Epitope-specific vaccines targeting the alpha toxin of Staphylococcus aureus

描述（由申请人提供）： 金黄色葡萄球菌已成为我们医院、疗养院以及越来越多的社区面临的多方面威胁。特别是耐甲氧西林的S.金黄色葡萄球菌（MRSA）在这些场所中的每一个都是日益严重的问题，并且对其他抗生素的耐药性，包括对万古霉素的不同程度的耐药性，使S.金黄色葡萄球菌感染该项目的目标是开发针对α毒素和酚可溶性调蛋白（PSM）的表位特异性疫苗，这是链球菌的两个关键毒力因子。金黄色葡萄球菌，用于预防金黄色葡萄球菌。金黄色葡萄球菌感染将通过在小鼠模型中体内筛选肽序列，在α毒素和PSM中鉴定抗体中和决定簇。然后，使用产生毒力α毒素和PSM的MRSA，筛选含有从α毒素中鉴定的通用异源辅助T细胞表位或自体辅助T细胞表位的多种抗原肽（MAP），共线性连接至中和B细胞决定簇，以确定其在鼠肺炎和皮肤脓肿激发模型中的疗效。将在体外评估保护的免疫相关性，包括抗体和毒素中和滴度和抗体亲和力，并用于模拟疫苗相关的预防S.金黄色葡萄球菌感染小鼠。在鼠模型中严格评价疫苗安全性后，将使用人用佐剂在远系繁殖兔中验证MAP疫苗的免疫原性，并在S.金黄色葡萄球菌感染，作为在非人灵长类动物中进一步临床试验的前奏。

DESCRIPTION (provided by applicant): Staphylococcus aureus has become a multifaceted threat faced in our hospitals, our nursing homes, and increasingly, in our communities. In particular, methicillin-resistant S. aureus (MRSA) has been an increasing problem in each of these venues, and resistance to other antibiotics, including varying degrees of resistance to vancomycin, is increasingly complicating management of S. aureus infections. The goal of this project is to develop epitope-specific vaccines targeting alpha toxin and the phenol-soluble modulins (PSMs), which are two critical virulence factors for S. aureus, for use in preventing S. aureus infections. Antibody neutralizing determinants will be identified in alpha toxin and the PSMs through screening of peptide sequences in vivo in the mouse model. Multiple antigenic peptides (MAPs) containing universal heterologous helper T cell epitopes or autologous helper T cell epitopes identified from alpha toxin, colinearly-linked to the neutralizing B cell determinants, will then be screened for efficacy in the murine pneumonia and cutaneous abscess challenge models employing virulent alpha toxin- and PSM-producing MRSA. Immune correlates of protection, including antibody and toxin neutralizing titer and antibody affinity, will be assessed in vitro and used to model vaccine-related efficacy in preventing morbidity and mortality from S. aureus infections in mice. Following a rigorous evaluation of vaccine safety in the murine model, MAP vaccines will be validated for immunogenicity in outbred rabbits using human use adjuvants, and the rabbit antisera will be evaluated for protective efficacy using passive transfer protocols in the mouse models of S. aureus infection, as a prelude to further clinical testing in nonhuman primates.