Disabling Vaccinia IFNr: A New Smallpox Vaccine

复制能力牛痘病毒（W），目前的天花疫苗，可引起严重的 接种疫苗后的并发症，特别是在免疫抑制的人。我们正在寻求发展 具有复制能力的W减毒菌株，因此将诱导强烈的免疫应答， 而不会出现与接种现有疫苗相关的并发症。因此，其目的是 一项建议是进一步开发现有的牛痘病毒株，这些病毒株在一个关键的先天性 免疫逃避基因，E3 L干扰素抗性基因，作为安全有效的替代品， 建议的天花疫苗。我们已经删除了E3 L基因从组织培养适应的变异体， W的NYCBH菌株，ACAM 2000。本研究旨在评价其相对免疫原性、毒性和安全性， 将在小鼠中比较ACAM 2000 delE 3L与ACAM 2000和Dryvax（免疫原性和生物学活性）。 安全）。将在小鼠、兔和猴中检测对肢端病、兔痘和猴痘攻毒的有效性。 和猕猴相比，Dryvax。目的是使用这些数据来满足FDA动物 有效性规则，并为健康人类志愿者的I/II期临床试验铺平道路。

Replication competent vaccinia virus (W), the current vaccine for smallpox, can cause severe complications after vaccination, especially in immune suppressed individuals. We are seeking to develop attenuated strains of W that are replication competent, and thus will induce a strong immune response, without the complications associated with vaccination with the current vaccines. Thus, the Aim of this proposal is to further develop existing strains of vaccinia virus that contain mutations in a key innate immune evasion gene, the E3L IFN-resistance gene, as safe effective alternatives to the current and proposed smallpox vaccines. We have deleted the E3L gene from a tissue culture adapted variant of the NYCBH strain of W, ACAM2000. The relative immunogenicity, adjuvancy and safety of ACAM2000delE3L will be compared with that of ACAM2000 and Dryvax in mice (immunogenicity and safety). Efficacy will be tested against ectromelia, rabbitpox and monkeypox challenges in mice, rabbits and macaques, respectively, compared to Dryvax. The intent is to use this data to satisfy the FDA Animal Efficacy Rule, and pave the way for Phase l/ll Clinical Trials in healthy human volunteers.