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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2018.02619

DAMP-inducing adjuvant and PAMP adjuvants parallelly enhance protective type-2 and type-1 immune responses to influenza split vaccination

 Ken J. Ishii1, 2*,  Hayashi Tomoya3,  Masatoshi Momota4,  Etsushi Kuroda2, 4, Takato Kusakabe4,  Michelle S. Lee2,  Cevayir Coban2,  Hidetoshi Arima3*, Shingo Kobari4, Kotaro Makisaka3, Yoshitaka Ohno3, Yusuke Suzuki3*, Fumika Nakagawa3, Risako Onodera3, Taishi Higashi3 and Keiichi Motoyama3
  • 1Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation, Japan
  • 2Immunology Frontier Research Center, Osaka University, Japan
  • 3Kumamoto University, Japan
  • 4National Institutes of Bimedical Innovation, Health and Nutrition, Japan

Recently, it was reported that 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD), a common pharmaceutical additive, can act as a vaccine adjuvant to enhance protective type-2 immunogenicity to co-administered seasonal influenza split vaccine by inducing host-derived damage-associated molecular patterns (DAMPs). However, like most other DAMP-inducing adjuvants such as aluminum hydroxide (Alum), HP-beta-CyD may not be sufficient for the induction of protective type-1 (cellular) immune responses, thereby leaving room for improvement. Here, we demonstrate that a combination of HP-beta-CyD with a humanized TLR9 agonist, K3 CpG-ODN, a potent pathogen-associated molecular pattern (PAMP), enhanced the protective efficacy of the co-administered influenza split vaccine by inducing antigen-specific type-2 and type-1 immune responses, respectively. Moreover, substantial antigen-specific IgE induction by HP-beta-CyD, which can cause an allergic response to immunized antigen was completely suppressed by the addition of K3 CpG-ODN. Furthermore, HP-beta-CyD- and K3 CpG-ODN-adjuvanted influenza split vaccination protected the mice against lethal challenge with high doses of heterologous influenza virus, which could not be protected against by single adjuvant vaccines. Further experiments using gene deficient mice revealed the unique immunological mechanism of action in vivo, where type-2 and type-1 immune responses enhanced by the combined adjuvants were dependent on TBK1 and TLR9, respectively, indicating their parallel signaling pathways. Finally, the analysis of immune responses in the draining lymph node suggested that HP-beta-CyD promotes the uptake of K3 CpG-ODN by plasmacytoid dendritic cells and B cells, which may contributes to the activation of these cells and enhanced production of IgG2c. Taken together, the results above may offer potential clinical applications for the combination of DAMP-inducing adjuvant and PAMP adjuvant to improve vaccine immunogenicity and efficacy by enhancing both type-2 and type-1 immune responses in a parallel manner.

Keywords: 2-Hydroxypropyl-beta-cyclodextrin, CpG ODN, adjuvant, influenza vaccine, DAMPs (damage-associated molecular patterns)

Received: 11 Aug 2018; Accepted: 24 Oct 2018.

Edited by:

Swapan K. Ghosh, Indiana State University, United States

Reviewed by:

Ji Wang, Harvard Medical School, United States
Randy A. Albrecht, Icahn School of Medicine at Mount Sinai, United States  

Copyright: © 2018 Ishii, Tomoya, Momota, Kuroda, Kusakabe, Lee, Coban, Arima, Kobari, Makisaka, Ohno, Suzuki, Nakagawa, Onodera, Higashi and Motoyama. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Ken J. Ishii, National Institute of Biomedical Innovation, Laboratory of Adjuvant Innovation, Osaka, 567-0085, Osaka, Japan, kenishii@biken.osaka-u.ac.jp
Prof. Hidetoshi Arima, Kumamoto University, Kumamoto, Kumamoto, Japan, arimah@gpo.kumamoto-u.ac.jp
Dr. Yusuke Suzuki, Kumamoto University, Kumamoto, Kumamoto, Japan, 154p2017@st.kumamoto-u.ac.jp