A vaccine against Clostridium difficile infections

针对艰难梭菌感染的疫苗

基本信息

批准号：
8301558
负责人：
Barbara A Swanson
金额：
$ 29.27万
依托单位：
SORRENTO THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-14 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8301558
关键词：
Adjuvant Affect Aftercare Anaerobic Bacteria Animals Antibiotic Therapy Antibiotics Antibodies Antibody Formation Antigens Bacteria Bacterial Antibiotic Resistance Bacterial Infections Biochemical Biological Biological Assay Centers for Disease Control and Prevention (U.S.)Chemistry Clostridium Clostridium difficile Data Development Diarrhea Drug resistance Evaluation Failure Family suidae Generations Goals Growth Hamsters Health Health care facility Healthcare Systems Human Immune system Immunology Immunotherapy In Vitro Incidence Infection Invaded Iowa Laboratories Libraries Licensing Medical Microbiology Modeling Molecular Morbidity - disease rate Nosocomial Infections Patients Peptide antibodies Peptides Phage Display Phase Probability Production Protocols documentation Public Health Recurrence Relapse Reproduction spores Research Research Institute Research Personnel Research Proposals Resistance Resistance development Small Business Technology Transfer Research Solid Staphylococcus aureus Symptoms System Technology Testing Therapeutic Toxin Treatment Efficacy United States Universities Vaccination Vaccines Virulence Work antimicrobial base combat disorder prevention gut microbiota human disease human monoclonal antibodies in vivo in vivo Model mortality novel novel strategies pathogen pressure prevent quorum sensing research study response success vaccination strategy vaccine candidate

项目摘要

DESCRIPTION (provided by applicant): In this proposal we lay out a comprehensive research plan to evaluate our vaccination strategies targeting Clostridium difficile to prevent or treat infections. With the emergence of highly antibiotic-resistant bacterial strains, new approaches for combating bacterial infections are desperately needed. In this research proposal, Sorrento Therapeutics Inc. (STI) together with researchers from the University of Iowa have outlined experiments that will harness a powerful combination of chemistry, microbiology, and immunology to provide a solid rational basis for the development and evaluation of a quorum quenching vaccine to prevent C. difficile infections. We will first evaluate passive vaccination targeting the agr quorum sensing system of C. difficile for the protection against infections caused by antibiotic-sensitive and -resistant Clostridium difficile strains. We will then establish active vaccination protocols that result in high quorum quenching antibody titers as the basis for our ultimate goal, the development of an effective C. difficile vaccine. The specific projects of our STTR research proposal are (1) Isolate neutralizing human monoclonal anti- AIP antibodies. To establish the therapeutic efficacy of passive anti-AIP immunotherapy we will isolate anti- AIP-1 and AIP-2 binders from our proprietary human monoclonal antibody phage display library, convert them to IgGs, produce and purify them, and use an assay created by our collaborator, Dr. Horswill (University of Iowa), to select the best candidates for testing in an in vivo hamster challenge model. (2) Demonstrate protection by selected human anti-CDAP mAbs in a C. difficile hamster infection model in vivo. STI will produce four fully human QQ CDAP antibodies for in vivo evaluation in the standard C. difficile hamster infection model, to be performed by Dr. Ellermeier (University of Iowa). (3) Demonstrate protection by an anti-AIP active vaccine in a C. difficile hamster infection model in vivo. Accomplishment of projects (1) and (2) will prove the concept that interference with quorum sensing in vivo provides protection from C. difficile infection. In this final project, the same CDAP immunogens that were used to isolate the protective mAbs from the STI human mAb phage display library will be used to actively immunize hamsters prior to C. difficile challenge. Given our preliminary data and the expertise of the investigators, we believe there is a high probability of success for this project. In a subsequent Phase II application we would test carriers and adjuvants in combinations in the C. difficile hamster infection model and a neo-natal pig model. Antibody titers will be determined prior to C. difficile challenge and the best vaccine candidate developed. The proposed product, a unique C. difficile vaccine that targets quorum sensing, would provide a much needed alternative to antibiotic management of a serious and escalating health threat.

描述（由申请人提供）：在本提案中，我们制定了一项全面的研究计划，以评估我们针对艰难梭菌的疫苗接种策略，以预防或治疗感染。随着高度抗生素耐药菌株的出现，迫切需要对抗细菌感染的新方法。在这项研究提案中，Sorrento Therapeutics Inc. (STI) 与爱荷华大学的研究人员一起概述了实验，这些实验将利用化学、微生物学和免疫学的强大组合，为法定人数的开发和评估提供坚实的理性基础猝灭疫苗可预防艰难梭菌感染。我们将首先评估针对艰难梭菌 agr 群体感应系统的被动疫苗接种，以预防由抗生素敏感和耐药的艰难梭菌菌株引起的感染。然后，我们将建立积极的疫苗接种方案，从而产生高群体猝灭抗体滴度，作为我们最终目标（开发有效的艰难梭菌疫苗）的基础。我们的STTR研究计划的具体项目是（1）分离中和人单克隆抗AIP抗体。为了确定被动抗 AIP 免疫疗法的治疗效果，我们将从我们专有的人单克隆抗体噬菌体展示库中分离抗 AIP-1 和 AIP-2 结合物，将它们转化为 IgG，生产和纯化它们，并使用由我们的合作者 Horswill 博士（爱荷华大学）选择最佳候选者进行体内仓鼠挑战模型的测试。 (2) 在艰难梭菌仓鼠体内感染模型中展示选定的人抗 CDAP mAb 的保护作用。 STI 将生产四种全人 QQ CDAP 抗体，用于标准艰难梭菌仓鼠感染模型的体内评估，由 Ellermeier 博士（爱荷华大学）进行。 (3) 在艰难梭菌仓鼠体内感染模型中证明抗 AIP 活性疫苗的保护作用。项目（1）和（2）的完成将证明干扰体内群体感应可提供针对艰难梭菌感染的保护的概念。在这个最终项目中，用于从 STI 人 mAb 噬菌体展示库中分离保护性 mAb 的相同 CDAP 免疫原将用于在艰难梭菌攻击之前对仓鼠进行主动免疫。鉴于我们的初步数据和研究人员的专业知识，我们相信该项目成功的可能性很高。在随后的第二阶段应用中，我们将在艰难梭菌仓鼠感染模型和新生猪模型中测试载体和佐剂的组合。将在艰难梭菌攻击和开发最佳候选疫苗之前确定抗体滴度。拟议的产品是一种针对群体感应的独特艰难梭菌疫苗，将为严重且不断升级的健康威胁提供一种急需的抗生素管理替代方案。