Development of a Vaccine for Staphylococcal Infections

葡萄球菌感染疫苗的开发

• 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
• 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

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.

项目总结/摘要： 金黄色葡萄球菌导致皮肤和软组织感染（SSTI），导致1420万门诊就诊 每年有85万人入院。S.金黄色葡萄球菌感染与 免疫力低下，即使采用手术和抗生素治疗，经常发生复发性感染。的感染 抗虫S.金黄色葡萄球菌菌株，命名为MRSA（耐甲氧西林S.金黄色葡萄球菌）与 疾病结果不佳，目前在22%的医院分离株中发现。为了解决公众健康问题 我们正在开发一种疫苗来预防侵袭性的S。金黄色葡萄球菌感染S的主要特点 金黄色葡萄球菌病的主要原因是病原体对调理吞噬细胞杀伤（OPK）的抗性和对 宿主的适应性免疫反应葡萄球菌与免疫球蛋白（IG）的结合是由 葡萄球菌蛋白A（SpA），一种与IgG的Fc γ-结构域和重链结合的表面蛋白， VH 3族IgG和IgM链。虽然前者的活性提供了对诱导OPK的抗体的保护， 后者，通过IgM受体的交联，触发增殖和B细胞和非- 保护性VH 3抗体，从而破坏适应性免疫应答和保护性免疫应答的发展。 免疫力我们已经开发了SpA*，这是一种疫苗，它可以激发SpA中和抗体， OPK的病原体，同时也允许宿主产生许多不同的病原体特异性抗体， 排除S。金黄色葡萄球菌定植和降低侵袭性疾病的风险。第一阶段STTR提案 旨在通过确定其临床前安全性来确定生产SpA* 疫苗的可行性， 生物功效