Vaccine Prevention of Group A Streptococcal Infections

描述（由申请人提供）：本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。我们在开发渐进复杂的重组多价M蛋白疫苗方面取得了相当大的进展，这些疫苗含有来自多达30种不同的GAS M血清型的类型特异性保护肽，这些血清型占北美和欧洲感染的80-95%。来自ARF/RHD负担非常高的发展中国家的流行病学数据表明，30价疫苗的潜在有效性仅接近50%。在我们鉴定可与M蛋白结合以提高疫苗效力的GAS表面抗原的努力中，我们发现GAS的M相关蛋白（Mrp）引起针对同源和异源GAS血清型的杀菌抗体。在125种定义的M型GAS中，83%是MRP阳性。重要的是，分析的Mrp序列从11个血清型的GAS表明一个惊人的保守的结构之间的三个相关的“家庭”的Mrp，这表明交叉保护性免疫可以实现使用最少数量的蛋白质片段。因此，我们已经改进了我们的方法，以开发一种广泛的保护性疫苗，提出将目前的30价M蛋白为基础的疫苗与Mrp的交叉保护肽联合收割机结合。在本申请中，我们提出：a）定义由Mrp诱发的交叉保护性免疫的广度，B）确定含有交叉保护性表位的Mrp的共价结构，和c）定义将重组杂合Mrp肽与基于30价M蛋白的疫苗组合的疫苗在动物中的潜在保护效力。该项目利用了我们在设计和应用新型重组疫苗蛋白方面使用创新方法的经验，我们正在进行的确定马里和南非GAS感染流行病学的研究，以及我们发现Mrp在动物中引起血清型交叉保护性免疫应答。 公共卫生相关性：世界需要有效、安全和负担得起的疫苗来预防A组链球菌（GAS）感染。虽然大多数GAS感染是轻度的，但全世界有超过1800万人患有严重GAS疾病的慢性并发症，其中超过1500万人患有风湿性心脏病，每年发生另外200万例严重疾病，估计每年共有517，000例死亡是由于这种生物体。即使是这些威胁生命的疾病的一小部分的疫苗预防也可能对世界各地人民的健康产生重大影响。

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. PUBLIC HEALTH RELEVANCE: The world needs an effective, safe and affordable vaccine to prevent group A streptococcal (GAS) infections. Although most GAS infections are mild, there are more than 18 million people with a chronic complication of a severe GAS disease worldwide, over 15 million of whom have rheumatic heart disease, another 2 million cases of severe disease occur each year and a total of 517,000 deaths annually are estimated to be due to this organism. Vaccine prevention of even a fraction of these life-threatening diseases could have a significant impact on the health of people around the world.