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Volume 41 Issue 2
April 2026

    . doi: 10.1016/j.virs.2026.04.004
    Citation: Xianmiao Ye, Junnan Lu, Zirong Han, Zhishan Fan, Xinru Hu, Lichuang Jiao, Lisha Deng, Wenming Liu, Junqi Liu, Weiqi Pan, Ling Chen, Liqiang Feng, Caijun Sun. A semi-replicating VSV (srVSV)-based platform for developing broad-spectrum mucosal vaccines against influenza A viruses .VIROLOGICA SINICA, 2026, 41(2) : 423-438.  http://dx.doi.org/10.1016/j.virs.2026.04.004
    shu

    一种基于半复制型水疱性口炎病毒（srVSV）的甲型流感病毒广谱黏膜疫苗研究

    • a 中山大学公共卫生学院(深圳);

    • b 中山大学深圳校区, 深圳市病原微生物与生物安全重点实验室;

    • c 中国科学院广州生物医药与健康研究院, 中国-新西兰生物医学与健康联合实验室;

    • d 广州医科大学附属市八医院;

    • e 广州医科大学-中国科学院广州生物医药与健康研究院联合生命科学学院, 呼吸疾病国家重点实验室;

    • f 热带病防治研究教育部重点实验室(中山大学);

    • g中国科学院大学;

    • h 呼吸疾病国家重点实验室, 广州呼吸健康研究院, 广州医科大学附属第一医院;

    • i广州实验室

    • 甲型流感病毒（IAV）是重要的呼吸道病原体，具有突变率高和基因重配频繁等特征。因此，亟需开发能诱导强大且广泛保护的广谱黏膜疫苗。具有复制能力的水疱性口炎病毒（VSV）载体可有效诱导黏膜免疫，但其神经毒性带来了显著的安全隐患。本研究构建了一种半复制型VSV（semi-replicating VSV, srVSV）载体，由缺失糖蛋白（G）基因的VSV（rVSVΔG）和缺失L基因的VSV（rVSVΔL）组成，安全性更高。利用srVSV载体，研究构建了表达IAV神经氨酸酶1（N1）的单价疫苗（srVSV-N1）。单次鼻内接种srVSV-N1疫苗可激发N1特异性的系统性免疫和黏膜免疫，并对同源流感病毒感染提供完全保护。此外，研究还进一步构建了同时表达N1和N2的双价疫苗（srVSV-N1/N2）。单次鼻内接种srVSV-N1/N2可对异源IAV（H1N1和H3N2）提供80%的保护。值得注意的是，采用低剂量初免-高剂量加强的srVSV-N1/N2免疫方案，可使小鼠完全抵御致死剂量异源流感病毒攻击。这些结果提示srVSV可为开发针对IAV及其他呼吸道病毒的黏膜疫苗提供新型递送平台。

    A semi-replicating VSV (srVSV)-based platform for developing broad-spectrum mucosal vaccines against influenza A viruses

    • a. School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China;

    • b. Shenzhen Key Laboratory of Pathogen Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China;

    • c. China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;

    • d. Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou 510440, China;

    • e. GMU-GIBH Joint School of Life Sciences, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;

    • f. Key Laboratory of Tropical Disease Control, (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China;

    • g. University of Chinese Academy of Sciences, Beijing 100049, China;

    • h. State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510180, China;

    • i. Guangzhou National Laboratory, Guangzhou 510005, China

    • Influenza A viruses (IAVs) are significant respiratory pathogens characterized by high mutation rates and frequent genetic reassortments, underscoring the need for vaccines that can induce robust and broadly protective mucosal immunity. While replication-competent vesicular stomatitis virus (VSV) vectors have the potential to elicit mucosal immunity, their neurovirulence raises significant safety concerns. Herein, we report that a semi-replicating VSV (srVSV) vector, composed of one VSV with the glycoprotein (G) gene deleted (rVSVΔG) and another with the L gene deleted (rVSVΔL), has improved safety. Using srVSV, we constructed a monovalent vaccine (srVSV-N1), expressing the neuraminidase 1 (N1) of IAV. A single intranasal dose of srVSV-N1 elicited both systemic and mucosal immune responses against N1, and provided sterilizing immunity against homologous influenza virus. We further generated a bivalent IAV vaccine (srVSV-N1/N2), co-expressing N1 and N2. A single intranasal dose of srVSV-N1/N2 conferred 80% protection against heterologous IAVs (H1N1 and H3N2). Notably, low-dose priming immunization followed by a high-dose boost with srVSV-N1/N2 fully protected mice against lethal heterologous IAV challenges. These findings demonstrate the potential of the srVSV platform for developing mucosal vaccines against IAVs and other respiratory viruses.
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      A semi-replicating VSV (srVSV)-based platform for developing broad-spectrum mucosal vaccines against influenza A viruses

        Corresponding author: Junnan Lu, lu_junnan1@gibh.ac.cn
        Corresponding author: Liqiang Feng, feng_liqiang@gibh.ac.cn
        Corresponding author: Caijun Sun, suncaijun@mail.sysu.edu.cn
      • a. School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China;
      • b. Shenzhen Key Laboratory of Pathogen Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China;
      • c. China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;
      • d. Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou 510440, China;
      • e. GMU-GIBH Joint School of Life Sciences, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;
      • f. Key Laboratory of Tropical Disease Control, (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China;
      • g. University of Chinese Academy of Sciences, Beijing 100049, China;
      • h. State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510180, China;
      • i. Guangzhou National Laboratory, Guangzhou 510005, China
      • Received Date: 10 November 2025
      • Accepted Date: 07 April 2026

      Abstract: Influenza A viruses (IAVs) are significant respiratory pathogens characterized by high mutation rates and frequent genetic reassortments, underscoring the need for vaccines that can induce robust and broadly protective mucosal immunity. While replication-competent vesicular stomatitis virus (VSV) vectors have the potential to elicit mucosal immunity, their neurovirulence raises significant safety concerns. Herein, we report that a semi-replicating VSV (srVSV) vector, composed of one VSV with the glycoprotein (G) gene deleted (rVSVΔG) and another with the L gene deleted (rVSVΔL), has improved safety. Using srVSV, we constructed a monovalent vaccine (srVSV-N1), expressing the neuraminidase 1 (N1) of IAV. A single intranasal dose of srVSV-N1 elicited both systemic and mucosal immune responses against N1, and provided sterilizing immunity against homologous influenza virus. We further generated a bivalent IAV vaccine (srVSV-N1/N2), co-expressing N1 and N2. A single intranasal dose of srVSV-N1/N2 conferred 80% protection against heterologous IAVs (H1N1 and H3N2). Notably, low-dose priming immunization followed by a high-dose boost with srVSV-N1/N2 fully protected mice against lethal heterologous IAV challenges. These findings demonstrate the potential of the srVSV platform for developing mucosal vaccines against IAVs and other respiratory viruses.

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