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通过稳定参与融合蛋白结构转化的区域来设计通用副粘病毒疫苗。

Universal paramyxovirus vaccine design by stabilizing regions involved in structural transformation of the fusion protein.

机构信息

Janssen Vaccines & Prevention BV, Leiden, The Netherlands.

ForgeBio, Amsterdam, The Netherlands.

出版信息

Nat Commun. 2024 May 31;15(1):4629. doi: 10.1038/s41467-024-48059-w.

DOI:10.1038/s41467-024-48059-w
PMID:38821950
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11143371/
Abstract

The Paramyxoviridae family encompasses medically significant RNA viruses, including human respiroviruses 1 and 3 (RV1, RV3), and zoonotic pathogens like Nipah virus (NiV). RV3, previously known as parainfluenza type 3, for which no vaccines or antivirals have been approved, causes respiratory tract infections in vulnerable populations. The RV3 fusion (F) protein is inherently metastable and will likely require prefusion (preF) stabilization for vaccine effectiveness. Here we used structure-based design to stabilize regions involved in structural transformation to generate a preF protein vaccine antigen with high expression and stability, and which, by stabilizing the coiled-coil stem region, does not require a heterologous trimerization domain. The preF candidate induces strong neutralizing antibody responses in both female naïve and pre-exposed mice and provides protection in a cotton rat challenge model (female). Despite the evolutionary distance of paramyxovirus F proteins, their structural transformation and local regions of instability are conserved, which allows successful transfer of stabilizing substitutions to the distant preF proteins of RV1 and NiV. This work presents a successful vaccine antigen design for RV3 and provides a toolbox for future paramyxovirus vaccine design and pandemic preparedness.

摘要

副黏病毒科包括具有医学重要性的 RNA 病毒，包括人类呼肠孤病毒 1 和 3（RV1、RV3）以及尼帕病毒（NiV）等动物源性病原体。RV3 以前称为副流感病毒 3，尚未批准用于该病毒的疫苗或抗病毒药物，它可导致脆弱人群的呼吸道感染。RV3 融合（F）蛋白本质上是不稳定的，可能需要预融合（preF）稳定化以实现疫苗有效性。在这里，我们使用基于结构的设计来稳定参与结构转化的区域，从而产生具有高表达和稳定性的 preF 蛋白疫苗抗原，并且通过稳定卷曲螺旋茎区域，不需要异源三聚化结构域。该 preF 候选疫苗在雌性初免和预先暴露的小鼠中均诱导强烈的中和抗体反应，并在棉鼠攻毒模型（雌性）中提供保护。尽管副黏病毒 F 蛋白的进化距离较远，但它们的结构转化和不稳定的局部区域是保守的，这允许将稳定化取代成功转移到 RV1 和 NiV 的遥远的 preF 蛋白上。这项工作为 RV3 提供了一种成功的疫苗抗原设计，并为未来的副黏病毒疫苗设计和大流行准备提供了工具包。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/008a926c70f1/41467_2024_48059_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/0b2db362d1ee/41467_2024_48059_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/70eb0a306c16/41467_2024_48059_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/8a5b263ee75a/41467_2024_48059_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/9fa55e8914dd/41467_2024_48059_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/5dd66cd33868/41467_2024_48059_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/cd171b7030d3/41467_2024_48059_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/f0a73d51bb9e/41467_2024_48059_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/008a926c70f1/41467_2024_48059_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/0b2db362d1ee/41467_2024_48059_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/70eb0a306c16/41467_2024_48059_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/8a5b263ee75a/41467_2024_48059_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/9fa55e8914dd/41467_2024_48059_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/5dd66cd33868/41467_2024_48059_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/cd171b7030d3/41467_2024_48059_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/f0a73d51bb9e/41467_2024_48059_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a923/11143371/008a926c70f1/41467_2024_48059_Fig8_HTML.jpg

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