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：
10084265
负责人：
ASHRAF S. IBRAHIM
金额：
$ 102.25万
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 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084265
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 Human Immune system Immunity Immunotherapeutic agent Industry Infection Investments Klebsiella pneumoniae Laboratories Life Mediating Microbe Military Personnel Molecular Computations Monoclonal Antibodies Multi-Drug Resistance Multidrug-resistant Acinetobacter Mus Nosocomial Infections Passive Immunization Patients Phagocytes Phase Populations at Risk 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 base carbapenemase combat emerging pathogen experience factor A fungus global health healthcare-associated infections human pathogen 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 three dimensional structure vaccine candidate vaccine development vaccine efficacy

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.

该应用描述了靶向多药抗性（MDR）的广谱疫苗的开发有机体，主要与医疗保健相关感染（HAIS）有关。我们的前提是一种有效的方法预防抗菌素耐药性是通过疫苗而不是继续引入新药。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，一种多功能粘附素/invasin;和Hyr1p，它使白色念珠菌能够逃避吞噬细胞。小鼠疫苗接种两种抗原可为念珠菌引起的传播感染提供明显的保护由于白色念珠菌而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，我们确定了非常重要的三个 ALS3P和耐甲氧西林的葡萄球菌之间的尺寸（3-D）结构和功能同源性金黄色金融（MRSA）表面粘合分子，包括聚类因子A。类似地，HYR1P共享3-D结构与MRSA SRAP的同源性，这是对血小板的胶粘剂。 HYR1P还与 MDR ACINETOBACTER BAUMANNII（AB）和产生碳纤维酶的Klebsiella的Hemagglutin/Hemolysin（AB）肺炎（CPKP）。用ALS3P（RALS3P-N）重组N末端的重组N末端的主动免疫导致> 50％在葡萄球菌葡萄球菌的致命鼠模型中生存，并保护小鼠免受皮肤和皮肤结构的侵害由于MRSA引起的感染。同样，主动或被动免疫抑制（具有单克隆抗体）针对 HYR1P的重组N末端可保护小鼠免受MDR AB和CPKP感染。那是我们的愿景是发展靶向念珠菌，MRSA和MDR AB和CPKP的“跨王朝”双抗原疫苗。所有都是重要的领导 Hais的原因。具体目的是：a）通过协同评估对双重ralsp3-n/rhyr1p-n疫苗进行优化调整抗原剂量，并使用临床安全的新调节器； b）进行增强GLP的研究包括分析测定开发/优化，配方量表，以优化的双抗原疫苗和稳定性研究；和c）评估最终的疫苗配方，用于具有和没有抗生素的活性，并执行辅助GLP毒性研究最终疫苗配方的研究。通过与Novadigm Therapeutics合作，我们推进了RALS3P-N的开发从学术实验室到1B/2A期试验的氢氧化铝（即NDV-3A），显示了效率疫苗保护少于40岁的妇女免受复发性VVC的影响。那，该提议将利用我们的总和融合疫苗抗原的基本发现和产品开发的优势，可防止潜水员人类病原体。