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Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines

Nature Materials volume 9, pages 572–578 (2010)Cite this article

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An Erratum to this article was published on 01 August 2010

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Abstract

Nanotechnology is an innovative method of freely controlling nanometre-sized materials1. Recent outbreaks of mucosal infectious diseases have increased the demands for development of mucosal vaccines because they induce both systemic and mucosal antigen-specific immune responses2. Here we developed an intranasal vaccine-delivery system with a nanometre-sized hydrogel (‘nanogel’) consisting of a cationic type of cholesteryl-group-bearing pullulan (cCHP). A non-toxic subunit fragment of Clostridium botulinum type-A neurotoxin BoHc/A administered intranasally with cCHP nanogel (cCHP–BoHc/A) continuously adhered to the nasal epithelium and was effectively taken up by mucosal dendritic cells after its release from the cCHP nanogel. Vigorous botulinum-neurotoxin-A-neutralizing serum IgG and secretory IgA antibody responses were induced without co-administration of mucosal adjuvant. Importantly, intranasally administered cCHP–BoHc/A did not accumulate in the olfactory bulbs or brain. Moreover, intranasally immunized tetanus toxoid with cCHP nanogel induced strong tetanus-toxoid-specific systemic and mucosal immune responses. These results indicate that cCHP nanogel can be used as a universal protein-based antigen-delivery vehicle for adjuvant-free intranasal vaccination.

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Figure 1: Use of cCHP nanogel as a new antigen-delivery vehicle for intranasal vaccination.
Figure 2: Efficiency of BoHc/A with cCHP nanogel.
Figure 3: Chaperone-like activity of cCHP nanogel facilitates effective delivery of vaccine antigen into the nasal mucosa.
Figure 4: Antigen delivered to dendritic cells by cCHP nanogel stimulates the nasal immune system but does not accumulate in the CNS.

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  • 02 July 2010

    On the first page of the PDF and printed versions of this Letter originally published, the full list of authors and their affiliations should have been included. This has been corrected in the PDF version of this Letter.

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Acknowledgements

We thank J. Victor Garcia of The University of North Carolina for editing the manuscript and K. Kubota of the Institute of Medical Science, The University of Tokyo, for his technical support of the radioisotope study. We also thank A. Watanabe and K. Matsuzaki of Mercian Corporation for culturing the E. coli for preparation of BoHc/A. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Ministry of Health and Labour of Japan (H.K., K.A., Y.Y.); the Global Center of Excellence Program ‘Center of Education and Research for Advanced Genome-Based Medicine—For Personalized Medicine and the Control of Worldwide Infectious Diseases’ (H.K.); a Research Fellowship of the Japan Society for the Promotion of Science (T.N.); the Research and Development Program for New Bio-industry Initiatives of the Bio-oriented Technology Research Advancement Institution (Y.Y.); and the Global Center of Excellence Program, ‘International Research Center for Molecular Science in Tooth and Bone Diseases’ (K.A., Ha.T.).

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Author notes

  1. Tomonori Nochi

    Present address: Present address: Division of Infectious Diseases, Center for AIDS Research, University of North Carolina, Chapel Hill, North Carolina 27599, USA,

  2. Tomonori Nochi and Yoshikazu Yuki: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan

    Tomonori Nochi, Yoshikazu Yuki, Mio Mejima, Il Gyu Kong, Ayuko Sato, Nobuhiro Kataoka, Daisuke Tokuhara, Shiho Kurokawa, Yuko Takahashi & Hiroshi Kiyono

  2. Department of Organic Materials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan

    Haruko Takahashi, Shin-ichi Sawada & Kazunari Akiyoshi

  3. Department of Veterinary Science, Laboratory of Veterinary Epidemiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka 599-8531, Japan

    Tomoko Kohda & Shunji Kozaki

  4. PET Center, Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka 434-8601, Japan

    Norihiro Harada & Hideo Tsukada

Authors
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Contributions

T.N. and Y.Y. designed and carried out the experiments, analysed the results and wrote the manuscript. Hi.T., S. Kozaki, K.A. and H.K. designed the experiments and wrote the manuscript. Ha.T., S-i.S., M.M., T.K., N.H., N.K., I.G.K., A.S., D.T., S. Kurokawa and Y.T. carried out the experiments.

Corresponding authors

Correspondence to Yoshikazu Yuki or Hiroshi Kiyono.

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The authors declare no competing financial interests.

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Nochi, T., Yuki, Y., Takahashi, H. et al. Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines. Nature Mater 9, 572–578 (2010). https://doi.org/10.1038/nmat2784

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