RNA疫苗平台在通用流感疫苗研发中的前沿进展

Frontier Advances in RNA Vaccine Platforms for the Research and Development of Universal Influenza Vaccines

摘要

流感病毒的全球持续流行，对公共卫生体系构成严峻挑战。现有季节性流感疫苗因毒株特异性强、保护期有限，难以从根本上应对抗原漂移、跨物种传播及大流行风险，研发广谱长效保护的通用流感疫苗已成为领域迫切需求。2026 年 8 月，美国食品药品监督管理局（Food and Drug Administration，FDA）批准全球首款信使 RNA （messenger RNA，mRNA）季节性流感疫苗 mRNA-1010 上市，标志着 mRNA 平台在流感领域正式进入商业化应用阶段，也为通用流感疫苗的转化奠定了工艺与监管基础。该平台的获批凸显了 mRNA 技术相较于传统疫苗的独特优势：在多价抗原递呈方面更具灵活性与便捷性，能够精准复现天然表位构象，并可同时激活体液与细胞免疫，这些优势共同为通用疫苗研发提供了全新的策略路径。然而，免疫持久性不足仍是当前 mRNA 疫苗面临的主要技术瓶颈之一。通过系统综述传统 mRNA 以及自复制 RNA （self-replicating RNA，saRNA）与环状 RNA （circular RNA，circRNA）两类长效型 RNA 平台在通用流感疫苗中的研究进展，归纳靶向基质蛋白 2 胞外区（matrix protein 2 ectodomain，M2e）、血凝素（hemagglutinin，HA）茎区、神经氨酸酶（neuraminidase，NA）、核蛋白（nucleoprotein，NP）等保守表位的抗原设计方案，总结递送系统优化、免疫原性增强与佐剂联用等技术策略，旨在为广谱通用流感疫苗的开发提供参考，并助力未来 RNA 疫苗推动流感免疫策略向更长效、更广谱的方向演进。

Abstract

The persistent global circulation of influenza viruses poses severe challenges to public health systems. Current seasonal influenza vaccines, characterized by strong strain specificity and limited duration of protection, cannot fundamentally address the risks of antigenic drift, cross-species transmission and pandemics. Consequently, developing universal influenza vaccines with broad-spectrum and long-lasting protection has become an urgent need in the field. In August 2026, the U.S. Food and Drug Administration (FDA) approved mRNA-1010, the first commercial messenger RNA (mRNA) seasonal influenza vaccine in the world. This milestone marks the official entry of the mRNA platform into commercial application in the influenza field and establishes a manufacturing and regulatory foundation for the clinical translation of universal influenza vaccines. The approval of this platform underscores the distinctive advantages of mRNA technology over conventional vaccines: it offers greater flexibility and convenience in multivalent antigen presentation, precise recapitulation of native epitope conformations, and simultaneous activation of humoral and cellular immunity. Together, these advantages provide a novel strategic pathway for universal vaccine research and development. However, insufficient immune persistence remains one of the primary technical bottlenecks for current mRNA vaccines. Addressing this bottleneck, this review systematically examines recent advances in applying conventional mRNA and two long-acting RNA platforms—self-replicating RNA (saRNA) and circular RNA (circRNA) — to universal influenza vaccines. It summarizes antigen design strategies targeting conserved epitopes, such as the matrix protein 2 ectodomain (M2e), hemagglutinin (HA) stem region, neuraminidase (NA), and nucleoprotein (NP). It further consolidates technical strategies such as delivery system optimization, immunogenicity enhancement, and adjuvant combination. Ultimately, this review offers practical insights for the development of broad-spectrum universal influenza vaccines and helps advance influenza immunization strategies toward greater durability and broader coverage through future RNA vaccines.

关键词

RNA 疫苗平台 / 通用流感疫苗 / 广谱保护 / 抗原设计

Key words

RNA vaccine platforms / universal influenza vaccines / broad-spectrum protection / antigen design

参考文献

[1] Iuliano A D, Roguski K M, Chang H H,et al. Estimates of global seasonal influenza-associated respiratory mortality: a modelling study[J].Lancet, 2018, 391(10127): 1285-1300.

