Recombinant Attenuated Salmonella Vaccines for Humans

人用重组减毒沙门氏菌疫苗

• 批准号: 8073497
• 负责人: ROY CURTISS III
• 金额: $ 37.37万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073497
• 关键词: Accounting; Adherence; Adult; Animals; Antibody Formation; Antigen Presentation; Antigens; Attenuated; Behavior; Belief; Biological Containment; Birds; Birth; Blood group antigen S; Cells; Cellular Immunity; Cessation of life; Communicable Diseases; Cytolysis; DNA Vaccines; Development; Disease; Economics; Ensure; Exhibits; Health; Hepatitis B Virus; Human; Human Volunteers; Immunization; Individual; Infant; Infection; Infection prevention; Institutional Review Boards; Intestines; Legal patent; Life; Lymphoid Tissue; MHC Class I Genes; Membrane; Modeling; Modification; Morbidity - disease rate; Mycobacterium tuberculosis; Needles; Newborn Infant; Nuclear; Nucleosome Core Particle; Oral; Outcome; Parasites; Production; Protocols documentation; Quality of life; Recombinants; Research; Safety; Salmonella Vaccines; Salmonella paratyphi; Salmonella typhi; Secondary to; Seeds; Specific qualifier value; Streptococcus pneumoniae; T-Lymphocyte Epitopes; Technology; Tuberculosis; Typhoid Fever; Vaccines; Vesicle; Viral; Woodchuck Hepatitis B Virus; Work; base; cost; design and construction; improved; in vivo; nutrition; prevent; programs; research study; transmission process; vaccine candidate; vaccine delivery; vaccine development; vector; vector vaccine; virus core

DESCRIPTION (provided by applicant): Of the average 57 million annual deaths over the past ten years, about 14.8 million are directly due to infectious diseases with millions more due to secondary effects of infections (65). The numbers of annual deaths due to infections by Salmonella Typhi and S. Paratyphi A, hepatitis B virus (HBV), Streptococcus pneumoniae and Mycobacterium tuberculosis (Mtb) vary widely but may account for about 30 percent of the total deaths with an even greater cost being due to the severe morbidity associated with these diseases (232). In the belief that improving health, nutrition and economic well being (the latter dependent 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 (RASV). Our Specific Aims are (i) to enhance induction of mucosal and systemic antibody responses to RASV-expressed protective pneumococcal antigens (as a model antigen) by increased production and release of membrane vesicles and by altering RASV cell adherence attributes, (ii) to enhance biological containment of live RASV strains by ensuring inability to persist and/or to completely lyse in vivo and especially in the intestinal tracts of birds and animals, (iii) to design and construct S. Paratyphi A as an antigen and DNA vaccine delivery vector with a diversity of genetically-specified features to ensure safety and efficacy when used to immunize infants and adults to protect against enteric fever and additional infectious diseases, and (iv) to design, construct and evaluate recombinant attenuated S. Typhi and S. Paratyphi A vaccines to prevent infections by Mtb using delivery of protective antigens by Type II and III secretion and/or by regulated delayed lysis in vivo with lysis occurring in cell compartments to enhance antigen presentation either by MHC Class I or Class II and by regulated delayed lysis in vivo in the cytoplasmic compartment to release a DNA vaccine optimized for nuclear targeting leading to synthesis and modification of protective antigens by the immunized individual. We will also 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 human volunteers. PUBLIC HEALTH RELEVANCE: The research proposed will further develop and refine technologies for design and construction of live recombinant attenuated Salmonella vaccine (RASV) vectors to deliver after needle-free oral inoculation protective antigens and/or DNA vaccines to stimulate mucosal, systemic and cellular immunities against bacterial, viral and parasite infectious disease agents. More specifically, we will develop a safe, efficacious S. Paratyphi A vaccine vector for oral immunization of newborns and infants. We will use this S. Paratyphi A vector in addition to an S. Typhi vector to construct RASVs to prevent transmission and infection by Mycobacterium tuberculosis.

描述（由申请人提供）：过去十年平均每年有 5700 万人死亡，其中约 1480 万人直接死于传染病，还有数百万人死于感染的继发效应 (65)。每年因伤寒沙门氏菌、甲型副伤寒沙门氏菌、乙型肝炎病毒 (HBV)、肺炎链球菌和结核分枝杆菌 (Mtb) 感染而死亡的人数差异很大，但可能约占总死亡人数的 30%，且造成的损失更大这是由于与这些疾病相关的严重发病率（232）。我们相信，改善健康、营养和经济福祉（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，因此我们提出了一项疫苗开发计划基于我们最近在使用重组减毒沙门氏菌疫苗 (RASV) 方面的技术发展。我们的具体目标是（i）通过增加膜囊泡的产生和释放以及改变RASV细胞粘附属性来增强对RASV表达的保护性肺炎球菌抗原（作为模型抗原）的粘膜和全身抗体反应的诱导，（ii）通过确保无法在体内，特别是在鸟类和动物的肠道中持续存在和/或完全裂解，对活的RASV菌株进行生物遏制，（iii）设计和构建S.甲型副伤寒作为抗原和 DNA 疫苗递送载体，具有多种遗传特异特征，可确保用于婴儿和成人免疫以预防肠热病和其他传染病时的安全性和有效性，以及 (iv) 设计、构建和评估重组减毒伤寒沙门氏菌和甲型副伤寒沙门氏菌疫苗，通过 II 型和 III 型分泌和/或通过体内调节延迟裂解（在细胞区室中发生裂解以增强抗原呈递）递送保护性抗原来预防 Mtb 感染通过 I 类或 II 类 MHC 以及在细胞质室中体内受调节的延迟裂解，释放针对核靶向优化的 DNA 疫苗，从而导致免疫个体合成和修饰保护性抗原。我们还将添加到我们的主文件（向 FDA 提交）中，准备并充分描述候选疫苗主种子的稳定性和安全性，准备并提交 IRB 批准方案，提交获得 IND 所需的信息，并执行安排所需的任何其他工作在人类志愿者中对最佳候选疫苗进行临床评估。公共健康相关性：拟议的研究将进一步开发和完善重组减毒活沙门氏菌疫苗 (RASV) 载体的设计和构建技术，以在无针口服接种后提供保护性抗原和/或 DNA 疫苗，以刺激粘膜、全身和细胞免疫对抗细菌、病毒和寄生虫传染病。更具体地说，我们将开发一种安全、有效的甲型副伤寒沙门氏菌疫苗载体，用于新生儿和婴儿的口服免疫。除了伤寒沙门氏菌载体之外，我们还将使用甲型副伤寒沙门氏菌载体构建RASV，以预防结核分枝杆菌的传播和感染。