Disabling Vaccinia IFNr: A New Smallpox Vaccine

复制能力强的牛痘病毒(W)，目前用于天花的疫苗，可导致严重的 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 具有复制能力的减毒W菌株，因此将诱导强烈的免疫反应， 而不会出现与当前疫苗接种相关的并发症。因此，这样做的目的是 建议进一步开发现有的牛痘病毒株，这些病毒株包含一种关键的先天突变 免疫逃避基因，E3L-干扰素抗性基因，作为当前和 建议接种天花疫苗。我们已经从组织培养适应的变种中删除了E3L基因 W的NYCBH菌株，ACAM2000。疫苗的相对免疫原性、佐剂和安全性 ACAM2000delE3L将与ACAM2000和Dryvax在小鼠体内进行比较(免疫原性和 安全)。将在小鼠、兔身上测试针对皮疹、兔痘和猴痘的疗效 和猕猴，分别与Dryvax相比。目的是利用这些数据来满足FDA动物管理局的要求 疗效规则，并为健康人体志愿者的L/11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.