A New Approach to Staphylococcus aureus Vaccine Development - Resubmission 01

描述(申请人提供)：金黄色葡萄球菌是最常见的皮肤和软组织感染的原因。此外，严重侵袭性金黄色葡萄球菌病导致住院治疗，死亡率很高。在过去的十年里，美国发生了S金黄色葡萄球菌感染的疫情。这些感染绝大多数与社区有关，对甲氧西林耐药，即对除头孢他林外的所有β-内酰胺类抗生素耐药。美国最近一项关于侵袭性S金黄色葡萄球菌感染发生率的年度研究估计，每100,000人中就有600人感染。因此，仅在美国每年就可能有180万例S金黄色葡萄球菌感染病例，其中90%以上是性传播感染。这次S金黄色葡萄球菌感染疫情，治疗复杂，重点在预防。通过接种疫苗预防金黄色葡萄球菌感染并非易事。近年来，一些失败的疫苗试验评估了几种可能的保护性抗原的保护效果，包括胶囊多糖、脂磷壁酸、ISDB和ClfA。我们的建议旨在利用有关如何预防S金黄色葡萄球菌病的新想法。具体地说，我们与默克实验室、哈佛大学布里格姆和妇女医院合作筛选抗原，以及从实验动物恢复期血清的免疫学评估中提取的几种抗原，以在皮肤感染和侵袭性疾病的小鼠模型中表征保护性疫苗抗原，目的是确定最佳保护性抗原组合。在鉴定后，将探索新的联合疫苗的作用机制(S)。具体评估将是传统的吞噬细胞抗体的产生，但也是淋巴细胞亚群和细胞因子途径的选择性招募。预计我们的联合疫苗开发方案将为防御入侵的策略提供新的见解。 疾病和性传播疾病。

DESCRIPTION (provided by applicant): Staphylococcus aureus is the most commonest cause of skin and soft tissue infections. Additionally, severe invasive S. aureus disease results in hospitalization with high mortality. An epidemic of S aureus infections has occurred in the United States in the past decade. The great majority of these infections are community associated and are methicillin-resistant, i.e. resistant to all beta-lactam antibiotics with the exception of ceftaroline. A recent annualized US study of the incidence of invasive S aureus infections estimated 600 infections occurred per 100,000 population. Therefore, there may be 1.8 million cases of S aureus infections per year in the United States alone, more than 90% of which are SSTIs. This epidemic of S aureus infections has complicated treatment and focused efforts on prevention. Prevention of Staphylococcus aureus infections by vaccination has not been simple. A number of unsuccessful vaccine trials have evaluated the protective effect of several putative protective antigens in recent years including capsular polysachharides, lipoteichoic acid, isdB and clfA. Our proposal seeks to capitalize on new ideas about how to protect against S aureus disease. Specifically, we screen antigens in collaboration with Merck Laboratories, the Brigham and Women's Hospital at Harvard University, and several derived from immunologic evaluation of convalescent sera from experimental animals to characterize protective vaccine antigen in murine models of skin infections and invasive disease with the goal to identify an optimal protective antigen combination. Following its identification, the mechanism(s) by which the new combination vaccine works will be sought. Specifically assessed will be traditional production of opsonophagocytic antibody but also the selective recruitment of lymphocyte subsets and cytokine pathways. It is expected that our combination vaccine development protocol will offer new insight into strategies for protection against invasive disease and SSTIs.