In vitro generated antibodies guide thermostable ADDomer nanoparticle design for nasal vaccination and passive immunization against SARS-CoV-2
In vitro generated antibodies guide thermostable ADDomer nanoparticle design for nasal vaccination and passive immunization against SARS-CoV-2
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DOI：
10.1093/abt/tbad024
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发表时间：
2023-11-10
影响因子：
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通讯作者：
Berger, Imre
中科院分区：
文献类型：
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作者：
Buzas, Dora;Bunzel, Adrian H.;Berger, Imre
背景由于COVID-19，大流行准备成为一个关键的当务之急，需要新的方法来加速开发针对传染性病原体的试剂。方法在这里，我们开发了一种综合方法，将合成，计算和结构方法与体外抗体选择和体内免疫相结合，生产和验证基于天然纳米颗粒的试剂，以对抗严重急性呼吸系统综合征冠状病毒2（SARS-CoV-2）.结果我们的方法产生了两个创新：（i）称为ADDoCoV的热稳定鼻疫苗，其展示多个拷贝的SARS-CoV-2受体结合基序衍生的表位，和（ii）多价纳米颗粒超结合剂，称为抗体，针对SARS-CoV-2，包括免疫逃避变异的关注（VOC）。体外产生的中和纳米抗体和电子冷冻显微镜建立了由ADDoCoV展示的表位的真实性和可及性。包含多聚化纳米抗体的抗体以皮摩尔EC 50阻止SARS-CoV-2病毒粒子附着。接种小鼠导致抗体与包括Delta和Omicron在内的VOC发生交叉反应。结论我们的研究阐明了基于腺病毒衍生的十二聚体（ADDomer）的纳米颗粒用于主动和被动免疫，并为制作试剂以对抗呼吸道病毒感染提供了蓝图。COVID-19提醒我们防范大流行病的至关重要性，需要采用先进的方法来促进和加快试剂开发，以应对新出现的威胁。我们描述了一种集成的管道方法，用于快速并行制作用于疫苗接种和被动免疫的基于ADDomer的纳米颗粒，适用于许多传染病。
Background Due to COVID-19, pandemic preparedness emerges as a key imperative, necessitating new approaches to accelerate development of reagents against infectious pathogens.Methods Here, we developed an integrated approach combining synthetic, computational and structural methods with in vitro antibody selection and in vivo immunization to design, produce and validate nature-inspired nanoparticle-based reagents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Results Our approach resulted in two innovations: (i) a thermostable nasal vaccine called ADDoCoV, displaying multiple copies of a SARS-CoV-2 receptor binding motif derived epitope and (ii) a multivalent nanoparticle superbinder, called Gigabody, against SARS-CoV-2 including immune-evasive variants of concern (VOCs). In vitro generated neutralizing nanobodies and electron cryo-microscopy established authenticity and accessibility of epitopes displayed by ADDoCoV. Gigabody comprising multimerized nanobodies prevented SARS-CoV-2 virion attachment with picomolar EC50. Vaccinating mice resulted in antibodies cross-reacting with VOCs including Delta and Omicron.Conclusion Our study elucidates Adenovirus-derived dodecamer (ADDomer)-based nanoparticles for use in active and passive immunization and provides a blueprint for crafting reagents to combat respiratory viral infections.Statement of Significance: COVID-19 reminds us of the critical importance of pandemic preparedness, requiring sophisticated approaches to facilitate and accelerate reagent development against emerging threats. We described an integrated pipeline approach to rapidly craft in parallel ADDomer-based nanoparticles for vaccination and for passive immunization, applicable to many infectious diseases.