title: Optimization of physiological properties of hydroxyapatite as a vaccine adjuvant.
abstract: Various particles such as Alum or silica are known to act as an adjuvant if co-administered with vaccine antigens. Several reports have demonstrated that the adjuvanticity is strongly affected by the physicochemical properties of particles such as the size, shape and surface charge, although the required properties and its relationship to the adjuvanticity are still controversial. Hydroxyapatite particle (HAp) composed of calcium phosphate has been shown to work as adjuvant in mice. However, the properties of HAp required for the adjuvanticity have not been fully characterized yet. In this study, we examined the role of size or shape of HAps in the antibody responses after immunization with antigen. HAps whose diameter ranging between 100 and 400 nm provided significantly higher antibody responses than smaller or larger ones. By comparison between sphere and rod shaped HAps, rod shaped HAps induced stronger inflammasome-dependent IL-1β production than the sphere shaped ones in vitro. However, sphere- and rod-shaped HAp elicited comparable antibody response in WT mice. Vice versa, Nlrp3(-/-), Asc(-/-) or Caspase1(-/-) mice provided comparable level of antibody responses to HAp adjuvanted vaccination. Collectively, our results demonstrated that the size rather than shape is a more critical property, and IL-1β production via NLRP3 inflammasome is dispensable for the adjuvanticity of HAps in mice.
authors.affiliation: Laboratory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (iFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Vaccine Research Development Office, Biology Research Laboratories, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Kanagawa, Japan. Electronic address: Hayashi.Masayuki@me.mt-pharma.co.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Laboratory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (iFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: aoshi@biken.osaka-u.ac.jp.
authors.forename: Taiki
authors.initials: T
authors.lastname: Aoshi
authors.affiliation: Technical Development Center, SofSera Corporation, 2-7-1 Ayumino, Izumi, Osaka 594-1157, Japan. Electronic address: kogai@sofsera.co.jp.
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Kogai
authors.affiliation: Technical Development Center, SofSera Corporation, 2-7-1 Ayumino, Izumi, Osaka 594-1157, Japan. Electronic address: nomi@sofsera.co.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nomi
authors.affiliation: Laboratory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (iFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: y-sedaha@biken.osaka-u.ac.jp.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Haseda
authors.affiliation: Laboratory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (iFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: kuroetu@ifrec.osaka-u.ac.jp.
authors.forename: Etsushi
authors.initials: E
authors.lastname: Kuroda
authors.affiliation: Laboratory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (iFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: kobi@lji.org.
authors.forename: Kouji
authors.initials: K
authors.lastname: Kobiyama
authors.affiliation: Laboratory of Adjuvant Innovation, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (iFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: kenishii@biken.osaka-u.ac.jp.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D055598:Chemical Phenomena; D017886:Durapatite / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage; D014612:Vaccines / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D014612:Vaccines; D017886:Durapatite
keywords: Adjuvant; Calcium phosphate; Hydroxyapatite; Particles; Size; Vaccine