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通过寡聚化重新掩埋病毒亚单位疫苗的人为暴露表面可提高疫苗效力。

Re-burying Artificially Exposed Surface of Viral Subunit Vaccines Through Oligomerization Enhances Vaccine Efficacy.

机构信息

State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.

Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, China.

出版信息

Front Cell Infect Microbiol. 2022 Jun 29;12:927674. doi: 10.3389/fcimb.2022.927674. eCollection 2022.

DOI:10.3389/fcimb.2022.927674
PMID:35846760
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9278648/
Abstract

Viral subunit vaccines often suffer low efficacy. We recently showed that when taken out of the context of whole virus particles, recombinant subunit vaccines contain artificially exposed surface regions that are non-neutralizing and reduce their efficacy, and thus these regions need to be re-buried in vaccine design. Here we used the envelope protein domain III (EDIII) of Japanese encephalitis virus (JEV), a subunit vaccine candidate, to further validate this important concept for subunit vaccine designs. We constructed monomeric EDIII, dimeric EDIII a linear space, dimeric EDIII an Fc tag, and trimeric EDIII a foldon tag. Compared to monomeric EDIII or linearly linked dimeric EDIII, tightly packed EDIII oligomers the Fc or foldon tag induce higher neutralizing antibody titers in mice and also protect mice more effectively from lethal JEV challenge. Structural analyses demonstrate that part of the artificially exposed surface areas on recombinant EDIII becomes re-buried in Fc or foldon-mediated oligomers. This study further establishes the artificially exposed surfaces as an intrinsic limitation of subunit vaccines, and suggests that re-burying these surfaces through tightly packed oligomerization is a convenient and effective approach to overcome this limitation.

摘要

病毒亚单位疫苗通常效力较低。我们最近表明，当从完整病毒颗粒的背景中取出时，重组亚单位疫苗包含人为暴露的非中和表面区域，从而降低了它们的效力，因此这些区域需要在疫苗设计中重新埋藏。在这里，我们使用日本脑炎病毒 (JEV) 的包膜蛋白结构域 III (EDIII)，作为亚单位疫苗候选物，进一步验证了这一重要的亚单位疫苗设计概念。我们构建了单体 EDIII、线性空间中的二聚体 EDIII、Fc 标签上的二聚体 EDIII 和折叠子标签上的三聚体 EDIII。与单体 EDIII 或线性连接的二聚体 EDIII 相比，紧密堆积的 EDIII 寡聚体——Fc 或折叠子标签在小鼠中诱导更高的中和抗体滴度，并更有效地保护小鼠免受致死性 JEV 攻击。结构分析表明，重组 EDIII 上的部分人为暴露表面在 Fc 或折叠子介导的寡聚体中重新埋藏。这项研究进一步确立了人为暴露表面是亚单位疫苗的内在限制，并表明通过紧密堆积的寡聚化来重新埋藏这些表面是克服这种限制的一种方便有效的方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/348e/9278648/4c4c657534d6/fcimb-12-927674-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/348e/9278648/41246fa04783/fcimb-12-927674-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/348e/9278648/13f398611eb4/fcimb-12-927674-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/348e/9278648/1e0d5153fdd3/fcimb-12-927674-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/348e/9278648/ef39fa1f5930/fcimb-12-927674-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/348e/9278648/4c4c657534d6/fcimb-12-927674-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/348e/9278648/41246fa04783/fcimb-12-927674-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/348e/9278648/13f398611eb4/fcimb-12-927674-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/348e/9278648/1e0d5153fdd3/fcimb-12-927674-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/348e/9278648/ef39fa1f5930/fcimb-12-927674-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/348e/9278648/4c4c657534d6/fcimb-12-927674-g005.jpg

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Safety profile comparison of chimeric live attenuated and Vero cell-derived inactivated Japanese encephalitis vaccines through an active surveillance system in Australia.
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