Multivalent Toxoid Vaccine for recurrent Staphylococccus aureus disease

项目摘要 金黄色葡萄球菌（S.金黄色葡萄球菌（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，到侵袭性和危及生命 感染是SA死亡的主要原因。随着抗生素耐药性的增加，这一问题进一步恶化 和缺乏疫苗。SA有一种非凡的能力来逃避和操纵免疫反应，通过 一系列毒力因子，包括大量毒素，主要是成孔毒素（PFT）和 超抗原（SAg）。几种SA表面抗原疫苗在人体功效试验中进行了测试，并且都具有 失败.关于SA感染的保护性免疫应答的性质，存在着深刻的知识缺口。在 在过去的10-15年里，我们发现使用葡萄球菌表面抗原来增强调理吞噬细胞 清除SA不是一个可行的策略，对细胞相关抗原的反应可能引发有害的 免疫反应。抗毒素抗体和有效的T细胞应答是预防SA的关键 感染针对关键SA毒素（主要是PFT和SAg）的中和抗体与更好的临床疗效相关 结果。在本次更新申请之前的R 01中，我们开发了一种多组分疫苗， IBT-V02，并证明了其在包括原发性和复发性SSTI在内的多种模型中的疗效。骨成型球囊-V02 我从CARB-X和一家风险投资公司获得了进一步的资金，用于高级开发，现在计划进入 2022年1期临床试验。我们打算在随访中评估疫苗对复发性SSTI的疗效。 在原发性SA-SSTI患者中进行的II/III期试验。在当前的续订申请中，我们将测试 在人类中，中和PFT和SAgs通过保护PFT和SAgs降低SA-SSTI复发率的假设 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。在 目的1，我们将在Olive View-UCLA急诊科进行一项临床研究，纵向抽样 在一年内出现SA-SSTI的患者，并监测可能的复发。本研究将 通过严格定义的病例定义提供复发率的准确估计，并且首次， 在原发性感染期间和之后，通过 重现时间。在目标2中，将对细菌分离株和纵向免疫学样本进行表征， 免疫学标志物与复发概率的关系将通过 最先进的统计方法。在目标3中，使用人源化小鼠模型和细胞因子报告小鼠，我们将 检验PFT和SAgs的中和作用将使宿主挂载有效的Th 17和γδ T的假设 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团队， 与SA和生物统计学专家的数十年经验以及广泛的跟踪记录已汇集到 来解决这些问题。本研究的结果将提高我们对该病基础免疫学的认识。 葡萄球菌感染，也为临床开发这种病原体急需的疫苗提供了信息。

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.