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Cutaneous jet-injection of naked mRNA vaccine induces robust immune responses without systemic vaccine spillage

Saed Abbasi, Miki Matsui-Masai, Akimasa Hayashi, Theofilus A. Tockary, Shiro Akinaga, Kazunori Kataoka, View ORCID ProfileSatoshi Uchida
doi: https://doi.org/10.1101/2023.02.27.530188
Saed Abbasi
1Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan
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Miki Matsui-Masai
2Department of Research, NanoCarrier Co., Ltd., 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan
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Akimasa Hayashi
3Department of Pathology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan
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Theofilus A. Tockary
1Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan
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Shiro Akinaga
2Department of Research, NanoCarrier Co., Ltd., 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan
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Kazunori Kataoka
1Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan
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  • For correspondence: kkataoka@g.ecc.u-tokyo.ac.jp uchida.anme@tmd.ac.jp
Satoshi Uchida
1Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan
4Department of Advanced Nanomedical Engineering, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima Bunkyo-ku Tokyo 113-8510 Japan
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  • ORCID record for Satoshi Uchida
  • For correspondence: kkataoka@g.ecc.u-tokyo.ac.jp uchida.anme@tmd.ac.jp
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Abstract

Locally injected lipid nanoparticle (LNP)-based mRNA vaccines migrate systemically, which could raise safety concerns. From a mechanistic viewpoint, whether local or systemic antigen expression contributes to the vaccine effects remains unclear. Herein, we localized the antigen protein expression using naked mRNA and drastically improved the delivery efficiency in the skin by jet injection. Consequently, jet-injected naked mRNA outperformed a widely-used LNP in humoral immunity induction at the highest tolerable mRNA doses of each formulation in mice. A mechanistic investigation suggests that antigenpresenting cells taking up antigens at the jet-injection site of naked mRNA migrate to draining lymph nodes, enabling robust immunization without systemic mRNA distribution. Ultimately, jet injection of SARS-CoV-2 spike mRNA provided efficient antibody responses, neutralizing potential and cellular immunity in rodents and non-human primates with no reactogenicity. Conclusively, naked mRNA jet injection is a robust, tolerable, and simple vaccine candidate.

Competing Interest Statement

Sa.A., M.M., H.A., K.K., and S.U. have filed a patent application related to this study, and NanoCarrier Ltd. (M.M., Sh.A.) holds a right to the patent. K.K. is a founder and a member of the Board of NanoCarrier Ltd. M.M. is an employee of NanoCarrier Ltd. Sh.A. is a CEO and CSO of NanoCarrier Ltd.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 27, 2023.
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Cutaneous jet-injection of naked mRNA vaccine induces robust immune responses without systemic vaccine spillage
Saed Abbasi, Miki Matsui-Masai, Akimasa Hayashi, Theofilus A. Tockary, Shiro Akinaga, Kazunori Kataoka, Satoshi Uchida
bioRxiv 2023.02.27.530188; doi: https://doi.org/10.1101/2023.02.27.530188
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Cutaneous jet-injection of naked mRNA vaccine induces robust immune responses without systemic vaccine spillage
Saed Abbasi, Miki Matsui-Masai, Akimasa Hayashi, Theofilus A. Tockary, Shiro Akinaga, Kazunori Kataoka, Satoshi Uchida
bioRxiv 2023.02.27.530188; doi: https://doi.org/10.1101/2023.02.27.530188

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