Polyethylene glycol (PEG)-associated immune responses triggered by clinically relevant lipid nanoparticles in rats

Haiyang Wang; Yisha Wang; Changzheng Yuan; Xiao Xu; Wenbin Zhou; Yuhui Huang; Huan Lu; Yue Zheng; Gan Luo; Jia Shang; Meihua Sui

doi:10.1038/s41541-023-00766-z

Polyethylene glycol (PEG)-associated immune responses triggered by clinically relevant lipid nanoparticles in rats

NPJ Vaccines. 2023 Nov 2;8(1):169. doi: 10.1038/s41541-023-00766-z.

Authors

Haiyang Wang^#^{1

2}, Yisha Wang^#^{1

2}, Changzheng Yuan^#³, Xiao Xu⁴, Wenbin Zhou^{1

2}, Yuhui Huang³, Huan Lu^{1

2}, Yue Zheng^{1

2}, Gan Luo^{1

2}, Jia Shang⁴, Meihua Sui^{5

6}

Affiliations

¹ School of Basic Medical Sciences and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Cancer Center, Zhejiang University, Hangzhou, China.
³ School of Public Health, Zhejiang University School of Medicine, Hangzhou, China.
⁴ Zhejiang University School of Medicine, Hangzhou, 310006, China.
⁵ School of Basic Medical Sciences and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China. suim@zju.edu.cn.
⁶ Cancer Center, Zhejiang University, Hangzhou, China. suim@zju.edu.cn.

^# Contributed equally.

Abstract

With the large-scale vaccination of lipid nanoparticles (LNP)-based COVID-19 mRNA vaccines, elucidating the potential polyethylene glycol (PEG)-associated immune responses triggered by clinically relevant LNP has become imminent. However, inconsistent findings were observed across very limited population-based studies. Herein we initiated a study using LNP carrier of Comirnaty^® as a representative, and simulated real-world clinical practice covering a series of time points and various doses correlated with approved LNP-delivered drugs in a rat model. We demonstrated the time- and dose-dependency of LNP-induced anti-PEG antibodies in rats. As a thymus-independent antigen, LNP unexpectedly induced isotype switch and immune memory, leading to rapid enhancement and longer lasting time of anti-PEG IgM and IgG upon re-injection in rats. Importantly, initial LNP injection accelerated the blood clearance of subsequent dosing in rats. These findings refine our understandings on LNP and possibly other PEG derivatives, and may promote optimization of related premarket guidelines and clinical protocols.