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

项目摘要 中耳炎(OM)是一系列临床实体，给全球带来巨大的健康负担；事实上， OM是儿童最常见的感染性细菌性疾病。OM的后遗症包括听力障碍， 发育和语言延迟，甚至死亡，仅在美国每年就花费近50亿美元用于 医疗/外科管理和在职父母的工资损失。OM的主要致病因素是 肺炎链球菌(Spn)、非分型流感嗜血杆菌(NTHI)和卡他莫拉菌 (MCAT)。SPN曾经是急性OM(AOM)的主要原因；然而，肺炎球菌的引入 结合疫苗(PVC)显著减少了Spn相关的AOM，从而为NTHI铺平了道路 非疫苗Spn血清型占主导地位。接种疫苗仍然是最有效和最具成本效益的方式 预防OM，然而OM的不断变化的细菌学需要非传统的方法来解决，以及 理想的预防方式是预防这种全球性的儿科疾病。Clarametyx生物科学公司已经开发出CMTX-301疫苗 解决所有病原体OM的候选人。CMTX-301免疫将宿主免疫反应集中在 细菌生物膜组分中负责其结构稳定性的特定保护性表位。 当接触到这些抗体时，生物膜迅速崩溃，释放出驻留在生物膜上的细菌。vt.给出 认为生物膜是抵御疾病分解的最大防御机制，这些保护性物质的崩溃 堡垒已经被证明在多种不同的实验性疾病模型中增强了疾病的分辨率， 包括OM的模型。通过迅速分解细菌生物膜，接种CMTX-301疫苗可以使宿主的 以病原体不可知的方式对明确感染的自然免疫反应。迄今为止的数据已经证明 CMTX-301诱导22种以上细菌(均为革兰氏阴性)形成的生物膜崩溃的能力 和阳性)，包括高优先级的ESKAPEE病原体和所有三种主要的耳部病原体。 CMTX-301的初步评估表明，它能够预防龙猫病毒的疾病- 上行性NTHI致OM的细菌重叠感染模型。这里提出的计划将支持 需要研究将CMTX-301的研发前体优化为临床可行的 候选疫苗。我们已经纳入了旨在首先与FDA一起评估CMTX-301配方的研究 经批准的佐剂。然后，根据诱导免疫反应的多重特征和强度， 将在龙猫模型上测试铅和备用配方的相对保护效果。 实验性脊髓灰质炎大鼠模型的扩展验证性评价 奥姆。作为我们计划的一部分，我们包括对剂量方案和时间表的评估。此外，领头羊 候选人将接受安全评估和GMP制造，以支持调查 向FDA申请新药。该项目将CMTX-301定位为临床高级开发 儿科用药的试验和随后的商业化。

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.