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一种黄热病-寨卡嵌合病毒候选疫苗可预防小鼠感染寨卡病毒及先天性畸形。

A yellow fever-Zika chimeric virus vaccine candidate protects against Zika infection and congenital malformations in mice.

作者信息

Kum Dieudonné B, Mishra Niraj, Boudewijns Robbert, Gladwyn-Ng Ivan, Alfano Christian, Ma Ji, Schmid Michael A, Marques Rafael E, Schols Dominique, Kaptein Suzanne, Nguyen Laurent, Neyts Johan, Dallmeier Kai

机构信息

KU Leuven Department of Microbiology and Immunology, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium.

2GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège, Belgium.

出版信息

NPJ Vaccines. 2018 Dec 13;3:56. doi: 10.1038/s41541-018-0092-2. eCollection 2018.

DOI:10.1038/s41541-018-0092-2
PMID:30564463
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6292895/
Abstract

The recent Zika virus (ZIKV) epidemic in the Americas led to an intense search for therapeutics and vaccines. Here we report the engineering of a chimeric virus vaccine candidate (YF-ZIKprM/E) by replacing the antigenic surface glycoproteins and the capsid anchor of YFV-17D with those of a prototypic Asian lineage ZIKV isolate. By intracellular passaging, a variant with adaptive mutations in the E protein was obtained. Unlike YFV-17D, YF-ZIKprM/E replicates poorly in mosquito cells. Also, YF-ZIKprM/E does not cause disease nor mortality in interferon α/β, and γ receptor KO AG129 mice nor following intracranial inoculation of BALB/c pups. A single dose as low as 1 × 10 PFU results, as early as 7 days post vaccination, in seroconversion to neutralizing antibodies and confers full protection in AG129 mice against stringent challenge with a lethal inoculum (10 LD) of either homologous or heterologous ZIKV strains. Induction of multi-functional CD4 and CD8 T cell responses against ZIKV structural and YFV-17D non-structural proteins indicates that cellular immunity may also contribute to protection. Vaccine immunogenicity and protection was confirmed in other mouse strains, including after temporal blockade of interferon-receptors in wild-type mice to facilitate ZIKV replication. Vaccination of wild-type NMRI dams with YF-ZIKprM/E results in complete protection of foetuses against brain infections and malformations following a stringent intraplacental challenge with an epidemic ZIKV strain. The particular characteristic of YF-ZIKprM/E in terms of efficacy and its marked attenuation in mice warrants further exploration as a vaccine candidate.

摘要

近期美洲爆发的寨卡病毒（ZIKV）疫情引发了对治疗方法和疫苗的密集搜寻。在此，我们报告了一种嵌合病毒候选疫苗（YF-ZIKprM/E）的构建，该疫苗通过用一种亚洲谱系原型寨卡病毒分离株的抗原表面糖蛋白和衣壳锚定蛋白替换黄热病毒17D（YFV-17D）的相应蛋白而构建。通过细胞传代，获得了一种E蛋白带有适应性突变的变体。与YFV-17D不同，YF-ZIKprM/E在蚊细胞中的复制能力较差。此外，YF-ZIKprM/E在干扰素α/β和γ受体敲除的AG129小鼠中，以及在对BALB/c幼鼠进行颅内接种后，均不会引发疾病或导致死亡。低至1×10 PFU的单剂量疫苗，早在接种后7天就能使血清转化为中和抗体，并在AG129小鼠中提供完全保护，使其免受同源或异源寨卡病毒株致死剂量（10 LD）的严格攻击。针对寨卡病毒结构蛋白和YFV-17D非结构蛋白诱导多功能CD4和CD8 T细胞反应表明，细胞免疫也可能有助于提供保护。在其他小鼠品系中也证实了疫苗的免疫原性和保护作用，包括在野生型小鼠中暂时阻断干扰素受体以促进寨卡病毒复制之后。用YF-ZIKprM/E对野生型NMRI母鼠进行疫苗接种，可在其受到流行寨卡病毒株的严格胎盘内攻击后，使胎儿完全免受脑部感染和畸形影响。YF-ZIKprM/E在疗效方面的特殊特性及其在小鼠中的显著减毒特性，使其作为候选疫苗值得进一步探索。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6ad/6292895/987931c95a31/41541_2018_92_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6ad/6292895/5cfc2900da98/41541_2018_92_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6ad/6292895/1f052a83bad9/41541_2018_92_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6ad/6292895/17b5852fe865/41541_2018_92_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6ad/6292895/84db51eb432a/41541_2018_92_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6ad/6292895/92f636fe1a87/41541_2018_92_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6ad/6292895/987931c95a31/41541_2018_92_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6ad/6292895/5cfc2900da98/41541_2018_92_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6ad/6292895/1f052a83bad9/41541_2018_92_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6ad/6292895/17b5852fe865/41541_2018_92_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6ad/6292895/84db51eb432a/41541_2018_92_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6ad/6292895/92f636fe1a87/41541_2018_92_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6ad/6292895/987931c95a31/41541_2018_92_Fig6_HTML.jpg

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