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，以提高疫苗安全性。这件事的推动力 R21拨款提案是该实验室最近在2019年儿童神经病学杂志上发表的报告。的标题 文章：免疫功能正常的幼儿接种水痘疫苗后出现严重带状疱疹。的 该建议假设VZVORF 0是水痘活疫苗减毒的主要决定因素 vOka;此外，含有野生型ORF 0等位基因而不是vOka的当前疫苗产品的变体。 减弱的ORF 0等位基因更可能作为严重带状疱疹再激活。我的实验室和一个加拿大实验室 在我们对著名的艾伦实验室的整个基因组进行测序后， 株我们之前已经使用阿尔文实验室的SCID小鼠模型证明，艾伦品系甚至 比奥卡疫苗株更弱。当我们比较艾伦和沃卡的完整序列时， 我们有了一个完全无法预料的发现两株菌IE62基因的SNPs相同， 预期没有预料到的是发现Ellen实验室菌株（在1999年分离的野生型菌株） 格鲁吉亚在20世纪60年代）有一个疫苗型ORF 0基因。因此，VZV研究人员不知道的是， 该菌株在IE62（ORF 62）和ORF 0中获得了与疫苗极其相似的多态性 株R21赠款的目标是启动研究，将ORF 0定义为一个重要的决定因素， VZV疫苗中的减毒作用。因此，从本质上说，这项拨款建议，病毒学家谁第一次作出 20世纪70年代的活水痘疫苗在疫苗的后期设计中省略了一个步骤，这使得更多的人能够接种疫苗。 最终疫苗产品中包含的毒力变体。研究计划包括两个具体目标， 还包括两名顾问。这项研究的重要性与疫苗安全性有关。已经 已有数千例水痘疫苗接种后的不良事件报告，包括因传播性 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， Osaka，目前的商业疫苗产品含有具有野生型ORF 0等位基因的变体。我们建议 具有野生型ORF 0的疫苗亚种或变体可能导致许多严重的副作用， 水痘疫苗接种后。