Cross-Kingdom Vaccine Targeting Healthcare-Associated Priority Pathogens

针对医疗保健相关优先病原体的跨王国疫苗

基本信息

批准号：
10535474
负责人：
ASHRAF S. IBRAHIM
金额：
$ 115.18万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-09 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10535474
关键词：
3-Dimensional Acinetobacter baumannii Active Immunization Address Adhesives Adjuvant Advanced Development Age Years Agglutinins Aluminum Hydroxide Anti-Infective Agents Antibiotics Antigens Antimicrobial Resistance B-Lymphocytes Bacterial Adhesins Binding Bioinformatics Blood Platelets Candida Candida albicans Candida auris Cell Wall Cell surface Clinical Collaborations Communicable Diseases Development Dose Evaluation Evolution Formulation Goals Gram-Negative Bacteria Healthcare Hemagglutinin Hemolysin Hospitalization Human Immune system Immunity Immunotherapeutic agent Industry Infection Investments Klebsiella pneumoniae Laboratories Life Mediating Military Personnel Molecular Computations Monoclonal Antibodies Multi-Drug Resistance Multidrug-resistant Acinetobacter Mus Nosocomial Infections Passive Immunization Patients Phagocytes Phase Populations at Risk Predisposition Process Program Development Protein Family Proteins Recombinants Recording of previous events Recurrence Relapse Resistance Resistant candida Skin Source Staphylococcus aureus Structure Surface T-Lymphocyte Target Populations Testing Therapeutic Toxic effect United States National Institutes of Health Vaccinated Vaccination Vaccine Antigen Vaccines Virulence Vision Vulvovaginal Candidiasis Woman advanced analytics antimicrobial drug assay development carbapenemase combat drug resistant microorganism efficacy evaluation emerging pathogen experience factor A fungus global health healthcare-associated infections human pathogen infection risk innovation insight member methicillin resistant Staphylococcus aureus molecular modeling mortality mouse model multi-drug resistant pathogen novel therapeutics novel vaccines pathogen pathogenic microbe preclinical development prevent priority pathogen product development programs protective effect recruit research clinical testing response scale up success synergism vaccine candidate vaccine development vaccine efficacy vaccine formulation vaccine platform

项目摘要

This application describes development of a broad-spectrum vaccine targeting multidrug resistant (MDR) organisms, principally related to healthcare-associated infections (HAIs). Our premise is that an effective way to prevent antimicrobial resistance is through vaccines rather than continued introduction of new drugs. Our development program is based on two cell wall antigens of the fungus Candida albicans: Als3p, a multi- function adhesin/invasin; and Hyr1p, which enables C. albicans to evade phagocyte killing. Vaccination of mice with either antigen provides significant protection against disseminated infections caused by Candida species and vulvovaginal candidiasis (VVC) due to C. albicans. Importantly, vaccination with both antigens synergistically protect mice from VVC. Using innovative computational molecular modeling and bioinformatic strategies, we identified highly significant three dimensional (3-D) structural and functional homology between Als3p, and methicillin resistant Staphylococcus aureus (MRSA) surface adhesive molecules, including clumping factor A. Similarly, Hyr1p, shares 3-D structural homology to MRSA SraP, an adhesin to platelets. Hyr1p also shares striking structural homology with hemagglutinin/hemolysin of MDR Acinetobacter baumannii (AB) and carbapenemase-producing Klebsiella pneumoniae (CPKP). Active immunization with the recombinant N terminus of Als3p (rAls3p-N) results in >50% survival in an otherwise fatal murine model of staphylococcemia and protects mice from Skin and Skin Structure Infection due to MRSA. Similarly, active or passive immunization (with a monoclonal antibody) targeting the recombinant N-terminus of Hyr1p protects mice from MDR AB, and CPKP infections. Thus, our vision is to develop a “cross-kingdom” dual antigen vaccine targeting Candida, MRSA, and MDR AB and CPKP. All are important leading cause of HAIs. Specific aims are: a) optimization of the dual rAlsp3-N/rHyr1p-N vaccine by synergy evaluation, fine- tuning of antigen dose, and use of clinically-safe newer adjuvants; b) conduct GLP-enabling studies including analytical assay development/optimization, formulation scale up of an optimized dual antigen vaccine and stability studies; and c) evaluate the final vaccine formulation for activity with and without antibiotics and perform an IND-enabling GLP-toxicity study of the optimized final vaccine formulation. In collaboration with NovaDigm Therapeutics, we advanced the development of rAls3p-N formulated with aluminum hydroxide (i.e. NDV-3A) from the academic laboratory to a phase 1b/2a trial showing efficacy of the vaccine in protecting women <40 years old from recurrent VVC. Thus, this proposal will leverage our combined strengths in basic discovery and product development of convergent vaccine antigens protecting against diverse human pathogens.

该申请描述了针对多药耐药性 (MDR) 的广谱疫苗的开发微生物，主要与医疗保健相关感染 (HAI) 有关，我们的前提是找到一种有效的方法。预防抗菌药物耐药性是通过疫苗而不是不断推出新药。我们的开发计划基于真菌白色念珠菌的两种细胞壁抗原：Als3p，一种多抗原功能粘附素/侵袭素；和 Hyr1p，它使白色念珠菌能够逃避吞噬细胞的杀伤。与任一抗原结合可提供显着的保护，防止念珠菌引起的播散性感染和白色念珠菌引起的外阴阴道念珠菌病 (VVC) 重要的是，两种抗原的疫苗接种具有协同作用。保护小鼠免受 VVC 侵害。使用创新的计算分子模型和生物信息策略，我们确定了三个非常重要的 Als3p 与耐甲氧西林葡萄球菌之间的维度 (3-D) 结构和功能同源性金黄色葡萄球菌 (MRSA) 表面粘附分子，包括聚集因子 A。类似地，Hyr1p 具有 3-D 结构 Hyr1p 与 MRSA SraP（一种血小板粘附素）具有同源性，也与 MRSA SraP 具有惊人的结构同源性。耐多药鲍曼不动杆菌 (AB) 和产碳青霉烯酶克雷伯菌的血凝素/溶血素使用 Als3p 重组 N 末端 (rAls3p-N) 主动免疫可导致 >50% 的肺炎链球菌 (CPKP) 感染。在致命的葡萄球菌血症小鼠模型中存活并保护小鼠免受皮肤和皮肤结构的影响 MRSA 感染，主动或被动免疫（使用单克隆抗体） Hyr1p 的重组 N 末端可保护小鼠免受 MDR AB 和 CPKP 感染，因此，我们的愿景是开发这种药物。针对念珠菌、MRSA、MDR AB 和 CPKP 的“跨界”双抗原疫苗都是重要的领先产品。具体目标是：a) 通过协同作用评估优化 rAlsp3-N/rHyr1p-N 疫苗，调整抗原剂量，并使用临床安全的新型佐剂 b) 进行 GLP 支持研究，包括分析；测定开发/优化、优化双抗原疫苗的配方放大和稳定性研究；以及c) 评估最终疫苗配方在使用和不使用抗生素的情况下的活性，并执行支持 IND 的 GLP 毒性优化最终疫苗配方的研究。我们与 NovaDigm Therapeutics 合作，推进了 rAls3p-N 的开发，氢氧化铝（即 NDV-3A）从学术实验室到 1b/2a 期试验显示了其功效疫苗可保护 40 岁以下的女性免于复发性 VVC 因此，该提案将利用我们的联合成果。融合疫苗抗原的基础发现和产品开发方面的优势，可预防多种疾病人类病原体。