Multivalent Toxoid Vaccine for recurrent Staphylococccus aureus disease

用于复发性金黄色葡萄球菌病的多价类毒素疫苗

• 批准号: 10441657
• 负责人: M Javad Aman
• 金额: $ 70.29万
• 依托单位: INTEGRATED BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441657
• 关键词: Accident and Emergency department; Active Immunization; Acute; Address; Adult; Advanced Development; Animal Model; Antibiotic Resistance; Antibodies; Antibody titer measurement; Antigens; Antimicrobial Resistance; Bacteremia; Biometry; Breeding; Cardiovascular Surgical Procedures; Cells; Chills; Clinical; Clinical Research; Clinical Trials; Cytotoxic T-Lymphocytes; Development; Disease; Epidemiology; Failure; Funding; Future; Genus staphylococcus; Gram-Positive Bacteria; Grant; Heart; Human; Immune; Immune response; Immunologic Markers; Immunologics; Immunologist; Immunology; Incidence; Industry; Infection; Infectious Skin Diseases; Interleukin-17; Investments; Kinetics; Knowledge; Life; Methicillin Resistance; Methodology; Microbiology; Modeling; Monitor; Morbidity - disease rate; Mus; Nature; Olives - dietary; Operative Surgical Procedures; Orthopedic Surgery; Outcome; Passive Immunization; Pathogenicity; Patients; Peripheral Blood Mononuclear Cell; Phase I Clinical Trials; Phase II/III Trial; Pneumonia; Polysaccharides; Primary Infection; Probability; Prosthesis; Public Health; Recurrence; Reporter; Reporting; Role; Sampling; Schedule; Sepsis; Severity of illness; Shapes; Site; Skin; Skin Tissue; Soft Tissue Infections; Source; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus aureus infection; Superantigens; Surface Antigens; T cell response; T-Lymphocyte; Target Populations; Testing; Time; Tissues; Toxic Shock Syndrome; Toxin; Toxoids; Transgenic Mice; Vaccine Antigen; Vaccine Research; Vaccinee; Vaccines; Virulence Factors; Visit; antitoxin; arm; base; capsule; clinical development; cost; cytokine; efficacy evaluation; efficacy trial; epidemiology study; experience; human pathogen; humanized mouse; improved; indexing; insight; methicillin resistant Staphylococcus aureus; mortality; mouse model; neutralizing antibody; novel; pathogen; phase I trial; prevent; prospective; protective efficacy; rational design; recurrent infection; research and development; response; skin disorder; success; vaccine access; vaccine candidate; vaccine development; vaccine efficacy; γδ T cells

Project Summary Staphylococcus aureus (S. aureus; SA) is a major public health threat causing a variety of diseases from the skin and soft tissue infections (SSTI), comprising over 90% of infections, to invasive and life-threatening infections, the major cause of SA mortality. The problem is further exacerbated by growing antibiotic resistance and a lack of a vaccine. SA has a remarkable ability to evade and manipulate immune responses through a range of virulence factors, including a plethora of toxins, mainly the pore-forming toxins (PFTs) and superantigens (SAgs). Several SA surface antigen vaccines were tested in human efficacy trials and all have failed. There is a profound knowledge gap about the nature of a protective immune response to SA infection. In the past 10-15 years, we have learned that using staphylococcal surface antigens to enhance opsonophagocytic clearance is not a viable strategy against SA, and response to cell-associated antigens can trigger deleterious immune responses. Antitoxin antibodies and an effective T cell response are critical for protection against SA infection. Neutralizing antibodies against key SA toxins, primarily PFTs, and SAgs, correlate with better clinical outcomes. Under the prior R01 preceding this renewal application, we developed a multi-component vaccine, IBT-V02, and demonstrated its efficacy in multiple models including primary and recurrent SSTI. IBT-V02 received further funding from CARB-X and a VC firm for advanced development and is now scheduled to enter Phase 1 clinical trial in 2022. We intend to evaluate the efficacy of the vaccine against recurrent SSTI in a follow- on Phase 2/3 trial in patients presenting with a primary SA-SSTI. In the current renewal application, we will test the hypothesis, in humans, that neutralizing PFTs and SAgs reduce the rate of recurrent SA-SSTI by protecting tissues, innate immune cells, and T cells from the cytolytic and immune-modulatory effects of these toxins. In Aim 1, we will conduct a clinical study at Olive View-UCLA emergency Department with longitudinal sampling of patients presenting with SA-SSTI over a one-year period with monitoring for possible recurrence. This study will provide an accurate estimate of the rate of recurrence with a tightly defined case definition and, for the first time, provide longitudinal microbiological and immunological samples during and after a primary infection through the time of recurrence. In Aim 2, the bacterial isolates and longitudinal immunological samples will be characterized, and the relationship between immunological markers and probability of recurrence will be analyzed by state-of- the-art statistical methodologies. In Aim 3, using humanized mouse models and cytokine reporter mice, we will test the hypothesis that neutralization of PFTs and SAgs will enable the host to mount effective Th17 and γδ T cell responses. A highly experienced team of vaccine development experts, clinicians, and immunologists with decades of experience with SA and biostatistics experts with an extensive track record has been assembled to address these questions. The result of this study will elevate our understanding of basic immunology of staphylococcal infections and also inform clinical development of urgently needed vaccines for this pathogen.

