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本项目的目标是开发针对α毒素和酚溶性调节蛋白（PSM）的表位特异性疫苗，这两个因子是沙门氏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。 公共卫生相关性： 金黄色葡萄球菌已成为我们在战争与和平中面临的多方面威胁。它存在于战场上，在我们的医院，我们的养老院和我们的社区，把较小的伤害和疾病变成改变生活的灾难。它对我们的抗生素越来越有抗药性，正在逃脱我们的控制措施。该项目的目标是为退伍军人事务部和整个社会提供一种新的工具和新的方法，以应对S的人力和财政负担。通过开发针对两种关键毒力因子（α毒素和酚可溶性调节蛋白）的疫苗来对抗金黄色葡萄球菌感染。本工作可能会导致一个安全有效的毒力因子特异性S。金黄色葡萄球菌疫苗，可以广泛受益退伍军人和非退伍军人群体，并可能促进其他毒力因子疫苗的发展。

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. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus has become a multifaceted threat that confronts us in war and peace. It is present on the battlefield, in our hospitals, our nursing homes, and our communities, turning lesser injuries and illnesses into life-altering catastrophes. It is becoming increasingly resistant to our antibiotics, and is escaping our control measures. The goal of this project is to provide the VA, and society at large, with a new tool and a new approach for countering the human and financial burden of S. aureus infections by developing a vaccine that targets two critical virulence factors, alpha-toxin and the phenol-soluble modulins. This work may lead to a safe and effective virulence factor-specific S. aureus vaccine that could broadly benefit the veteran and non-veteran population, and may facilitate the development of other virulence factor vaccines.