基于融合前F蛋白呼吸道合胞病毒疫苗的研究进展

呼吸道合胞病毒(respiratory syncytial virus, RSV)是引起婴幼儿和老年人下呼吸道感染(lower respiratory tract infection, LRTI)的主要原因,尚无可用于预防的疫苗。目前,WHO已将研发RSV疫苗确定为其疫苗研发和生物标准化倡议的优先事项之一。RSV融合蛋白(fusion protein, F)是病毒表面的主要保护性抗原,主要介导病毒包膜和靶细胞膜的融合。在感染过程中,F蛋白从亚稳态的融合前F蛋白(prefusion fusion protein, PreF)转变为稳定的融合后F蛋白(postfusion fusion protein, PostF)。近年来,研究发现PreF在体内诱导产生RSV中和抗体能力更强,适合作为免疫原用于RSV疫苗的研发。现就RSV PreF的结构、稳定策略及其作为疫苗候选抗原的应用作一概述。     

呼吸道合胞病毒载体疫苗研究进展

人呼吸道合胞病毒(human respiratory syncytial virus, RSV)是引起婴幼儿下呼吸道感染的最重要的病毒病原,RSV载体疫苗可在人细胞内从头合成,形成的蛋白质构象与RSV自然感染后表达的完全相同,不会导致抗原表位的丧失或变化,形成的免疫力更利于抵抗随后的自然感染;经黏膜途径免疫不会产生疾病增强作用,且能突破母传抗体的干扰,因而受到广泛关注。对近年来RSV载体疫苗的研究进展进行了综述。     

基于融合蛋白的呼吸道合胞病毒疫苗的研究进展

呼吸道合胞病毒(respiratory syncytial virus,RSV)是一种引起严重下呼吸道感染的病原体,易感人群为婴幼儿、老年人及免疫功能低下者。目前尚无有效的抗病毒药物和预防疫苗。RSV融合蛋白(fusion protein,F蛋白)具有高度保守性,其诱导的抗体可同时抑制A型和B型两个亚型的RSV感染。因此,以F蛋白作为靶抗原的RSV亚单位疫苗、颗粒样疫苗和病毒载体疫苗是目前研究的主要策略。现就基于F蛋白的RSV疫苗研究进展作一综述。     

呼吸道合胞病毒疫苗研究进展

呼吸道合胞病毒(RSV)是引起严重下呼吸道感染的重要病原体,尽管经历了半个多世纪的努力,至今仍未有安全有效的RSV疫苗上市。近年来在RSV F蛋白结构生物学方面的研究进展为新一代RSV疫苗的开发提供了新方向,同时更多的采用不同技术、或针对不同人群的RSV侯选疫苗也在迅速发展,尤其是针对婴幼儿及老年人的RSV侯选苗已有60多种在研究中,大部分已处于临床前研究阶段,18种侯选苗已进入临床试验。我们简要介绍RSV疫苗的最新研究进展。     

人呼吸道合胞病毒活疫苗研究进展

人呼吸道合胞病毒是引起婴幼儿支气管炎和肺炎的主要原因,也可导致免疫缺陷病人及老年人群显著发病和死亡.人呼吸道合胞病毒疫苗已被世界卫生组织(World Health Organization,WHO)列为全球最优先发展的疫苗之一.经过50多年的研究,尤其是随着重组技术和反向遗传学的出现,对RSV疫苗的研究取得了重要进展,...     

呼吸道合胞病毒疫苗研究进展

呼吸道合胞病毒(RSV)是引起婴幼儿支气管炎和肺炎的主要原因,并可致免疫缺陷病人显著发病和死亡,RSV疫苗已被WHO列为全球最优先发展的疫苗之一。经过几十年的研究,虽然取得了显著进展,但尚未有RSV疫苗上市。目前RSV疫苗的研究主要集中于亚单位疫苗、减毒活疫苗和DNA疫苗等,其中亚单位疫苗和减毒活疫苗被认为最有前途,已分别进行了的临床试验。     

