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

项目总结

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.