Disabling Vaccinia IFNr: A New Smallpox Vaccine

描述（由申请方提供）：可复制牛痘病毒（W）是目前的天花疫苗，可在接种后引起严重并发症，尤其是在免疫抑制个体中。我们正在寻求开发具有复制能力的W减毒菌株，从而诱导强烈的免疫应答，而没有与当前疫苗接种相关的并发症。因此，本提案的目的是进一步开发现有的牛痘病毒株，其包含关键先天免疫逃避基因E3 L IFN抗性基因的突变，作为当前和提议的天花疫苗的安全有效的替代品。我们已经从W的NYCBH株的组织培养适应变体ACAM 2000中删除了E3 L基因。将在小鼠中比较ACAM 2000 delE 3L与ACAM 2000和Dryvax的相对免疫原性、毒性和安全性（免疫原性和安全性）。与Dryvax相比，将分别在小鼠、兔和猕猴中检测其对肢端病、兔痘和猴痘攻毒的有效性。目的是使用这些数据来满足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.