Recombinant Attenuated Salmonella Vaccines for Humans

描述（由申请人提供）：在每年因传染病死亡的1890万人（1997年）中，除了严重的发病率外，约有750万人死于伤寒沙门氏菌、甲型副伤寒沙门氏菌、乙型肝炎病毒（HBV）、恶性疟原虫、肺炎链球菌和结核分枝杆菌感染。相信改善健康、营养和经济福利（后者取决于前两者）是提高全球生活质量的最佳手段，从而减少导致战争和恐怖行为的条件，我们根据我们最近在使用重组减毒沙门氏菌疫苗方面的技术发展，提出了一项疫苗开发计划。我们的目标包括：(a)设计、构建和评估副伤寒沙门氏菌a的减毒衍生物，该衍生物将通过在免疫个体的效应淋巴组织中表现出受调节的延迟裂解，作为抗原递送载体，释放乙型肝炎病毒（HBV）核心颗粒编码(i) HBV前$1、前$2和t细胞表位，作为预防/治疗性HBV疫苗；（ii）恶性疟原虫环孢子子表位，作为疟疾疫苗；(b)构建和评价菌株背景和RpoS*表型对伤寒沙门氏菌减毒疫苗株表达的重组抗原免疫原性的贡献；(c)设计、构建和评估重组减毒伤寒沙门氏菌疫苗，以表达和传递由遗传信息指定的保护性抗原，以预防由不同荚膜血清型菌株引起的肺炎球菌疾病，以及（ii）结核分枝杆菌作为预防性/治疗性疫苗。我们还将开发我们的主文件，准备和充分表征候选疫苗的主种子的稳定性和安全性，准备和提交IRB批准的方案，提交获得INDs所需的信息，并执行任何其他需要的工作，以安排最佳候选疫苗在人类志愿者中进行临床评估。

DESCRIPTION (provided by applicant): 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 typhi, 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.