# Immunological mechanism of muscle-localizing self-replicating RNA vaccines

> **NIH NIH R01** · HDT BIO CORPORATION · 2024 · $1,074,519

## Abstract

PROJECT SUMMARY/ABSTRACT
As evident in the ongoing “tripledemic” of severe acute respiratory syndrome-Coronavirus-2, Respiratory
Syncytial virus, and Influenza virus, as well as re-emergence of enterovirus D68, virus infection is an important
health threat and a huge economic burden. Multivalent RNA vaccination is an effective measure for counteracting
virus infections and cancerous threats. However, multivalent vaccines need to inject relatively larger doses of
RNA than monovalent vaccines, which can trigger a potent innate immune response in vivo, causing reduced
transgene expression and unwanted reactogenicity. We have recently found that high dose RNA vaccination can
be safely achieved in mice by delivering self-amplifying replicon RNA (repRNA) with a family of muscle-localizing
cationic nanocarriers, LIONTM. In vivo delivery of repRNA by LION restricted the formulation to the muscle and
local lymph nodes without inducing unwanted systemic cytokine responses. Systemic blockade of type I IFN
signaling increased transgene expression and the subsequent antibody and T cell responses. Notably, we also
found that CD11b+ cells [mostly monocyte dendritic cells (DC)] expand over time after intramuscular injection of
repRNA/LION. However, the role of the muscle-infiltrating cells in immunogenicity is unknown. Consequently,
many questions remain about how repRNA/LION vaccines induce adaptive immune responses and how
transgene expression and adaptive immune responses are inhibited by the type I IFN system. So, Aim 1 looks
at skeletal muscle DC (SMDC) and characterizes their immunological function both in vitro and in vivo. Aim 2
focuses on type I IFN signaling and seeks to identify how type I IFN signaling limits transgene expression and
adaptive immune responses to repRNA vaccines. Aim 3 spotlights the inflammatory responses to muscle
damage and their role in inducing adaptive immune responses to repRNA/LION vaccines. The proposed studies
will test the following hypotheses that (1) the muscle plays a critical role in eliciting the immune response to
intramuscular-based RNA vaccines, and (2) muscle-restricted activation of the immune system is a novel
strategy for RNA vaccines to achieve high efficacy with reduced reactogenicity.

## Key facts

- **NIH application ID:** 10781834
- **Project number:** 1R01AI180195-01
- **Recipient organization:** HDT BIO CORPORATION
- **Principal Investigator:** Taishi Kimura
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,074,519
- **Award type:** 1
- **Project period:** 2024-09-13 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10781834

## Citation

> US National Institutes of Health, RePORTER application 10781834, Immunological mechanism of muscle-localizing self-replicating RNA vaccines (1R01AI180195-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10781834. Licensed CC0.

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