携带呼吸道合胞病毒(RSV)融合糖蛋白表位位点三个重复序列的冷适应流感疫苗可保护BALB/c小鼠和棉鼠免受RSV感染。
Cold-adapted influenza vaccine carrying three repeats of a respiratory syncytial virus (RSV) fusion glycoprotein epitope site protects BALB/c mice and cotton rats against RSV infection.
作者信息
Xu Yongru, Sun Fang, Chuai Zhengran, Wang Junyun, Bai Zhifang, Bian Chengrong, Wang Xiliang, Zhao Zhongpeng, Liu Yongzhuang, Yang Penghui
机构信息
The First Medical Center of Chinese PLA General Hospital, Faculty of Hepato-Pancreato-Biliary Surgery, Institute of Hepatobiliary Surgery of Chinese PLA, Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, 100853, China.
The First Medical Center of Chinese PLA General Hospital, Faculty of Hepato-Pancreato-Biliary Surgery, Institute of Hepatobiliary Surgery of Chinese PLA, Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, 100853, China; Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, 100039, China.
出版信息
Antiviral Res. 2024 Sep;229:105960. doi: 10.1016/j.antiviral.2024.105960. Epub 2024 Jul 8.
Respiratory syncytial virus is the major cause of respiratory viral infections, particularly in infants, immunocompromised populations, and the elderly (over 65 years old), the prevention of RSV infection has become a priority. In this study, we generated a chimeric influenza virus, termed LAIV/RSV/HA-3F, using reverse genetics technology which contained three repeats of the RSV fusion protein neutralizing epitope site II to the N terminal in the background of the hemagglutinin (HA) gene of cold adapted influenza vaccine A/California/7/2009 ca. LAIV/RSV/HA-3F exhibited cold-adapted (ca) and attenuated (att) phenotype. BALB/c mice immunized intranasally with LAIV/RSV/HA-3F showed robust immunogenicity, inducing viral-specific antibody responses against both influenza and RSV, eliciting RSV-specific humoral, cellular and mucosal immune responses. LAIV/RSV/HA-3F also conferred protection as indicated by reduced viral titers and improved lung histopathological alterations against live RSV virus challenge. Mechanismly, single-cell RNA sequencing (scRNA-seq) and single-cell T cell antigen receptor (TCR) sequencing were employed to characterize the immune responses triggered by chimeric RSV vaccine, displaying that LAIV/RSV/HA-3F provided protection mainly via interferon-γ (IFN-γ). Moreover, we found that LAIV/RSV/HA-3F significantly inhibited viral replication in the challenged lung and protected against subsequent RSV challenge in cotton rats without causing lung disease. Taken together, our findings demonstrated that LAIV/RSV/HA-3F has potential as a promising bivalent vaccine with dual purpose candidate for the prevention of influenza and RSV, and preclinical and clinical studies warrant further investigations.
呼吸道合胞病毒是呼吸道病毒感染的主要原因,尤其是在婴儿、免疫功能低下人群和老年人(65岁以上)中,预防呼吸道合胞病毒感染已成为当务之急。在本研究中,我们利用反向遗传学技术构建了一种嵌合流感病毒,称为LAIV/RSV/HA-3F,其在冷适应流感疫苗A/California/7/2009 ca的血凝素(HA)基因背景下,N端包含呼吸道合胞病毒融合蛋白中和表位位点II的三个重复序列。LAIV/RSV/HA-3F表现出冷适应(ca)和减毒(att)表型。用LAIV/RSV/HA-3F经鼻免疫BALB/c小鼠显示出强大的免疫原性,诱导针对流感和呼吸道合胞病毒的病毒特异性抗体反应,引发呼吸道合胞病毒特异性体液、细胞和黏膜免疫反应。LAIV/RSV/HA-3F还提供了保护作用,表现为病毒滴度降低以及针对活呼吸道合胞病毒攻击的肺组织病理学改变得到改善。机制上,采用单细胞RNA测序(scRNA-seq)和单细胞T细胞抗原受体(TCR)测序来表征嵌合呼吸道合胞病毒疫苗引发的免疫反应,显示LAIV/RSV/HA-3F主要通过干扰素-γ(IFN-γ)提供保护。此外,我们发现LAIV/RSV/HA-3F显著抑制攻击肺中的病毒复制,并在棉鼠中预防随后的呼吸道合胞病毒攻击而不引起肺部疾病。综上所述,我们的研究结果表明,LAIV/RSV/HA-3F作为一种有潜力的双价疫苗,具有预防流感和呼吸道合胞病毒的双重用途,临床前和临床研究值得进一步探讨。