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

这项赠款提案是在PA-18-872研究项目下提交的，目的是提高疫苗安全性。这其中的推动力 R21拨款提案是该实验室最近在《2019年儿童神经病学杂志》上发表的一份报告。《纽约时报》的标题 文章：免疫能力较强的幼儿接种水痘疫苗后出现严重带状疱疹。这个 这一建议的假设是VZV ORF0是水痘活疫苗中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 减毒的ORF0等位基因更有可能在严重带状疱疹时重新激活。我的实验室和加拿大的一个实验室 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衰减的关键发现 紧张。我们之前曾使用Arvin实验室的SCID小鼠模型显示，Ellen品系是均匀的 比Oka疫苗株更弱。当我们比较艾伦和沃卡的完整序列时， 我们有了一个完全不可预测的发现。这两个菌株在IE62基因上有共同的SNPs， 预期中。令人意想不到的是，埃伦实验室的菌株(一种分离于 佐治亚州在20世纪60年代)拥有疫苗类型的ORF0基因。因此，VZV研究人员不知道的是，Ellen 该毒株在IE62(ORF62)和ORF0中都获得了与疫苗极其相似的多态 紧张。R21赠款的目标是启动研究，将ORF0定义为ORF0的重要决定因素 VZV疫苗的减毒作用。因此，从本质上讲，这笔拨款表明，最早提出 20世纪70年代的水痘活疫苗S省略了疫苗后期设计中的一个步骤，这使得更多的 毒力变种将包括在最终疫苗产品中。研究计划包括两个具体目标和 还包括两名顾问。这项研究的重要性与疫苗安全相关。有 数以千计的水痘疫苗接种后的不良事件报告，包括死于传播 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在#年克隆 大阪，目前的商业疫苗产品包含一种带有野生型ORF0等位基因的变种。我们建议 带有野生型ORF0的疫苗亚种或变种可能会导致许多严重的副作用 在接种水痘疫苗后。

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.