mRNA疫苗非临床安全性评价的关注点

Key points for nonclinical safety evaluation of mRNA vaccines

摘要

mRNA疫苗已经成为治疗多种疾病的最有前景的平台,包括传染病、癌症、遗传性疾病和自身免疫性疾病。本文重点综述了mRNA疫苗发展现状、存在的挑战、非临床评价相关指导原则、非临床安全性评价的关注点,重点探讨非临床研究需关注概念验证、给药途径、种属选择和毒性特点(如炎症反应、肝脾毒性和免疫反应),以期为未来研究提供重要参考。

Abstract

mRNA therapeutics have emerged as a promising platform in treating a wide range of diseases, including cancers, infections, genetic disorders, and autoimmune diseases. This article reviews the current development status of mRNA vaccines, existing challenges, relevant guidelines for nonclinical evaluation, and key focuses of nonclinical safety evaluation. Nonclinical research should focus on proof of concept, administration routes, species selection, and toxicity characteristics (such as inflammatory responses, hepatosplenic toxicity, and immune responses). This article systematically summarizes the research progress and safety evaluation strategies of mRNA vaccines, providing important references for future studies.

关键词

mRNA疫苗 / 非临床安全性评价 / 脂质纳米颗粒 / 免疫毒性 / 炎症反应 / 肝脾毒性

Key words

mRNA vaccine / non-clinical safety evaluation / lipid nanoparticles / immunotoxicity / inflammatory response / liver and spleen toxicity

