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

• 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
• 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

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.

该拨款提案根据 PA-18-872 研究提交，旨在提高疫苗安全性。这样做的动力 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。这 该提议的假设是 VZV ORF0 是水痘活疫苗减毒的主要决定因素 沃卡；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 等位基因更有可能重新激活为严重的带状疱疹。我的实验室和加拿大实验室做了一个 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 拉紧。我们之前使用 Arvin 实验室的 SCID 小鼠模型证明，Ellen 品系甚至 比 Oka 疫苗株的减毒效果更强。当我们比较 Ellen 和 vOka 的完整序列时， 我们有了一个完全不可预测的发现。两株菌株的IE62基因具有共同的SNP， 预期的。出乎意料的是，我们发现艾伦实验室菌株（一种在 20世纪60年代的乔治亚州）有一个疫苗型ORF0基因。因此，VZV 研究人员不知道的是，Ellen 该菌株在 IE62 (ORF62) 和 ORF0 中获得了与疫苗极其相似的多态性 拉紧。 R21 资助的目标是启动研究，将 ORF0 定义为重要的决定因素 VZV 疫苗的减毒作用。因此，从本质上讲，这笔赠款建议首先进行研究的病毒学家 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 将包含在最终疫苗产品中的强毒变体。该研究计划包括两个具体目标 还包括两名顾问。这项研究的重要性与疫苗安全相关。有 已有数千份关于水痘疫苗接种后不良事件的报告，包括传播性死亡 疫苗病毒感染。由于高桥实验室从未克隆出最初的疫苗病毒库存 大阪目前的商业疫苗产品含有带有野生型 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。