PT  - JOURNAL ARTICLE
AU  - Saed Abbasi
AU  - Miki Matsui-Masai
AU  - Akimasa Hayashi
AU  - Theofilus A. Tockary
AU  - Shiro Akinaga
AU  - Kazunori Kataoka
AU  - Satoshi Uchida
TI  - Cutaneous jet-injection of naked mRNA vaccine induces robust immune responses without systemic vaccine spillage
AID  - 10.1101/2023.02.27.530188
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.02.27.530188
4099  - http://biorxiv.org/content/early/2023/02/27/2023.02.27.530188.short
4100  - http://biorxiv.org/content/early/2023/02/27/2023.02.27.530188.full
AB  - 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 StatementSa.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.