Recombinant Attenuated Salmonella Vaccines for Humans

人用重组减毒沙门氏菌疫苗

基本信息

批准号：
7626814
负责人：
ROY CURTISS III
金额：
$ 38.13万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
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/7626814
关键词：
Accounting Adherence Adult Animals Antibody Formation Antigen Presentation Antigens Attenuated Behavior Belief Biological Containment Birds Birth 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 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 Program Development Protocols documentation Quality of life Recombinants Research Research Ethics Committees 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 public health relevance research study transmission process vaccine candidate vaccine delivery vaccine development vector vector vaccine virus core

项目摘要

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）：在过去十年中平均每年5700万例死亡中，约有1,480万是由于感染性疾病，由于感染的次要影响，还增加了数百万的传染病（65）。鼠伤寒沙门氏菌和链球菌A，丙型肝炎病毒（HBV），肺炎链球菌和结核病（MTB）造成的年死亡人数差异很大，但可能占总成本较高的总成本，这些疾病的成本较大，但这些损失较大，这些损失较大，这些差异较大，这些均与这些严重的差异相关联（23.23）为了相信改善健康，营养和经济健康（后者取决于前两个）提供了提高全球生活质量的最佳手段，从而降低了导致战争和恐怖行为的条件，我们提出了一项疫苗开发计划，基于我们最近使用重组衰减的沙门氏菌疫苗（RASV）的技术发展。 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鸟类和动物的肠道，（iii）设计和建造链球菌作为抗原和DNA疫苗输送载体具有多样性的遗传学特征，以确保安全和功效，用于免疫婴儿和成人以防止肠子发烧和额外的感染性疾病和（iv），以置于肠子和评估（IV），以置于构造，s。通过通过II和III型分泌递送保护性抗原和/或通过在细胞隔室中发生裂解的受调节延迟裂解的疫苗以防止MTB感染，以增强MHC I类或II类，并通过裂解在体内发生延迟裂解，并通过II类或II类，以及通过较高的裂解范围内的延迟裂解，以释放细胞质的延迟裂解，以释放DNA的核定效应，DNA降低了DNA的核能，DNA的效率是DNA的核能。免疫个体的抗原。我们还将添加到主文件（向FDA提交），准备并充分表征候选疫苗主种子以保持稳定性和安全性，为IRB批准准备和提交协议，提交必要的信息以获取IND，并执行任何其他工作，以安排在人类志愿者中对临床评估的最佳候选疫苗。公共卫生相关性：提出的研究将进一步开发和完善技术，以设计和建造活体重组疫苗（RASV）载体（RASV）向量，以在无针头口服接种后提供保护性抗原和/或DNA疫苗后提供，以刺激粘膜，全身性和细胞免疫，抗细菌和抗细菌性，抗细菌，病毒和帕氏病。更具体地说，我们将开发一种安全，有效的副链球菌作为新生儿和婴儿口服免疫的疫苗载体。除了孢子链球菌载体外，我们还将使用该链球链球菌A载体来构建RASVS，以防止结核分枝杆菌的传播和感染。