对世界卫生组织预防传染病mRNA疫苗非临床评价技术要点的解析

Analysis of Key Technical Points for Nonclinical Evaluation of the World Health Organization's Messenger RNA Vaccines for the Prevention of Infectious Diseases

目的:了解WHO最新发布的《预防传染病mRNA疫苗质量、安全及有效性评价法规考虑》中关于mRNA疫苗非临床评价的主要内容,为我国评价此类产品非临床研究提供参考。方法:分析mRNA疫苗的主要特点,对照《预防传染病mRNA疫苗质量、安全及有效性评价法规考虑》,梳理mRNA疫苗非临床研究特别是药效学和毒理学研究设计、实施和分析的关键要点。结果与结论:mRNA技术已成为疫苗研发的前沿技术,作为新型生物制品,mRNA疫苗具有诸多不同于传统生物制品的特点。WHO认为非临床研究的设计、实施和分析应充分考虑mRNA产品的技术特点,相关药效学和毒理学研究应着重解决免疫应答的持久性或持久性免疫细胞表型、Ⅰ型干扰素介导的固有免疫应答、mRNA和LNPs的生物分布和持久性、全身和局部的毒性和炎症反应、非自然修饰核苷的潜在毒性、脂质纳米颗粒中新型脂质的毒性等方面问题,并提出了在公共卫生突发事件背景下针对优先病原体的mRNA疫苗非临床加速评价的考虑要点,对我国非临床评价此类产品具有很好的指导作用和应用价值。

Objective:To understand the main contents of nonclinical evaluation of mRNA vaccines in the latest WHO guidance on Regulatory Considerations for Evaluation of the Quality,Safety and Effi cacy of Messenger RNA Vaccines for the Prevention of Infectious Diseases,and provide references for nonclinical evaluation of such products in China.Methods:The main characteristics of mRNA vaccines were analyzed,and key points on design,conduct and analysis of nonclinical studies,especially studies related to the pharmacology and toxicology of mRNA vaccines,were summarized based on the Regulatory Considerations for Evaluation of the Quality,Safety and Effi cacy of Messenger RNA Vaccines for the Prevention of Infectious Diseases.Results and Conclusion:mRNA technology has become the leading technology in vaccine research and development.As a new biological product,mRNA vaccines have many characteristics diff erent from traditional biological products.According to WHO guidance,the technical characteristics of mRNA products should be fully considered in the design,implementation and analysis of nonclinical studies.Some issues such as durability of immune responses or persistent immune cell phenotypes,intrinsic immune responses mediated by type I interferon,biodistribution and persistence of mRNA and LNPs,systemic and local toxicity and infl ammatory responses,potential toxicity from unnatural nucleoside modifi cations and novel lipids in LNPs should be addressed in the studies related to pharmacology and toxicology.The key points for accelerating nonclinical evaluation of mRNA vaccines against priority pathogens in the context of public health emergency were proposed.They have good guiding roles and application values for nonclinical evaluation of such products in China.