Vaccine Prevention of Rheumatic Fever

风湿热疫苗预防

• 批准号: 7490667
• 负责人: JAMES B. DALE
• 金额: $ 47.06万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490667
• 关键词: Academia; Acute; Acute Pharyngitis; Address; Adjuvant; Adult; Africa; Animals; Antibodies; Antibody Formation; Antigens; Biological Assay; Cells; Centers for Disease Control and Prevention (U.S.); Cervical lymph node group; Child; Chronic; Clinical Distribution; Clinical Research; Combined Vaccines; Consensus; Country; DNA; Data; Developed Countries; Developing Countries; Development; Disease; Dose; Drug Formulations; Enzyme-Linked Immunosorbent Assay; Epidemiology; Facility Construction Funding Category; Funding; Genes; Goals; Guanosine Monophosphate; Health; Heart Diseases; Immune response; In Vitro; Incidence; Individual; Industry; Infection; Intramuscular; Laboratory Study; Lipid A; Liposomes; Lymphocyte Activation; Maryland; Medical Surveillance; Mononuclear; Mus; Nicaragua; North America; One-Step dentin bonding system; Peptides; Pharyngeal structure; Pharyngitis; Phase; Phase I Clinical Trials; Plasmids; Prevalence; Prevention; Production; Prospective Studies; Proteins; Protocols documentation; Publishing; Recombinant Vaccines; Recombinants; Reporting; Research; Research Personnel; Rheumatic Fever; Rheumatic Heart Disease; Route; Safety; Saliva; Schedule; Selection Criteria; Serotyping; Serum; Site; Source; Spleen; Standards of Weights and Measures; Streptococcal Infections; Streptococcal Vaccines; Streptococcus; Streptococcus pyogenes; Subunit Vaccines; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Toxic effect; Translating; Universities; Upper arm; Vaccine Design; Vaccines; Western Europe; Work; aluminum sulfate; base; cytokine; design; design and construction; enzyme linked immunospot assay; experience; immunogenic; immunogenicity; improved; intraperitoneal; lymph nodes; member; mouse model; multicatalytic endopeptidase complex; multiple myeloma M Protein; novel vaccines; preclinical study; prevent; programs; prototype; recombinant peptide; research clinical testing; research study; response; vaccine delivery; vaccine efficacy; volunteer

The overall goal of this project is to develop a safe and effective multivalent M protein-base d vaccine to prevent acute rheumatic fever (ARF). Rheumatic fever is triggered by group A streptococcal infections of the throat. Although the incidence of ARF has declined markedly in the U.S. and other developed countries over the past 50 years, the disease remains rampant in developing countries of the world. Rheumatic heart disease (RHD) is the leading cause of heart disease in children throughout the world. An estimated 12 million people suffer from chronic RHD and 400,000 die from the disease each year. Thus, the development of an effective vaccine designed to prevent the streptococcal infections that cause ARF and RHD could significantly improve the health of millions of children around the world. The aims of this proposal are: 1) To determine the distribution of group A streptococcal serotypes causing acute pharyngitis in countries where ARF is common, 2) to determine the optimal formulation and route of delivery of multivalent group A streptococcal vaccines using an established mouse model, 3) to identify T cell epitopes within multivalent vaccines in order to enhance the overall protective antibody responses to the multivalent vaccines, 4) to translate these findings into the design, construction, GMP production, and formulation of a multivalent vaccine to prevent rheumatic fever, and 5) to perform a phase I clinical trial to assess the safety and immunogenicity of the vaccine in adult volunteers. Prospective studies will be conducted in Mall, West Africa and Leon, Nicaragua to identify the prevalent rheumatogenic serotypes. This information will be combined with available data on the emm-type distribution of clinical isolates from around the world. Laboratory studies in animals will establish the optimal formulation and route of delivery for the vaccine. The final vaccine will be produced and manufactured to GMP standards by ID Biomedical Corporation. The proposed phase I clinical trial will be performed at the University of Maryland and will establish the safety and immunogenicity of the vaccine in human adult volunteers. Successful completion of these studies will bring us one step closer to determining whether acute rheumatic fever is a vaccine preventable disease.

该项目的总体目标是开发一种安全有效的以M蛋白为基础的多价疫苗，以预防急性风湿热(ARF)。风湿热是由喉咙的A组链球菌感染引发的。尽管在过去的50年里，ARF在美国和其他发达国家的发病率显著下降，但这种疾病在世界发展中国家仍然猖獗。风湿性心脏病(RHD)是全世界儿童心脏病的主要原因。据估计，每年有1200万人患有慢性风湿性心脏病，40万人死于这种疾病。因此，开发一种有效的疫苗，旨在预防导致ARF和RHD的链球菌感染，可以显著改善世界各地数百万儿童的健康。这项建议的目的是：1) 研究目的：1)确定引起急性咽炎的A组链球菌血清型在急性肾衰竭常见国家的分布情况；2)使用已建立的小鼠模型确定多价A组链球菌疫苗的最佳配方和给药途径；3)确定多价疫苗内的T细胞表位，以增强对多价疫苗的整体保护性抗体反应；4)将这些发现转化为预防风湿热的多价疫苗的设计、构建、GMP生产和制剂；5)进行I期临床试验，以评估疫苗在成年志愿者中的安全性和免疫原性。将在西非的Mall进行前瞻性研究 和尼加拉瓜的里昂，以确定流行的风湿性血清型。这些信息将与世界各地临床分离株EMM型分布的现有数据结合起来。在动物身上进行的实验室研究将确定疫苗的最佳配方和给药途径。最终疫苗将由ID Biomedical Corporation按照GMP标准生产和制造。拟议的I期临床试验将在马里兰大学进行，并将在人类成年志愿者身上确定疫苗的安全性和免疫原性。这些研究的成功完成将使我们离确定急性风湿热是否是疫苗可预防的疾病又近了一步。