项目概要 金黄色葡萄球菌（S. aureus；SA）是一种主要的公共卫生威胁，可导致多种疾病 皮肤和软组织感染 (SSTI)，占感染的 90% 以上，具有侵袭性和危及生命的特点 感染是 SA 死亡的主要原因，抗生素耐药性的增加进一步加剧了这一问题。 而且缺乏疫苗，SA 具有通过免疫反应逃避和操纵免疫反应的非凡能力。 一系列毒力因子，包括大量毒素，主要是成孔毒素（PFT）和 多种 SA 表面抗原疫苗已在人体功效试验中进行了测试，并且均具有超级抗原 (SAgs) 的特性。 关于 SA 感染的保护性免疫反应的性质存在深刻的知识差距。 在过去的10-15年里，我们了解到使用葡萄球菌表面抗原来增强调理吞噬细胞 清除并不是针对 SA 的可行策略，并且对细胞相关抗原的反应可能引发有害的 抗毒素抗体和有效的 T 细胞反应对于预防 SA 至关重要。 针对关键 SA 毒素（主要是 PFT 和 SAgs）的中和抗体与更好的临床相关。 根据本次更新申请之前的 R01 成果，我们开发了一种多成分疫苗， IBT-V02，并在包括原发性和复发性 SSTI 在内的多种模型中证明了其功效。 获得了 CARB-X 和一家风险投资公司的进一步资金用于高级开发，现在计划进入 2022 年进行 1 期临床试验。我们打算在后续阶段评估该疫苗针对复发性 SSTI 的功效。 在患有原发性 SA-SSTI 的患者中进行 2/3 期试验 在当前的更新申请中，我们将进行测试。 在人类中，中和 PFT 和 SAgs 的假设通过保护来降低 SA-SSTI 复发率 组织、先天免疫细胞和 T 细胞免受这些毒素的细胞溶解和免疫调节作用。 目标 1，我们将在 Olive View-UCLA 急诊科进行一项临床研究，纵向抽样 这项研究将在一年内对出现 SA-SSTI 的患者进行监测，以监测可能的复发情况。 通过严格定义的病例定义来准确估计复发率，并且首次 通过以下方式提供初次感染期间和之后的纵向微生物和免疫学样本 在目标 2 中，将对细菌分离株和纵向免疫样本进行表征， 免疫学标志物与复发概率之间的关系将通过state-of-进行分析 在目标 3 中，我们将使用人源化小鼠模型和细胞因子报告小鼠。 检验以下假设：中和 PFT 和 SAgs 将使宿主能够安装有效的 Th17 和 γδ T 一个由疫苗开发专家、忠诚者和免疫学家组成的经验丰富的团队 与具有丰富记录的 SA 和生物统计专家数十年的经验相结合， 解决这些问题将提高我们对基础免疫学的理解。 葡萄球菌感染，并为该病原体急需的疫苗的临床开发提供信息。