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: 8465176
• 负责人: Rajan P Adhikari
• 金额: $ 29.08万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465176
• 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.

描述（由申请人提供）：金黄色葡萄球菌是一种革兰氏阳性的人类病原体，会引起广泛的感染，从皮肤和软组织感染到威胁生命的疾病，如败血症和肺炎。金黄色葡萄球菌以其获得和进化抗药性机制的能力而闻名，同时，对所有可用于临床实践的抗生素具有抗药性，强调了一种非常需要的新方法来对抗这些病原体。目前，没有可用于预防或治疗由金黄色葡萄球菌引起的疾病的疫苗或治疗剂。金黄色葡萄球菌是医院获得感染的最普遍的原因，近年来，其在社区中的传播率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，最突出的并发症之一，仅美国就有50,000例病例。金黄色葡萄球菌肺炎传统上一直是呼吸机相关的，但近年来，它也被认为是社区获得肺炎的主要原因，主要是在其他健康的儿童和年轻人中。金黄色葡萄球菌可产生各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，众所周知，包括我们的多种毒素是最有效的毒素之一，我们的研究表明，α-血素蛋白（HLA）也称为α毒素（AT），在反映人类疾病的动物模型中测试时，在测试中，似乎是aureus肺炎链球菌和皮肤感染的关键毒力因子。由于其有毒作用，HLA不能用作野生型形式的疫苗。该阶段I SBIR的主要目标是完成基于晶体学结构设计的新型HLA疫苗的概念研究证明。已经设计了两个候选疫苗候选物，代表了参与寡聚的N末端的结构结构域：i）N端62 AT（AT-62AA）和II）的N末端62氨基酸和II）包括氨基酸1-62和223-236的扩展构建体。 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).该提案在三个具体目的中概述：在AIM 1中，我们将使用三种不同的辅助剂（使用有执照的产品（校友）或临床试验中的人类使用（CPG和IDC-1001）中的三种不同的佐剂来鉴定基于HIS标记的AT-62AA蛋白的免疫原性研究（CPG和IDC-1001）（CPG和IDC-1001），并确定最佳辅助抗体。在特定目标2中，我们将开发一种初步程序，用于为AIM 1选择的疫苗构建体生产和纯化无标签蛋白。我们还将通过生物物理方法来表征该蛋白质，并进行桥接研究以确认其在体内的免疫原性。在特定的目标3中，我们将执行一套概念研究证明，以显示四种不同小鼠感染模型中最佳疫苗候选者的保护作用：肺炎，皮下脓肿模型，代表SSTI，细菌/脓毒症和手术伤口伤口感染。这项建议是IBT和Jean Lee博士在Brigham妇女医院实验室之间的合作努力。第一阶段完成后，我们设想了II期SBIR，重点是完成临床前开发，从而使研究新药（IND）向食品药品管理局提出了申请。