An inoculation site-retained mRNA vaccine induces robust immune responses against SARS-CoV-2 variants
Lei Huang, Fanfan Zhao, Muye He, Yi Fang, Xiaoping Ma, Shuaiyao Lu, Entao Li, Hui Xiao, Hanfei Zhu, Xueli Wang, Siyuan Tang, Bo Yu, Jie Wang, Dong Zhao, Chao Wang, Hangwen Li, Yuwei Gao, Xiaozhong Peng, Haifa Shen
Abstract
mRNA-based vaccines and therapeutic agents hold great promise in prevention and treatment of human diseases, yet high percentage of systemic adverse effect in clinic remains a big safety concern. One major potential cause is a high level of leakage of the locally inoculated mRNA vaccine nanoparticles into circulation. We have screened and optimized a core-shell structured lipopolyplex (LPP) formulation for mRNA with a tissue-retention property. Upon intramuscular inoculation, the mRNA-encapsulated LPP nanoparticles were preferentially taken up by the phagocytic antigen-presentation cells, and potently promoted dendritic cell maturation. We applied the new formulation to prepare a prophylactic vaccine for SARS-CoV-2, and observed potent humoral and cellular immune responses from the vaccine in both murine models and non-human primates. More importantly, the vaccine demonstrated a benign safety profile in non-human primates, with limited side effects after repeated treatment with high dosages of LPP/mRNA. Taken together, the inoculation site-retained vaccine formulation serves as a promising vehicle for mRNA vaccines and therapeutic agents.