A New Approach to Staphylococcus aureus Vaccine Development - Resubmission 01

描述（由申请人提供）：金黄色葡萄球菌是皮肤和软组织感染的最常见原因。此外，严重侵袭性金黄色葡萄球菌疾病导致住院治疗，死亡率高。在过去的十年里，金黄色葡萄球菌感染在美国流行起来。这些感染绝大多数与社区有关，并具有甲氧西林耐药性，即对除头孢他林以外的所有β -内酰胺类抗生素都具有耐药性。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病例，其中90%以上是性传播感染。这种金黄色葡萄球菌感染的流行使治疗复杂化，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，一些不成功的疫苗试验评估了几种假定的保护性抗原的保护作用，包括荚膜多糖、脂质胆酸、isdB和clfA。我们的建议旨在利用关于如何预防金黄色葡萄球菌病的新想法。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估中获得一些抗原，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。在确定后，将寻求新的联合疫苗的作用机制。具体评估将是调理吞噬细胞抗体的传统生产，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防止侵入性的保护策略提供新的见解

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.