Recombinant Attenuated Salmonella Vaccines for Humans

在每年因传染病死亡的1890万人（1997年）中， 显著的发病率，是由伤寒沙门氏菌感染的结果。甲型副伤寒，B型肝炎病毒（HBV）， 恶性疟原虫、肺炎链球菌和结核分枝杆菌。因为相信 改善健康、营养和经济福利（后者取决于前两者）是最好的 提高全球生活质量的手段，从而减少导致战争和恐怖主义的条件 行为，我们提出了一个疫苗开发计划的基础上，我们最近的技术发展，在使用 重组减毒沙门氏菌疫苗。我们的目标包括：（a）设计、建造和评估 S的一种减毒衍生物。甲型副伤寒，其将通过表现出受调节的 免疫个体中效应淋巴组织内的延迟裂解以释放B型肝炎病毒（HBV） 作为预防性/治疗性疫苗的编码（i）HBV前体$1、前体$2和T细胞表位的核心颗粒 （ii）作为抗疟疾疫苗的恶性疟原虫环子孢子表位;（B）构建 并评估菌株背景和RpoS* 表型对a 减毒沙门氏菌表达的重组抗原。伤寒疫苗株;以及（c）设计、构建和 评价重组减毒沙门氏菌。伤寒疫苗表达和递送特定的保护性抗原 遗传信息来自（i）S.预防肺炎球菌引起的疾病的菌株具有多样性 荚膜血清型和（ii）M.结核病作为预防/治疗疫苗。色葡萄甲型副伤寒和S. 伤寒重组疫苗还应提供对沙门氏菌感染的免疫力。甲型副伤寒和S. TyphL 我们还将开发我们的主文件，准备并充分表征候选疫苗主种子， 稳定性和安全性，准备并提交IRB批准的方案，提交获得 IND，并执行安排最佳候选疫苗进行临床评价所需的任何其他工作 在人类志愿者中。

Of the 18.9 million annual deaths (1997) due to infectious diseases, about 7.5 million, in addition to significant morbidity, are the result of infections by Salmonella typhL S. paratyphi A, hepatitis B virus (HBV), Plasmodium falciparum, Streptococcus pneumoniae and Mycobacterium tuberculosis. In the belief that improving health, nutrition and economic well-being (the later dependant on the first two) provides the best means to enhance the quality of life globally and thus reduces conditions that result in warlike and terrorist behavior, we propose a vaccine development program based on our recent technical developments in using recombinant attenuated Salmonella vaccines. Our objectives include: (a) to design, construct and evaluate an attenuated derivative of S. paratyphi A that will serve as an antigen delivery vector by exhibiting regulated delayed lysis within effector lymphoid tissues in the immunized individual to release hepatitis B virus (HBV) core particles encoding (i) HBV pre $1, pre $2 and T-cell epitopes as a preventative/therapeutic vaccine against HBV and (ii) P. falciparum circumsporozoite epitopes as a vaccine against malaria; (b) to construct and evaluate the contribution of strain background and the RpoS* phenotype on immunogenicity of a recombinant antigen expressed by attenuated S. typhi vaccine strains; and (c) to design, construct and evaluate recombinant attenuated S. typhi vaccines to express and deliver protective antigens specified by genetic information from (i) S. pneumoniae to prevent pneumococcal disease caused by strains with diverse capsular serotypes and (ii) M. tuberculosis as a preventative/therapeutic vaccine. The S. paratyphi A and S. typhi recombinant vaccines should also provide immunity to infection by S. paratyphi A and S. typhL We will also develop our Master File, prepare and fully characterize candidate vaccine Master Seeds for stability and safety, prepare and submit protocols for IRB approvals, submit information necessary to obtain INDs, and perform any other work needed to arrange that the best candidate vaccines be clinically evaluated in human volunteers.