诱导广泛中和抗体的登革病毒样颗粒疫苗制剂表面表位的重新出现。

Epitope resurfacing on dengue virus-like particle vaccine preparation to induce broad neutralizing antibody.

机构信息

Microbial Genomics Ph.D. Program, National Chung Hsing University and Academia Sinica, Taichung City, Taiwan.

Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung-Hsing University, Taichung City, Taiwan.

出版信息

Elife. 2018 Oct 18;7:e38970. doi: 10.7554/eLife.38970.

Dengue fever is caused by four different serotypes of dengue virus (DENV) which is the leading cause of worldwide arboviral diseases in humans. Virus-like particles (VLPs) containing flavivirus prM/E proteins have been demonstrated to be a potential vaccine candidate; however, the structure of dengue VLP is poorly understood. Herein VLP derived from DENV serotype-2 were engineered becoming highly matured (mD2VLP) and showed variable size distribution with diameter of ~31 nm forming the major population under cryo-electron microscopy examination. Furthermore, mD2VLP particles of 31 nm diameter possess a T = 1 icosahedral symmetry with a groove located within the E-protein dimers near the 2-fold vertices that exposed highly overlapping, cryptic neutralizing epitopes. Mice vaccinated with mD2VLP generated higher cross-reactive (CR) neutralization antibodies (NtAbs) and were fully protected against all 4 serotypes of DENV. Our results highlight the potential of 'epitope-resurfaced' mature-form D2VLPs in inducing quaternary structure-recognizing broad CR NtAbs to guide future dengue vaccine design.

登革热是由四种不同血清型的登革病毒（DENV）引起的，它是全球人类虫媒病毒病的主要病因。含有黄病毒前膜/包膜蛋白的病毒样颗粒（VLPs）已被证明是一种有潜力的疫苗候选物；然而，登革热 VLP 的结构仍不清楚。在此，我们对来自登革热病毒血清型 2 的 VLP 进行了工程改造，使其高度成熟（mD2VLP），并在冷冻电镜检查下显示出不同的粒径分布，直径约为 31nm，形成主要群体。此外，直径为 31nm 的 mD2VLP 颗粒具有 T=1 二十面体对称结构，在 E 蛋白二聚体附近的 2 倍顶点处有一条位于其中的凹槽，暴露出高度重叠的、隐匿的中和表位。用 mD2VLP 免疫的小鼠产生了更高的交叉反应（CR）中和抗体（NtAbs），并能完全抵抗所有 4 种血清型的 DENV。我们的结果强调了“表位重新出现”的成熟形式 D2VLP 在诱导识别四级结构的广泛 CR NtAbs 方面的潜力，为未来的登革热疫苗设计提供了指导。