[2] Dawood F S, Iuliano A D, Reed C,et al. Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study[J].Lancet Infect Dis, 2012, 12(9): 687-695.

[3] Russell C A, Fouchier R A M, Ghaswalla P,et al. Seasonal influenza vaccine performance and the potential benefits of mRNA vaccines[J].Hum Vaccin Immunother, 2024, 20(1): 2336357.

[4] Osterholm M T, Kelley N S, Sommer A,et al. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis[J].Lancet Infect Dis, 2012, 12(1): 36-44.

[5] Erbelding E J, Post D J, Stemmy E J,et al. A universal influenza vaccine: the strategic plan for the national institute of allergy and infectious diseases[J].J Infect Dis, 2018, 218(3): 347-354.

[6] World Health Organization. WHO preferred product characteristics for next generation influenza vaccines, second edition[R/OL].2025-12-04. https://www.who.int/publications/i/item/9789240114982.

[7] Sun X, Subbiah J, Belser J A,et al. Effect of seasonal influenza vaccines on avian influenza A(H5N1) clade 2.3.4.4b virus infection in ferrets[J].Emerg Infect Dis, 2025, 31(10): 1950-1960.

[8] Brüssow H. Avian influenza virus cross-infections as test case for pandemic preparedness: from epidemiological hazard models to sequence-based early viral warning systems[J].Microb Biotechnol, 2024, 17(1): e14389.

[9] Sah P, Alfaro-Murillo J A, Fitzpatrick M C,et al. Future epidemiological and economic impacts of universal influenza vaccines[J].Proc Natl Acad Sci USA, 2019, 116(41): 20786-20792.

[10] Pardi N, Hogan M J, Porter F W,et al. mRNA vaccines - a new era in vaccinology[J].Nat Rev Drug Discov, 2018, 17(4): 261-279.

[11] Fitz-Patrick D, McVinnie D S, Jackson L A,et al. Efficacy, immunogenicity, and safety of modified mRNA influenza vaccine[J].N Engl J Med, 2025, 393(20): 2001-2011.

[12] Bloom K, van den Berg F, Arbuthnot P. Self-amplifying RNA vaccines for infectious diseases[J].Gene Ther, 2021, 28: 117-129.

[13] CSL. European Commission approves CSL and Arcturus Therapeutics' KOSTAIVE^®, the first self-amplifying mRNA COVID-19 vaccine[EB/OL]. (2025-02-14)[2026-06-13].https://newsroom.csl.com/2025-02-14-European-Commission-Approves-CSL-and-Arcturus-Therapeutics-KOSTAIVE-R-,-the-First-Self-amplifying-mRNA-COVID-19-Vaccine.

[14] Enuka Y, Lauriola M, Feldman M E,et al. Circular RNAs are long-lived and display only minimal early alterations in response to a growth factor[J].Nucleic Acids Res, 2016, 44(3): 1370-1383.

[15] Lasda E, Parker R. Circular RNAs: diversity of form and function[J].RNA, 2014, 20(12): 1829-1842.

[16] Qu L, Yi Z, Shen Y,et al. Circular RNA vaccines against SARS-CoV-2 and emerging variants[J].Cell, 2022, 185(10): 1728-1744.e16.

[17] Wesselhoeft R A, Kowalski P S, Parker-Hale F C,et al. RNA circularization diminishes immunogenicity and can extend translation duration in vivo [J].Mol Cell, 2019, 74(3): 508-520.e4.

[18] Villanueva M T. Circular RNA vaccines expose cryptic peptides[J].Nat Rev Drug Discov, 2024, 23(2): 103.

[19] Chang C, Patel H, Ferrari A,et al. Sa-mRNA influenza vaccine raises a higher and more durable immune response than mRNA vaccine in preclinical models[J].Vaccine, 2025, 51: 126883.