呼吸道合胞病毒非结构蛋白NS1、NS2的研究进展

呼吸道合胞病毒(reespiratory syncytial virus,RSV)是引起婴幼儿和老年人下呼吸道感染的重要病原体之一.由于该病毒的致病机理还不太清楚导致目前尚无有效治疗RSV的方法.研究表明,呼吸道合胞病毒的非结构蛋白NS1、NS2具有抗细胞凋亡的作用,同时可以逃避宿主免疫系统(IFN)对病毒的干扰,有利于病毒复制.敲除这两种基因的减毒活疫苗和袁达沉默NS1的小干扰RNA(siRNA)的质粒研究已经取得了一定的进展.对非结构蛋白功能的深入研究有助于了解RSV的致病机理,同时为预防和治疗RSV感染奠定理论基础.     

人呼吸道合胞病毒亚单位疫苗的研究进展

呼吸道合胞病毒(RSV)是在世界范围内引起婴幼儿下呼吸道感染的重要病毒之一,WHO要求对RSV要严加监控。RSV是副粘病毒科肺炎病毒属的单股负链非节段性RNA病毒。RSV疫苗的研制已有40多年的历史,但至今未被批准使用其疫苗。RSV膜表面融合蛋白F和黏附蛋白G两种糖蛋白,是激发机体产生保护性抗体的最主要的病毒抗原,亚单位疫苗的开发主要针对这两个蛋白。目前研究的有纯化的F糖蛋白(PFP)、BBG2Na、嵌合型F-G糖蛋白及纯化的F、G和基质蛋白M。本文就目前国内外所研究的RSV亚单位疫苗作一综述。     

呼吸道合胞病毒mRNA疫苗的研究进展

呼吸道合胞病毒(respiratory syncytial virus, RSV)是引起急性呼吸道感染的主要病原体之一,给婴幼儿和老年人带来了沉重的疾病负担。自福尔马林灭活呼吸道合胞病毒疫苗(FI-RSV)失败以来,RSV疫苗研究进展缓慢。但近年随着对RSV F蛋白(fusion protein, F)结构研究的不断深入,RSV的候选疫苗取得了快速进展,RSV的候选疫苗种类也逐渐增多,包括RSV mRNA疫苗、重组载体疫苗、亚单位疫苗、病毒样颗粒疫苗、减毒活疫苗和嵌合疫苗等。其中,RSV mRNA疫苗具有成本低、免疫原性强、生产工艺简单、研发周期短、安全性高和易于标准化生产等特点,适合应对新发传染性疾病的防控。现就RSV疫苗的研究现状、RSV mRNA疫苗发展历程及临床研究进展作一概述。     

抗呼吸道合胞病毒的免疫预防

呼吸道合胞病毒(RSV)感染是一个影响婴幼儿健康的全球性的问题,目前尚未有令人满意的治疗药物,免疫预防就显得尤为重要。近年研究表明,免疫预防在疫苗、单克隆抗体以及免疫球蛋白等领域均取得较大进展。     

Screening of phage-displayed peptide libraries with a monoclonal antibody raised against the F protein of the bovine respiratory syncytial virus

Summary Most of the monoclonal antibodies (MAbs) raised against the fusion (F) protein of the bovine respiratory syncytial virus recognize discontinuous epitopes on the protein. In order to find mimotopes of these epitopes, phage-displayed peptide libraries were screened with MAbs. The results obtained with MAb AL11C2 are described here. After four or five pannings, colony immunoscreening with AL11C2 allowed the isolation of positive clones that are specific for this monoclonal antibody. Four different sequences were determined on isolated phages, three of which are cysteine-constrained peptides in fusion with PVIII and one is a hexapeptide in fusion with PIII. In the case of the peptides containing two cysteines, the binding to AL11C2 was shown to be dependent on the presence of a disulfide bridge. The recombinant phages were also shown to inhibit the binding of AL11C2 to its natural antigen in a competitive ELISA assay.     

