A multivalent vaccine for Staphylococcus aureus

金黄色葡萄球菌多价疫苗

• 批准号: 10421262
• 负责人: JON OSCHERWITZ
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10421262
• 关键词: Adjuvant; Aerosols; Amino Acids; Antibodies; Antigens; Bacillus anthracis; Bacteria; Bacterial Endocarditis; Biological Assay; Centers for Disease Control and Prevention (U.S.); Chickenpox; Clinical Trials; Communicable Diseases; Communities; Community Hospitals; Cytolysins; Cytotoxin; Data; Development; Disease; Epitopes; Evaluation; Gram-Positive Bacteria; Growth; HIV-1; Hemolysin; Hepatitis; Hospitals; Host Defense; Human; Humoral Immunities; Immune Sera; Immunity; Immunization; In Vitro; Individual; Infection; Infectious Skin Diseases; Malaria; Mediating; Medical Economics; Methicillin Resistance; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; Oryctolagus cuniculus; Panton-Valentine leukocidin; Performance; Pertussis; Phase; Pneumonia; Poliomyelitis; Production; Public Health; Reproduction spores; Sepsis; Services; Skin injury; Specificity; Staphylococcal Vaccines; Staphylococcus aureus; Staphylococcus aureus infection; Superantigens; Toxin; United States; Vaccination; Vaccines; Validation; Vancomycin; Virulence; Virulence Factors; Virulent; Virus-like particle; Work; alpha Toxin; cytotoxicity; design; economic impact; efficacy evaluation; human disease; immunogenic; leukotoxin; lung injury; member; methicillin resistant Staphylococcus aureus; military veteran; mortality; mouse model; nanoparticle; neutralizing antibody; pathogen; prevent; protective efficacy; prototype; resistant strain; response; success; tissue injury; vaccine failure; vaccine trial

Staphylococcus aureus is a gram positive bacteria that possesses a multitude of virulence factors. It is a frequent and severe pathogen in hospitals and of increasing concern in the community, where it results in severe skin infections, pneumonia, sepsis and lethal bacterial endocarditis. A significant proportion of these infections are the result of methicillin-resistant S. aureus (MRSA). We have developed a highly immunogenic prototype nanoparticle vaccine capable of rapidly eliciting antibody against the pore neutralizing determinant (PND) within alpha toxin (AT), a ubiquitous and critical virulence factor of MRSA. Previous work has demonstrated that Ab against the PND is highly efficacious in preventing tissue injury and bacterial growth in a rigorous mouse dermonecrosis model, and in protecting mice in a lethal model of S. aureus pneumonia. In this project, we will utilize the human hepatitis core antigen platform to develop nanoparticle vaccines capable of neutralizing the key leukotoxins including gamma toxin, Panton Valentine leukocidin, LukED and LukGH, which are critical, secreted virulence factors which enable S. aureus to evade host immunity, and a nanoparticle vaccine targeting the previously validated PND of AT. The vaccines emerging from these studies will be uniquely effective against MRSA infections and will ideally be the basis of an efficacious, multivalent nanoparticle vaccine for MRSA.

金黄色葡萄球菌是一种革兰氏阳性细菌，具有多种毒力 因素。它是医院中常见且严重的病原体，并且越来越受到人们的关注。 社区，导致严重的皮肤感染、肺炎、败血症和致命 细菌性心内膜炎。这些感染中有很大一部分是由于 耐甲氧西林金黄色葡萄球菌 (MRSA)。我们开发了一种高免疫原性 能够快速引发针对孔的抗体的原型纳米颗粒疫苗 α毒素（AT）中的中和决定簇（PND）是一种普遍存在且至关重要的毒素 MRSA 的毒力因子。先前的工作表明，针对 PND 的 Ab 是 在严格小鼠中非常有效地防止组织损伤和细菌生长 皮肤坏死模型，以及保护金黄色葡萄球菌肺炎致死模型中的小鼠。 在这个项目中，我们将利用人类肝炎核心抗原平台来开发 能够中和包括伽玛在内的关键白细胞毒素的纳米颗粒疫苗 毒素、Panton Valentine 杀白细胞素、LukED 和 LukGH，这些是关键的、分泌的 使金黄色葡萄球菌能够逃避宿主免疫的毒力因子，以及纳米颗粒 针对先前验证的 AT 的 PND 的疫苗。疫苗诞生于 这些研究将对 MRSA 感染具有独特的功效，并且理想地成为 有效的多价 MRSA 纳米颗粒疫苗的基础。