Epitope-specific vaccines targeting the alpha toxin of Staphylococcus aureus

针对金黄色葡萄球菌α毒素的表位特异性疫苗

• 批准号: 8212753
• 负责人: Kemp Bailey Cease
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212753
• 关键词: Abscess; Adjuvant; Adverse effects; Alhydrogel; Antibiotics; Antibodies; Antibody Affinity; Antigen-Antibody Complex; Antigens; Autologous; Autopsy; B-Lymphocyte Epitopes; B-Lymphocytes; Bacillus anthracis; Biological Assay; Body Weight; CD4 Positive T Lymphocytes; Chemistry; Combined Vaccines; Communities; Cutaneous; Data; Deposition; Development; Epitopes; Evaluation; Goals; Helper-Inducer T-Lymphocyte; Hematology; Histopathology; Hospitals; Human; Immune; Immune Sera; Immune response; Immunity; In Vitro; Individual; Infection; Injury; Lead; Life; Linear Regressions; Link; Measures; Mediating; Modeling; Monitor; Morbidity - disease rate; Mus; N-terminal; Nursing Homes; Organ; Oryctolagus cuniculus; Peptide Vaccines; Peptides; Peripheral Blood Mononuclear Cell; Phenols; Pneumonia; Population; Protocols documentation; Qualifying; Resistance; Safety; Screening procedure; Societies; Staphylococcus aureus; T-Lymphocyte Epitopes; Testing; Toxic effect; Toxin; Vaccination; Vaccines; Vancomycin; Veterans; Virulence Factors; Virulent; War; Work; alpha Toxin; candidate validation; cytokine; cytotoxic; immunogenicity; in vitro Assay; in vivo; lymph nodes; methicillin resistant Staphylococcus aureus; mortality; mouse model; neutralizing antibody; nonhuman primate; novel strategies; peace; pre-clinical; prevent; protective efficacy; protein aminoacid sequence; prototype; public health relevance; research clinical testing; tool; vaccine candidate; vaccine development; vaccine efficacy; vaccine safety; validation studies

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.

描述（由申请人提供）： 金黄色葡萄球菌已成为我们的医院、疗养院以及越来越多的社区面临的多方面威胁。特别是，耐甲氧西林金黄色葡萄球菌 (MRSA) 在这些场所中已成为一个日益严重的问题，而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，使金黄色葡萄球菌感染的管理变得越来越复杂。该项目的目标是开发针对 α 毒素和酚溶性调节蛋白 (PSM)（金黄色葡萄球菌的两个关键毒力因子）的表位特异性疫苗，用于预防金黄色葡萄球菌感染。通过在小鼠模型中筛选体内肽序列，将在 α 毒素和 PSM 中鉴定抗体中和决定簇。然后，将筛选含有从 α 毒素中鉴定出的通用异源辅助 T 细胞表位或自体辅助 T 细胞表位、与中和 B 细胞决定簇共线连接的多种抗原肽 (MAP)，以评估其在使用产生剧毒 α 毒素和 PSM 的 MRSA 的小鼠肺炎和皮肤脓肿攻击模型中的功效。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，将在体外进行评估，并用于模拟预防小鼠金黄色葡萄球菌感染发病和死亡的疫苗相关功效。在对小鼠模型中的疫苗安全性进行严格评估后，将使用人用佐剂在近交系兔子中验证 MAP 疫苗的免疫原性，并将在金黄色葡萄球菌感染的小鼠模型中使用被动转移方案评估兔抗血清的保护功效，作为在非人灵长类动物中进一步临床测试的前奏。 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时期面临的多方面威胁。它存在于战场、我们的医院、我们的疗养院和我们的社区，将较轻的伤害和疾病变成了改变生活的灾难。它对我们的抗生素的抵抗力越来越强，并且正在逃避我们的控制措施。该项目的目标是通过开发针对两种关键毒力因子（α-毒素和酚溶性调节蛋白）的疫苗，为退伍军人管理局和整个社会提供一种新工具和新方法，以应对金黄色葡萄球菌感染造成的人力和经济负担。这项工作可能会产生一种安全有效的毒力因子特异性金黄色葡萄球菌疫苗，使退伍军人和非退伍军人群体广泛受益，并可能促进其他毒力因子疫苗的开发。