Antibodies generated in vitro and in vivo elucidate design of a thermostable ADDomer COVID-19 nasal nanoparticle vaccine-猫眼课题宝

DOI：

10.1101/2023.03.17.533092

发表时间：

2023-03

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Dora Buzas;H. Bunzel;Oskar Staufer;E. Milodowski;Grace Edmonds;beatriz Vidana Matteo;C. Schaffitzel;Sathish K. N. Yadav;K. Gupta;Charlotte Fletcher;M. Williamson;Alexandra Harrison;Ufuk Borucu;Julien Capin;Ore Francis;Georgia Balchin;Sophie Hall;Mirella Vivoli Vega;F. Durbesson;R. Vincentelli;Joe Roe;L. Wooldridge;R. Burt;Ross J L Anderson;A. Mulholland;J. Hare;Mick Bailey;A. Davidson;A. Finn;David Morgan;Jamie F S Mann;Joachim P. Spatz;F. Garzoni;J. Bufton;I. Berger

COVID-19 继续损害全世界的人口、社区和经济。疫苗减少了与 COVID-19 相关的住院治疗和死亡人数，主要是在发达国家。持续的感染率以及导致重复和突破性感染的高传播性 SARS-CoV-2 关注变种 (VOC)，凸显了持续需要新的治疗方法以实现全球解决方案。基于 ADDomer（一种自组装蛋白纳米颗粒支架），我们创建了 ADDoCoV，这是一种热稳定的 COVID-19 候选疫苗，显示出 SARS-CoV-2 受体结合基序 (RBM) 衍生表位的多个副本。体外生成的中和纳米抗体与分子动力学 (MD) 模拟和电子冷冻显微镜 (cryo-EM) 相结合，确定了所显示表位的真实性和可及性。由多聚化纳米抗体组成的 Gigabody 可防止 SARS-CoV-2 病毒粒子附着，EC50 为皮摩尔级。免疫小鼠产生的抗体与 Delta 和 Omicron 等 VOC 发生交叉反应。我们的研究阐明了基于 ADDomer 的纳米粒子经鼻给药可用于针对 SARS-CoV-2 的主动和被动免疫，并为设计对抗呼吸道病毒感染的纳米粒子试剂提供了蓝图。

COVID-19 continues to damage populations, communities and economies worldwide. Vaccines have reduced COVID-19-related hospitalisations and deaths, primarily in developed countries. Persisting infection rates, and highly transmissible SARS-CoV-2 Variants of Concern (VOCs) causing repeat and breakthrough infections, underscore the ongoing need for new treatments to achieve a global solution. Based on ADDomer, a self-assembling protein nanoparticle scaffold, we created ADDoCoV, a thermostable COVID-19 candidate vaccine displaying multiple copies of a SARS-CoV-2 receptor binding motif (RBM)-derived epitope. In vitro generated neutralising nanobodies combined with molecular dynamics (MD) simulations and electron cryo-microscopy (cryo-EM) established authenticity and accessibility of the epitopes displayed. A Gigabody comprising multimerized nanobodies prevented SARS-CoV-2 virion attachment with picomolar EC50. Antibodies generated by immunising mice cross-reacted with VOCs including Delta and Omicron. Our study elucidates nasal administration of ADDomer-based nanoparticles for active and passive immunisation against SARS-CoV-2 and provides a blueprint for designing nanoparticle reagents to combat respiratory viral infections.

Antibodies generated in vitro and in vivo elucidate design of a thermostable ADDomer COVID-19 nasal nanoparticle vaccine

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