Multivalent Toxoid Vaccine for recurrent Staphylococccus aureus disease

项目摘要 金黄色葡萄球菌(S.aureus；SA)是一种主要的公共卫生威胁，可引起多种疾病。 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 感染是金黄色葡萄球菌死亡的主要原因。抗生素耐药性的增长进一步加剧了这一问题。 以及缺乏疫苗。SA具有非凡的能力，可以通过一种 一系列致病因子，包括过多的毒素，主要是形成毛孔的毒素(PFTs)和 超抗原(SAG)。几种SA表面抗原疫苗在人体疗效试验中进行了测试，所有疫苗都有 失败了。关于对SA感染的保护性免疫反应的性质，存在着深刻的知识差距。在……里面 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吞噬细胞的能力 清除不是对抗SA的可行策略，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细胞反应是预防SA的关键 感染。针对关键SA毒素的中和抗体，主要是PFTs和SAG，与更好的临床相关 结果。在本次续期申请之前的R01之前，我们开发了一种多组分疫苗， IBT-V02，并在包括原发和复发性SSTI在内的多种模型上证明了其有效性。IBT-V02 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。我们打算在接下来的一项研究中评估疫苗对复发的SSTI的疗效。 在2/3期试验中，患者表现为原发的SA-SSTI。在目前的续费申请中，我们将测试 在人类中，假设中和PFTs和SSAG通过保护 来自这些毒素的细胞溶解和免疫调节作用的组织、先天免疫细胞和T细胞。在……里面 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 患者在一年内出现SA-SSTI，并监测可能的复发。这项研究将 通过严格定义的病例定义提供对复发率的准确估计，并首次 在初次感染期间和之后通过以下途径提供纵向微生物和免疫样本 复发时间。在目标2中，将对细菌分离株和纵向免疫样本进行表征， 免疫标志物和复发概率之间的关系将通过-状态分析 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 测试假设，PFT和SAG的中和将使宿主能够安装有效的Th17和γδT 细胞反应。由经验丰富的疫苗开发专家、临床医生和免疫学家组成的团队 拥有丰富记录的SA和生物统计专家数十年的经验已经积累到 回答这些问题。这项研究的结果将提高我们对基础免疫学的理解。 葡萄球菌感染，并为临床开发这种病原体迫切需要的疫苗提供信息。

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.