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.

该赠款提案根据PA-18-872研究提交，以提高疫苗安全。为此推动 R21赠款提案是该实验室的最新报告，《 2019年儿童神经病学杂志》。 文章：在免疫能力幼儿疫苗接种后，严重的疱疹带状疱疹。 该提议的假设是VZV ORF0是现场水痘疫苗中衰减的主要决定因素 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 衰减的ORF0等位基因更有可能重新激活为严重的疱疹带状疱疹。我的实验室和加拿大实验室做了 在我们测序众所周知的艾伦实验室的整个基因组之后，关于VZV衰减的批判发现 拉紧。我们先前使用Arvin Lab的SCID小鼠模型表明，Ellen菌株甚至是 比OKA疫苗菌株更衰减。当我们比较艾伦和沃卡的完整序列时 我们做出了一个完全不可预测的发现。这两种菌株在IE62基因中具有常见的SNP， 预期的。没想到的是发现Ellen Lab菌株（在 1960年代的佐治亚州具有疫苗型ORF0基因。因此，VZV研究人员不知道Ellen 菌株在IE62（ORF62）和ORF0中都获得了与疫苗极为相似的多态性 拉紧。 R21赠款的目的是启动研究以将ORF0定义为重要的确定器 VZV疫苗的衰减。因此，从本质上讲，这项赠款提出的提议是首先提出的病毒学家 1970年代的现场水痘疫苗省略了疫苗晚期设计的一步，这允许更多 最终疫苗产品中包含的有毒变体。研究计划包括两个具体目标， 还包括两名顾问。这项研究的重要性具有疫苗安全的相关性。那里有 是在水痘疫苗接种后成千上万的不良事件的报告，包括散布死亡 疫苗病毒感染。由于疫苗病毒的原始库存从未被高桥实验室克隆 大阪，当前的商业疫苗产品包含具有野生型ORF0等位基因的变体。我们建议这样做 疫苗亚种或具有野生型ORF0的变体可能导致许多严重的副作用 水痘疫苗接种。