Designed nanoparticles elicit cross-reactive antibody responses to conserved influenza virus hemagglutinin stem epitopes.

IF 6.7 1区 医学 Q1 Immunology and Microbiology
PLoS Pathogens Pub Date : 2023-08-28 eCollection Date: 2023-08-01 DOI:10.1371/journal.ppat.1011514
Dustin M McCraw, Mallory L Myers, Neetu M Gulati, Madhu Prabhakaran, Joshua Brand, Sarah Andrews, John R Gallagher, Samantha Maldonado-Puga, Alexander J Kim, Udana Torian, Hubza Syeda, Seyhan Boyoglu-Barnum, Masaru Kanekiyo, Adrian B McDermott, Audray K Harris
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引用次数: 1

Abstract

Despite the availability of seasonal vaccines and antiviral medications, influenza virus continues to be a major health concern and pandemic threat due to the continually changing antigenic regions of the major surface glycoprotein, hemagglutinin (HA). One emerging strategy for the development of more efficacious seasonal and universal influenza vaccines is structure-guided design of nanoparticles that display conserved regions of HA, such as the stem. Using the H1 HA subtype to establish proof of concept, we found that tandem copies of an alpha-helical fragment from the conserved stem region (helix-A) can be displayed on the protruding spikes structures of a capsid scaffold. The stem region of HA on these designed chimeric nanoparticles is immunogenic and the nanoparticles are biochemically robust in that heat exposure did not destroy the particles and immunogenicity was retained. Furthermore, mice vaccinated with H1-nanoparticles were protected from lethal challenge with H1N1 influenza virus. By using a nanoparticle library approach with this helix-A nanoparticle design, we show that this vaccine nanoparticle construct design could be applicable to different influenza HA subtypes. Importantly, antibodies elicited by H1, H5, and H7 nanoparticles demonstrated homosubtypic and heterosubtypic cross-reactivity binding to different HA subtypes. Also, helix-A nanoparticle immunizations were used to isolate mouse monoclonal antibodies that demonstrated heterosubtypic cross-reactivity and provided protection to mice from viral challenge via passive-transfer. This tandem helix-A nanoparticle construct represents a novel design to display several hundred copies of non-trimeric conserved HA stem epitopes on vaccine nanoparticles. This design concept provides a new approach to universal influenza vaccine development strategies and opens opportunities for the development of nanoparticles with broad coverage over many antigenically diverse influenza HA subtypes.

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设计的纳米颗粒引发对保守的流感病毒血凝素干表位的交叉反应性抗体反应。
尽管有季节性疫苗和抗病毒药物,但由于主要表面糖蛋白血凝素(HA)的抗原区域不断变化,流感病毒仍然是一个主要的健康问题和大流行威胁。开发更有效的季节性和通用流感疫苗的一种新兴策略是以结构为导向设计纳米颗粒,显示HA的保守区域,如干细胞。使用H1 HA亚型来建立概念验证,我们发现来自保守茎区(helix-A)的α螺旋片段的串联拷贝可以显示在衣壳支架的突出尖峰结构上。这些设计的嵌合纳米颗粒上HA的干区具有免疫原性,并且纳米颗粒在生物化学上是坚固的,因为热暴露不会破坏颗粒,并且保留了免疫原性。此外,用H1纳米颗粒接种的小鼠受到保护,免受H1N1流感病毒的致命攻击。通过使用这种helix-a纳米颗粒设计的纳米颗粒库方法,我们表明这种疫苗纳米颗粒构建体设计可以适用于不同的流感HA亚型。重要的是,H1、H5和H7纳米颗粒引发的抗体显示出与不同HA亚型结合的同亚型和异亚型交叉反应性。此外,使用helix-A纳米颗粒免疫分离小鼠单克隆抗体,该抗体表现出异亚型交叉反应性,并通过被动转移保护小鼠免受病毒攻击。这种串联螺旋-A纳米颗粒构建体代表了一种新的设计,可以在疫苗纳米颗粒上显示数百个非三聚体保守的HA干表位。这一设计理念为通用流感疫苗开发策略提供了一种新的方法,并为开发覆盖多种抗原多样的流感HA亚型的纳米颗粒开辟了机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
PLoS Pathogens
PLoS Pathogens 生物-病毒学
CiteScore
11.40
自引率
3.00%
发文量
598
审稿时长
2 months
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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