【CODEX翻譯】新型冠狀病毒預防用mRNA疫苗藥學研究

技術指導原則（試行）-英文版

新型冠狀病毒預防用mRNA疫苗藥學研究技術指導原則（試行）

Technical Guidelines for Pharmaceutical Research on Preventive mRNA Vaccine against 2019 Novel Coronavirus (Trial)

一、前言

二、模板設計、轉錄模板質粒構建和菌種庫研究資料

（一）目標抗原選擇和DNA模板設計

（二）轉錄模板質粒的構建和制備

（三）種子庫的建立和檢定

三、生產工藝

（一）一般要求

（二）mRNA原液生產

（三）制劑處方及生產工藝

四、質量特性研究

（一）mRNA的結構分析和理化性質分析

（二）納米顆粒的結構分析和理化性質分析

（三）雜質分析

（四）生物學活性研究

五、質量標準

（一）DNA轉錄模板

（二）mRNA原液

（三）制劑中間產物

（四）成品

（五）方法學研究和方法學驗證

（六）標準品

六、穩定性研究

七、直接接觸制品的包裝材料和容器的來源、選擇依據及質量標準等研究

八、應急狀態下藥學研發的階段性考慮與研發期間的變更

（一）種子庫

（二）生產工藝

（三）質量特性研究

（四）質量標準

（五）臨床申報階段應提供能夠支持臨床試驗開展的穩定性研究數據

（六）研發期間的工藝變更

九、名詞解釋

十、參考文獻

I. Introduction

II. Template Design, Transcription Template Plasmid Construction and Strain Bank Research Data

(I) Target antigen selection and DNA template design

(II) Construction and preparation of transcription template plasmid

(III) Establishment and verification of seed bank

III Production Process

(I) General requirements

(II) Production of mRNA drug substance

(III) Drug substance prescription and production process

IV. Research on quality characteristics

(I) Analysis of the structure and physicochemical properties of mRNA

(II) Analysis of the structure and physicochemical properties of nanoparticles

(III) Impurity analysis

(IV) Research on biological activity

V. Quality standard

(I) DNA transcription template

(II) mRNA drug substance

(III) Drug product intermediates

(IV) Finished Product

(V) Methodological research and methodological verification

(VI) Standard products

VI. Stability Research

VII. Research on the source, selection basis and quality standards of packaging materials and containers that directly contact products

VIII. Phased Considerations of Pharmaceutical Research and Development under Emergency Conditions and Changes during Research and Development

(I) Seed bank

(II) Production process

(III) Research on quality characteristics

(IV) Quality standard

(V) Stability research data that can support the development of clinical trials shall be provided in the clinical application stage

(VI) Process changes during research and development

IX. Terminology

X. References

一、前言

I. Introduction

      mRNA疫苗是將外源目的基因序列通過轉錄、合成等工藝制備的mRNA通過特定的遞送系統導入機體細胞并表達目的蛋白、刺激機體產生特異性免疫學反應，從而使機體獲得免疫保護的一種核酸制劑。

mRNA疫苗具有以下特點：（1）能導入細胞，在體內表達相應的抗原蛋白，避免了體外蛋白表達、純化過程；（2）能夠刺激免疫系統產生體液免疫和/或細胞免疫應答，發揮相應的免疫預防和/或免疫治療作用；（3）其遞送系統具有類似佐劑的部分特性，能夠通過刺激機體免疫系統產生多種細胞因子等方式增強機體免疫反應能力或改變免疫應答類型；（4）由于mRNA的降解是通過細胞正常代謝完成，降低了因感染或整合誘發基因突變的潛在風險。

mRNA vaccine is a kind of nucleic acid preparation, which introduces mRNA prepared from the foreign target gene sequence through transcription, synthesis and other processes into the body's cells through a specific delivery system, expresses the target protein, and stimulates the body to produce a specific immunological response, thereby enabling the body to obtain immune protection.

      盡管mRNA疫苗在巨細胞病毒(CMV)、流感病毒、埃博拉病毒和寨卡病毒等多種傳染病臨床研究中取得了一定的研究進展，但尚存在待確證的諸多問題，如，mRNA本身具有的潛在免疫原性；遞送系統（如，脂質納米顆粒）的穩定性、納米劑型安全性及所使用陽離子聚合物/脂質體安全性、遞送靶向性及遞送效力等諸多問題，影響疫苗的有效性、安全性和質量可控性。

The mRNA vaccine has the following characteristics: (1) It can be introduced into cells to express the corresponding antigen protein in vivo, avoiding the process of protein expression and purification in vitro; (2) It can stimulate the immune system to produce humoral and/or cellular immune response, and play the corresponding role of immune prevention and/or immunotherapy; (3) Its delivery system has some characteristics similar to adjuvants, which can enhance the immune response ability or change the type of immune response by stimulating the immune system of the body to produce a variety of cytokines; (4) Since the degradation of mRNA is accomplished through normal cell metabolism, the potential risk of gene mutation induced by infection or integration is reduced.

      mRNA疫苗通常需采用較為復雜的制劑系統，其藥學研發和生產控制涉及諸多特殊考慮，包括：（1）mRNA序列的分子設計對mRNA穩定性、目的抗原的表達效率、免疫原性均可能產生影響，如加帽結構的選擇、非翻譯區序列的選擇及序列的改構、目的序列的優化、核苷酸的化學修飾等方面；（2）制劑組成、結構和工藝具有特殊性，主要特點是涉及陽離子聚合物或脂質材料、遞送系統的結構多樣性及納米級粒徑特性、工藝復雜性等，需要通過研究確認主要的考察指標來進行制劑處方組成和工藝的優化以及控制策略的建立；（3）同時可能涉及新免疫調節組分表達及新輔料的使用，必要時，需要單獨的安全性研究支持。

Although mRNA vaccine has made some progress in clinical research of many infectious diseases, such as cytomegalovirus (CMV), influenza virus, Ebola virus and Zika virus, there are still many problems to be confirmed, such as the potential immunogenicity of mRNA itself; many issues such as the stability of the delivery system (e.g., lipid nanoparticles), the safety of the nano dosage form, the safety of the cationic polymer/liposome used, the delivery targeting and the delivery effectiveness, etc., affect the effectiveness, safety and quality controllability of the vaccine.

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