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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要中耳炎 (OM) 是一系列临床疾病，实际上给全球带来了巨大的健康负担； 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、发育和语言迟缓，甚至死亡，仅在美国每年就花费近 5B 美元医疗/手术治疗和工作父母的工资损失是 OM 的主要原因。肺炎链球菌 (Spn)、不可分型流感嗜血杆菌 (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) 显着减少了 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具影响力和成本效益的方法。预防 OM，但不断变化的 OM 细菌学需要非传统方法来解决，并且为了理想地预防这种全球儿科疾病，Clarametyx Biosciences 开发了 CMTX-301 疫苗。 CMTX-301 的免疫反应集中于宿主免疫反应。细菌生物膜成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，生物膜迅速崩溃并释放生物膜驻留细菌。生物膜是对抗疾病消退的最大防御机制，这些保护性的崩溃事实证明，堡垒可以在多种不同的实验疾病模型中增强疾病的解决能力，包括 OM 模型，通过快速瓦解细菌生物膜，接种 CMTX-301 可以使宿主迄今为止的数据已经证明，以与病原体无关的方式对清除感染进行自然免疫反应。 CMTX-301 能够诱导超过 22 种细菌（均为革兰氏阴性细菌）形成的生物膜崩溃 -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 的初步评估已证明其预防龙猫病毒性疾病的能力上行 NTHI 诱导的 OM 细菌重复感染模型本文提出的程序将支持。将 CMTX-301 的研发前体优化为临床可行的药物所需的研究我们纳入了旨在首先与 FDA 评估 CMTX-301 配方的研究。然后，根据诱导的免疫反应的多种特征和强度，批准佐剂。将在龙猫模型中对主要制剂和备用制剂的保护功效进行相对测试实验性 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。候选人将根据需要接受安全评估和 GMP 生产，以支持研究该项目将把 CMTX-301 定位于临床高级开发。儿科用途的试验和随后的商业化。