Vaccine Prevention of Rheumatic Fever

该项目的总体目标是开发一种安全有效的多价M蛋白基疫苗来预防急性风湿热（ARF）。风湿热是由喉咙的A组链球菌感染引起的。尽管近50年来，ARF在美国和其他发达国家的发病率明显下降，但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RHD， 40万人死于这种疾病。因此，开发一种有效的疫苗，以预防引起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。本建议的目的是：1)

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.