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是儿童最常见的细菌性传染病。OM的后遗症包括听力障碍， 发展和语言延迟，甚至死亡，仅在美国每年就花费近50亿美元用于 医疗/手术管理和工作父母的工资损失。OM的主要病原体是 肺炎链球菌（Spn）、无法分型的流感嗜血杆菌（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 和非疫苗Spn血清型占主导地位。疫苗接种仍然是最有效和最具成本效益的方式， 预防OM，但不断变化的OM细菌学需要非传统方法来解决， 理想地预防这种全球儿科疾病。Clarametyx Biosciences开发了CMTX-301疫苗 解决所有病原体OM的候选人。用CMTX-301免疫使宿主免疫应答集中于 细菌生物膜组分内的特异性保护性表位负责其结构稳定性。 当暴露于这些抗体时，生物膜迅速崩溃，释放生物膜驻留细菌。给定 生物膜是对抗疾病的最大防御机制， Fortresses已被证明在多种不同的实验疾病模型中增强疾病解决， 包括OM的模型。通过快速破坏细菌生物膜，接种CMTX-301可以使宿主的 以病原体不可知的方式对清除感染的自然免疫应答。迄今为止的数据表明， CMTX-301诱导由超过22种细菌物种（均为革兰氏阴性）形成的生物膜塌陷的能力 和阳性），包括高优先级ESKAPEE病原体和所有三种主要耳病原体。 CMTX-301的初步评估表明，它能够预防灰鼠病毒性疾病， 上行NTHI诱导OM的细菌重叠感染模型。本文提出的方案将支持 研究需要优化CMTX-301的研究和开发前体，使其成为临床上可行的药物。 候选疫苗我们纳入了旨在首先与FDA评估CMTX-301制剂的研究 批准的佐剂。然后，基于诱导的免疫应答的多种特征和强度， 将在灰鼠模型中测试先导制剂和备用制剂的相对保护效力， 实验NTHI诱导的OM模型，并在Spn诱导的大鼠模型中进行扩展验证性评价 OM。我们包括剂量方案和时间表的评估作为我们计划的一部分。此外，铅 候选人将根据需要接受安全性评价和GMP生产，以支持研究 向FDA提交新药申请。该项目将定位CMTX-301用于临床的高级开发 试验和随后的商业化用于儿科用途。

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.