Development of a Safer 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。我们正在寻求开发具有复制能力的VV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，本提案的目的是制备VV的条件突变体，其依赖于FDA批准的药物进行复制，或者可通过FDA批准的药物治疗。对于药物敏感的病毒，出现并发症的人可以用FDA批准的药物治疗。对于依赖药物的病毒，如果出现并发症，可以从接种疫苗的个体中撤回药物作为治疗。依赖药物的病毒还有一个额外的优势，即它们不能以活的形式从接种疫苗的个体传播给接触者。将在免疫活性小鼠（免疫原性和安全性）和免疫缺陷SCID小鼠（仅安全性）中比较这两种策略与当前疫苗（Dryvax）的相对免疫原性和安全性。这些毒株中最有前途的毒株将被改造成适合人类使用的病毒背景，在GMP条件下制备，并在黑猩猩和人类中进行安全性和免疫原性测试，与Dryvax相比。

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 strains of VV 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 prepare conditional mutants of VV that are either dependent on an FDA-approved drug for replication, or are treatable by an FDA-approved drug. For drug-sensitive viruses, individuals who experience complications could be treated with the FDA-approved drug. For drug-dependent viruses, should complications arise, the drug could be withdrawn from vaccinated individuals as a treatment. Drug-dependent viruses have the added advantage that they would not be able to spread in a viable form from vaccinated individuals to contacts. The relative immunogenicity and safety of these two strategies will be compared with that of a current vaccine (Dryvax) in immunocompetent mice (immunogenicity and safety), and in immunodeficient SCID mice (safety only). The most promising of these strains will be engineered into a virus background suitable for use in humans, prepared under GMP conditions and tested in chimpanzees and humans for safety and immunogenicity, compared to Dryvax.