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

基本信息

批准号：
8597331
负责人：
Kemp Bailey Cease
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
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/8597331
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 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 screening tool vaccine candidate vaccine development vaccine efficacy vaccine safety validation studies

项目摘要

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医院，疗养院以及我们社区越来越多的多方面威胁。特别是，在每个场所中，耐甲氧西林的金黄色葡萄球菌（MRSA）一直是一个越来越多的问题，对其他抗生素的抗性，包括对万古霉素的耐药性的不同程度，正在越来越复杂化金黄色葡萄球菌感染。该项目的目的是开发针对α毒素的表位特异性疫苗和苯酚可溶蛋白（PSMS），这是用于预防金黄色葡萄球菌感染的两个关键毒力因子。通过在小鼠模型中筛选体内肽序列，将在α毒素和PSM中鉴定中和决定因素。多种抗原肽（MAP）含有通用异型助手T细胞表位或从α毒素中鉴定出的自体助手T细胞表位，并连接到中和B细胞决定因素，然后将其在小鼠肺炎和可爱的pshane pshane pshaumos cabless Alpha-prodmapla-propa-propla-propla-propla-propla-propla toxs筛选为中和B细胞的决定性。保护的免疫相关性，包括抗体和中和抗体亲和力在内，将在体外进行评估，并用于模拟与疫苗相关的功效，以防止小鼠的金黄色葡萄球菌感染的发病率和死亡率。在对鼠模型中对疫苗安全性进行严格评估后，将对使用人类使用佐剂在近代兔子中的免疫原性进行验证，并将评估兔抗血清，以使用S. aureus Infection的小鼠模型中的被动转移方案进行保护效率，作为在非脑性底漆中进一步的临床临床测试。公共卫生相关性：金黄色葡萄球菌已成为战争与和平面临的多方面威胁。它出现在战场上，在我们的医院，我们的疗养院和我们的社区中，将较小的伤害和疾病变成改变生活的灾难。它越来越对我们的抗生素具有抵抗力，并且正在逃脱我们的控制措施。该项目的目的是通过开发针对两个关键的毒力因子，α-毒素和苯酚 - 溶解剂量的疫苗来应对金黄色葡萄球菌感染的人类和金黄色葡萄球菌感染的新工具和新方法。这项工作可能会导致安全有效的毒力因子特异性金黄色链球菌疫苗，该疫苗可能会广泛地使退伍军人和非退伍军人人口受益，并可能促进其他毒力因子疫苗的发展。