Recombinant Attenuated Salmonella Vaccines for Humans

简介(申请人提供)：在每年1,890万人死于传染病(1997年)中，约有750万人除发病率高外，还因感染伤寒沙门氏菌、甲型副伤寒沙门氏菌、乙肝病毒、恶性疟原虫、肺炎链球菌和结核分枝杆菌而死亡。我们相信，改善健康、营养和经济福祉(后者依赖于前两者)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，我们根据我们在使用重组减毒沙门氏菌疫苗方面的最新技术发展，提出了一个疫苗开发计划。我们的目标包括：(A)设计、构建和评价甲型副伤寒沙门氏菌的减毒衍生物作为抗原递送载体，在免疫个体的效应性淋巴组织内表现出调节的延迟裂解，以释放编码(I)HBVpre1、pre$2和T细胞表位作为预防/治疗疫苗的乙肝病毒(HBVPre$1)核心粒子和(Ii)作为抗疟疾疫苗的恶性疟原虫环子孢子表位；(B)构建和评价菌株背景和rpos*表型对减毒伤寒沙门氏菌疫苗株表达的重组抗原免疫原性的贡献；以及(C)设计、构建和评价重组减毒伤寒沙门氏菌疫苗，以表达和传递由来自(I)肺炎沙门氏菌的遗传信息指定的保护性抗原，以预防由不同衣壳血清型菌株引起的肺炎球菌疾病，以及(Ii)作为预防/治疗性疫苗。甲型副伤寒沙门氏菌和伤寒沙门氏菌重组疫苗还应提供对甲型副伤寒沙门氏菌和伤寒沙门氏菌感染的免疫力。我们还将开发我们的主文件，准备和充分描述候选疫苗主种子的稳定性和安全性，准备和提交IRB批准方案，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身上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.