[20] Sun Z, Liu Y, Zhang H,et al. A novel alphavirus-based saRNA platform for enhanced vaccination efficacy and organ-specific targeting[J].Vaccine, 2026, 72: 128055.

[21] Cui X, Vervaeke P, Gao Y,et al. Immunogenicity and biodistribution of lipid nanoparticle formulated self-amplifying mRNA vaccines against H5 avian influenza[J].NPJ Vaccines, 2024, 9(1): 138.

[22] Chang C, Music N, Cheung M,et al. Self-amplifying mRNA bicistronic influenza vaccines raise cross-reactive immune responses in mice and prevent infection in ferrets[J].Mol Ther Methods Clin Dev, 2022, 27: 195-205.

[23] Wan J, Wang C, Wang Z,et al. CXCL13 promotes broad immune responses induced by circular RNA vaccines[J].Proc Natl Acad Sci USA, 2024, 121(44): e2406434121.

[24] Yue X, Zhong C, Cao R,et al. CircRNA based multivalent neuraminidase vaccine induces broad protection against influenza viruses in mice[J].npj Vaccines, 2024, 9: 170.

[25] Zhang Y, Xu Y, Tang W,et al. Pulmonary delivery of small circular RNA vaccines for influenza prevention[J].J Control Release, 2025, 387: 114198.

[26] Neirynck S, Deroo T, Saelens X,et al. A universal influenza A vaccine based on the extracellular domain of the M2 protein [J].Nat Med, 1999, 5(10): 1157-1163.

[27] Grovenstein P, Bhatnagar N, Kim K H,et al. Influenza 5xM2e mRNA lipid nanoparticle vaccine confers broad immunity and significantly enhances the efficacy of inactivated split vaccination when coadministered[J].J Immunol, 2025, 214(1): 104-114.

[28] Nath Neerukonda S, Vassell R, Weiss C D. Neutralizing antibodies targeting the conserved stem region of influenza hemagglutinin[J].Vaccines, 2020, 8(3): 382.

[29] Arevalo C P, Bolton M J, Le Sage V,et al. A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes[J].Science, 2022, 378(6622): 899-904.

[30] Krammer F, Pica N, Hai R,et al. Chimeric hemagglutinin influenza virus vaccine constructs elicit broadly protective stalk-specific antibodies[J].J Virol, 2013, 87(12): 6542-6550.

[31] Chen Y Q, Wohlbold T J, Zheng N Y,et al. Influenza infection in humans induces broadly cross-reactive and protective neuraminidase-reactive antibodies[J].Cell, 2018, 173(2): 417-429.e10.

[32] Lv K, Li X, Zhu X,et al. Broad neuraminidase antibodies confer protection against seasonal and avian influenza viruses [J].Nat Commun, 2025, 16(1): 7103.

[33] Gote V, Bolla P K, Kommineni N,et al. A comprehensive review of mRNA vaccines[J].Int J Mol Sci, 2023, 24(3): 2700.

[34] Abramson J, Adler J, Dunger J,et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3[J].Nature, 2024, 630(8016): 493-500.

[35] Hayes T, Rao R, Akin H,et al. Simulating 500 million years of evolution with a language model[J].Science, 2025, 387(6736): 850-858.

[36] Wohlwend J, Nathan A, Shalon N,et al. Deep learning enhances the prediction of HLA class I-presented CD8⁺ T cell epitopes in foreign pathogens[J].Nat Mach Intell, 2025, 7(2): 232-243.

[37] Jumper J, Evans R, Pritzel A,et al. Highly accurate protein structure prediction with AlphaFold[J].Nature, 2021, 596(7873): 583-589.

[38] Liu D J, Zhong X Q, Ru Y X,et al. Disulfide-stabilized trimeric hemagglutinin ectodomains provide enhanced heterologous influenza protection[J].Emerg Microbes Infect, 2024, 13(1): 2389095.

