Vaccine Prevention of Rheumatic Fever

本项目的总体目标是开发一种安全有效的基于M蛋白的多价疫苗来预防急性风湿热（ARF）。风湿热是由A组链球菌感染咽喉引起的。尽管在过去的50年里，ARF的发病率在美国和其他发达国家明显下降，但这种疾病在世界上的发展中国家仍然猖獗。风湿性心脏病（RHD）是世界各地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来预防导致ARF和RHD的链球菌感染，可以显着改善世界各地数百万儿童的健康。这项建议的目的是：（1） 确定在ARF常见的国家中引起急性咽炎的A组链球菌血清型的分布，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制剂和递送途径，3）鉴定多价疫苗内的T细胞表位，以增强对多价疫苗的总体保护性抗体应答，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生产和配方，5）进行I期临床试验，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Leon，尼加拉瓜鉴定流行的致风湿血清型。该信息将与世界各地临床分离株的emm型分布的可用数据相结合。动物实验室研究将确定疫苗的最佳配方和接种途径。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州大学进行，并将在人类成年志愿者中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更接近于确定急性风湿热是否是一种疫苗可预防的疾病。

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.