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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.

本申请描述了针对多药耐药（MDR）的广谱疫苗的开发。微生物，主要与卫生保健相关感染（HAI）有关。我们的前提是，预防抗生素耐药性是通过疫苗，而不是不断引进新的药物。我们的开发计划是基于真菌白色念珠菌的两种细胞壁抗原：Als 3 p，一种多细胞壁抗原，功能adhesin/invasin;和Hyr 1 p，其使C.白色念珠菌逃避吞噬细胞的杀伤。接种小鼠与任一种抗原联合使用，可显著预防念珠菌属引起的播散性感染和念珠菌性外阴阴道炎（VVC）。白色念珠菌重要的是，用两种抗原协同接种保护小鼠免受VVC。使用创新的计算分子建模和生物信息学策略，我们确定了三个非常重要的 Als 3 p和耐甲氧西林葡萄球菌之间的三维（3-D）结构和功能同源性金黄色葡萄球菌（MRSA）表面粘附分子，包括凝集因子A。类似地，Hyr 1 p，共享3-D结构与MRSA SraP同源，是血小板粘附素。Hyr 1 p还与耐药鲍曼不动杆菌（AB）和产碳青霉烯酶克雷伯菌的血凝素/溶血素肺炎链球菌（CPKP）。用Als 3 p的重组N末端（rAls 3 p-N）主动免疫导致>50%的在葡萄球菌血症的其他致命小鼠模型中存活，并保护小鼠免受皮肤和皮肤结构 MRSA引起的感染类似地，靶向免疫球蛋白的主动或被动免疫（用单克隆抗体）也可以用于免疫治疗。 Hyr 1 p的重组N-末端保护小鼠免受MDR AB和CPKP感染。因此，我们的愿景是发展靶向念珠菌、MRSA和MDR AB和CPKP的“跨王国”双抗原疫苗。都是重要的领导因为HAIs。具体目的是：a）通过协同作用评价优化双重rAlsp 3-N/rHyr 1 p-N疫苗，抗原剂量的调整和临床安全的新佐剂的使用; B）进行GLP-使能研究，包括分析测定开发/优化，优化的双抗原疫苗的制剂规模扩大和稳定性研究;和c）评价含和不含抗生素的最终疫苗制剂的活性，并进行IND使能GLP毒性研究优化的最终疫苗制剂。与NovaDigm Therapeutics合作，我们推进了rAls 3 p-N的开发，氢氧化铝（即NDV-3A）从学术实验室到1b/2a期试验，显示了疫苗可保护40岁以下女性免于复发VVC。因此，该提案将利用我们的联合在基础发现和产品开发方面的优势，人类病原体