Assays for acceleration: from fit-for-purpose models to scalable assays of broad systemic and mucosal protection against all strains of Group A Streptococcus

加速测定：从适合目的模型到针对 A 组链球菌所有菌株的广泛全身和粘膜保护的可扩展测定

• 批准号: 10576786
• 负责人: Anna Norrby-Teglund
• 金额: $ 47.23万
• 依托单位: MURDOCH CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576786
• 关键词: Acceleration; Adjuvant; Adult; Animal Model; Antigens; Bacteria; Biological Assay; Blood specimen; Cells; Cellular Immunology; Characteristics; Child; Clinical; Clinical Trials; Development; Disease; Failure; Funding; Future; Gene Expression; Goals; Human; Immune; Immune response; Immunoassay; Immunocompetent; Immunology; Infection prevention; Inflammatory Response; International; Investments; Knowledge; Liquid substance; Modeling; Mucosal Immune Responses; Mucous Membrane; Oral; Outcome; Outcomes Research; Pathway interactions; Peripheral Blood Mononuclear Cell; Pharyngitis; Phase; Pre-Clinical Model; Public Health; Publishing; Research; Sampling; Scourge; Signal Transduction; Source; Specimen; Standardization; Streptococcal Infections; Streptococcal Vaccines; Streptococcus pyogenes; Syndrome; System; Techniques; Testing; Tissue Model; Tissues; Tonsil; Tube; Vaccinated; Vaccine Antigen; Vaccine Clinical Trial; Vaccine Design; Vaccines; Whole Blood; burden of illness; cytokine; design; experience; functional group; human model; immunogenicity; in vitro Assay; in vivo; insight; next generation; novel; pathogen; pathogenic bacteria; pre-clinical; programs; research and development; response; sample collection; systemic inflammatory response; tool; transcriptomics; vaccine candidate; vaccine development; vaccine discovery; vaccine evaluation; vaccine-induced immunity

PROJECT SUMMARY/ABSTRACT There is renewed international momentum to develop vaccines to prevent infections caused by the highly adapted, human-restricted bacterial pathogen Group A Streptococcus (GAS). However, the lack of a known correlate of human immune protection against GAS infection and the limitations of current in vitro assays and preclinical models have impeded development of promising preclinical vaccine candidates and threatens future investment in GAS vaccine discovery and design. To overcome this roadblock, we will undertake a cross- disciplinary collaborative research program, drawing on highly relevant human samples and developing a new human ex vivo tissue model, to discover broadly applicable potential human correlates of protection that will inform design of practical immunoassays fit for deployment in clinical vaccine trials. Rather than adhering to the constraints of historical GAS immunoassays, we are explicitly targeting preferred characteristics for clinical immunogenicity assays to support vaccine development, such as practicality, accuracy and broad application to relevant syndromes and strains. GAS naturally infects humans only, therefore we will take a human-centred approach, purposefully moving away from animal models that do not adequately represent relevant complexities of the human immune response. We will apply cutting edge immunology approaches to study diverse human samples from parallel research programs, including from externally funded trials using our own GAS human challenge model to evaluate vaccine protection against pharyngitis, the primary target indication for vaccine development efforts. Initial published findings from the GAS pharyngitis human challenge model show that protection may be associated with robust early mucosal and systemic Th1 inflammatory responses, in clear alignment with recent preclinical animal model findings, and highlighting vaccine-induced antigen-specific Th1 responses as a correlate of protection for multicomponent vaccines. We will characterize the transcriptomic basis for this immune response using our existing human sample collection. We will draw on our experience with human whole blood stimulation assays and tissue models to establish whole-blood and organotypic tonsil tissue models as our primary research tools. This approach will allow us to interrogate ex vivo human immune responses to whole bacteria, culture supernatant, and vaccine antigens to discover potential systemic and mucosal correlates of protection. These broad-ranging efforts to identify immune pathways implicated in vaccine-induced protection will inform the design of a practical, scalable, and strain-agnostic whole-blood in-tube assay (analogous to cytokine release assays), and a high-throughput functional oral fluid mucosal assay to test in forthcoming clinical trials of novel GAS vaccines.

项目概要/摘要 国际上出现了新的动力来开发疫苗来预防由高度流感病毒引起的感染 适应人类限制的细菌病原体 A 组链球菌 (GAS)。然而，缺乏已知的 人体针对 GAS 感染的免疫保护与当前体外测定的局限性之间的相关性 临床前模型阻碍了有前景的临床前候选疫苗的开发，并威胁到未来 投资 GAS 疫苗发现和设计。为了克服这一障碍，我们将采取跨 学科合作研究计划，利用高度相关的人类样本并开发新的 人类离体组织模型，以发现广泛适用的潜在人类保护相关性 为适合临床疫苗试验的实用免疫测定的设计提供信息。而不是恪守 历史 GAS 免疫测定的限制，我们明确针对临床的首选特征 支持疫苗开发的免疫原性测定，例如实用性、准确性和广泛应用 相关的综合症和菌株。 GAS自然只感染人类，因此我们将采取以人为本的方法，有目的地远离 来自不能充分代表人类免疫反应的相关复杂性的动物模型。我们 将应用尖端免疫学方法来研究平行研究中的不同人类样本 计划，包括使用我们自己的 GAS 人类挑战模型来评估疫苗的外部资助试验 预防咽炎，这是疫苗开发工作的主要目标适应症。初次发表 GAS 咽炎人类挑战模型的研究结果表明，保护可能与强健的咽炎相关 早期粘膜和全身 Th1 炎症反应，与最近的临床前动物模型明显一致 研究结果，并强调疫苗诱导的抗原特异性 Th1 反应与保护的相关性 多组分疫苗。我们将使用我们的方法来描述这种免疫反应的转录组学基础 现有的人类样本收集。我们将借鉴人类全血刺激试验的经验 和组织模型，建立全血和器官型扁桃体组织模型作为我们的主要研究工具。 这种方法将使我们能够研究离体人体对整个细菌、培养物的免疫反应。 上清液和疫苗抗原，以发现潜在的系统和粘膜保护相关性。这些 确定与疫苗诱导的保护有关的免疫途径的广泛努力将为设计提供信息 实用的、可扩展的、与菌株无关的全血管内测定（类似于细胞因子释放测定）， 以及高通量功能性口腔粘膜测定，以在即将进行的新型 GAS 临床试验中进行测试 疫苗。