Wild-type allele found in varicella vaccine virus during severe herpes zoster

严重带状疱疹期间水痘疫苗病毒中发现野生型等位基因

基本信息

批准号：
10038935
负责人：
Charles F. Grose
金额：
$ 22.68万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-21 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10038935
关键词：
Acyclovir Admission activity Adverse event Alleles Applications Grants Arginine Arvin Asians Asthma Attenuated Attenuated Live Virus Vaccine Autoimmune Diseases Cessation of life Chickenpox Chickenpox Vaccine Child Country Data Disease European Exanthema FDA approved Genes Genetic Polymorphism Genome Goals Grant Hearing Herpes zoster disease Immunize Immunocompetent Infection Injections Iowa Journals Lead Left Mutate Mutation North America Nucleotides Open Reading Frames Patients Pediatric Neurology Physicians Proteins Reporting Research Research Personnel Risk Factors Role SCID Mice Scientist Secondary to Site Skin Spinal Ganglia Structure Terminator Codon Thigh structure Transverse Myelitis Travel United States VZV vaccine Vaccination Vaccine Design Vaccines Variant Viral Viremia Virulence Virulent Virus Virus Diseases Work afferent nerve attenuation base dermatome improved mouse model side effect vaccine safety varicella-zoster virus glycoprotein gp1 varicella-zoster virus immediate early protein 62 virtual whole genome

项目摘要

This grant proposal is submitted under PA-18-872 Research to advance vaccine safety. The impetus for this R21 grant proposal is a recent report from this lab in the Journal of Child Neurology 2019. The title of the article: Severe herpes zoster following varicella vaccination of immunocompetent young children. The hypothesis for this proposal is that VZV ORF0 is a major determinant of attenuation in the live varicella vaccine vOka; further, a variant of the current vaccine product that contains the wild-type ORF0 allele rather than the attenuated ORF0 allele is more likely to reactivate as severe herpes zoster. My lab and a Canadian lab made a critical discovery about VZV attenuation after we sequenced the entire genome of the well-known Ellen lab strain. We had previously shown, using the Arvin lab’s SCID mouse model, that the Ellen strain was even more attenuated than the Oka vaccine strain. When we compared the complete sequence of Ellen and vOka, we made a completely unpredictable discovery. The two strains had common SNPs in IE62 gene, as expected. What was not expected was the discovery that the Ellen lab strain (a wild type strain isolated in Georgia in the 1960s) had a vaccine-type ORF0 gene. Unbeknownst to VZV researchers, therefore, the Ellen strain had acquired polymorphisms in both IE62 (ORF62) and ORF0 that were extremely similar to the vaccine strain. The goal of the R21 grant is to initiate studies to define ORF0 as an important determinant of attenuation in the VZV vaccine. Essentially, therefore, this grant proposes that the virologists who first made the live varicella vaccine in the 1970’s omitted a step in the late design of the vaccine, which allowed a more virulent variant to be included in the final vaccine product. The research plan includes two specific aims and also includes two consultants. The importance of this research has vaccine safety relevance. There have been thousands of reports of adverse event after varicella vaccination, including death from disseminated vaccine virus infection. Since the original stocks of vaccine virus were never cloned by the Takahashi lab in Osaka, the current commercial vaccine product contains a variant with wild-type ORF0 allele. We suggest that the vaccine subspecies or variant with wild-type ORF0 may be causing many of the severe side effects following varicella vaccination.

该拨款提案是根据 PA-18-872 研究提交的，以促进疫苗安全。 R21 资助提案是该实验室最近在《2019 年儿童神经病学杂志》上发表的一份报告。文章：免疫功能健全的幼儿接种水痘疫苗后出现严重带状疱疹。该提议的假设是 VZV ORF0 是水痘活疫苗减毒的主要决定因素 vOka；此外，当前疫苗产品的变体包含野生型 ORF0 等位基因，而不是减弱的 ORF0 等位基因更有可能在严重带状疱疹时重新激活。在我们对著名的 Ellen 实验室的整个基因组进行测序后，关于 VZV 减弱的重要发现我们之前使用 Arvin 实验室的 SCID 小鼠模型表明，Ellen 菌株是均匀的。当我们比较 Ellen 和 vOka 的完整序列时，比 Oka 疫苗株的减毒效果更强。我们得到了一个完全出乎意料的发现，这两个菌株在 IE62 基因中有共同的 SNP。出乎意料的是发现了艾伦实验室菌株（一种分离于的野生型菌株）。 20 世纪 60 年代的乔治亚州）有一种疫苗型 ORF0 基因，因此 VZV 研究人员并不知道。该菌株在 IE62 (ORF62) 和 ORF0 中获得了与疫苗极其相似的多态性 R21 资助的目标是启动研究，将 ORF0 定义为菌株的重要决定因素。因此，从本质上讲，这项拨款建议首先研制出 VZV 疫苗的病毒学家。 1970 年代的水痘活疫苗省略了疫苗后期设计中的一个步骤，这使得更多该研究计划包括两个具体目标和还包括两名顾问，这项研究与疫苗安全相关。已有数千起关于水痘疫苗接种后不良事件的报告，包括传播性死亡由于高桥实验室从未克隆过疫苗病毒的原始库存。大阪目前的商业疫苗产品含有野生型 ORF0 等位基因的变体，我们建议。具有野生型 ORF0 的疫苗亚种或变体可能会引起许多严重的副作用接种水痘疫苗后。