Vaccine Prevention of Group A Streptococcal Infections

描述(申请人提供)：该项目的总体目标是开发一种安全有效的疫苗，以预防A组链球菌(GAS)感染及其最严重的并发症、急性风湿热(ARF)、风湿性心脏病(RHD)和侵袭性疾病。我们在开发包含多达30种不同M血清型GAS的类型特异性保护肽的逐步复杂的重组多价M蛋白疫苗方面取得了相当大的进展，这些M血清型占北美和欧洲感染的80%-95%。来自发展中国家的流行病学数据表明，30价疫苗的潜在效力仅接近50%，在这些国家，ARF/RHD的负担非常高。在寻找可与M蛋白结合以提高疫苗效力的GAS表面抗原的过程中，我们发现GAS的M相关蛋白(MRP)可激发针对同源和异种GAS血清型的杀菌抗体。在125种定义的M类气体中，83%的气体是MRP阳性。重要的是，对11种血清型GAS的MRP序列的分析表明，三个相关的MRP家族之间的结构具有显著的保守性，这表明可以使用最少数量的蛋白质片段来实现交叉保护免疫。因此，我们改进了我们开发广泛保护性疫苗的方法，建议将目前基于M蛋白的30价疫苗与MRP的交叉保护肽结合起来。在这一应用中，我们建议：a)确定MRP引起的交叉保护免疫的广度，b)确定包含交叉保护表位的MRP的共价结构，c)确定重组杂交MRP多肽与30价M蛋白疫苗相结合的疫苗在动物中的潜在保护效果。该项目利用了我们在设计和应用新型重组疫苗蛋白方面的创新方法的经验，我们正在进行的确定马里和南非气体感染流行病学的研究，以及我们发现MRP在动物中激发血清型交叉保护性免疫反应。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop a safe and effective vaccine to prevent group A streptococcal (GAS) infections and their most serious complications, acute rheumatic fever (ARF), rheumatic heart disease (RHD) and invasive disease. We have made considerable progress in developing progressively complex recombinant multivalent M protein-based vaccines containing type-specific protective peptides from as many as 30 different M serotypes of GAS that account for 80-95% of infections in North America and Europe. Epidemiologic data from developing countries, where the burden of ARF/RHD is extraordinarily high, suggest that the potential efficacy of the 30-valent vaccine would only approach 50%. In our efforts to identify surface antigens of GAS that could be combined with M proteins to improve vaccine efficacy, we discovered that M- related protein (Mrp) of GAS evokes bactericidal antibodies against homologous and heterologous serotypes of GAS. Eighty-three percent of the 125 defined M types of GAS are Mrp-positive. Importantly, analysis of the Mrp sequences from 11 serotypes of GAS indicates a striking conservation of structure among three related "families" of Mrp, suggesting that cross-protective immunity may be achieved using a minimum number of protein fragments. Therefore, we have refined our approach to the development of a broadly protective vaccine by proposing to combine the current 30-valent M protein-based vaccine with cross-protective peptides of Mrp. In this application, we propose to: a) define the breadth of cross-protective immunity evoked by Mrp, b) determine the covalent structures of Mrp that contain cross-protective epitopes, and c) define the potential protective efficacy in animals of vaccines combining recombinant hybrid Mrp peptides with the 30-valent M protein-based vaccine. This project takes advantage of our experience using innovative approaches in the design and application of novel recombinant vaccine proteins, our ongoing studies to determine the epidemiology of GAS infections in Mali and South Africa, and our discovery that Mrp evokes serotype cross- protective immune responses in animals.