title: A new adjuvanted nanoparticle-based H1N1 influenza vaccine induced antigen-specific local mucosal and systemic immune responses after administration into the lung.
abstract: Annually influenza virus infections are responsible for hospitalization and mortality, especially in high risk groups. Constant antigenic changes in seasonal influenza viruses resulted from antigenic shifts and antigenic drifts, enable emerging of novel virus subtypes that may reduce current vaccine efficacy and impose the continuous revision of vaccine component. Currently available vaccines are usually limited by their production processes in terms of rapid adaptation to new circulating subtypes in high quantities meeting the global demand. Thus, new approaches to rapidly manufacture high yields of influenza vaccines are required. New technologies to reach maximal protection with minimal vaccine doses also need to be developed. In this study, we evaluated the systemic and local immunogenicity of a new double-adjuvanted influenza vaccine administered at the site of infection, the respiratory tract. This vaccine combines a plant-produced H1N1 influenza hemagglutinin antigen (HAC1), a silica nanoparticle-based (SiO₂) drug delivery system and the mucosal adjuvant candidate bis-(3',5')-cyclic dimeric guanosine monophosphate (c-di-GMP). Mice were vaccinated by intratracheal route with HAC1/SiO₂ or HAC1/c-di-GMP (single-adjuvanted vaccine) or HAC1/SiO₂/c-di-GMP (double-adjuvanted vaccine) and evaluated for target-specific immune responses, such as hemagglutination inhibition and hemagglutinin-specific IgG titers, as well as local antibody (IgG and IgA) titers in the bronchoalveolar lavage (BAL). Furthermore, the HAC1-specific T-cell re-stimulation potential was assessed using precision-cut lung slices (PCLS) of vaccinated mice. The double-adjuvanted vaccine induced high systemic antibody responses comparable to the systemic vaccination control. In addition, it induced local IgG and IgA responses in the BAL. Furthermore, HAC1 induced a local T-cell response demonstrated by elevated IL-2 and IFN-γ levels in PCLS of c-di-GMP-vaccinated mice upon re-stimulation. Overall, the present study showed the potential of the double-adjuvanted vaccine to induce systemic humoral immune responses in intratracheally vaccinated mice. Furthermore, it induced a strong mucosal immune response, with evidence of antigen-primed T-cells in the lung.
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Nikolai-Fuchs-Straße 1, 30625 Hannover, Germany, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Centre for Lung Research (DZL).
authors.forename: Vanessa
authors.initials: V
authors.lastname: Neuhaus
authors.affiliation: Fraunhofer USA Center for Molecular Biotechnology, 9 Innovation Way, Newark, DE 19711, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Chichester
authors.affiliation: Helmholtz Centre for Infection Research, Department of Vaccinology and Applied Microbiology, Inhoffenstraße 7, 38124 Braunschweig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ebensen
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Nikolai-Fuchs-Straße 1, 30625 Hannover, Germany, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Centre for Lung Research (DZL).
authors.forename: Katharina
authors.initials: K
authors.lastname: Schwarz
authors.affiliation: Fraunhofer USA Center for Molecular Biotechnology, 9 Innovation Way, Newark, DE 19711, USA.
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Hartman
authors.affiliation: Fraunhofer USA Center for Molecular Biotechnology, 9 Innovation Way, Newark, DE 19711, USA.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shoji
authors.affiliation: Helmholtz Centre for Infection Research, Department of Vaccinology and Applied Microbiology, Inhoffenstraße 7, 38124 Braunschweig, Germany.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Guzmán
authors.affiliation: Fraunhofer USA Center for Molecular Biotechnology, 9 Innovation Way, Newark, DE 19711, USA.
authors.forename: Vidadi
authors.initials: V
authors.lastname: Yusibov
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Nikolai-Fuchs-Straße 1, 30625 Hannover, Germany, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Centre for Lung Research (DZL).
authors.forename: Katherina
authors.initials: K
authors.lastname: Sewald
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine, Nikolai-Fuchs-Straße 1, 30625 Hannover, Germany, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Centre for Lung Research (DZL); Institute of Immunology, Hannover Medical School, Hannover, Germany. Electronic address: armin.braun@item.fraunhofer.de.
authors.forename: Armin
authors.initials: A
authors.lastname: Braun
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000280:Administration, Inhalation; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D005260:Female; D006385:Hemagglutination Inhibition Tests; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype; D007252:Influenza Vaccines / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage*; D009976:Orthomyxoviridae Infections / Q000517:prevention & control*; D014611:Vaccination / Q000379:methods
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007252:Influenza Vaccines
keywords: HAC1; Influenza vaccine; Mucosal adjuvant; Plant-based; Silica nanoparticle; c-di-GMP