A New Approach to Staphylococcus aureus Vaccine Development - Resubmission 01

描述（由申请方提供）：金黄色葡萄球菌是皮肤和软组织感染的最常见原因。此外，严重的侵袭性S.金黄色葡萄球菌病导致住院，死亡率高。在过去的十年中，金黄色葡萄球菌感染的流行病在美国发生。这些感染中的绝大多数是社区相关的，并且是甲氧西林耐药的，即对除头孢洛林之外的所有β-内酰胺抗生素耐药。美国最近一项关于侵袭性金黄色葡萄球菌感染发生率的年度研究估计，每10万人中发生600例感染。因此，仅在美国每年就可能有180万例金黄色葡萄球菌感染，其中90%以上是SSTI。这种流行的金黄色葡萄球菌感染使治疗复杂化，并将重点放在预防上。通过接种疫苗预防金黄色葡萄球菌感染并不简单。近年来，许多不成功的疫苗试验已经评估了几种推定的保护性抗原的保护作用，包括荚膜多糖、脂磷壁酸、isdB和clfA。我们的提案旨在利用有关如何预防金黄色葡萄球菌疾病的新想法。具体而言，我们与默克实验室、哈佛大学布里格姆妇女医院合作筛选抗原，并从实验动物恢复期血清的免疫学评价中筛选出几种抗原，以表征皮肤感染和侵袭性疾病小鼠模型中的保护性疫苗抗原，目的是确定最佳保护性抗原组合。在其鉴定之后，将寻求新组合疫苗的作用机制。具体评估的将是调理吞噬抗体的传统产生，以及淋巴细胞亚群和细胞因子途径的选择性募集。预计我们的联合疫苗开发方案将为预防侵袭性疾病的策略提供新的见解。 疾病和SSTI。

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.