Disabling Vaccinia IFNr: A New Smallpox Vaccine

描述（由申报人提供）：目前的天花疫苗——复制型能干牛痘病毒(W)，可在接种后引起严重的并发症，特别是在免疫抑制的个体中。我们正在寻求开发具有复制能力的W病毒减毒株，从而诱导强烈的免疫反应，而不会出现与目前疫苗接种相关的并发症。因此，本建议的目的是进一步开发含有关键先天免疫逃避基因E3L ifn抗性基因突变的现有牛痘病毒株，作为当前和拟议的天花疫苗的安全有效替代品。我们从W的NYCBH菌株ACAM2000的组织培养适应变体中删除了E3L基因。将ACAM2000delE3L与ACAM2000和Dryvax在小鼠体内的相对免疫原性、佐剂性和安全性进行比较（免疫原性和安全性）。与Dryvax相比，将分别在小鼠、兔子和猕猴身上测试该疫苗对抗鼠痘、兔痘和猴痘的效果。目的是利用这些数据来满足FDA动物功效规则，并为健康人类志愿者的i / ii期临床试验铺平道路。

DESCRIPTION (provided by applicant): 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.