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

IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Antiviral research Pub Date : 2024-07-08 DOI:10.1016/j.antiviral.2024.105960
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Abstract

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.

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冷适应流感疫苗携带三个重复的呼吸道合胞病毒(RSV)融合糖蛋白表位位点,可保护 BALB/c 小鼠和棉鼠免受 RSV 感染。
呼吸道合胞病毒是呼吸道病毒感染的主要病因,尤其是在婴儿、免疫力低下人群和老年人(65 岁以上)中,预防 RSV 感染已成为当务之急。在这项研究中,我们利用反向遗传学技术生成了一种名为 LAIV/RSV/HA-3F 的嵌合型流感病毒,它在冷适应流感疫苗 A/California/7/2009 ca 的血凝素(HA)基因背景的 N 端含有三个重复的 RSV 融合蛋白中和表位点 II。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 小鼠显示出很强的免疫原性,可诱导针对流感和 RSV 的病毒特异性抗体反应,引起 RSV 特异性体液、细胞和粘膜免疫反应。LAIV/RSV/HA-3F还具有保护作用,这表现在病毒滴度降低和肺组织病理学改变改善,从而抵御活的RSV病毒挑战。从机制上讲,我们采用了单细胞RNA测序(scRNA-seq)和单细胞T细胞抗原受体(TCR)测序来描述嵌合型RSV疫苗引发的免疫反应,结果显示LAIV/RSV/HA-3F主要通过干扰素-γ(IFN-γ)提供保护。此外,我们还发现,LAIV/RSV/HA-3F 能显著抑制受挑战小鼠肺部的病毒复制,并能保护棉鼠免受随后的 RSV 挑战,而不会导致肺部疾病。总之,我们的研究结果表明,LAIV/RSV/HA-3F 有潜力成为一种具有双重用途的双价疫苗,用于预防流感和 RSV,临床前和临床研究值得进一步研究。
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来源期刊
Antiviral research
Antiviral research 医学-病毒学
CiteScore
17.10
自引率
3.90%
发文量
157
审稿时长
34 days
期刊介绍: Antiviral Research is a journal that focuses on various aspects of controlling viral infections in both humans and animals. It is a platform for publishing research reports, short communications, review articles, and commentaries. The journal covers a wide range of topics including antiviral drugs, antibodies, and host-response modifiers. These topics encompass their synthesis, in vitro and in vivo testing, as well as mechanisms of action. Additionally, the journal also publishes studies on the development of new or improved vaccines against viral infections in humans. It delves into assessing the safety of drugs and vaccines, tracking the evolution of drug or vaccine-resistant viruses, and developing effective countermeasures. Another area of interest includes the identification and validation of new drug targets. The journal further explores laboratory animal models of viral diseases, investigates the pathogenesis of viral diseases, and examines the mechanisms by which viruses avoid host immune responses.
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