设计一种新型组合多抗原表位疫苗“MarVax”抗马尔堡病毒-一种反向疫苗学和免疫信息学方法。

IF 3.6 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Journal, genetic engineering & biotechnology Pub Date : 2023-11-28 DOI:10.1186/s43141-023-00575-w
Bishal Debroy, Sribas Chowdhury, Kuntal Pal
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摘要

背景:马尔堡病毒(MARV)是丝状病毒科的成员,在人类和灵长类动物中引起马尔堡病毒病(MVD)。由于致死率高达88%,目前还没有商业化的治疗方法或疫苗来对抗这种感染。美国国家过敏和传染病研究所(NIAID)将MARV列为优先病原体A,这预示着需要一种能够提供稳定、长期适应性免疫的候选疫苗。表面糖蛋白(GP)和融合蛋白(FP)通过TIM-I受体介导病毒的粘附、融合和进入宿主细胞。作为重要的抗原决定因素,研究表明GP和FP容易发生进化突变,强调了能够引发强大和持续免疫反应的疫苗结构的需求。在本计算研究中,采用反向疫苗学方法,利用MARV必需病毒蛋白GP、VP24、VP30、VP35和VP40的保守抗原表位和内源性蛋白大聚合酶(L)设计组合疫苗。方法:使用TepiTool和ElliPro分别预测t细胞和b细胞的表位。利用蛋白肽对接平台MdockPeP筛选表面暴露的tlr如TLR2、TLR4和TLR5的高结合亲和力表位。选择最佳的结合表位并与连接体组装,设计重组多表位疫苗结构,并在Robetta上建立模型。对重组疫苗进行了计算机生物物理和生化分析。利用WebGro和CABS-Flex对疫苗进行对接和MD模拟,支持候选疫苗与tlr的稳定结合。利用C-ImmSim服务器进行虚拟免疫仿真,验证其即时和长期免疫原性。结果:重组蛋白疫苗的生化特性及与MD模拟的对接研究表明,重组蛋白疫苗构建的MarVax是一种稳定、抗原性强的疫苗分子。免疫模拟研究揭示了1年的被动免疫,这需要通过体内研究来验证。
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Designing a novel and combinatorial multi-antigenic epitope-based vaccine "MarVax" against Marburg virus-a reverse vaccinology and immunoinformatics approach.

Context: Marburg virus (MARV) is a member of the Filoviridae family and causes Marburg virus disease (MVD) among humans and primates. With fatality rates going up to 88%, there is currently no commercialized cure or vaccine to combat the infection. The National Institute of Allergy and Infectious Diseases (NIAID) classified MARV as priority pathogen A, which presages the need for a vaccine candidate which can provide stable, long-term adaptive immunity. The surface glycoprotein (GP) and fusion protein (FP) mediate the adherence, fusion, and entry of the virus into the host cell via the TIM-I receptor. Being important antigenic determinants, studies reveal that GP and FP are prone to evolutionary mutations, underscoring the requirement of a vaccine construct capable of eliciting a robust and sustained immune response. In this computational study, a reverse vaccinology approach was employed to design a combinatorial vaccine from conserved and antigenic epitopes of essential viral proteins of MARV, namely GP, VP24, VP30, VP35, and VP40 along with an endogenous protein large polymerase (L).

Methods: Epitopes for T-cell and B-cell were predicted using TepiTool and ElliPro, respectively. The surface-exposed TLRs like TLR2, TLR4, and TLR5 were used to screen high-binding affinity epitopes using the protein-peptide docking platform MdockPeP. The best binding epitopes were selected and assembled with linkers to design a recombinant multi-epitope vaccine construct which was then modeled in Robetta. The in silico biophysical and biochemical analyses of the recombinant vaccine were performed. The docking and MD simulation of the vaccine using WebGro and CABS-Flex against TLRs support the stable binding of vaccine candidates. A virtual immune simulation to check the immediate and long-term immunogenicity was carried out using the C-ImmSim server.

Results: The biochemical characteristics and docking studies with MD simulation establish the recombinant protein vaccine construct MarVax as a stable, antigenic, and potent vaccine molecule. Immune simulation studies reveal 1-year passive immunity which needs to be validated by in vivo studies.

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