Development of a Vaccine for Staphylococcal Infections

葡萄球菌感染疫苗的开发

基本信息

批准号：
10255984
负责人：
Dominique M. Missiakas
金额：
$ 25.78万
依托单位：
IMMUNARTES LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-16 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10255984
关键词：
Abscess Address Anaphylaxis Animals Antibiotic Resistance Antibiotic Therapy Antibiotics Antibodies Antibody-mediated protection B-Cell Antigen Receptor B-Lymphocytes Bacteremia Bacteria Binding Biological Biological Assay Blood Circulation Catheters Cavia Cell Degranulation Cell secretion Cells Chicago Childhood Clinical Communities Community Hospitals Cyclic GMP Detection Development Devices Disease Disease Outcome Endotoxins Escherichia coli Exhibits Fc domain Future Generations Genus staphylococcus Goals Health Histamine Release Hospitalization Hospitals Human Immune Immune Evasion Immune response Immunity Immunization Immunoblotting Immunoglobulin G Immunoglobulin Idiotypes Immunoglobulin M Immunoglobulins Immunotherapeutic agent Immunotherapy Individual Infection Lead Lesion Lung infections Mediating Membrane Proteins Molecular Mus Natural Immunity Nosocomial Infections Operative Surgical Procedures Outcome Outpatients Paste substance Patients Phase Population Prevalence Preventive Preventive vaccine Process Production Property Proteins Public Health Recurrence Research Residual state Resistance Risk Risk Factors Safety Sales Sepsis Skin Tissue Small Business Technology Transfer Research Soft Tissue Infections Staphylococcal Infections Staphylococcal Protein A Staphylococcus aureus Staphylococcus aureus infection Structure of mucous membrane of nose Superantigens Surface Surgical Wound Infection Testing Time Treatment Efficacy United States United States Food and Drug Administration Universities Vaccinated Vaccine Design Vaccines Variant Visit Work adaptive immune response cell bank clinical efficacy clinically significant commercial application cost crosslink design efficacy testing improved improved outcome mast cell methicillin resistant Staphylococcus aureus mortality mouse model neutralizing antibody novel therapeutics pathogen preclinical development preclinical efficacy preclinical safety prevent programs public health relevance receptor recurrent infection response safety study safety testing skeletal soft tissue therapeutic vaccine vaccine candidate vaccine development vaccine-induced immunity ventilator-associated pneumonia virtual

项目摘要

Project Summary / abstract: Staphylococcus aureus causes skin and soft tissue infections (SSTI) that result in 14.2 million outpatient visits per year and 850,000 hospital admissions. S. aureus infection is not associated with the development of immunity and, even with surgical and antibiotic therapy, recurrent infections occur frequently. Infections with antibiotic-resistant S. aureus strains, designated MRSA (methicillin-resistant S. aureus) are associated with poor disease outcomes and are now identified in 22% of hospital isolates. In order to address the public health crisis of MRSA, we are developing a vaccine to prevent invasive S. aureus infections. Key features of S. aureus disease are the pathogen’s resistance to opsonophagocytic killing (OPK) and the suppression of the host’s adaptive immune responses. Staphylococcal binding to immunoglobulin (Ig) is mediated by staphylococcal protein A (SpA), a surface protein that associates with the Fc-domain of IgG and the heavy chain of VH3 clan IgG and IgM. While the former activity provides protection from antibodies that induce OPK, the latter, through the crosslinking of IgM receptors, triggers proliferation and B cells and secretion of non- protective VH3 antibodies, thereby disrupting adaptive immune responses and the development of protective immunity. We have developed SpA*, a vaccine that elicits SpA-neutralizing antibodies that effectively promote OPK of the pathogen while also allowing the host to generate many different pathogen specific antibodies that together eliminate S. aureus colonization and reduce the risk of invasive disease. This phase I STTR proposal aims to establish the feasibility of generating the SpA* vaccine by establishing its preclinical safety and biological efficacy.

项目概要/摘要：金黄色葡萄球菌引起皮肤和软组织感染 (SSTI)，导致 1,420 万人次就诊每年有 850,000 例金黄色葡萄球菌感染与该病的发生无关。免疫力，即使经过手术和抗生素治疗，感染也经常发生。抗生素耐药性金黄色葡萄球菌菌株，称为 MRSA（耐甲氧西林金黄色葡萄球菌）与疾病结果不佳，目前已在 22% 的医院分离株中发现，以解决公共卫生问题。 MRSA 危机，我们正在开发一种疫苗来预防侵袭性金黄色葡萄球菌感染。金黄色葡萄球菌病的病因是病原体对调理吞噬杀伤 (OPK) 的抵抗力以及对调理吞噬杀伤 (OPK) 的抑制宿主的适应性免疫反应是由葡萄球菌与免疫球蛋白 (Ig) 的结合介导的。葡萄球菌蛋白 A (SpA)，一种与 IgG 的 Fc 结构域和重链结合的表面蛋白 VH3 族 IgG 和 IgM 链虽然前一种活性可提供针对诱导 OPK 的抗体的保护，后者通过 IgM 受体的交联，触发 B 细胞增殖和非- 保护性 VH3 抗体，从而破坏适应性免疫反应和保护性免疫反应的发展我们开发了 SpA*，这是一种可引发 SpA 中和抗体的疫苗，可有效促进免疫。病原体的 OPK，同时还允许宿主产生许多不同的病原体特异性抗体，共同消除金黄色葡萄球菌定植并降低侵袭性疾病的风险这一阶段的 STTR 提案。旨在通过确定其临床前安全性和生产 SpA* 疫苗的可行性生物学功效。