Development of a Vaccine for Staphylococcal Infections

项目摘要/摘要： 金黄色葡萄球菌导致皮肤和软组织感染(SSTI)，导致1420万门诊就诊 每年有850,000人入院。金黄色葡萄球菌感染与该病的发生无关 而且，即使使用外科手术和抗生素治疗，反复感染也经常发生。感染： 耐药金黄色葡萄球菌菌株，命名为MRSA(耐甲氧西林金黄色葡萄球菌)与 疾病结局不佳，目前已在22%的医院分离株中发现。为了解决公共卫生问题 在MRSA危机之际，我们正在开发一种疫苗，以防止金黄色葡萄球菌的侵袭性感染。S。 金黄色葡萄球菌病是病原体对吞噬细胞杀伤(OPK)的抵抗力和对 宿主的适应性免疫反应。葡萄球菌与免疫球蛋白(Ig)的结合是由 葡萄球菌蛋白A(SpA)，一种与免疫球蛋白Fc结构域和重链相关的表面蛋白 VH3家族免疫球蛋白和免疫球蛋白M链。虽然前者的活性提供了对诱导OPK的抗体的保护， 后者通过IgM受体的交联，触发B细胞的增殖和分泌非 保护性VH3抗体，从而扰乱获得性免疫反应和保护性 豁免权。我们已经开发出SpA*，这是一种疫苗，可以诱导SpA中和抗体，有效地促进 OPK，同时也允许宿主产生许多不同的病原体特异性抗体， 共同消除金黄色葡萄球菌的定植，降低侵袭性疾病的风险。这项第一阶段的短期租约建议 旨在通过建立其临床前安全性和安全性来确定生产SpA*疫苗的可行性 生物功效。

Project Summary / abstract: Staphylococcus aureus causes skin and soft tissue infections (SSTI) that result in 14.2 million outpatient visits per year and 850,000 hospital admissions. S. aureus infection is not associated with the development of immunity and, even with surgical and antibiotic therapy, recurrent infections occur frequently. Infections with antibiotic-resistant S. aureus strains, designated MRSA (methicillin-resistant S. aureus) are associated with poor disease outcomes and are now identified in 22% of hospital isolates. In order to address the public health crisis of MRSA, we are developing a vaccine to prevent invasive S. aureus infections. Key features of S. aureus disease are the pathogen’s resistance to opsonophagocytic killing (OPK) and the suppression of the host’s adaptive immune responses. Staphylococcal binding to immunoglobulin (Ig) is mediated by staphylococcal protein A (SpA), a surface protein that associates with the Fc-domain of IgG and the heavy chain of VH3 clan IgG and IgM. While the former activity provides protection from antibodies that induce OPK, the latter, through the crosslinking of IgM receptors, triggers proliferation and B cells and secretion of non- protective VH3 antibodies, thereby disrupting adaptive immune responses and the development of protective immunity. We have developed SpA*, a vaccine that elicits SpA-neutralizing antibodies that effectively promote OPK of the pathogen while also allowing the host to generate many different pathogen specific antibodies that together eliminate S. aureus colonization and reduce the risk of invasive disease. This phase I STTR proposal aims to establish the feasibility of generating the SpA* vaccine by establishing its preclinical safety and biological efficacy.