title: System vaccinology for the evaluation of influenza vaccine safety by multiplex gene detection of novel biomarkers in a preclinical study and batch release test.
abstract: Vaccines are beneficial and universal tools to prevent infectious disease. Thus, safety of vaccines is strictly evaluated in the preclinical phase of trials and every vaccine batch must be tested by the National Control Laboratories according to the guidelines published by each country. Despite many vaccine production platforms and methods, animal testing for safety evaluation is unchanged thus far. We recently developed a systems biological approach to vaccine safety evaluation where identification of specific biomarkers in a rat pre-clinical study evaluated the safety of vaccines for pandemic H5N1 influenza including Irf7, Lgals9, Lgalsbp3, Cxcl11, Timp1, Tap2, Psmb9, Psme1, Tapbp, C2, Csf1, Mx2, Zbp1, Ifrd1, Trafd1, Cxcl9, β2m, Npc1, Ngfr and Ifi47. The current study evaluated whether these 20 biomarkers could evaluate the safety, batch-to-batch and manufacturer-to-manufacturer consistency of seasonal trivalent influenza vaccine using a multiplex gene detection system. When we evaluated the influenza HA vaccine (HAv) from four different manufactures, the biomarker analysis correlated to findings from conventional animal use tests, such as abnormal toxicity test. In addition, sensitivity of toxicity detection and differences in HAvs were higher and more accurate than with conventional methods. Despite a slight decrease in body weight caused by HAv from manufacturer B that was not statistically significant, our results suggest that HAv from manufacturer B is significantly different than the other HAvs tested with regard to Lgals3bp, Tapbp, Lgals9, Irf7 and C2 gene expression in rat lungs. Using the biomarkers confirmed in this study, we predicted batch-to-batch consistency and safety of influenza vaccines within 2 days compared with the conventional safety test, which takes longer. These biomarkers will facilitate the future development of new influenza vaccines and provide an opportunity to develop in vitro methods of evaluating batch-to-batch consistency and vaccine safety as an alternative to animal testing.
authors.affiliation: Laboratory of Blood and Vaccine safety, Department of Safety Research on Blood and Biologicals, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Mizukami
authors.affiliation: Laboratory of Blood and Vaccine safety, Department of Safety Research on Blood and Biologicals, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Momose
authors.affiliation: Laboratory of Blood and Vaccine safety, Department of Safety Research on Blood and Biologicals, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Kuramitsu
authors.affiliation: Laboratory of Blood and Vaccine safety, Department of Safety Research on Blood and Biologicals, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takizawa
authors.affiliation: Laboratory of Blood and Vaccine safety, Department of Safety Research on Blood and Biologicals, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Araki
authors.affiliation: Laboratory of Blood and Vaccine safety, Department of Safety Research on Blood and Biologicals, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Furuhata
authors.affiliation: Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation (NIBIO), Osaka, Japan; Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (WPI-IFREC), Osaka University, Osaka, Japan.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.affiliation: Laboratory of Blood and Vaccine safety, Department of Safety Research on Blood and Biologicals, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Hamaguchi
authors.affiliation: Laboratory of Blood and Vaccine safety, Department of Safety Research on Blood and Biologicals, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology; D007252:Influenza Vaccines / Q000009:adverse effects*; D008297:Male; D051381:Rats; D012449:Safety; D012621:Seasons; D018675:Toxicity Tests / Q000379:methods*; D059467:Transcriptome / Q000276:immunology*
chemical_list: D015415:Biomarkers; D007252:Influenza Vaccines