Recombinant Attenuated Salmonella Vaccines for Humans

描述（由申请人提供）：在过去十年中，每年平均有5700万人死亡，其中2000多万人直接死于传染病，还有数百万人死于感染的继发影响。每年因伤寒沙门氏菌、肺炎链球菌和结核分枝杆菌感染而死亡的人数差别很大，但可能占死亡总数的13%左右，由于与这些疾病有关的严重发病率，造成的损失甚至更大。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，我们根据我们最近在使用重组减毒沙门氏菌疫苗（RASV）方面的技术进展，提出了一项疫苗开发计划。我们的具体目标是：(1)评估最近完善和改进基因型的鼠伤寒沙门氏菌rasv递送五种不同的肺炎链球菌保护蛋白抗原，并比较三种菌株混合递送抗原与单一菌株递送所有五种抗原的抗原递送，以最大限度地诱导粘膜和全身抗体反应，并评估(i)抗体对代表全球分布的主要血清型肺炎链球菌多样性的亲和力和（ii）诱导保护性免疫(2)用最优的鼠伤寒沙门氏菌RASV和基本相同基因型的伤寒沙门氏菌RASV进行所有必要的临床前研究，以验证伤寒沙门氏菌RASV，以便在未来的人类临床试验中进行评估，然后通过提供菌株和试剂以及在必要时协助评估和验证来支持此类临床试验；(3)完善改进的RASV调控的延迟裂解系统，通过T2SS、T3SS和裂解在真核细胞胞浆中递送Mtb抗原，产生CD4和cd8依赖的Mtb感染免疫，并评估单独接种RASV-Mtb疫苗和初次接种牛支卡介苗对Mtb感染的保护作用；构建和评估重组减毒伤寒沙门氏菌调节的延迟裂解系统，产生Mtb抗原的最佳组合（由Specific Aim 3确定，由T2SS、T3SS和裂解在真核细胞胞浆中传递），以授予对Mtb感染的保护。我们将添加我们的主文件（向FDA提交），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，并执行任何其他必要的工作，以安排最佳候选疫苗在未来的研究中进行临床评估。

DESCRIPTION (provided by applicant): Of the average 57 million annual deaths over the past ten years, more than 20 million are directly due to infectious diseases with millions more due to secondary effects of infections. The numbers of annual deaths due to infections by Salmonella Typhi, Streptococcus pneumoniae and Mycobacterium tuberculosis (Mtb) vary widely but may account for about 13 per cent of the total deaths with an even greater cost due to the severe morbidity associated with these diseases. In the belief that improving health, nutrition and economic well being (the latter dependent on the first two) provide the best means to enhance the quality of life globally, we propose a vaccine development program based on our recent technical developments in using recombinant attenuated Salmonella vaccines (RASV). Our Specific Aims are: (1) to evaluate S. Typhimurium RASVs with recently perfected and improved genotypes to deliver five different S. pneumoniae protective protein antigens and compare antigen delivery by a mixture of three strains versus a single strain delivering all five antigens o maximize induction of mucosal and systemic antibody responses and to evaluate (i) antibody affinity to a diversity of S. pneumoniae strains representing the major serotypes distributed globally and (ii) induction of protective immunity to intranasal colonization and lethal challenge with mouse-adapted S. pneumoniae strains, (2) to conduct all needed preclinical studies with the optimal S. Typhimurium RASV and with the S. Typhi RASV of essentially the same genotype to validate the S. Typhi RASV for evaluation in future human clinical trials and to then support such clinical trials by providing strains and reagents and assisting in evaluations and verifications, as necessary, (3) to perfect the improved RASV regulated delayed lysis system for delivery of Mtb antigens by T2SS, T3SS and lysis in eukaryotic cell cytosol to generate both CD4- and CD8-dependent immunities against Mtb infection and to evaluate protection conferred by immunization by RASV-Mtb vaccines alone and following initial immunization with M. bovis BCG, and (4) to design, construct and evaluate recombinant attenuated S. Typhi regulated delayed lysis systems producing the optimal combination of Mtb antigens (determined from Specific Aim 3 and delivered by T2SS, T3SS and lysis in the eukaryotic cell cytosol to confer protection against Mtb infection. We will add to our Master File (filed with FDA), 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 future studies.