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.

项目摘要 金黄色葡萄球菌（S.金黄色葡萄球菌； SA）是一种主要的公共卫生威胁，导致各种疾病 皮肤和软组织感染（SSTI），包括超过90％的感染，以侵入性和威胁生命 感染，是SA死亡率的主要原因。通过增长的抗生素耐药性进一步加剧了问题 缺乏疫苗。 SA具有非凡的能力，可以通过一个 病毒因子范围，包括大量毒素，主要是形成孔的毒素（PFTS）和 超抗原（SAGS）。在人类效率试验中测试了几种SA表面抗原疫苗，并且都有 失败的。关于受保护的免疫反应对SA感染的性质的性质存在深远的知识差距。在 在过去的10 - 15年中，我们了解到使用葡萄球菌表面抗原增强了opsonoponophopytic 清除不是针对SA的可行策略，对细胞相关抗原的反应会引发有害的 免疫反应。抗毒素抗体和有效的T细胞反应对于保护SA至关重要 感染。对钥匙sa毒素，原发性PFT和突干性的中和抗体与更好的临床相关 结果。在此更新应用之前的先前R01下，我们开发了一种多组分疫苗， IBT-V02，并在包括主要和复发SSTI在内的多个模型中证明了其效率。 IBT-V02 从Carb-X获得了进一步的资金和高级开发的风险投资公司，现在计划进入 2022年的1阶段临床试验。我们打算评估疫苗针对随后的SSTI的疫苗的效率。 在2/3阶段试验中，患有原发性SA-SSTI的患者。在当前的续订应用程序中，我们将测试 在人类中，中和PFT和下垂的假设通过保护降低了经常性SA-STI的速率 这些毒素的细胞和免疫调节作用的组织，先天免疫细胞和T细胞。 AIM 1，我们将在Olive View-UCLA急诊科进行临床研究，并进行纵向采样 在一年内出现SA-SSTI的患者，并监测可能的复发。这项研究会 提供准确估算复发率的速度，并首次定义了案例定义，这是 在原发性感染期间和之后，通过 复发时间。在AIM 2中，将表征细菌分离株和纵向免疫学样本， 免疫标记和复发概率之间的关系将通过最新 艺术统计方法。在AIM 3中，使用人源化的小鼠模型和细胞因子记者小鼠，我们将 检验中和PFT和下垂的假设将使宿主能够安装有效的Th17和γδT 细胞反应。一支经验丰富的疫苗开发专家，临床医生和免疫学家的团队 拥有广泛记录的SA和生物统计学专家的数十年经验已汇集到 解决这些问题。这项研究的结果将提高我们对基本免疫学的理解 葡萄球菌感染，还为这种病原体的急需疫苗的临床发育提供了信息。