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

• 批准号: 10728900
• 负责人: ASHRAF S. IBRAHIM
• 金额: $ 8.31万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 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/10728900
• 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

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重耐药性 (MDR) 的广谱疫苗的开发 微生物，主要与医疗保健相关感染 (HAI) 相关。我们的前提是，有一个有效的方法 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。小鼠疫苗接种 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 以及由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。同样，Hyr1p 具有 3-D 结构 与 MRSA SraP（一种血小板粘附素）同源。 Hyr1p 还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 肺炎链球菌（CPKP）。使用 Als3p 重组 N 末端 (rAls3p-N) 进行主动免疫可导致 >50% 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。同样，主动或被动免疫（使用单克隆抗体）针对 Hyr1p 的重组 N 末端可保护小鼠免受 MDR AB 和 CPKP 感染。因此，我们的愿景是开发 针对念珠菌、MRSA、MDR AB 和 CPKP 的“跨界”双抗原疫苗。都是重要的引领 HAI 的原因。具体目标是：a) 通过协同作用评估优化 rAlsp3-N/rHyr1p-N 双重疫苗，精细化 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；和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 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。

项目成果

Serum bridging molecules drive candidal invasion of human but not mouse endothelial cells.

• DOI: 10.1371/journal.ppat.1010681
• 发表时间: 2022-07
• 期刊: PLoS pathogens
• 影响因子: 6.7

An evolutionarily diverged mitochondrial protein controls biofilm growth and virulence in Candida albicans.

• DOI: 10.1371/journal.pbio.3000957
• 发表时间: 2021-03
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Mamouei Z;Singh S;Lemire B;Gu Y;Alqarihi A;Nabeela S;Li D;Ibrahim A;Uppuluri P
• 通讯作者: Uppuluri P

Design and synthesis of new drugs inhibitors of Candida albicans hyphae and biofilm formation by upregulating the expression of TUP1 transcription repressor gene.

• DOI: 10.1016/j.ejps.2020.105327
• 发表时间: 2020-05-30
• 期刊: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
• 作者: Hamdy R;Soliman SSM;Alsaadi AI;Fayed B;Hamoda AM;Elseginy SA;Husseiny MI;Ibrahim AS
• 通讯作者: Ibrahim AS

Protective Efficacy of Anti-Hyr1p Monoclonal Antibody against Systemic Candidiasis Due to Multi-Drug-Resistant Candida auris.

• DOI: 10.3390/jof9010103
• 发表时间: 2023-01-12
• 期刊: Journal of fungi (Basel, Switzerland)

Antibodies targeting Candida albicans Als3 and Hyr1 antigens protect neonatal mice from candidiasis.

• DOI: 10.3389/fimmu.2022.925821
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3