疫苗前沿 | 綜述：結構疫苗學助力流感與呼吸道合胞病毒新一代疫苗理性設計研發

Fig. 1.Design strategies for universal influenza vaccines.A Schematic diagram of influenza virus HA polypeptide and prefusion HA structure. The folded HA1 polypeptide mostly forms the head domain; a minor part forms the stalk domain with the HA2 polypeptide. FP denotes the fusion peptide. This full-length HA structure model is derived from the solved structure model with PDB ID 6HJR. B Design strategy for soluble HA trimeric protein with transmembrane and cytoplasmic domains removed (Liu, D.J. et al., 2024b). The interprotomer disulfide bonds are formed by cysteine residues on two separate protomers, which are shown in red and blue, respectively, in close-up stick model views. C Construction of head-swapped chimeric HA antigen and mosaic HA antigen designs. Head domains and spots therein in either navy blue or red colors denote peptide fragments derived from exotic avian influenza viruses. D Universal influenza vaccine antigens designed based on the HA stem domain. The structural design of HAssF features eight HA stem trimer antigens (blue) displayed on the self-assembling ferritin nanoparticle core (grey) (Yassine et al., 2015). In the structural diagram of the miniH1 stem trimer (Impagliazzo et al., 2015), the yellow-labeled α-helix at the apex corresponds to the exogenous GCN4 motif fragment.

在RSV疫苗研發領域，文章回顧了RSV免疫預防的曲折歷程與近年的突破性進展：早年福爾馬林滅活 RSV 疫苗（FI-RSV）因引發增強性呼吸疾病（ERD） 宣告失敗，核心原因是未保留關鍵保護性表位，并誘導失衡的 Th2 型免疫應答。結構研究證實，融合前 F 蛋白（pre-F） 是 RSV 疫苗核心抗原，其獨有的? 位點為最關鍵中和表位。基于此，研究人員通過二硫鍵固定、疏水填充、電荷中和、脯氨酸替換等策略，成功構建 DS-Cav1、SC-DM、DS2 等一系列穩定 pre-F 抗原；最新研發的無 foldon 標簽 pre-F去除外源性三聚化基序，更接近天然構象，可降低非特異性免疫干擾，在動物模型中表現出優異保護力。目前，多款 pre-F 疫苗獲批用于老年人群，nirsevimab 等長效單抗及孕婦疫苗用于嬰兒防護，RSV 進入全面免疫預防新階段。

Fig. 2.Schematic diagrams of RSV pre-F and post-F protein antigens and introduction to modification hotspots.A Schematic of the trimeric structure of pre-F protein and the localization and distribution of antigenic sites including ?, I, II, III, IV, and V. The key neutralizing antigenic site ? is mainly composed of the S62-N70 polypeptide fragment of F2 and the L196-K209 polypeptide fragment of F1. The presented pre-F protein structure model is built based the model with PDB ID: 5C6B. B Schematic representation of the post-F protein trimeric structure and the positional distribution of residues of each antigenic site after prominent structural rearrangement. The post-F counterpart is derived from the model with PDB ID: 3RRR. C A single F protein protomer (derived from the model with PDB ID: 5C6B) shows multiple critical mutation sites on the structure of stabilized recombinant F proteins and secondary structures emphasized during the modification process.

流感與 RSV 疫苗研發具有共同技術規律：以高分辨率結構為基礎，精準定位保守中和表位；通過二硫鍵、疏水填充、脯氨酸突變、電荷中和等通用策略穩定抗原構象；反向疫苗學 2.0整合免疫學、計算生物學、人工智能等技術，推動疫苗從天然抗原篩選轉向靶向免疫應答的定制化抗原設計。當前研究仍面臨流感疫苗保護廣度待驗證、RSV 疫苗在嬰幼兒中應用受限、人群免疫印記影響效果等挑戰。

綜上，文章系統梳理了流感與 RSV 新一代疫苗的研發突破，明確結構疫苗學在理性抗原設計中的核心作用，深化了對新一代疫苗設計原理與方法的認知。相關技術體系與設計理念不僅為流感、RSV 防控提供關鍵支撐，也為其他新發、再發傳染病疫苗研發提供了重要借鑒，推動疫苗研發進入更精準、高效、廣譜的新時代。

本文亮點

• 反向疫苗學 2.0（RV 2.0）支持精準表位設計，是靶向誘導中和抗體的關鍵途徑

• preF抗原設計可有效實現保護性免疫，并解決疫苗相關的增強性呼吸道疾病

• 強效的血凝素（HA）莖部靶向免疫，是推進通用流感疫苗理性設計的核心目標

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