A novel Structure Based Vaccine for staphylococcal alpha hemolysin

一种新型结构的葡萄球菌α溶血素疫苗

• 批准号: 8251485
• 负责人: Rajan P Adhikari
• 金额: $ 30万
• 依托单位: INTEGRATED BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251485
• 关键词: Abscess; Adjuvant; Advanced Development; Alhydrogel; Amino Acids; Animal Model; Antibiotic Resistance; Antibiotics; Award; Bacteremia; Bacteria; Biological Assay; Biological Response Modifier Therapy; Cell Surface Proteins; Child; Clinical; Clinical Trials; Combined Vaccines; Communities; Comparative Study; Cyclic GMP; Data; Development; Disease; Distant; Drug Formulations; Enterotoxins; Future; Goals; Growth; Health; Hemolysin; Hospitals; Human; Immune; Immune response; In Vitro; Individual; Infection; Infectious Skin Diseases; Intellectual Property; Investigational Drugs; Investigational New Drug Application; Kidney; Laboratories; Legal patent; Licensing; Life; Life Extension; Liver; Lung; Lung Abscess; Measurement; Methods; Modeling; Monitor; Mus; N-terminal; National Institute of Allergy and Infectious Disease; Nosocomial Infections; Organ; Panton-Valentine leukocidin; Pathogenicity; Pathology; Phase; Phase I Clinical Trials; Pneumonia; Polysaccharides; Prevention; Procedures; Process; Production; Proteins; Reporting; Resistance; Safety; Sepsis; Serum; Skin; Skin Tissue; Small Business Innovation Research Grant; Soft Tissue Infections; Spleen; Staging; Staphylococcal Infections; Staphylococcus alpha toxin; Staphylococcus aureus; Structure; Surface; Surgical Wound Infection; Surgical wound; Testing; Therapeutic; Tissues; Toxic effect; Toxin; Translational Research; United States; United States Food and Drug Administration; Vaccine Design; Vaccines; Ventilator; Virulence Factors; Woman; alpha Toxin; aluminum sulfate; antimicrobial drug; base; clinical practice; combat; commercialization; comparative; design; experience; human disease; immunogenicity; in vivo; mouse model; neutralizing antibody; novel; novel strategies; pathogen; pre-clinical; preclinical study; programs; protective efficacy; resistance mechanism; scale up; subcutaneous; vaccine candidate; vaccine development; wound

DESCRIPTION (provided by applicant): Staphylococcus aureus is a gram positive human pathogen that causes a wide range of infections ranging from skin and soft tissue infections to life threatening diseases like sepsis and pneumonia. S. aureus is well known for its ability to acquire and evolve resistance mechanisms towards antimicrobial agents and meanwhile there are resistances towards all antibiotics available for clinical practice emphasizing a great need fo novel approaches to combat these pathogens. Currently there are no vaccines or therapeutics available for prevention or treatment of diseases caused by S. aureus. S. aureus is the most prevalent cause of hospital acquired infections and in recent years its rate of spread through the community has also been rising to an alarming level. Pneumonia is one of the most severe and prominent complications of S. aureus infection leading with 50,000 cases per year in the US alone. S. aureus pneumonia has been traditionally ventilator associated but in recent years it has been recognized also as a major cause of community acquired pneumonia primarily in otherwise healthy children and young individuals. S. aureus produces a wide range of secreted toxins with immune evasion and immune modulatory functions. Among these alpha hemolysin is known to be one of the most potent toxins and studies from multiple groups including ours show that alpha- hemolysin (Hla) also known as alpha toxin (AT) seems to be a a key virulence factor for S. aureus pneumonia and skin infection when tested in animal models reflecting human diseases. Hla cannot be used as a vaccine in its wild type form due to its toxic effect. The main goal of this Phase I SBIR is to complete proof of concept studies on a novel Hla vaccine designed based on crystallographic structure. Two vaccine candidates have been designed that represent a structural domain at the N terminus of Hla involved in oligomerization: i) the N-terminal 62 amino acids of AT (AT-62aa) and ii) an extended construct including amino acids 1-62 and 223-236 denoted as AT-79aa. Preliminary data presented in this proposal indicate induction of neutralizing antibodies and protective efficacy of AT-62aa in a pneumonia model of S. aureus infection, while a previously described AT-50aa (which disrupts the domain structure) only afforded a slight extension of life but was not protective when used with Alhydrogel adjuvant (in contrast to previous reports using IFA). This proposal is outlined in three specific Aims: In Aim 1, we will identify the best vaccine candidate based on immunogenicity studies of His-tagged AT-62aa protein using three different adjuvants that are either in licensed products (alum) or in clinical trial for human use (CpG and IDC-1001) and identify the optimal adjuvant. In specific Aim 2, we will develop a preliminary procedure for production and purification of a tag-free protein for the vaccine construct selected in Aim 1. We will also characterize the protein by biophysical methods, and perform a bridging study to confirm its immunogenicity in vivo. In specific Aim 3, we will perform a full set of proof of concept studies to show the protective efficacy of the optimal vaccine candidate in four different mouse models of infection: pneumonia, subcutaneous abscess model representing SSTI, bacteremia/sepsis, and surgical wound infection. This proposal is a collaborative effort between IBT and Dr. Jean Lee's laboratory at Brigham Women Hospital. Upon completion of the Phase I we envision a Phase II SBIR focused on completing preclinical development leading to submission of an Investigational New Drug (IND) application to the Food and Drug Administration. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus is a bacteria that causes a wide range of infections ranging from skin and soft tissue infections to life threatening diseases like sepsis and pneumonia. Pneumonia is one of the most severe and prominent complications of S. aureus infection leading with 50,000 cases per year in the US alone. S. aureus is becoming increasingly resistant to antibiotics. In this proposal we seek to develop a vaccine for alpha hemolysin, one of the most potent toxins produced by S. aureus. This toxin is critically involved in pneumonia and skin infections. A vaccine against alpha hemolysin is expected to protect humans from life threatening complications of staphylococcal infections.

