Disabling Vaccinia IFNr: A New Smallpox Vaccine

说明(申请人提供)：复制能力强的痘苗病毒(W)，目前的天花疫苗，可在接种疫苗后引起严重并发症，特别是在免疫抑制的人。我们正在寻求开发具有复制能力的W减毒株，从而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，这项建议的目的是进一步开发包含关键的先天免疫逃避基因E3L干扰素抗性基因突变的现有痘苗病毒株，作为当前和建议的天花疫苗的安全有效的替代品。我们已经从W的NYCBH菌株的组织培养适应变体ACAM2000中删除了E3L基因。比较ACAM2000delE3L与ACAM2000和Dryvax在小鼠体内的相对免疫原性、佐剂和安全性。与Dryvax相比，将分别在小鼠、兔子和猕猴身上测试针对皮疹、兔痘和猴痘的疗效。其目的是利用这些数据来满足FDA的动物疗效规则，并为在健康人类志愿者中进行L/11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.