title: A novel vaccinological evaluation of intranasal vaccine and adjuvant safety for preclinical tests.
abstract: Vaccines are administered to healthy humans, including infants, so the safety and efficacy must be very high. Therefore, evaluating vaccine safety in preclinical and clinical studies, according to World Health Organization guidelines, is crucial for vaccine development and clinical use. A change in the route of administration is considered to alter a vaccine's immunogenicity. Several adjuvants have also been developed and approved for use in vaccines. However, the addition of adjuvants to vaccines may cause unwanted immune responses, including facial nerve paralysis and narcolepsy. Therefore, a more accurate and comprehensive strategy must be used to develope next-generation vaccines for ensuring vaccine safety. Previously, we have developed a system with which to evaluate vaccine safety in rats using a systematic vaccinological approach and 20 marker genes. In this study, we developed a safety evaluation system for nasally administered influenza vaccines and adjuvanted influenza vaccines using these marker genes. Expression of these genes increased dose-dependent manner when mice were intranasally administered the toxicity reference vaccine. When the adjuvant CpG K3 or a CpG-K3-combined influenza vaccine was administered intranasally, marker gene expression increased in a CpG-K3-dose-dependent way. A histopathological analysis indicated that marker gene expression correlated with vaccine- or adjuvant-induced phenotypic changes in the lung and nasal mucosa. We believe that the marker genes expression analyses will be useful in preclinical testing, adjuvant development, and selecting the appropriate dose of adjuvant in nasal administration vaccines.
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, 4-7-1 Gakuen, Musashi-Murayama, Tokyo 208-0011, Japan.
authors.forename: Eita
authors.initials: E
authors.lastname: Sasaki
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, 4-7-1 Gakuen, Musashi-Murayama, Tokyo 208-0011, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Kuramitsu
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, 4-7-1 Gakuen, Musashi-Murayama, Tokyo 208-0011, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Momose
authors.affiliation: Laboratory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Kouji
authors.initials: K
authors.lastname: Kobiyama
authors.affiliation: Laboratory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; Vaccine Dynamics Project, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka 565-0871, Japan.
authors.forename: Taiki
authors.initials: T
authors.lastname: Aoshi
authors.affiliation: Toxicogenomics Informatics Project, National Institutes of Biomedical, Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Laboratory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; Laboratory of Vaccine Science, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, 4-7-1 Gakuen, Musashi-Murayama, Tokyo 208-0011, Japan. Electronic address: tmiz@nih.go.jp.
authors.forename: Takuo
authors.initials: T
authors.lastname: Mizukami
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Disease, 4-7-1 Gakuen, Musashi-Murayama, Tokyo 208-0011, Japan. Electronic address: 130hama@nih.go.jp.
authors.forename: Isao
authors.initials: I
authors.lastname: Hamaguchi
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000281:Administration, Intranasal; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis*; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004353:Drug Evaluation, Preclinical; D005260:Female; D015870:Gene Expression; D006801:Humans; D007252:Influenza Vaccines / Q000008:administration & dosage*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015164:Vaccines, Inactivated
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D015415:Biomarkers; C408982:CPG-oligonucleotide; D016207:Cytokines; D007252:Influenza Vaccines; D026901:Membrane Transport Proteins; D009838:Oligodeoxyribonucleotides; D015164:Vaccines, Inactivated
keywords: Adjuvant; Influenza vaccine; Marker gene; Nasal vaccine; Safety test