描述（由申请人提供）：金黄色葡萄球菌是一种革兰氏阳性人类病原体，可引起多种感染，从皮肤和软组织感染到败血症和肺炎等危及生命的疾病。金黄色葡萄球菌以其获得和进化对抗菌药物的耐药机制的能力而闻名，同时对所有可用于临床实践的抗生素都存在耐药性，这强调了对抗这些病原体的新方法的巨大需求。目前没有疫苗或治疗方法可用于预防或治疗金黄色葡萄球菌引起的疾病。金黄色葡萄球菌是医院获得性感染的最普遍原因，近年来其在社区中的传播速度也已上升到令人震惊的水平。肺炎是金黄色葡萄球菌感染最严重和最突出的并发症之一，仅在美国每年就有 50,000 例病例。金黄色葡萄球菌肺炎传统上与呼吸机相关，但近年来，它也被认为是社区获得性肺炎的主要原因，主要发生在其他健康的儿童和青少年中。金黄色葡萄球菌产生多种具有免疫逃避和免疫调节功能的分泌毒素。在这些α溶血素中，已知是最有效的毒素之一，包括我们在内的多个小组的研究表明，在反映人类疾病的动物模型中进行测试时，α-溶血素（Hla）也称为α毒素（AT）似乎是金黄色葡萄球菌肺炎和皮肤感染的关键毒力因子。由于其毒性作用，Hla 野生型形式不能用作疫苗。第一阶段 SBIR 的主要目标是完成基于晶体结构设计的新型 Hla 疫苗的概念验证研究。已经设计了两种候选疫苗，它们代表参与寡聚化的 Hla N 末端的结构域：i) AT 的 N 末端 62 个氨基酸 (AT-62aa) 和 ii) 包括氨基酸 1-62 和 223-236 的扩展构建体，表示为 AT-79aa。该提案中提供的初步数据表明，AT-62aa 在金黄色葡萄球菌感染的肺炎模型中具有中和抗体的诱导作用和保护功效，而之前描述的 AT-50aa（破坏结构域结构）仅能稍微延长寿命，但与 AlHydrogel 佐剂一起使用时没有保护作用（与之前使用 IFA 的报告相反）。该提案概述了三个具体目标：在目标 1 中，我们将使用许可产品（明矾）或人用临床试验（CpG 和 IDC-1001）中的三种不同佐剂对 His 标记的 AT-62aa 蛋白进行免疫原性研究，以确定最佳候选疫苗，并确定最佳佐剂。在具体目标 2 中，我们将为目标 1 中选择的疫苗构建体开发一种生产和纯化无标签蛋白的初步程序。我们还将通过生物物理方法表征该蛋白，并进行桥接研究以确认其体内免疫原性。在具体目标 3 中，我们将进行全套概念验证研究，以展示最佳候选疫苗在四种不同小鼠感染模型中的保护功效：肺炎、代表 SSTI 的皮下脓肿模型、菌血症/败血症和手术伤口感染。该提案是 IBT 和布莱根妇女医院 Jean Lee 博士实验室的合作成果。第一阶段完成后，我们预计第二阶段 SBIR 的重点是完成临床前开发，从而向美国食品和药物管理局提交研究性新药 (IND) 申请。 公共卫生相关性：金黄色葡萄球菌是一种细菌，可引起多种感染，从皮肤和软组织感染到败血症等危及生命的疾病 和肺炎。肺炎是金黄色葡萄球菌感染最严重和最突出的并发症之一，仅在美国每年就有 50,000 例病例。金黄色葡萄球菌对抗生素的耐药性越来越强。在这项提案中，我们寻求开发一种针对α溶血素的疫苗，α溶血素是金黄色葡萄球菌产生的最有效的毒素之一。这种毒素与肺炎和皮肤感染密切相关。针对α溶血素的疫苗有望保护人类免受葡萄球菌感染的危及生命的并发症。