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Porous maltodextrin nanoparticles for the intranasal delivery of vaccines

HAL (Le Centre pour la Communication Scientifique Directe) (2016)

Beatrice Bernocchi

Nanoparticles technology for mucosal delivery of vaccines received a growing interest in the last decades. Intranasal administration owns great advantages for immune system stimulation, such as local and systemic protection against infectious diseases. However delivery systems and adjuvants are often required to efficiently trigger mucosal and systemic immune responses. In this thesis, nanoparticles (NP) have been evaluated as delivery system for a nasal universal influenza vaccine in a People Program of the European Union Seventh Framework Program FP7 called UniVacFlu. The aim of the UniVacFlu network is to develop a universal influenza vaccine administered through the mucosal route. We used porous maltodextrin nanoparticles with a lipidic core (NPL). We loaded an adjuvanted antigen named CTA1-3M2e-DD in the NPL. CTA1-3M2e-DD is composed of the A1 subunit of the cholera toxin and a conserved epitope of influenza A virus (M2e), while DD, dimer of the synthetic analogue of the Staphyloccous aureus protein A, targets B cells. Interestingly the antigen loading in NPL was quantitative for the antigen: NPL 1:5 mass ratio and the formulation was stable for at least six months at 4°C. We assessed the successful delivery of the antigen by NPL in airway epithelial cells and macrophages. These formulations are currently evaluated by the UniVacFlu consortium in mice.One of the main issues of intranasal vaccines is the toxicity that can be elicited by the nose-brain passage of one of their components. We investigated the loading of antigens in NPL and their delivery in airway mucosa. We observed a high endocytosis of NPL and an increased protein delivery into the cells. On a transwell model of the airway mucosa we assessed the absence of transcytosis and paracellular passage of the NPL. In vivo results confirmed the lack of nose-brain passage of the NPL, as NPL were found not to cross the mucosa. Interestingly, we observed an increased nasal residence time of the protein targeted by NPL. The particles after having delivered their payload are totally eliminated through the gastrointestinal tract, making these nanoparticles good candidates for mucosal delivery system. These results highlight the interest of NPL as vectors for mucosal delivery of drugs.

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Nasal nanovaccines

International Journal of Pharmaceutics (2017)

Beatrice Bernocchi Rodolphe Carpentier Didier Betbeder

10.1016/j.ijpharm.2017.07.012

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Citations (74)