[39] Liu X, Ji S, Cai Y,et al. Advances in mRNA-LNP lung-targeted delivery strategies[J].Microstructures, 2025, 5(4): 2025076.

[40] Styles T M, Akhtar A, Gu C,et al. Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in Rhesus macaques [J].Cell Rep Med, 2025, 6(10): 102369.

[41] Lokugamage M P, Vanover D, Beyersdorf J,et al. Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs[J].Nat Biomed Eng, 2021, 5(9): 1059-1068.

[42] Marecki E K, Oh K W, Knight P R,et al. Poly(lactic-co-glycolic acid) nanoparticle fabrication, functionalization, and biological considerations for drug delivery[J].Biomicrofluidics, 2024, 18(5): 051503.

[43] Herrmann I K, Wood M J A, Fuhrmann G. Extracellular vesicles as a next-generation drug delivery platform[J].Nat Nanotechnol, 2021, 16(7): 748-759.

[44] Goodfellow L, Procter S R, Koltai M,et al. The potential global health impact and cost-effectiveness of next-generation influenza vaccines: a modelling analysis[J].PLoS Med, 2025, 22(6): e1004655.

[45] Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics: developing a new class of drugs[J].Nat Rev Drug Discov, 2014, 13(10): 759-780.

[46] Wesselhoeft R A, Kowalski P S, Anderson D G. Engineering circular RNA for potent and stable translation in eukaryotic cells[J].Nat Commun, 2018, 9(1): 2629.

[47] Shen M, Jiang X, Peng Q,et al. The cGAS-STING pathway in cancer immunity: mechanisms, challenges, and therapeutic implications[J].J Hematol Oncol, 2025, 18(1): 40.

[48] Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition[J].Int Immunol, 2009, 21(4): 317-337.

[49] Kayesh M E H, Kohara M, Tsukiyama-Kohara K. TLR agonists as vaccine adjuvants in the prevention of viral infections: an overview[J].Front Microbiol, 2023, 14: 1249718.

[50] Shen Y, Huang W, Nie J,et al. Progress update on STING agonists as vaccine adjuvants[J].Vaccines, 2025, 13(4): 371.

[51] Moderna, Inc. Moderna receives U. S. FDA approval for influenza vaccine mFLUSIVA [EB/OL]. (2026-08-06) [2026-08-13].https://www.accessnewswire.com/newsroom/en/healthcare-and-pharmaceutical/moderna-receives-u.s.-fda-approval-for-influenza-vaccine-mflusiva-1201472.

[52] Leroux-Roels I, Huang G, Ferguson M,et al. Efficacy and safety of an mRNA seasonal influenza vaccine in adults[J].N Engl J Med, 2026, 394(18): 1803-1813.

[53] Soens M, Ananworanich J, Hicks B,et al. A phase 3 randomized safety and immunogenicity trial of mRNA-1010 seasonal influenza vaccine in adults[J].Vaccine, 2025, 50: 126847.

[54] Kaplonek P, Vargas R, Lee J S,et al. mRNA-1010 influenza vaccine elicits distinct and enhanced humoral immunity compared to adjuvanted inactivated vaccines[J].NPJ Vaccines, 2025, 11(1): 19.

[55] Arcturus Therapeutics. Arcturus Therapeutics announces second-quarter 2025 financial update and pipeline progress [EB/OL]. (2025-08-11)[2026-06-13].https://www.businesswire.com/news/home/20250811954049/en/Arcturus-Therapeutics-Announces-Second-Quarter-2025-Financial-Update-and-Pipeline-Progress.

[56] National Institute of Allergy and Infectious Diseases, National Institutes of Health. The Collaborative Influenza Vaccine Innovation Centers (CIVICs) Program[EB/OL]. [2026-06-13].https://www.niaidcivics.org/about-civics/.

[57] Kozma G T, Shimizu T, Ishida T,et al. Anti-PEG antibodies: properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals[J].Adv Drug Deliv Rev, 2020, 154: 163-175.

[58] 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.

基金资助

国家自然科学基金资助项目(82402135)