Development of a Multi-species Vaccine for Prevention of Bacterial Otitis Media

预防细菌性中耳炎的多物种疫苗的开发

• 批准号: 10541902
• 负责人: Charles C. McOsker
• 金额: $ 76.26万
• 依托单位: CLARAMETYX BIOSCIENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541902
• 关键词: Acute; Address; Adjuvant; Advanced Development; Antibiotics; Antibodies; Antigens; Bacteria; Bacterial Infections; Bacterial Vaccines; Bacteriology; Behavior; Biological Products; Biological Sciences; Cessation of life; Characteristics; Child; Childhood; Chinchilla (genus); Chronic; Clinical; Clinical Trials; Custom; DNA Binding; Data; Defense Mechanisms; Development; Developmental Delay Disorders; Disease; Dose; Education; Epitopes; Evaluation; Experimental Models; Exposure to; FDA approved; Formulation; Health; Immune; Immune response; Immune system; Immunization; In Vitro; Infection; Integration Host Factors; Investigational New Drug Application; Laboratories; Language; Language Delays; Lead; Left; Mediating; Medical; Microbial Biofilms; Microbiology; Modeling; Moraxella catarrhalis; Nontypable Haemophilus influenza; Office Visits; Operative Surgical Procedures; Otitis Media; Parents; Pathogenesis; Pathogenicity; Phase; Pneumococcal conjugate vaccine; Positioning Attribute; Prevention; Preventive measure; Protein Family; Proteins; Qualifying; Rattus; Recurrence; Regimen; Research Design; Research Personnel; Resolution; Safety; Schedule; Serotyping; Streptococcus pneumoniae; Structure; Surgical Management; Testing; Toxic effect; Treatment Effectiveness; Vaccination; Vaccines; Viral; Wages; Work; analytical method; assay development; co-infection; commercialization; cost effective; design; economic impact; global health; hearing impairment; lead candidate; manufacture; meetings; member; model design; pathogen; pathogenic bacteria; permanent hearing loss; pre-Investigational New Drug meeting; preclinical evaluation; preclinical safety; prevent; programs; protective efficacy; research and development; research clinical testing; response; superinfection; vaccine candidate; vaccine development; vaccine efficacy

Project Summary Otitis media (OM) is a spectrum of clinical entities that presents a tremendous global health burden; in fact, OM is the most common infectious bacterial disease in children. Sequelae of OM include hearing impairment, developmental and language delays, and even death, with nearly $5B spent annually in the US alone for medical/surgical management and lost wages for working parents. The primary causative agents of OM are Streptococcus pneumoniae (Spn), nontypeable Haemophilus influenzae (NTHI) and Moraxella catarrhalis (Mcat). Spn was once the leading cause of acute OM (AOM); however, the introduction of pneumococcal conjugate vaccines (PVCs) has significantly reduced Spn-associated AOM, thereby paving the way for NTHI and non-vaccine Spn serotypes to dominate. Vaccination remains the most impactful and cost-effective way to prevent OM, yet the ever-changing bacteriology of OM requires non-traditional approaches to resolve, and ideally prevent, this global pediatric disease. Clarametyx Biosciences has developed the CMTX-301 vaccine candidate to address all-pathogen OM. Immunization with CMTX-301 focuses the host immune response on specific protective epitopes within components of the bacterial biofilm responsible for its structural stability. When exposed to these antibodies, biofilms rapidly collapse with release of biofilm-resident bacteria. Given that biofilms are the greatest defense mechanism against disease resolution, collapse of these protective fortresses has proven to augment disease resolution in multiple diverse models of experimental disease, including models of OM. By rapidly collapsing bacterial biofilms, vaccination with CMTX-301 allows the host’s natural immune response to clear infection in a pathogen-agnostic manner. Data to date have demonstrated the ability of CMTX-301 to induce collapse of biofilms formed by over 22 bacterial species (both Gram-negative and -positive), including the high priority ESKAPEE pathogens and all three predominant otopathogens. Preliminary evaluation of CMTX-301 has demonstrated its ability to prevent disease in a chinchilla viral- bacterial superinfection model of ascending NTHI-induced OM. The program proposed herein will support studies needed to optimize the research and development precursor of CMTX-301 into a clinically-viable vaccine candidate. We have included studies designed to first evaluate formulations of CMTX-301 with FDA approved adjuvants. Then, based on multiple characteristics and strengths of the induced immune response, the lead and a backup formulation will be tested for relative protective efficacy in a chinchilla model of experimental NTHI-induced OM model with expanded confirmatory evaluation in a rat model of Spn-induced OM. We include evaluation of dose regimen and schedule as part of our program. Additionally, the lead candidate will undergo safety evaluation and GMP manufacturing, as needed to support an Investigational New Drug application with the FDA. This project will position CMTX-301 for advanced development to clinical trials and subsequent commercialization for pediatric use.

项目摘要 中耳炎培养基（OM）是临床实体的范围，它呈现出巨大的全球健康伯恩；实际上， OM是儿童中最常见的传染性细菌疾病。 OM的后遗症包括听力障碍， 发育和语言延误，甚至死亡，仅在美国每年花费近5B美元 医疗/手术管理，因工作父母而失去工资。 OM的主要休闲代理是 肺炎链球菌（SPN），不可用的嗜血性嗜血杆菌影响（NTHI）和莫拉氏菌Catarrhalis （MCAT）。 SPN曾经是急性OM（AOM）的主要原因；但是，引入肺炎 共轭疫苗（PVC）显着降低了SPN相关的AOM，从而为NTHI覆盖了道路 和非疫苗SPN血清型要占主导地位。疫苗接种仍然是最有影响力，最具成本效益的方法 防止OM，但是OM的不断变化的细菌学需要解决非传统方法，并且 理想情况下，这种全球小儿疾病。 Clarametyx Biosciences开发了CMTX-301疫苗 候选人解决​​全疾病原OM。用CMTX-301免疫将宿主免疫反应聚焦于 细菌生物膜的组成部分内的特定保护表位负责其结构稳定性。 当暴露于这些抗体时，生物膜会随着生物膜居民的释放而迅速崩溃。给出 生物膜是针对疾病解决的最大防御机制，这些受保护的崩溃 事实证明，要塞可以在多种潜水员的实验疾病模型中增加疾病的解决， 包括OM的模型。通过快速崩溃的细菌生物膜，CMTX-301的疫苗接种允许宿主的 天然对清除感染的自然免疫反应以病原体敏锐的方式。迄今为止已证明的数据 CMTX-301诱导超过22种细菌形成的生物膜塌陷的能力 和 - 阳性），包括高优先级Eskapee病原体和所有三个主要的眼科疾病。 CMTX-301的初步评估证明了其预防龙猫病毒疾病的能力 上升nthi诱导的OM的细菌超感染模型。本文提出的计划将支持 需要将CMTX-301的研发前体优化为临床可行的研究和开发前体 疫苗候选人。我们纳入了旨在首先用FDA评估CMTX-301公式的研究 批准的调节器。然后，基于诱导免疫反应的多种特征和强度， 铅和备份公式将在龙猫模型中的相对保护效率进行测试 实验N-THI诱导的OM模型，在SPN诱导的大鼠模型中具有扩展的确认评估 om。我们将剂量方案和时间表的评估作为我们计划的一部分。另外，领先者 候选人将根据需要进行安全评估和GMP制造 使用FDA的新药施用。该项目将定位CMTX-301用于高级开发到临床 小儿使用的试验和随后的商业化。