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，除了显著的发病率外，约有750万人是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。相信改善健康，营养和经济福祉（后者依赖于前两个）提供了最好的手段，以提高全球生活质量，从而减少导致战争和恐怖行为的条件，我们提出了一个疫苗开发计划，根据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、构建和评价S.甲型副伤寒，其将通过在免疫个体的效应淋巴组织内表现出调节的延迟裂解以释放肝炎B病毒（HBV）核心颗粒而充当抗原递送载体，所述核心颗粒编码（i）HBV前$1、前$2和T细胞表位作为针对HBV的预防性/治疗性疫苗，和（ii）恶性疟原虫环子孢子表位作为针对疟疾的疫苗;（B）构建并评估菌株背景和RpoS* 表型对减毒链球菌表达的重组抗原的免疫原性的贡献。伤寒疫苗株;（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由来自（i）S.肺炎支原体以预防由具有不同荚膜血清型的菌株引起的肺炎球菌疾病，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，准备和充分表征候选疫苗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IND所需的信息，并执行安排最佳候选疫苗在人类志愿者中进行临床评估所需的任何其他工作。

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.