[1] PARDI N, HOGAN MJ, PORTER FW, et al. mRNA vaccines: a new era in vaccinology[J]. Nat Rev Drug Discov, 2018, 17(4): 261-279.
[2] BADEN LR, EL SAHLY HM, ESSINK B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine[J]. N Engl J Med, 2021, 384(5): 403-416.
[3] ARUNACHALAM PS, SCOTT MKD, HAGAN T, et al. Systems vaccinology of the BNT162b2 mRNA vaccine in humans[J]. Nature, 2021, 596(7872): 410-416.
[4] VISHWESHWARAIAH YL, DOKHOLYAN NV. mRNA vaccines for cancer immunotherapy[J]. Front Immunol, 2022, 13: 1029069.
[5] PASCOLO S. Vaccination with messenger RNA (mRNA)[J]. Handb Exp Pharmacol, 2008(183): 221-235.
[6] REICHMUTH AM, OBERLI MA, JAKLENEC A, et al. mRNA vaccine delivery using lipid nanoparticles[J]. Ther Deliv, 2016, 7(5): 319-334.
[7] MILANE L, AMIJI M. Clinical approval of nanotechnology-based SARS-CoV-2 mRNA vaccines: impact on translational nanomedicine[J]. Drug Deliv Transl Res, 2021, 11(4): 1309-1315.
[8] WEBER JS, CARLITO MS, KHATTAK A, et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study[J]. Lancet, 2024, 403(10427): 632-644.
[9] MULRONEY TE, PÖYRY T, YAM-PUC JC, et al. N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting[J]. Nature, 2024, 625(7993): 189-194.
[10] SHIMABUKURO TT, COLE M, SU JR. Reports of anaphylaxis after receipt of mRNA COVID-19 vaccines in the US-December 14, 2020-January 18, 2021[J]. JAMA, 2021, 325(11): 1101-1102.
[11] IGYÁRTÓ BZ, QIN Z. The mRNA-LNP vaccines-the good, the bad and the ugly?[J]. Front Immunol, 2024, 15: 1336906.
[12] World Health Organization. Guidelines on nonclinical evaluation of vaccines[EB/OL].(2005-01-01)[2025-11-04].https://www.who.int/publications/m/item/nonclinical-evaluation-of-vaccines-annex-1-trs-no-927.
[13] The International Council for Harmonisation of Technical Requir ements for Pharmaceuticals for Human Use. Prelinical Safety Evaluation of Biotechnology derived Pharmaceuticals S6 (R1)[S]. 2011-06-11.
[14] The International Council for Harmonisation of Technical Require ments for Pharmaceuticals for Human Use. Detection of reproductive and developmental toxicity for human pharmaceuticals S5 (R3)[S]. 2020-02-18.
[15] 国家药品监督管理局药品审评中心. 《预防用疫苗临床前研究技术指导原则》[EB/OL].(2010-04-22)[2025-11-04].https://www.cde.org.cn/zdyz/domesticinfopage?zdyzIdCODE=46fd86e0b9cf56da7a61fa3068 894fca.
[16] FDA. Guidance for industry: Development and licensure of vaccines to prevent COVID-19[EB/OL].(2023-10)[2025-11-04].https://www.fda.gov/regulatory-information/search-fda-guidance-documents/development-and-licensure-vaccines-prevent-covid-19.
[17] WANG YH, ZHANG L, XU ZH, et al. mRNA vaccine with antigen-specific checkpoint blockade induces an enhanced immune response against established melanoma[J]. Mol Ther, 2018, 26(2): 420-434.
[18] CHOI Y, LEE S, KIM K, et al. Studying cancer immunotherapy using patient-derived xenografts (PDXs) in humanized mice[J]. Exp Mol Med, 2018, 50(8): 1-9.
[19] DO ASS, AMANO T, EDWARDS LA, et al. CD133 mRNA-loaded dendritic cell vaccination abrogates glioma stem cell propagation in humanized glioblastoma mouse model[J]. Mol Ther Oncolytics, 2020, 18: 295-303.
[20] EMA. EMA Public Assessment-Report of COVID-19 Vaccine Moderna[EB/OL].(2021-02)[2025-11-04].https://www.ema.europa.eu/en/documents/assessment-report/comirnaty-epar-public-assessment-report_en.pdf.
[21] FDA. Public Assessment Report Authorisation for Temporary Supply COVID-19 mRNA vaccine BNT162[EB/OL].(2023-10)[2025-11-04].https://www.fda.gov/vaccines-blood-biologics/comirnaty.
[22] NDEUPEN S, QIN Z, JACOBSEN S, et al. The mRNA-LNP platform's lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory[J]. iScience, 2021, 24(12): 103479.
[23] BITOUNIS D, JACQUINET E, ROGERS MA, et al. Strategies to reduce the risks of mRNA drug and vaccine toxicity[J]. Nat Rev Drug Discov, 2024, 23(4): 281-300.
[24] TEO SP. Review of COVID-19 mRNA vaccines: BNT162b2 and mRNA-1273[J]. J Pharm Pract, 2022, 35(6): 947-951.
[25] 梁春苏, 左玮, 都丽萍, 等. mRNA-LNP新冠疫苗过敏反应及其体内药代动力学[J]. 药学学报, 2023, 58(4): 867-874.
[26] PARHIZ H, BRENNER JS, PATEL PN, et al. Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE)[J]. J Control Release, 2022, 344: 50-61.
[27] HAMMEL M, FAN YC, SARODE A, et al. Correlating the structure and gene silencing activity of oligonucleotide-loaded lipid nanoparticles using small-angle X-ray scattering[J]. ACS Nano, 2023, 17(12): 11454-11465.
[28] CÁRDENAS M, CAMPBELL RA, YANEZ ARTETA M, et al. Review of structural design guiding the development of lipid nanoparticles for nucleic acid delivery[J]. Curr Opin Colloid Interface Sci, 2023, 66: 101705.
[29] SEDIC M, SENN JJ, LYNN A, et al. Safety evaluation of lipid nanoparticle-formulated modified mRNA in the sprague-dawley rat and Cynomolgus monkey[J]. Vet Pathol, 2018, 55(2): 341-354.
[30] NOVAKOWSKI S, JIANG K, PRAKASH G, et al. Delivery of mRNA to platelets using lipid nanoparticles[J]. Sci Rep, 2019, 9(1): 552.
[31] TENCHOV R, SASSO JM, ZHOU QA. PEGylated lipid nanoparticle formulations: immunological safety and efficiency perspective[J]. Bioconjug Chem, 2023, 34(6): 941-960.
[32] DOBROVOLSKAIA MA. Lessons learned from immunological characterization of nanomaterials at the Nanotechnology Characterization Laboratory[J]. Front Immunol, 2022, 13: 984252.
[33] 孙婷, 吴琦, 朱嘉亮, 等. mRNA-LNP递送系统免疫激活机制的研究进展[J]. 中国现代应用药学, 2026, 43(3): 508-521.
[34] 赵欣, 马岩松, 杨丹, 等. 人用狂犬病疫苗研发药学研究思考[J]. 中国新药杂志, 2025, 34(6): 650-655.
[35] 娄经虎, 吴智能, 程艺, 等. 流感血凝素mRNA脂质纳米颗粒疫苗诱导呼吸道黏膜免疫[J]. 中国医药导刊, 2026, 28(5): 536-547.

基金资助

长三角区域药品领域创新与高质量发展监管科学研究资助项目(24692122700)