Immunogenicity of recombinant measles vaccine expressing fusion protein of respiratory syncytial virus in cynomolgus monkeys

Respiratory syncytial virus (RSV) is a common cause of respiratory infections in infants. Effective vaccines are currently being sought, but no vaccine is thus far available. In our previous study, recombinant AIK‐C measles vaccine expressing the RSV fusion protein (MVAIK/RSV/F) was developed and protective immunity against RSV demonstrated in cotton rats. In the present study, the immunogenicity and protective effects were investigated in three cynomolgus monkeys immunized with MVAIK/RSV/F. Neutralizing test antibodies against RSV were detected and no infectious virus was recovered from the lungs of monkeys immunized with MVAIK/RSV/F after challenge. MVAIK/RSV/F has the potential to inhibit RSV infection.

     

Development of mRNA vaccines against respiratory syncytial virus (RSV)

Respiratory syncytial virus (RSV) is a single-stranded negative-sense RNA virus that is the primary etiologic pathogen of bronchitis and pneumonia in infants and the elderly. Currently, no preventative vaccine has been approved for RSV infection. However, advances in the characterization, and structural resolution, of the RSV surface fusion glycoprotein have revolutionized RSV vaccine development by providing a new target for preventive interventions. In general, six different approaches have been adopted in the development of preventative RSV therapeutics, namely, particle-based vaccines, vector-based vaccines, live-attenuated or chimeric vaccines, subunit vaccines, mRNA vaccines, and monoclonal antibodies. Among these preventive interventions, MVA-BN-RSV, RSVpreF3, RSVpreF, Ad26. RSV.preF, nirsevimab, clesrovimab and mRNA-1345 is being tested in phase 3 clinical trials, and displays the most promising in infant or elderly populations. Accompanied by the huge success of mRNA vaccines in COVID-19, mRNA vaccines have been rapidly developed, with many having entered clinical studies, in which they have demonstrated encouraging results and acceptable safety profiles. In fact, Moderna has received FDA approval, granting fast-track designation for an investigational single-dose mRNA-1345 vaccine against RSV in adults over 60 years of age. Hence, mRNA vaccines may represent a new, more successful, chapter in the continued battle to develop effective preventative measures against RSV. This review discusses the structure, life cycle, and brief history of RSV, while also presenting the current advancements in RSV preventatives, with a focus on the latest progress in RSV mRNA vaccine development. Finally, future prospects for this field are presented.     

呼吸道合胞病毒疫苗增强性疾病小鼠模型的建立与评价

呼吸道合胞病毒(respiratory syncytial virus,RSV)是导致婴幼儿严重下呼吸道感染的最重要病原体,但该病毒的灭活疫苗可引起RSV疫苗增强性疾病(RSV vaccine-enhanced disease,RVED),因此至今仍未研制出安全、有效的疫苗。RVED的发生机制目前仍不清楚。使用能有效模拟RVED的动物模型是探索RVED发生机制的主要手段,而本研究的目的就是建立能稳定模拟RVED表现的小鼠模型。将BALB/c小鼠分成3组,即甲醛灭活RSV疫苗接种组(FV组)、活RSV接种组(VV组)和对照组(BV组),并模拟自然感染对其攻毒。通过小鼠体重监测、肺组织苏木精-伊红染色、荧光定量聚合酶链反应(polymerase chain reaction,PCR)、流式细胞术等,观察FV组小鼠感染RSV后的病毒载量、肺部炎症和T细胞免疫状态。结果显示,与VV组和BV组相比,FV组小鼠RSV攻毒后的体重占初始体重百分比显著降低,肺部炎症最明显,且仅FV组出现支气管和毛细血管周围有大量淋巴细胞浸润及嗜酸性粒细胞浸润。荧光定量PCR显示,FV组小鼠的肺部RSV载量最低。流式细胞术显示,攻毒4d后FV组CD~(4+) T细胞数与其他两组相比显著增加,且CD~(4+) T细胞分泌的白细胞介素4(interleukin 4,IL-4)及IL-4/γ干扰素(interferonγ,IFN-γ)比值显著高于其他两组,而CD~(8+) T细胞分泌的肿瘤坏死因子α(tumor necrosis factorα,TNF-α)和IFN-γ低于VV组。结果提示,RVED小鼠呈现出Th2优势型免疫应答及CD~(8+) T细胞功能不足,模型初步建立成功,为RVED发生机制的探索和RSV疫苗的研发奠定了良好基础。     

The preventive effect of vaccine prophylaxis on severe respiratory syncytial virus infection:A meta-analysis

