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，以评估针对艰难梭菌梭菌以预防或治疗感染的疫苗接种策略。随着高度抗生素耐药性细菌菌株的出现，迫切需要打击细菌感染的新方法。在这项研究建议中，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有力组合，为进行艰难的艰难杆菌感染提供了稳固的合理基础，以开发和评估Quorum淬火疫苗。我们将首先评估针对艰难梭菌的AGR法定人类感应系统的无源疫苗接种，以防止抗生素敏感和耐药性艰难梭菌菌株引起的感染。然后，我们将建立主动的疫苗接种方案，从而导致高法定人数淬抗抗体滴度，作为我们最终目标的基础，即有效的艰难梭菌疫苗的发展。我们的STTR研究建议的特定项目是（1）隔离中和人类单克隆抗AIP抗体。 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）在体内的艰难梭菌仓鼠感染模型中，通过选定的人类抗CDAP mAb进行保护。 STI将在标准的艰难梭菌仓鼠感染模型中生产四种用于体内评估的完全人类QQ CDAP抗体，由爱荷华大学（University of Iowa）进行。（3）在体内的艰难梭菌仓鼠感染模型中证明了抗AIP活性疫苗的保护。项目（1）和（2）的完成将证明一个概念，即在体内对法定人类感测的干扰可提供艰难梭菌感染的保护。在这个最后一个项目中，用于分离出从STI人MAB噬菌体显示库中隔离保护性mAB的CDAP免疫原子将用于在发生艰难梭菌挑战之前积极免疫仓鼠。鉴于我们的初步数据和调查人员的专业知识，我们认为该项目很有可能成功。在随后的II期应用中，我们将在艰难梭菌仓鼠感染模型和新产猪模型中的组合中测试载体和佐剂。抗体滴度将在艰难梭菌挑战之前确定，并开发出最佳的疫苗候选者。拟议中的产品是一种针对法定人物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急需的替代方法。