Respiratory syncytial virus(RSV) is the key underlying cause of acute lower respiratory tract infection in infants; however, no licensed vaccine against RSV infection is currently available. This study was undertaken to assess the preventive effect of vaccine on RSV infection. In this metaanalysis, 1,792 published randomized clinical trials of RSV vaccines from Jan 1973 to Sep 2015 were examined. Among thirteen studies that met the inclusion criteria, eleven studies estimated the impact of RSV vaccines and four studies estimated the effect of adjuvants. The odds ratios(ORs) were 0.31(95% CI, 0.15–0.67) and 0.62(95% CI, 0.29–1.34), respectively. We found that RSV subunit vaccines can significantly reduce the incidence of RSV infection and that whether vaccination with adjuvant therapy was an effective strategy still remained to be studied. This analysis of the preventive effect of vaccines on RSV infection has direct applications for the prevention of RSV infections.     

Discovery of a potent respiratory syncytial virus RNA polymerase inhibitor

Targeting viral polymerases has been a proven and attractive strategy for antiviral drug discovery. Herein we describe our effort in improving the antiviral activity and physical properties of a series of benzothienoazepine compounds as respiratory syncytial virus (RSV) RNA polymerase inhibitors. The antiviral activity and spectrum of this class was significantly improved by exploring the amino substitution of the pyridine ring, resulting in the discovery of the most potent RSV A polymerase inhibitors reported to date.     

呼吸道合胞病毒F蛋白抗体的研究进展

呼吸道合胞病毒(respiratory syncytial virus,RSV)感染,是造成婴幼儿、学龄前儿童、免疫缺陷患者、老年人等高危群体住院治疗及死亡的重要病因。目前,多个预防RSV感染的候选疫苗正处于研发中,尚无安全、有效的疫苗面世。对RSV感染的处理仍以治疗为主,使用帕利珠单抗(Palivizumab)是当前仅有的预防药物。在过去数年间出现的新型抗体药物,如多克隆抗体、单克隆抗体、纳米抗体等有些已进入了临床前或I、II、III期临床试验阶段。融合蛋白(fusion protein,F蛋白)在RSV感染过程中是不可或缺的,它介导病毒包膜与宿主细胞膜的融合。在感染过程中,F蛋白从亚稳态的融合前构象状态(prefusion fusion protein,pre F)转变为热力学稳定的融合后状态(postfusion fusionprotein,post F)。近年来,研究人员通过不断筛选,获得了多株针对pre F的抗体。与结合post F的抗体相比,这些抗体具有更强的RSV中和活性。一些更新的抗体药物候选品,在实验中显示出了效力强、药代动力学特征明显、半衰期长等特点,并能以其他途径给药,而且能降低其制备成本。现就抗RSV pre F的抗体研究进展作一概述。     

呼吸道合胞病毒IgG酶联检测试剂盒的研制

为了研制检测呼吸道合胞病毒IgG的酶联检测试剂盒,以呼吸道合胞病毒Long株病毒液作为包被抗原,HRP标记羊抗人IgG作为信号抗体,制备ELISA抗体检测试剂盒。结果表明建立的RSV酶联检测试剂盒敏感性与进口试剂盒接近,特异性达 95. 24%,重复性好,批内变异系数为 6. 35%,试剂盒置于 37℃ 0天与 7天检测结果无显著差异。成功制备了RSVIgG酶联检测试剂盒。     

Toll 样受体通路激活改善呼吸道合胞病毒疫苗诱导免疫应答的研究进展

呼吸道合胞病毒（RSV）是导致婴幼儿严重下呼吸道感染的最重要病原体,但该病毒的灭活疫苗可引起RSV疫苗增强性疾病（RVED）。RVED的机制目前仍不清楚。Toll样受体（TLR）及其信号转导对 RSV的识别和宿主免疫的激发均有重要作用,其在RVED机制中的作用也日益受到关注。本文主要介绍TLR在抗RSV天然免疫和获得性免疫中的角色及其信号通路激活状态改变对RVED免疫格局的影响,提示RVED机制可能与TLR信号通路激活不足有关,从而为RSV疫苗研制提供新的策略和方法。